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Competing Interests: Declaration of competing interest The authors certify that all of their affiliations and/or financial involvement with any organization, or any financial conflicts with the subject matter discussed in the manuscript are disclosed in the Acknowledgement section of the manuscript.

Far ultraviolet-C irradiation at 222 nm has potent bactericidal effects against severe infections such as peritonitis, with minimal cytotoxicity. Bacterial peritonitis due to bowel perforation is a serious condition with high mortality despite current treatments. This study investigated the safety and efficacy of intraperitoneal far ultraviolet-C irradiation at 222 nm. In vitro experiments optimized the fluid conditions for bacterial or protein concentrations prior to in vivo evaluation. In vivo efficacy was assessed in a rat peritonitis model induced by Escherichia coli, measuring intra-abdominal bacterial concentration, blood cytokine levels, and mortality rates. Safety was evaluated by analyzing cyclobutane pyrimidine dimers as markers of DNA damage in five abdominal organs: stomach, small intestine, colon, liver, and spleen. Statistical analyses employed parametric methods for normally distributed data and non-parametric methods for data without normality. Optimal in vitro conditions included 106 CFU/mL bacteria, 0.5 mW/cm2 irradiation, and 10-3 mg/mL protein. In the rat model, far ultraviolet-C irradiation at 222 nm significantly decreased intra-abdominal bacteria, reduced blood cytokines (interleukin-1β and interleukin-6), and elevated survival rates from 20% to 60%, compared to lavage alone. The formation of cyclobutane pyrimidine dimers was significantly lower with 222 nm irradiation than with 254 nm, suggesting reduced DNA damage. These findings indicate that far ultraviolet-C irradiation at 222 nm, when combined with lavage, represents a promising therapeutic strategy for bacterial peritonitis, providing effective bacterial reduction and a favorable safety profile. Further research is needed to verify these findings and investigate long-term safety and potential clinical applications., Competing Interests: Because this research required specialized experimental equipment, it was started as a joint research project between Kobe University, Ushio Inc., and Hamamatsu University of Medicine. This experiment was performed at Hamamatsu University School of Medicine. The staff of Ushio Inc. and Kobe University lent specialized equipment used in another study to the Hamamatsu University School of Medicine, evaluated its appropriate use, assessed the validity of the methods and results, and confirmed the reproducibility of some data. Thus, the funders had no role in data collection and analysis. Based on the result of this research, Hamamatsu University School of Medicine have received funds from Ushio Inc. associated with this collaborative project. Kobe University School of Medicine and Hamamatsu University School of Medicine are funded by Ushio Inc. for collaborating research. RK, MS, TK, and HO have received support in the form of salaries from Ushio Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2024 Sugiyama 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: Crohn's disease causes acute and chronic inflammation that often make the preoperative evaluation of surgical risks difficult. Myosteatosis is used for the evaluation of muscle quality to assess sarcopenia. However, data on the relationship between myosteatosis and surgical outcomes in patients with Crohn's disease are lacking., Methods: Among patients with Crohn's disease who underwent surgery between 2007 and 2022, we investigated the impact of myosteatosis on postoperative complications using intramuscular adipose tissue content (IMAC). Our study included data from 97 patients who underwent analysis for cutoff values and factors associated with IMAC and 72 who underwent analysis for risk factors of postoperative complications., Results: Body mass index (BMI; P < .001) and visceral adipose tissue/height index (P < .001) were significantly correlated with IMAC. High BMI (P < .001) and a history of abdominal surgery for Crohn's disease (P = .012) were identified as factors affected with high IMAC. Multivariate analysis revealed high IMAC and external fistulas as independent risk factors for postoperative complications (odds ratio [OR], 5.010; 95% CI, 1.300-19.30; P = .019 and OR, 7.850; 95% CI, 1.640-37.50; P = .010, respectively), especially infectious complications., Conclusions: This study established IMAC as a valuable marker for sarcopenic obesity and predicting postoperative complications in patients with Crohn's disease. Furthermore, evaluating myosteatosis using IMAC will facilitate the decision of the optimal timing of surgery, prediction of complications, and treatment of sarcopenia in patients with Crohn's disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Study Design: Retrospective study., Objectives: To investigate the impact of diabetes mellitus on neurological recovery and determine the relationship between moderate-severe diabetes and neurological recovery in patients with cervical spinal cord injury (CSCI) without bone injury., Methods: A retrospective study was conducted on 389 consecutive patients aged ≥65 years with CSCI without bone injury across 33 medical institutes. The patients were divided into a nondiabetic group (n = 270) and a diabetic group (n = 119). Neurological outcomes were compared between the two groups through propensity score matching. The impact of moderate-severe diabetes (defined as hemoglobin A1c ≥ 7.0% or requiring insulin treatment) on neurological recovery was evaluated through multiple linear regression analysis., Results: Propensity score matching revealed no significant differences between the diabetic and nondiabetic groups in terms of American Spinal Injury Association (ASIA) impairment scale grade and mean total ASIA motor scores (AMS) at 6 months post-injury. Multiple linear regression analysis indicated that age on admission (B = -0.34; 95% confidence interval [CI], -0.59 to -0.08; P = 0.01), dementia (B = -16.50; 95% CI, -24.99 to -8.01; P < 0.01), and baseline total AMS (B = -0.62; 95% CI, -0.72 to -0.51; P < 0.01) were negative predictors of neurological recovery at 6 months post-injury. The presence of moderate-severe diabetes did not influence neurological recovery at 6 months post-injury., Conclusions: Diabetic patients with CSCI without bone injury achieved improvements in neurological function comparable to those of nondiabetic patients. Moderate-severe diabetes did not affect neurological recovery in patients with CSCI without bone injury., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Epithelial ovarian cancer is characterized by aggressive peritoneal dissemination. Neutrophils are mobilized to peritoneal cavity in some patients with ovarian cancer dissemination; however, its pathological significance remains unknown. This study aimed to investigate the role of neutrophil extracellular traps (NETs) in ovarian cancer dissemination. We conducted a retrospective analysis of clinical data and samples from 340 patients with ovarian cancer who underwent primary surgery between 2007 and 2016 at the Osaka University Hospital. In vitro, NETs formation was induced by stimulating human peripheral neutrophils. The human ovarian cancer cell line, OVCAR8, was cocultured with NETs. For an ovarian cancer dissemination mouse model, we performed an intraperitoneal injection of OVCAR8 cells into nude mice. The association between NETs and peritoneal dissemination was explored, and model mice were treated with the PAD4 inhibitor GSK484 to assess antitumor efficacy. Neutrophilia (neutrophil count >7000/mm3) correlated with shorter survival, advanced peritoneal dissemination, elevated granulocyte colony-stimulating factor (G-CSF) levels, increased neutrophil count in ascites, and augmented NETs foci in peritoneal dissemination sites. In vitro assays revealed that G-CSF stimulated neutrophils to form NETs, promoting cancer cell adhesion. In vivo investigations revealed that G-CSF-producing tumor-bearing mice had accelerated peritoneal dissemination and poor prognosis. NETs formation was pathologically observed at the peritoneal dissemination sites. Inhibition of NETs formation by GSK484 significantly delayed peritoneal dissemination in vivo. In conclusion, G-CSF was associated with intra-abdominal NETs formation and increased peritoneal dissemination. NETs represent potential therapeutic targets for ovarian cancer, particularly in patients with neutrophilia., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: We aimed to evaluate the comparative efficacy and acceptability of cognitive behavioral therapy for insomnia (CBT-I), pharmacotherapy, and their combination in the long and short terms among adults with chronic insomnia disorder., Methods: We searched multiple databases to December 27, 2023. We included trials in hypnotic-free adults with chronic insomnia comparing at least two of CBT-I, pharmacotherapy, or their combination. We assessed the confidence in evidence using CINeMA. The primary outcome was long-term remission. Secondary outcomes included all-cause dropout and self-reported sleep continuity measures in the long term, and the same outcomes in the short term. We performed frequentist random-effects network meta-analyses (CRD42024505519)., Findings: We identified 13 trials including 823 randomized participants (mean age, 47.8 years; 60% women). CBT-I was more beneficial than pharmacotherapy in the long term (median duration, 24 weeks [range, 12 to 48 weeks]; remission odds ratio, 1.82 [95% confidence interval (CI), 1.15-2.87]; [certainty of evidence: high]), while there was weaker evidence of benefit of combination against pharmacotherapy (1.71 [95% CI, 0.88-3.30: moderate]) and no clear difference of CBT-I against combination (1.07 [95% CI, 0.63-1.80: moderate]). CBT-I was associated with fewer dropouts than pharmacotherapy. Short-term outcomes favored CBT-I over pharmacotherapy except total sleep time. Given the average long-term remission rate in the pharmacotherapy-initiating arms of 28%, CBT-I resulted in a long-term remission rate of 41% (95% CI, 31%-53%) and combination 40% (95% CI, 25%-56%)., Interpretation: The current study found that starting with CBT-I for chronic insomnia leads to better outcomes than pharmacotherapy. Combination may be better than pharmacotherapy alone, but unlikely to be worth the additional burden over CBT-I alone., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Although distal tibial oblique osteotomy (DTOO) has usually been indicated for non-inflammatory diseases such as osteoarthritis, we encountered three patients with rheumatoid arthritis (RA) who underwent DTOO. We evaluated radiographic parameters and clinical scores, including self-reported scores for the foot and ankle (SAFE-Q) and the Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot scale. In all three cases, radiographic improvements were achieved along with improvements in SAFE-Q and JSSF scores after mid-term follow-up. Supramalleolar osteotomy including DTOO could be indicated even for inflammatory diseases such as RA, if erosive changes are not evident in the ankle joint., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Objectives: According to the conventional postoperative procedure after total ankle arthroplasty (TAA), mobilization and weight-bearing is currently started after completion of wound healing. Recently, early mobilization for dorsiflexion after TAA with modified antero-lateral approach was reported to be feasible and safe. To investigate the further possibility of expediting rehabilitation, this study evaluated the feasibility and safety of early full weight-bearing and gait exercise after cemented TAA., Materials and Methods: This retrospective, observational study investigated 23 consecutive ankles (OA: 14 ankles, RA: 9 ankles) that had received cemented TAA with a modified antero-lateral approach. These ankles were divided into three groups 1. conventional postoperative protocol, 2. early dorsiflexion protocol, 3. early dorsiflexion+full weight-bearing protocol. Postoperative wound complications were observed and recorded. Number of days for hospitalization was also evaluated., Results: No postoperative complications related to wound healing were observed even after early full weight-bearing and gait exercise. Days for hospitalization was significantly shortened in early full weight-bearing and gait exercise group (group 3) from 35-38 days to 24 days., Conclusions: Within this small number of cases, early full weight-bearing and gait exercise from 7 days after cemented TAA was feasible and safe with the modified antero-lateral approach. Combination of early dorsiflexion mobilization and weight-bearing/gait exercise contributed to shortening the hospitalization day. Innovations in postoperative procedures for rehabilitation after TAA can be expected., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Objective Mucuna pruriens (MP) is a legume whose seeds contain levodopa (LD), which has potential therapeutic effects against Parkinson's disease (PD). However, further research is needed to thoroughly evaluate its efficacy and safety for treating this condition. In this study, we analyzed the pharmacokinetics of MP grown in Japan and investigated its mechanism of action in PD. Methods MP seeds ground after roasting (containing 4.02% LD per MP powder) were used as the reagent and compared with an equivalent LD/carbidopa (CD) preparation. This clinical trial was conducted using a crossover design among PD patients attending our institution. Each patient received a single dose of 100/10 mg LD/CD tablets and 11 g of MP reagent. Results Among the seven patients with PD, MP prolonged the ON time 2-fold compared to LD/CD. The LD concentrations after MP intake were higher than those after LD/CD intake, whereas dyskinesia did not increase. An analysis of the LD metabolites showed that the 3-O-methyl-dopa/LD metabolic ratio was significantly lower after MP ingestion than after LD/CD ingestion, indicating that MP has a catechol-O-methyl transferase inhibitory effect. Conclusions This is the first report of a pharmacokinetic analysis conducted on actual patients with PD showing that MP significantly prolongs the ON time. The advantages of MP as a treatment for PD have been confirmed: it is inexpensive, as effective as LD, works faster and longer than LD, and does not increase dyskinesia.

Durvalumab plus tremelimumab (Durva/Treme) combined immunotherapy is the first-line therapy recommended for unresectable hepatocellular carcinoma (HCC). Since sequential therapy is more effective in improving prognosis, tumor markers have been used as predictive biomarkers for response to systemic therapy. This study aimed to investigate the predictive ability of objective response (OR) by tumor markers for Durva/Treme therapy against HCC. In this multicenter study, 110 patients with HCC who received Durva/Treme therapy were retrospectively enrolled. The OR rate was 15.5%. To aid early decision-making regarding OR, we evaluated the predictors contributing to OR in two steps: before (first step) and 4 weeks after (second step) treatment induction. Changes in tumor markers (alpha-fetoprotein [AFP] and des-gamma-carboxy prothrombin [DCP]) from baseline to 4 weeks after treatment (ΔAFP/ΔDCP) were included as the input factors. In the first step, multivariable analysis identified only the baseline AFP level (odds ratio 3.497, p = 0.029) as a predictor of OR. Patients with AFP ≥ 400 ng/mL had a significantly higher OR rate than those with < 400 ng/mL (28.2 vs. 8.5%, p = 0.011), and there was no significant difference in progression-free survival (PFS) between the two groups. When AFP/DCP response was defined as a ≥10% reduction from baseline, multivariable analysis showed that AFP response (odds ratio 6.023, p = 0.042) and DCP response (odds ratio 11.657, p = 0.006) were both independent predictors of OR in the second step. The PFS of patients with AFP or DCP response was significantly longer than that of patients without AFP or DCP response. The study demonstrated that the use of AFP and DCP can predict the OR of patients with HCC receiving Durva/Treme therapy., Competing Interests: I.S.: Lecture fees from AstraZeneca, and Eisai Co. Ltd., S.S.: Lecture fees from AstraZeneca, Eisai Co. Ltd., T.I.: Lecture fees from AstraZeneca, and Chugai Pharmaceutical Co., Ltd., and research funding from Chugai Pharmaceutical Co., Ltd., H.K.: Research funding from Chugai Pharmaceutical Co., Ltd. T.K.: Lecture fees from ASKA Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Kowa Company, Ltd., AbbVie GK., Eisai Co., Ltd., Novo Nordisk Pharma Ltd., Janssen Pharmaceutical K.K., Otsuka Pharmaceutical Co., Ltd., EA Pharma Co., Ltd. T.T.: Lecture fee from Gilead Sciences, Inc., AbbVie GK., Otsuka Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd. The remaining authors have no conflicts of interest., (Copyright: © 2024 Saeki 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: Internet-based cognitive behavioral therapy (iCBT) shows promise in the prevention of depression. However, the specific iCBT components that contribute to its effectiveness remain unclear., Objective: We aim to evaluate the effects of iCBT components in preventing depression among university students., Methods: Using a smartphone cognitive behavioral therapy (CBT) app, we randomly allocated university students to the presence or absence of 5 different iCBT components: self-monitoring, behavioral activation, cognitive restructuring, assertiveness training, and problem-solving. The active intervention lasted 8 weeks but the app remained accessible through the follow-up. The primary outcome was the onset of a major depressive episode (MDE) between baseline and the follow-up after 52 weeks, as assessed with the computerized World Health Organization Composite International Diagnostic Interview. Secondary outcomes included changes in the 9-item Patient Health Questionnaire, 7-item General Anxiety Disorder, and CBT Skills Scale., Results: During the 12-month follow-up, 133 of 1301 (10.22%) participants reported the onset of an MDE. There were no significant differences in the incidence of MDEs between the groups with or without each component (hazard ratios ranged from 0.85, 95% CI 0.60-1.20, for assertiveness training to 1.26, 95% CI 0.88-1.79, for self-monitoring). Furthermore, there were no significant differences in the changes on the 9-item Patient Health Questionnaire, 7-item General Anxiety Disorder, or for CBT Skills Scale between component allocation groups. However, significant reductions in depression and anxiety symptoms were observed among all participants at the 52-week follow-up., Conclusions: In this study, we could not identify any specific iCBT components that were effective in preventing depression or the acquisition of CBT skills over the 12-month follow-up period, but all participants with and without intervention of each iCBT component demonstrated significant improvements in depressive and anxiety symptoms. Further research is needed to explore the potential impact of frequency of psychological assessments, nonspecific intervention effects, natural change in the mental state, and the baseline depression level., (© Yukako Nakagami, Teruhisa Uwatoko, Tomonari Shimamoto, Masatsugu Sakata, Rie Toyomoto, Kazufumi Yoshida, Yan Luo, Nao Shiraishi, Aran Tajika, Ethan Sahker, Masaru Horikoshi, Hisashi Noma, Taku Iwami, Toshi A Furukawa. Originally published in JMIR Mental Health (https://mental.jmir.org).)

Objective: Cognitive behavioral therapy for insomnia (CBT-I) has demonstrated efficacy for both insomnia and depression. With a tenfold increase in expected participant numbers, we aimed to update the systematic review and meta-analysis of CBT-I for major depressive disorders (MDD)., Methods: Multiple databases were searched up to March 27th 2024 to include all randomized controlled trials examining CBT-I among adults with MDD. The certainty of evidence was evaluated using GRADE. The primary outcome was depression response at post-treatment. Secondary outcomes included insomnia remission and all-cause dropout at post-treatment. Frequentist random-effects pairwise meta-analyses were performed using odds ratio (OR) for dichotomous outcomes. This study was prospectively registered (https://osf.io/kcndz/)., Results: Nineteen trials with 4808 randomized participants were identified (mean age, 33.2 [standardized deviation 15.0] years, 73.2 % women. Mean Insomnia Severity Index 19.2 [5.4], median Patient Health Questionnaire-9 16 [range, 8-21]). CBT-I was more beneficial than control conditions for depression response (OR 2.28 [95 % Confidence Interval (CI), 1.67-3.12; GRADE certainty of evidence: moderate), insomnia remission (OR 3.57 [95%CI, 2.48-5.14]: moderate) but could lead to more dropout (OR 1.69 [95%CI, 0.98-2.89]: low). Depression improvement was seen beyond the sleep domain. With a control condition depression response rate of 17 % at post-treatment (median 8 weeks), CBT-I yielded a 32 % response rate (95 % CI, 26 %-39 %)., Conclusions: This meta-analysis indicates that CBT-I has significant effects on depressive symptoms beyond the sleep domain among people with MDD. Despite higher dropout rates, these findings suggest CBT-I is an effective treatment for depression comorbid with insomnia., Competing Interests: Declaration of competing interest Y.F. has received consultancy fee from Panasonic and lecture fee from Otsuka outside the submitted work. H.N.T. is an employee of Awarefy Inc. M.S. reports personal fee from SONY outside submitted work. S.N. has received grants from JSPS KAKENHI (21H00956, 23H01050, 24 K00492), AMED(JP21zf0127005), and S'UIMIN Inc. R.Y. belongs to the Edogawa University Sleep Research Institute, which conducts joint research with Paramount Bed Holdings Co. Ltd. and receives research funds. E.S. has received grants from Mitsubishi Foundation within last 36 month, and is currently working as an occupational physician at Sumitomo Mitsui Trust Bank. M.P. wrote treatment manuals and books for CBTI, teaches CBTI, and is a founder of Hypknowledge LLC. K.Kasai. reports grants from Teijin, Takeda, Lily, Otsuka, Daiichi-Sankyo, Shionogi, Tanabe-Mitsubishi, and Sumitomo; and personal fees from Sumitomo, Meiji-Seika, Ricoh, Fuji-film Wako, Takeda, Otsuka, and Astellas outside the submitted work in the past 36 months. Others report no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Clozapine-induced inflammation, such as myocarditis and pneumonia, can occur during initial titration and can be fatal. Fever is often the first sign of severe inflammation, and early detection and prevention are essential. Few studies have investigated the effects of clozapine titration speed and concomitant medication use on the risk of clozapine-induced inflammation., Aims: We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date., Method: We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days., Results: Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset., Conclusion: A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications.

Introduction: Sarcopenia is a skeletal muscle disease manifesting as low muscle mass and impaired muscle function. It has been reported that sarcopenia correlates with a low quality of life (QOL) and an increased risk of falls in patients with Parkinson's disease (PD). Nevertheless, few studies have investigated the prevalence, impact, and screening methods of sarcopenia in Japanese patients with PD., Methods: Sarcopenia was diagnosed based on the Asian Working Group for Sarcopenia 2019 consensus. We compared demographic characteristics, severity of PD, levodopa equivalent daily dose, QOL, fatigue, impulsive and compulsive behaviors, body mass index (BMI), calf circumference, skeletal muscle mass index (SMI), handgrip strength, a 4-meter gait speed, a five-time sit-to-stand test (FTSST), short physical performance battery, and SARC-F questionnaire scores between sarcopenia and non-sarcopenia groups. Furthermore, to investigate the best tool for screening sarcopenia in PD, the sensitivity and specificity of calf circumference, handgrip strength, FTSST, and SARC-F questionnaire were compared., Results: The prevalence of sarcopenia in PD was 31.9% (15/47). The sarcopenia group showed significantly higher age (77.3 ± 5.12 versus 70.3 ± 8.17, p = 0.0042), lower BMI (19.3 ± 2.99 versus 23.3 ± 3.18, p = 0.0002), higher rate of decreased calf circumference (86.6% versus 34.3%, p = 0.0013) and SMI (100% versus 6.25%, p < 0.0001), and worse FTSST (15.5 ± 5.57 versus 12.0 ± 4.12, p = 0.0219). The other parameters were not significantly different. Among screening tools, calf circumference had the highest sensitivity (86%) and specificity (65%). All screening tools had higher sensitivity and specificity in men than in women. The SARC-F questionnaire was not useful in distinguishing sarcopenia but was significantly correlated with the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale Part 3 (r = 0.41, p = 0.0037) and the 39-item Parkinson's Disease QOL Scale (r = 0.71, p < 0.0001)., Conclusion: This study investigated the characteristics of PD patients with sarcopenia in Japan. Calf circumference was found to be the most useful tool for screening sarcopenia in PD. Handgrip strength and FTSST also showed high sensitivities, particularly in men. Conversely, the SARC-F questionnaire is not suitable for diagnosing sarcopenia in PD., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Local Ethics Committee of National Hospital Organization Wakayama Hospital issued approval 05-4. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Murakami et al.)

Background: 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) is commonly used for diagnosis of dementia because brain glucose metabolism reflects neuronal activity. However, as [ 18 F]FDG is an analogue of glucose, accumulation of tracer in the brain is affected by plasma glucose levels. In contrast, cerebral blood flow (CBF) tracers are theoretically unaffected by plasma glucose levels and are therefore expected to be useful alternatives for the diagnosis of dementia in patients with diabetes. The techniques currently used for CBF imaging using single photon emission computed tomography (SPECT) and [ 15 O]H 2 O positron emission tomography (PET), but these are limited by their insufficient resolution and sensitivity for regional brain imaging, especially in patients with brain atrophy. N-isopropyl-4-[ 11 C]methylamphetamine ([ 11 C]MMP) is a possible CBF tracer with high resolution and sensitivity that exhibits comparable performance to that of [ 15 O]H 2 O in conscious monkey brains. We performed process validation of the radiosynthesis and preclinical development of [ 11 C]MMP prior to clinical translation., Results: The decay-corrected yields of [ 11 C]MMP at the end of synthesis were 41.4 ± 6.5%, with 99.7 ± 0.3% radiochemical purity, and 192.3 ± 22.5 MBq/nmol molar activity. All process validation batches complied with the product specifications. The acute toxicity of MMP was evaluated at a dose of 3.55 mg/kg body weight, which is 10,000 times the potential maximum clinical dose of [ 11 C]MMP. The acute toxicity of [ 11 C]MMP injection at 150 or 200 times, to administer a postulated dose of 740 MBq of [ 11 C]MMP, was also evaluated after the decay-out of 11 C. No acute toxicity of MMP and [ 11 C]MMP injection was found. No mutagenic activity was observed for MMP. The effective dose calculated according to the Medical Internal Radiation Dose (MIRD) method was 5.4 µSv/MBq, and the maximum absorbed dose to the bladder wall was 57.6 µGy/MBq. MMP, a derivative of phenylalkylamine, showed binding to the sigma receptor, but had approximately 1/100 of the affinity of existing sigma receptor imaging agents. The affinity for other brain neuroreceptors was low., Conclusions: [ 11 C]MMP shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [ 11 C]MMP PET imaging is well within the acceptable dose limit., (© 2024. The Author(s).)

This study promotes the use of nanobiochar (NBC) as an environmentally friendly substitute to conventional fillers to improve various properties of biopolymers such as their mechanical strength, thermal stability and crystallization properties. TGA analysis showed a slight increase in onset thermal degradation temperature of the composites by up to 5 °C with the addition of 4 wt% NBC. Non-isothermal DSC analysis determined that the addition of NBC into PHBHHx increases the crystallization temperature and degree of crystallinity of PHBHHx while isothermal DSC analysis demonstrated higher crystallization rate in PHBHHx/NBC composited by up to 54%. PHBHHx incorporated with NBC also exhibited superior tensile strength and modulus versus neat PHBHHx. Increase in mechanical strength was further proven via DMA where PHBHHx/NBC composites maintained higher storage modulus at higher temperatures when compared to neat PHBHHx. PHBHHx/NBC also exhibited no cytotoxicity effect against HaCat cells. This study demonstrates the ability of biochar to act as both nucleating agents and reinforcing agents in biodegradable polymers such as PHBHHx, which could be suitable for packaging application., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: Histone deacetylase 6 (HDAC6) has emerged as a therapeutic target for neurodegenerative diseases such as Alzheimer's disease. Noninvasive imaging of HDAC6 in the brain by positron emission tomography (PET) would accelerate research into its roles in these diseases. We recently discovered an 18 F-labeled derivative of the selective HDAC6 inhibitor SW-100 ([ 18 F]FSW-100) as a potential candidate for brain HDAC6 radioligand. As a mandatory step prior to clinical translation, we performed preclinical validation of [ 18 F]FSW-100., Methods: Process validation of [ 18 F]FSW-100 radiosynthesis for clinical use and assessment of preclinical toxicity and radiation dosimetry estimated from mouse distribution data were performed. In vitro selectivity of FSW-100 for 28 common receptors in the brain and HDAC isoforms was characterized. [ 18 F]FSW-100 PET imaging was performed in non-human primates in a conscious state to estimate the feasibility of HDAC6 imaging in humans., Results: Three consecutive validation runs of the automated radiosynthesis gave [ 18 F]FSW-100 injections with radiochemical yields of 12%, and the injections conformed to specified quality control criteria for batch release. No acute toxicity was observed for non-radiolabeled FSW-100 or radioactivity decayed [ 18 F]FSW-100 injection, and the former was negative in the Ames test. The whole-body effective dose estimated from biodistribution in mice was within the range of that of previously reported 18 F-radioligands in humans. In vitro selectivity against common receptors and other HDAC isoforms was confirmed. [ 18 F]FSW-100 demonstrated good penetration in monkey brain, and in vivo blocking studies suggested that the uptake was specific., Conclusion: These results support the clinical utility of [ 18 F]FSW-100 for in vivo imaging of HDAC6 in the brain., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Seromucinous borderline tumors (SMBT) are papillary neoplasms without invasive capabilities. Originally categorized as ovarian tumors, SMBT, being an endometriosis-related tumor, can manifest beyond the ovaries. To date, only four cases of extraovarian SMBT have been documented in literature. In this report, we present our experience with the first case of SMBT in the uterine cervix, which exhibited highly elevated CA19-9 levels. The patient, initially clinically diagnosed with cervical cancer, underwent treatment with radical hysterectomy and was later pathologically diagnosed with SMBT of the uterine cervix. While extraovarian SMBT, especially in the uterine cervix, is extremely rare, this condition should be considered in patients with cervical masses lacking pathological evidence of malignant disease but displaying elevated CA19-9 levels., (© 2024 Japan Society of Obstetrics and Gynecology.)

Background: We aimed to investigate the trends in the incidence and treatment of endometrial cancer (EC) during potentially reproductive age in Japan, with a special focus on the relative oncologic safety of hormonal therapy (HT) over surgery., Methods: This population-based retrospective cohort study was conducted using data from the Osaka Cancer Registry from 2004 to 2018. Women with EC were first identified and then distributions of age, stage, histology, and initial treatment were examined. Then, the relative oncologic safety of HT over surgery in patients under the age of 50 years was evaluated., Results: Among the 9417 patients with EC, 1937 were diagnosed during their potentially reproductive age (< 50 years). The incidence of EC during potentially reproductive age has increased from 18.5% in 2004-2011 to 21.9% in 2012-2018. ECs during potentially reproductive age more frequently displayed favorable characteristics, such as endometrioid histology, and lower histological grade than those in non-potentially reproductive age. Among the 1223 patients diagnosed with localized endometrioid EC, 74 cases (6.0%) received HT as an initial treatment, while 1100 cases (90.0%) underwent surgery as their initial treatment. When the two treatment groups were compared, there was no significant difference in overall survival (p = 0.3713). The estimated 5-year survival rates were 100 and 98.8% in the HT and surgery groups, respectively., Conclusion: EC is increasingly diagnosed during potentially reproductive age in Japan. The use of HT as an initial treatment is increasing, and achieved comparable survival outcomes to urgery against localized endometrioid EC during the potentially reproductive age., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Although durvalumab plus tremelimumab (Dur/Tre) has been approved as first-line therapy for patients with unresectable hepatocellular carcinoma (u-HCC), its outcomes in real-world clinical practice are unclear. The present study aimed to evaluate the efficacy and safety of Dur/Tre treatment. This multicenter study was conducted between March 2023 and January 2024, and included 120 patients with u-HCC treated with Dur/Tre. Among the patients, 44 had no history of systemic treatment. Progression-free survival (PFS), therapeutic response and adverse events (AEs) were assessed. The objective response rate (ORR) and disease control rates (DCR) were 15.8 and 53.3%, respectively. The median PFS was 3.9 months. The incidence rates of AEs of any grade and those grade 3 or higher were 83.3 and 36.7%, respectively. Liver injury was the most frequent AE of any grade and grade 3 or higher. Although there was no significant difference in ORR and PFS between the first and later line groups (ORR 15.8 vs. 15.7%, P=0.986; PFS 4.5 vs. 3.6 months, P=0.213), there was a significant difference in DCR between the two groups (65.8 vs. 45.9%, P=0.034). No significant differences were noted between the first- and later-line treatment groups regarding the incidence rate of AEs. Decision tree analysis revealed that poor liver function and advanced age were significant variables for discontinuation owing to AEs. In conclusion, Dur/Tre as first-line therapy had better disease control responses compared with later-line therapy; however, this regimen should be carefully administered to patients with deteriorating hepatic function or advanced age., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Shimose et al.)

Background: To identify predictive factors associated with successful transition to conversion therapy following combination therapy with atezolizumab and bevacizumab in the treatment of unresectable hepatocellular carcinoma (HCC)., Methods: In total, 188 patients with HCC, who received atezolizumab plus bevacizumab combination therapy as the first-line chemotherapy, were studied. Patients who achieved complete response (CR) with systemic chemotherapy alone were excluded. Clinical factors possibly linked to successful transition to conversion therapy and the achievement of cancer-free status were identified., Results: Fifteen (8.0%) patients underwent conversion therapy. In the conversion group, there was a significantly higher proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage A or B (73.3% versus [vs.] 45.1%; p = .03) and tended to have lower Child-Pugh scores and alpha-fetoprotein levels. Multivariate analysis revealed that BCLC stage was a predictive factor for the implementation of conversion therapy (A or B; odds ratio 3.7 [95% CI: 1.1-13]; p = .04). Furthermore, 10 (66.7%) patients achieved cancer-free status and exhibited a smaller number of intrahepatic lesions at the start of treatment (3.5 vs. 7; p < .01), and a shorter interval between systemic chemotherapy induction and conversion therapy (131 vs. 404 days; p < .01). In addition, the rate of achieving cancer-free status by undergoing surgical resection or ablation therapy was significantly higher (p = .03)., Conclusion: BCLC stage was the sole predictive factor for successful transition to conversion therapy when using combination therapy with atezolizumab and bevacizumab to treat HCC. Furthermore, a small number of intrahepatic lesions and early transition to conversion therapy were associated with the achievement of cancer-free status., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Study Design: Retrospective multicenter study., Objectives: To investigate changes over a 10-years period in the profile of cervical spine and spinal cord injuries among the elderly in Japan., Methods: The current multicenter study was a retrospective analysis of inpatients aged ≥65 years, suffering cervical fracture (CF) and/or cervical spinal cord injury (CSCI). We analyzed 1413 patients' epidemiology (from 2010 to 2019). Moreover, 727 patients who underwent surgical treatment were analyzed in 2 groups: the early (2010-2014) and late period (2015-2019)., Results: Both the number of patients and number of surgical patients showed a significant increasing trend ( P < .001), while the mean age, the distribution of injury levels and paralysis severity, and the proportion of surgical indications remained the same. The number of surgical patients doubled from 228 to 499 from the early to late periods. Posterior surgery was the most common approach (90.4%), instrumentation surgery with screws increased significantly, and the range of fusion was significantly longer in the late period (2.1 vs 2.7 levels, P = .001). Significantly worsening neurological symptoms were recorded in the late period (1.3% vs 5.8%, P = .006), with C5 palsy being the major one. Otherwise, perioperative, major, and other complications, including mortality, did not differ significantly in incidence., Conclusions: Both the number of elderly CF and/or CSCI patients and number of patients undergoing surgery increased dramatically over the decade without any change in profile. Instrumentation surgeries with screws increased, without an increase in systemic complications., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: To assess the impact of perioperative prognostic nutritional index (PNI) changes on prognosis and recurrence after colorectal cancer surgery., Methods: A total of 475 patients who underwent curative resection for primary colorectal adenocarcinoma and were diagnosed with pathological stage (pStage) II/III were retrospectively reviewed. The patients were divided into two groups: the high group (preoperative PNI ≤ postoperative PNI, n  = 290) and the low group (preoperative PNI > postoperative PNI, n  = 185)., Results: The low group exhibited significantly higher recurrence and mortality rates (all p  < 0.001). Kaplan-Meier analysis showed worse overall and recurrence-free survival in the low group (all p  < 0.001). Perioperative PNI changes predicted prognosis and recurrence independent of preoperative nutritional conditions. Subgroup analyses showed better overall survival and recurrence-free survival in the high group across various parameters, such as patient background, surgical outcomes, adjuvant chemotherapy, and pathological characteristics. Multivariate analysis revealed that the low group based on perioperative PNI changes (hazard ratio [HR]: 5.809, 95% confidence interval [CI]: 3.451-9.779, p  < 0.001), pathological T stage (HR: 1.962, 95% CI: 1.184-3.253, p  = 0.009), and pathological N stage (HR: 3.434, 95% CI: 1.964-6.004, p  < 0.001) were identified as independent predictors of worse overall survival., Conclusions: Patients with pStage II/III colorectal cancer who demonstrate a lower postoperative PNI levels compared to preoperative had poorer overall survival and recurrence-free survival. Perioperative PNI changes can serve as useful biomarkers for predicting survival and recurrence., Competing Interests: Authors declare no conflict of interests for this article. Hiroya Takeuchi is an editorial board member of Annals of Gastroenterological Surgery., (© 2024 The Author(s). Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

This study aimed to evaluate the impact of shear stress on surgery-related sacral pressure injury (PI) after laparoscopic colorectal surgery performed in the lithotomy position. We included 37 patients who underwent this procedure between November 2021 and October 2022. The primary outcome was average horizontal shear stress caused by the rotation of the operating table during the operation, and the secondary outcome was interface pressure over time. Sensors were used to measure shear stress and interface pressure in the sacral region. Patients were divided into two groups according to the presence or absence of PI. PI had an incidence of 32.4%, and the primary outcome, average horizontal shear stress, was significantly higher in the PI group than in the no-PI group. The interface pressure increased over time in both groups. At 120 min, the interface pressure was two times higher in the PI group than in the no-PI group (PI group, 221.5 mmHg; no-PI group, 86.0 mmHg; p < 0.01). This study suggested that shear stress resulting from rotation of the operating table in the sacral region by laparoscopic colorectal surgery performed in the lithotomy position is the cause of PI. These results should contribute to the prevention of PI., (© 2024. The Author(s).)

Background: Previous systematic reviews suggest that nurse-led interventions improve short-term blood pressure (BP) control for people with hypertension. However, the long-term effects, adverse events, and appropriate target BP level are unclear. This study aimed to evaluate the long-term efficacy and safety of nurse-led interventions., Methods: We conducted a systematic review and meta-analysis. We searched the Cochrane Central Register of Controlled Trials, PubMed, and CINAHL, as well as three Japanese article databases, as relevant randomized controlled trials from the oldest possible to March 2021. This search was conducted on 17 April 2021. We did an update search on 17 October 2023. We included studies on adults aged 18 years or older with hypertension. The treatments of interest were community-based nurse-led BP control interventions in addition to primary physician-provided care as usual. The comparator was usual care only. Primary outcomes were long-term achievement of BP control goals and serious adverse events (range: 27 weeks to 3 years). Secondary outcomes were short-term achievement of BP control goals and serious adverse events (range: 4 to 26 weeks), change of systolic and diastolic BP from baseline, medication adherence, incidence of hypertensive complications, and total mortality., Results: We included 35 studies. Nurse-led interventions improved long-term BP control (RR 1.10, 95%CI 1.03 to 1.18). However, no significant differences were found in the short-term effects of nurse-led intervention compared to usual care about BP targets. Little information on serious adverse events was available. There was no difference in mortality at both terms between the two groups. Establishing the appropriate target BP from the extant trials was impossible., Conclusions: Nurse-led interventions may be more effective than usual care for achieving BP control at long-term follow-up. It is important to continue lifestyle modification for people with hypertension. We must pay attention to adverse events, and more studies examining appropriate BP targets are needed. Nurse-led care represents an important complement to primary physician-led usual care., (© 2024. The Author(s).)

Objectives: This study aimed to investigate the utility of the RAND/UCLA appropriateness method (RAM) in validating expert consensus-based multiple-choice questions (MCQs) on electrocardiogram (ECG)., Methods: According to the RAM user's manual, nine panelists comprising various experts who routinely handle ECGs were asked to reach a consensus in three phases: a preparatory phase (round 0), an online test phase (round 1), and a face-to-face expert panel meeting (round 2). In round 0, the objectives and future timeline of the study were elucidated to the nine expert panelists with a summary of relevant literature. In round 1, 100 ECG questions prepared by two skilled cardiologists were answered, and the success rate was calculated by dividing the number of correct answers by 9. Furthermore, the questions were stratified into "Appropriate," "Discussion," or "Inappropriate" according to the median score and interquartile range (IQR) of appropriateness rating by nine panelists. In round 2, the validity of the 100 ECG questions was discussed in an expert panel meeting according to the results of round 1 and finally reassessed as "Appropriate," "Candidate," "Revision," and "Defer.", Results: In round 1 results, the average success rate of the nine experts was 0.89. Using the median score and IQR, 54 questions were classified as " Discussion." In the expert panel meeting in round 2, 23% of the original 100 questions was ultimately deemed inappropriate, although they had been prepared by two skilled cardiologists. Most of the 46 questions categorized as "Appropriate" using the median score and IQR in round 1 were considered "Appropriate" even after round 2 (44/46, 95.7%)., Conclusions: The use of the median score and IQR allowed for a more objective determination of question validity. The RAM may help select appropriate questions, contributing to the preparation of higher-quality tests., (© 2024. The Author(s).)

Purpose: Bayesian penalised likelihood (BPL) reconstruction, which incorporates point-spread-function (PSF) correction, provides higher signal-to-noise ratios and more accurate quantitation than conventional ordered subset expectation maximization (OSEM) reconstruction. However, applying PSF correction to brain PET imaging is controversial due to Gibbs artefacts that manifest as unpredicted cortical uptake enhancement. The present study aimed to validate whether BPL without PSF would be useful for amyloid PET imaging., Methods: Images were acquired from Hoffman 3D brain and cylindrical phantoms for phantom study and 71 patients administered with [ 18 F]flutemetamol in clinical study using a Discovery MI. All images were reconstructed using OSEM, BPL with PSF correction, and BPL without PSF correction. Count profile, %contrast, recovery coefficients (RCs), and image noise were calculated from the images acquired from the phantoms. Amyloid β deposition in patients was visually assessed by two physicians and quantified based on the standardised uptake value ratio (SUVR)., Results: The overestimated radioactivity in profile curves was eliminated using BPL without PSF correction. The %contrast and image noise decreased with increasing β values in phantom images. Image quality and RCs were better using BPL with, than without PSF correction or OSEM. An optimal β value of 600 was determined for BPL without PSF correction. Visual evaluation almost agreed perfectly (κ = 0.91-0.97), without depending on reconstruction methods. Composite SUVRs did not significantly differ between reconstruction methods., Conclusion: Gibbs artefacts disappeared from phantom images using the BPL without PSF correction. Visual and quantitative evaluation of [ 18 F]flutemetamol imaging was independent of the reconstruction method. The BPL without PSF correction could be the standard reconstruction method for amyloid PET imaging, despite being qualitatively inferior to BPL with PSF correction for [ 18 F]flutemetamol amyloid PET imaging., (© 2024. The Author(s).)

Study Design: Retrospective cohort study., Objectives: To define the prognosis and predictive factors for neurological improvement in older patients with incomplete spinal cord injury (SCI) of American Spinal Injury Association Impairment Scale grade C (AIS-C)., Settings: Multi-institutions in Japan., Methods: We included patients aged ≥65 years with traumatic SCI of AIS-C who were treated conservatively or surgically with >3 follow-up months. To identify factors related to neurological improvement, patients were divided into three groups according to their neurological status at the final follow-up, with univariate among-group comparisons of demographics, radiographic, and therapeutic factors. Significant variables were included in the multivariate logistic regression analysis., Results: Overall, 296 older patients with SCI of AIS-C on admission were identified (average age: 75.2 years, average follow-up: 18.7 months). Among them, 190 (64.2%) patients improved to AIS-D and 21 (7.1%) patients improved to AIS-E at final follow-up. There were significant among-group differences in age (p = 0.026), body mass index (p = 0.007), status of pre-traumatic activities of daily living (ADL) (p = 0.037), and serum albumin concentrations (p = 0.011). Logistic regression analysis showed no significant differences in variables in the stratified group of patients who improved to AIS-D. Meanwhile, serum albumin was a significant variable in patients who improved to AIS-E (p = 0.026; OR: 6.20, pre-traumatic ADL was omitted due to data skewness)., Conclusions: Most older patients with incomplete AIS-C SCI demonstrated at least 1 grade of neurological improvement. However, <10% of patients achieved complete recovery. Key predictors of complete recovery were high serum albumin levels on admission and independent pre-traumatic ADL., Sponsorship: No funding was received for this study., (© 2024. The Author(s), under exclusive licence to International Spinal Cord Society.)

Importance: Chronic insomnia disorder is highly prevalent, disabling, and costly. Cognitive behavioral therapy for insomnia (CBT-I), comprising various educational, cognitive, and behavioral strategies delivered in various formats, is the recommended first-line treatment, but the effect of each component and delivery method remains unclear., Objective: To examine the association of each component and delivery format of CBT-I with outcomes., Data Sources: PubMed, Cochrane Central Register of Controlled Trials, PsycInfo, and International Clinical Trials Registry Platform from database inception to July 21, 2023., Study Selection: Published randomized clinical trials comparing any form of CBT-I against another or a control condition for chronic insomnia disorder in adults aged 18 years and older. Insomnia both with and without comorbidities was included. Concomitant treatments were allowed if equally distributed among arms., Data Extraction and Synthesis: Two independent reviewers identified components, extracted data, and assessed trial quality. Random-effects component network meta-analyses were performed., Main Outcomes and Measures: The primary outcome was treatment efficacy (remission defined as reaching a satisfactory state) posttreatment. Secondary outcomes included all-cause dropout, self-reported sleep continuity, and long-term remission., Results: A total of 241 trials were identified including 31 452 participants (mean [SD] age, 45.4 [16.6] years; 21 048 of 31 452 [67%] women). Results suggested that critical components of CBT-I are cognitive restructuring (remission incremental odds ratio [iOR], 1.68; 95% CI, 1.28-2.20) third-wave components (iOR, 1.49; 95% CI, 1.10-2.03), sleep restriction (iOR, 1.49; 95% CI, 1.04-2.13), and stimulus control (iOR, 1.43; 95% CI, 1.00-2.05). Sleep hygiene education was not essential (iOR, 1.01; 95% CI, 0.77-1.32), and relaxation procedures were found to be potentially counterproductive(iOR, 0.81; 95% CI, 0.64-1.02). In-person therapist-led programs were most beneficial (iOR, 1.83; 95% CI, 1.19-2.81). Cognitive restructuring, third-wave components, and in-person delivery were mainly associated with improved subjective sleep quality. Sleep restriction was associated with improved subjective sleep quality, sleep efficiency, and wake after sleep onset, and stimulus control with improved subjective sleep quality, sleep efficiency, and sleep latency. The most efficacious combination-consisting of cognitive restructuring, third wave, sleep restriction, and stimulus control in the in-person format-compared with in-person psychoeducation, was associated with an increase in the remission rate by a risk difference of 0.33 (95% CI, 0.23-0.43) and a number needed to treat of 3.0 (95% CI, 2.3-4.3), given the median observed control event rate of 0.14., Conclusions and Relevance: The findings suggest that beneficial CBT-I packages may include cognitive restructuring, third-wave components, sleep restriction, stimulus control, and in-person delivery but not relaxation. However, potential undetected interactions could undermine the conclusions. Further large-scale, well-designed trials are warranted to confirm the contribution of different treatment components in CBT-I.

Curcumin (CUR), a polyphenol, is an attractive component of functional foods, owing to various physiological activities. However, CUR is highly hydrophobic, insoluble in water, and difficult to absorb in the body. Here, we report an amorphous CUR formulation containing the dispersant polyglycerol fatty acid ester (PGFE), demonstrating high and stable water solubility. Improved water solubility enhanced the absorbability of CUR in our amorphous formulation along with enhanced triglyceride inhibition, compared to that in a commercial formulation. Nuclear Overhauser effect spectroscopy (NOESY) analysis revealed that PGFE reduced CUR-CUR interaction, resulting in higher dispersion and improved solubility of CUR. Taylor dispersion analysis showed a lower diffusion coefficient of CUR in the highly water-soluble formulation (with PGFE) than that in the low water-soluble formulation (without PGFE), which prevents recontact and recrystallization of CUR, which is trapped by PGFE. Overall, the amorphous CUR with high solubility could be used as a promising functional food., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Climate change has a significant impact on rice grain appearance quality; in particular, high temperatures during the grain filling period increase the rate of chalky immature grains, reducing the marketability of rice. Heat-tolerant cultivars have been bred and released to reduce the rate of chalky grain and improve rice quality under high temperatures, but the ability of these cultivars to actually reduce chalky grain content has never been demonstrated due to the lack of integrated datasets. Here, we present a dataset collected through a systematic literature search from publicly available data sources, for the quantitative analysis of the impact of meteorological factors on grain appearance quality of various rice cultivars with contrasted heat tolerance levels. The dataset contains 1302 field observations of chalky grain rates (%) - a critical trait affecting grain appearance sensitive to temperature shocks - for 48 cultivars covering five different heat-tolerant ranks (HTRs) collected at 44 sites across Japan. The dataset also includes the values of key meteorological variables during the grain filling period, such as the cumulative mean air temperature above the threshold temperature (TaHD), mean solar radiation, and mean relative humidity over 20 days after heading, obtained from a gridded daily meteorological dataset with a 1-km resolution developed by the National Agriculture and Food Research Organization. The dataset covers major commercial rice cultivars cultivated in Japan in different environmental conditions. It is a useful resource for analyzing the climate change impact on crop quality and assess the effectiveness of genetic improvements in heat tolerance. Its value has been illustrated in the research article entitled "Effectiveness of heat tolerance rice cultivars in preserving grain appearance quality under high temperatures - A meta-analysis", where the dataset was used to develop a statistical model quantifying the effects of high temperature on grain quality as a function of cultivar heat tolerance., (© 2024 The Author(s).)

This retrospective cohort study established malnutrition's impact on mortality and neurological recovery of older patients with cervical spinal cord injury (SCI). It included patients aged ≥ 65 years with traumatic cervical SCI treated conservatively or surgically. The Geriatric Nutritional Risk Index was calculated to assess nutritional-related risk. Overall, 789 patients (mean follow-up: 20.1 months) were examined and 47 had major nutritional-related risks on admission. One-year mortality rate, median survival time, neurological recovery, and activities of daily living (ADL) at 1 year post-injury were compared between patients with major nutrition-related risk and matched controls selected using 1:2 propensity score matching to adjust for age, pre-traumatic neurological impairment, and activity. In the Kaplan-Meier analysis, the median survival times were 44.9 and 76.5 months for patients with major nutrition-related risk and matched controls, respectively (p = 0.015). Matched controls had more individuals with a neurological improvement of American Spinal Injury Association Impairment Scale ≥ 1 grade (p = 0.039) and independence in ADL at 1 year post-injury than patients with major nutrition-related risk (p < 0.05). In conclusion, 6% of older patients with cervical SCI had major nutrition-related risks; they showed a significantly higher 1 year mortality rate, shorter survival time, poorer neurological improvement, and lower ADL at 1 year post-injury than matched controls., (© 2024. The Author(s).)

Introduction: Pareidolias, or visual misperceptions, are a non-motor symptom of Parkinson's disease (PD) with unclear pathophysiology. The noise pareidolia test (NPT) is a tool for screening pareidolias. The usefulness of the NPT in differentiating PD from atypical parkinsonian syndromes (APS) is also unknown., Methods: We retrospectively investigated 74 patients with PD and 18 patients with APS who took the NPT. Correlations between the number of pareidolic responses, gray matter volume, and cerebral blood flow were also examined in the patients with PD., Results: The median number of pareidolic responses in patients with PD and patients with APS was 0 (interquartile range (IQR): 0-3) and 0 (IQR: 0-1), respectively, and tended to be higher in patients with PD than in those with APS (p = 0.077). It was significantly higher in patients with PD who had hallucinations (2; IQR: 0-9) (p = 0.016). The area under the receiver operating characteristic curve for the number of pareidolic responses in the NPT was 0.62 when used to differentiate PD and APS, and the optimal cutoff number of pareidolic responses was 2/3. Sensitivity and specificity were 25.7% and 100%, respectively. In the PD group, the number of pareidolic responses was correlated with age (r = 0.27; p = 0.021) and the Frontal Assessment Battery (FAB) score (r = -0.34; p = 0.0099). Magnetic resonance imaging showed no significant correlation between the number of pareidolic responses and the volume of focal gray matter. On cerebral hypoperfusion mapping, the left parietal lobe had a significant correlation with the number of pareidolic responses (r = 0.35; p = 0.027)., Conclusion: The number of pareidolic responses in NPT was suggested to be useful as a red flag to rule out APS in differentiating PD from APS. In PD without dementia, the number of pareidolic responses was associated with reduced blood flow in the left parietal lobe., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Matsumoto et al.)

Purpose: The long-term prognosis of stapled and hand-sewn ileal pouch-anal anastomoses in familial adenomatous polyposis patients in Japan remains unknown. This study aimed to compare the overall survival in familial adenomatous polyposis patients who underwent stapled or hand-sewn ileal pouch-anal anastomosis., Methods: This multicenter retrospective study was conducted at 12 institutions in Shizuoka Prefecture, Japan. The clinical outcomes of 53 eligible familial adenomatous polyposis patients who underwent stapled (n = 24) and hand-sewn (n = 29) ileal pouch-anal anastomosis were compared., Results: The median follow-up duration was 171.5 months. The incidence of adenoma in the remnant rectum or anal transitional zone and metachronous rectal cancer was significantly more common in stapled ileal pouch-anal anastomosis (adenoma: stapled, 45.8%, vs. hand-sewn, 10.3%, p = 0.005; metachronous rectal cancer: 29.2%, vs. none, p = 0.002). The number of deaths was remarkably higher in stapled ileal pouch-anal anastomosis (p = 0.002). Metachronous rectal cancer was the most common cause of death. Overall survival was worse in stapled ileal pouch-anal anastomosis than in hand-sewn ileal pouch-anal anastomosis (120 months, 90.7% vs. 96.6%; 240 months, 63.7% vs. 96.6%; p = 0.044). Cox regression analysis revealed the independent effects of preoperative advanced colorectal cancer and stapled ileal pouch-anal anastomosis on overall survival., Conclusion: Stapled ileal pouch-anal anastomosis negatively affected the overall survival of familial adenomatous polyposis patients. Therefore, hand-sewn ileal pouch-anal anastomosis is recommended for better prognosis in these patients., (© 2024. The Author(s).)

Subthreshold depression impairs young people's quality of life and places them at greater risk of developing major depression. Cognitive behavioral therapy (CBT) is an evidence-based approach for addressing such depressive states. This study identified subtypes of university students with subthreshold depression and revealed discrete profiles of five CBT skills: self-monitoring, cognitive restructuring, behavioral activation, assertive communication, and problem solving. Using data from the Healthy Campus Trial (registration number: UMINCTR-000031307), a hierarchical clustering analysis categorized 1,080 students into three clusters: Reflective Low-skilled, Non-reflective High-skilled, and Non-reflective Low-skilled students. Non-reflective Low-skilled students were significantly more depressed than other students ( p  < .001). The severity of depression seemed to be related to the combination of self-monitoring skills and other CBT skills. Considering the high prevalence of poor self-monitoring skills in persons with autism, the most severe depression was observed in the significant association between Non-reflective Low-skilled students and autistic traits ( p  = .008). These findings suggest that subthreshold depression can be categorized into three subtypes based on CBT skill profiles. The assessment of autistic traits is also suggested when we provide CBT interventions for Non-reflective Low-skilled students.

Background: Although previous studies have demonstrated the advantages of early surgery for traumatic spinal cord injury (SCI), the appropriate surgical timing for cervical SCIs (CSCIs) without bone injury remains controversial. Here, we investigated the influence of relatively early surgery within 48 h of injury on the neurological recovery of elderly patients with CSCI and no bone injury., Methods: In this retrospective multicenter study, we reviewed data from 159 consecutive patients aged ≥65 years with CSCI without bone injury who underwent surgery in participating centers between 2010 and 2020. Patients were followed up for at least 6 months following CSCI. We divided patients into relatively early (≤48 h after CSCI, n = 24) and late surgery (>48 h after CSCI, n = 135) groups, and baseline characteristics and neurological outcomes were compared between them. Multivariate analysis was performed to identify factors associated with neurological recovery., Results: The relatively early surgery group demonstrated a lower prevalence of cardiac disease, poorer baseline American Spinal Injury Association (ASIA) impairment scale grade, and lower baseline ASIA motor score (AMS) than those of the late surgery group (P < 0.030, P < 0.001, and P < 0.001, respectively). Although the AMS was lower in the relatively early surgery group at 6 months following injury (P = 0.001), greater improvement in this score from baseline to 6-months post injury was observed (P = 0.010). Multiple linear regression analysis revealed that relatively early surgery did not affect postoperative improvement in AMS, rather, lower baseline AMS was associated with better AMS improvement (P < 0.001). Delirium (P = 0.006), pneumonia (P = 0.030), and diabetes mellitus (P = 0.039) negatively influenced postoperative improvement., Conclusions: Although further validation by future studies is required, relatively early surgery did not show a positive influence on neurological recovery after CSCI without bone injury in the elderly., (Copyright © 2023 The Japanese Orthopaedic Association. All rights reserved.)

Numerous cyanobacteria capable of oxygenic photosynthesis possess multiple large plasmids exceeding 100 kbp in size. These plasmids are believed to have distinct replication and distribution mechanisms, as they coexist within cells without causing incompatibilities between plasmids. However, information on plasmid replication proteins (Rep) in cyanobacteria is limited. Synechocystis sp. PCC 6803 hosts four large plasmids, pSYSM, pSYSX, pSYSA, and pSYSG, but Rep proteins for these plasmids, except for CyRepA1 on pSYSA, are unknown. Using Autonomous Replication sequencing (AR-seq), we identified two potential Rep genes in Synechocystis 6803, slr6031 and slr6090 , both located on pSYSX. The corresponding Rep candidates, Slr6031 and Slr6090, share structural similarities with Rep-associated proteins of other bacteria and homologs were also identified in various cyanobacteria. We observed autonomous replication activity for Slr6031 and Slr6090 in Synechococcus elongatus PCC 7942 by fusing their genes with a construct expressing GFP and introducing them via transformation. The slr6031/slr6090 -containing plasmids exhibited lower copy numbers and instability in Synechococcus 7942 cells compared to the expression vector pYS. While recombination occurred in the case of slr6090 , the engineered plasmid with slr6031 coexisted with plasmids encoding CyRepA1 or Slr6090 in Synechococcus 7942 cells, indicating the compatibility of Slr6031 and Slr6090 with CyRepA1. Based on these results, we designated Slr6031 and Slr6090 as CyRepX1 (Cyanobacterial Rep-related protein encoded on pSYSX) and CyRepX2, respectively, demonstrating that pSYSX is a plasmid with "two Reps in one plasmid." Furthermore, we determined the copy number and stability of plasmids with cyanobacterial Reps in Synechococcus 7942 and Synechocystis 6803 to elucidate their potential applications. The novel properties of CyRepX1 and 2, as revealed by this study, hold promise for the development of innovative genetic engineering tools in cyanobacteria., 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 Ohdate, Sakata, Maeda, Sakamaki, Nimura-Matsune, Ohbayashi, Hess and Watanabe.)

mRNA-based therapeutics are revolutionizing the landscape of medical interventions. However, the short half-life of mRNA and transient protein expression often limits its therapeutic potential, demanding high treatment doses or repeated administrations. Self-replicating RNA (RepRNA)-based treatments could offer enhanced protein production and reduce the required dosage. Here, we developed polymeric micelles based on flexible poly(ethylene glycol)-poly(glycerol) (PEG-PG) block copolymers modified with phenylalanine (Phe) moieties via biodegradable ester bonds for the efficient delivery of RepRNA. These polymers successfully encapsulated RepRNA into sub-100 nm micelles assisted by the hydrophobicity of the Phe moieties and their ability to π-π stack with the bases in RepRNA. The micelles made from Phe-modified PEG-PG (PEG-PG(Phe)) effectively maintained the integrity of the loaded RepRNA in RNase-rich serum conditions. Once taken up by cells, the micelles triggered a pH-responsive membrane disruption, promoted by the strong protonation of the amino groups at endosomal pH, thereby delivering the RepRNA to the cytosol. The system induced strong protein expression in vitro and outperformed commercial transfecting reagents in vivo, where it resulted in enhanced and long-lasting protein expression.

Objective: This study aimed to investigate the prognostic significance of tumor size and number of positive pelvic lymph nodes (PLN) in International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IIIC1 cervical cancer patients., Methods: Clinical data from 626 women with cervical cancer treated at Osaka International Cancer Center in 2010-2020 were retrospectively reviewed. Using the cutoff value obtained on the receiver operating characteristic analysis, the prognostic significance of tumor size and number of positive PLN in stage IIIC1 patients was first evaluated via uni- and multivariate analyses. Then, the impact of incorporating tumor size and number of positive PLN into the FIGO staging system was investigated using the Kaplan-Meier method., Results: Among 196 women with Stage IIIC1 disease, larger tumors (>4 cm) and multiple PLN metastases (≥4) were independent predictors of progression-free survival (PFS) in patients with stage IIIC1 cervical cancer. The PFS of patients with stage IIIC1 disease was inversely associated with the number of risk factors. Although patients with stage IIIC1 disease had significantly increased survival rates compared to those with stage IIIA or IIIB disease in the original FIGO 2018 staging system, this reversal phenomenon was resolved by incorporating larger tumors (>4 cm) and multiple PLN metastases (≥4) into the revised staging system., Conclusions: Incorporating tumor size and number of metastatic lymph nodes into the FIGO staging system allows additional risk stratification for women with stage IIIC1 cervical cancer and improves survival prediction performance., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Many glaucoma treatments focus on lowering intraocular pressure (IOP), with novel drugs continuing to be developed. One widely used model involves raising IOP by applying a laser to the trabecular iris angle (TIA) of cynomolgus monkeys to damage the trabecular meshwork. This model, however, presents challenges such as varying IOP values, potential trabecular meshwork damage, and risk of animal distress. This study investigated whether animals with naturally high IOP (>25 mmHg) could be used to effectively evaluate IOP-lowering drugs, thereby possibly replacing laser-induced models. Relationships between TIA size, IOP, and pupil diameter were also examined. Three representative IOP-lowering drugs (latanoprost, timolol, ripasudil) were administered, followed by multiple IOP measurements and assessment of corneal thickness, TIA, and pupil diameter via anterior segment optical coherence tomography (AS-OCT). There was a positive correlation was noted between IOP and corneal thickness before instillation, and a negative correlation between IOP and TIA before instillation. Our findings suggest animals with naturally high IOP could be beneficial for glaucoma research and development as a viable replacement for the laser-induced model and that measuring TIA using AS-OCT along with IOP yields a more detailed evaluation., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Chloroplast starch granules (cpSGs) store energy harvested through photosynthesis in plants, and cpSG dynamics have important roles in plant energy metabolism and stress responses. To date, cpSGs have been visualized using several methods, such as iodine staining; however, no method can be used to specifically visualize cpSGs in living cells from various plant species. Here, we report a simple method to visualize cpSGs in living plant cells in various species by staining with fluorescein, a commonly used fluorescent dye. We show that fluorescein is taken up into chloroplasts and interacts with cpSGs similarly to iodine. Fluorescein also interacts with refined starch in vitro. Using a fluorescein derivative for ultrabright cpSG imaging, we produced high-quality 3D reconstructions of cpSGs and evaluated their accumulation in multiple plant species. As fluorescein is well known and readily purchasable, our fluorescein-based staining method should contribute to all research regarding starch., Competing Interests: Conflict of interest statement. The authors declare that they have no conflict of interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Background: Internet-based cognitive-behavioural therapy (iCBT) is effective for subthreshold depression. However, iCBT has problems with adherence, especially when unaccompanied by human guidance. Knowledge on how to enhance adherence to iCBT without human involvement can contribute to improving the effectiveness of iCBT., Objective: This is an implementation study to examine the effect of an automated chatbot to improve the adherence rate of iCBT., Methods: We developed a chatbot to increase adherence to an existing iCBT programme, and a randomised controlled trial was conducted with two groups: one group using iCBT plus chatbot (iCBT+chatbot group) and one group not using the chatbot (iCBT group). Participants were full-time employees with subthreshold depression working in Japan (n=149, age mean=41.4 (SD=11.1)). The primary endpoint was the completion rate of the iCBT programme at 8 weeks., Findings: We analysed data from 142 participants for the primary outcome. The completion rate of the iCBT+chatbot group was 34.8% (24/69, 95% CI 23.5 to 46.0), that of the iCBT group was 19.2% (14/73, 95% CI 10.2 to 28.2), and the risk ratio was 1.81 (95% CI 1.02 to 3.21)., Conclusions: Combining iCBT with a chatbot increased participants' iCBT completion rate., Clinical Implications: Encouraging messages from the chatbot could improve participation in an iCBT programme. Further studies are needed to investigate whether chatbots can improve adherence to the programme in the long term and to assess their impact on depression, anxiety and well-being., Trial Registration Number: UMIN000047621., Competing Interests: Competing interests: TK, SY, TT, KY and RK are employees of Sony Corporation. TAF, HN and MS acted as advisors during the study. TAF reports personal fees from Boehringer Ingelheim, DT Axis, Kyoto University Original, MSD, Shionogi and Sony, and a grant from Shionogi, beyond the submitted work. In addition, TAF has patents 2020-548587 and 2022-082495 pending, and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe. HN reports personal fees from Boehringer Ingelheim, Kyowa Kirin, Toyota Motor Corporation, GlaxoSmithKline, Ono Pharmaceutical, Sony and Terumo beyond the submitted work. MS reports personal fees from Sony beyond the submitted work. All other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. Published by BMJ.)

Background: To support parental decision-making it is important to understand parents' perspectives on vaccination for their children and the factors that contribute to their vaccine hesitancy. There have been relatively few studies in this area in Japan, particularly with longitudinal and mixed methodologies., Methods: We used an explanatory sequential mixed methods approach to describe longitudinal changes in vaccine acceptance and to explore factors associated with parental coronavirus 2019 (COVID-19) vaccine hesitancy. We recruited parents who had children aged 6 months to 11 years old from five facilities in Japan. Two cross-sectional online surveys and semi-structured online interviews were conducted. Logistic regression analysis was used to explore factors associated with parents' vaccine hesitancy for their children, and thematic analysis was used to analyze the interview data., Results: In total, 134 parents responded to both online surveys and, of those, 10 participated in interviews. Acceptance rates of COVID-19 vaccination for their children were 19.4% (26/134) at the first survey and 11.2% (15/134) at the second survey. Integration of the data identified that the main factors for vaccine hesitancy included vaccine safety, vaccine effectiveness, government policy, and recommendations from people close to parents., Conclusions: Readily available and more balanced information, and community-wide support from people close to parents and familiar health-care providers are likely to provide better support for parents' decision-making. Further investigation is required on how to provide information in an easily understood manner., (© 2024 The Author(s). Pediatrics International published by John Wiley & Sons Australia, Ltd on behalf of Japan Pediatric Society.)

Background: The corrected QT interval (QTc) is affected by changes in autonomic sympathovagal modulation. The aim of this study was to determine whether children with orthostatic dysregulation (OD) have a longer QTc while standing than children without OD., Methods: We retrospectively assessed patients who underwent the Schellong test and electrocardiography between November 2016 and November 2019. Patients who met the criteria of OD subtypes according to the Japanese clinical guidelines for juvenile OD (version 1) were classified as OD positive (the OD-positive group), and patients who did not meet the criteria were classified as OD negative (the OD-negative group)., Results: There were 73 patients in the OD-positive group and 52 patients in the OD-negative group. Baseline heart rate, QT interval, and QTc were comparable between the OD-positive and OD-negative groups. Heart rate after standing was significantly higher in the OD-positive group than in the OD-negative group (median: 33 bpm vs. 21 bpm, p < 0.001). Further, shortening of QT interval after standing was greater in the OD-positive group than in the OD-negative group (median: 19 ms vs. 8 ms, p = 0.015). The QTc significantly increased from baseline to standing in both groups. Changes in the QT interval corrected by Bazett's formula were greater in the OD-positive group than in the OD-negative group (median: 73 ms vs. 42 ms, p < 0.001)., Conclusions: The QTc increased significantly from baseline to standing in the OD-positive group. Thus, a high QTc while standing could be considered an auxiliary marker for OD diagnosis., (© 2024 Japan Pediatric Society.)

Background: Cortical neurodegenerative processes may precede the emergence of disease symptoms in patients with Alzheimer's disease (AD) by many years. No study has evaluated the free water of patients with AD using gray matter-based spatial statistics., Objective: The aim of this study was to explore cortical microstructural changes within the gray matter in AD by using free water imaging with gray matter-based spatial statistics., Methods: Seventy-one participants underwent multi-shell diffusion magnetic resonance imaging, 11C-Pittsburgh compound B positron emission tomography, and neuropsychological evaluations. The patients were divided into two groups: healthy controls (n = 40) and the AD spectrum group (n = 31). Differences between the groups were analyzed using voxel-based morphometry, diffusion tensor imaging, and free water imaging with gray matter-based spatial statistics., Results: Voxel-based morphometry analysis revealed gray matter volume loss in the hippocampus of patients with AD spectrum compared to that in controls. Furthermore, patients with AD spectrum exhibited significantly greater free water, mean diffusivity, and radial diffusivity in the limbic areas, precuneus, frontal lobe, temporal lobe, right putamen, and cerebellum than did the healthy controls. Overall, the effect sizes of free water were greater than those of mean diffusivity and radial diffusivity, and the larger effect sizes of free water were thought to be strongly correlated with AD pathology., Conclusions: This study demonstrates the utility of applying voxel-based morphometry, gray matter-based spatial statistics, free water imaging and diffusion tensor imaging to assess AD pathology and detect changes in gray matter.

Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)