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Currently, natural bioactive ingredients and/or raw materials are of significant interest to scientists around the world. Flavonoids and other polyphenols are a major group of phytochemicals that have been researched and noted as bioactive molecules. They offer several pharmacological and medical benefits. This current review aims to (1) illustrate their benefits for human health, such as antioxidant, anti-aging, anti-cancer, anti-inflammatory, anti-microbial, cardioprotective, neuroprotective, and UV-protective effects, and also (2) to perform a quality evaluation of traditional medicines for future application. Consequently, keywords were searched on Scopus, Google Scholar, and PubMed so as to search for related publications. Then, those publications were carefully checked in order to find current and non-redundant studies that matched the objective of this review. According to this review, researchers worldwide are very interested in discovering the potential of flavonoids and other polyphenols, used in traditional medicines and taken from medicinal plants, in relation to medical and pharmaceutical applications. Many studies focus on the health benefits of flavonoids and other polyphenols have been tested using in silico, in vitro, and in vivo models. However, few studies have been carried out using clinical trials that have trustworthy subject sizes and are in accordance with clinical practice guidelines. Additionally, interesting research directions and perspectives for future studies are highlighted in this work.

Most follicular lymphomas (FLs) demonstrate an indolent clinical course with favorable outcomes; however, a fraction of patients experiences progression of disease within 24 months (POD24) and has adverse outcomes. This study aimed to determine the predictive risk factors for POD24 in patients with FL, and the characteristics of the microenvironment in FL with POD24. By multivariate analysis, we revealed that increased Ki-67 expression was associated with POD24 events in patients with FL (hazard ratio [HR]: 6.29, 95% confidence interval [CI]: 1.96-20.22, p = 0.0020). Additionally, patients with FL with POD24 demonstrated immune cell reduction by immunohistochemistry analysis. Our results help better understand the therapeutic strategies for FL with POD24.

Background: Various reduced-intensity conditioning/reduced-toxicity conditioning regimens have been developed for patients receiving allogeneic hematopoietic cell transplantation. The balance between disease relapse and toxicity can be partly dependent on reduced-intensity conditioning/reduced-toxicity conditioning regimens. This retrospective study aimed to compare the nonrelapse mortality, relapse incidence, progression-free survival, and overall survival rates between the fludarabine/melphalan/reduced-dose busulfan (Flu/Mel/Bu2; busulfan at a dose of 6.4 mg/kg intravenously) and fludarabine/melphalan/full-dose busulfan (Flu/Mel/Bu4; busulfan at a dose of 12.8 mg/kg intravenously) regimens in patients receiving umbilical cord blood transplantation., Method: Eighty-seven adult patients who received the Flu/Mel/Bu2 (n = 45) or Flu/Mel/Bu4 (n = 42) regimen as a conditioning regimen before umbilical cord blood transplantation at our institution between January 2013 and December 2022 were included in this study., Results: There were no significant differences in terms of clinical outcomes including nonrelapse mortality, relapse incidence, progression-free survival, and overall survival rates between the two regimens. Further, even in higher-risk patients classified according to the Refined Disease Risk Index, the Flu/Mel/Bu2 regimen was comparable to the Flu/Mel/Bu4 regimen., Conclusion: The novel Flu/Mel/Bu2 regimen could be applied in clinical settings as it can be tolerated and effective in older patients., 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 article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diffuse large B-cell lymphoma (DLBCL) exhibits clinical, genetic, and immunohistochemical heterogeneity. However, the differences between primary extranodal or nodal DLBCL and double-expressor lymphoma (DEL), which is characterized by high MYC and BCL2 expression, remain unclear. This study aimed to elucidate the clinicopathological features, response to therapy, and clinical outcomes of primary extranodal (n=61) and nodal (n=128) DLBCL. Patients with primary nodal DLBCL had higher BCL2 expression than those with extranodal DLBCL (p=0.048), with high MYC expression and DEL as poor prognostic factors. Conversely, in patients with primary extranodal DLBCL, high BCL2 expression, low BCL6 expression, non-germinal center B-cell-like type, and DEL indicated poor prognosis. DEL was significantly associated with progression free survival and overall survival in patients with primary extranodal DLBCL (p=0.014 and p=0.021, respectively) but not in patients with primary nodal DLBCL (p=0.37 and p=0.084, respectively). Our findings highlight primary extranodal DEL as a strong adverse prognostic factor in DLBCL., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Purpose: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study aimed to clarify differences in clinical features and prognostic outcomes between IC and CLTI, and prognostic factors in patients undergoing endovascular therapy (EVT)., Materials and Methods: A total of 692 patients with 808 limbs were enrolled from 20 institutions in Japan. The primary measurements were the 3-year rates of major adverse cardiovascular event (MACE) and reintervention., Results: Among patients, 79.0% had IC and 21.0% had CLTI. Patients with CLTI were more frequently women and more likely to have impaired functional status, undernutrition, comorbidities, hypercoagulation, hyperinflammation, distal artery disease, short single antiplatelet and long anticoagulation therapies, and late cilostazol than patients with IC. Aortoiliac and femoropopliteal diseases were dominant in patients with IC and infrapopliteal disease was dominant in patients with CLTI. Patients with CLTI underwent less frequently aortoiliac intervention and more frequently infrapopliteal intervention than patients with IC. Longitudinal change of ankle-brachial index (ABI) exhibited different patterns between IC and CLTI (pinteraction=0.002), but ABI improved after EVT both in IC and in CLTI (p<0.001), which was sustained over time. Dorsal and plantar skin perfusion pressure in CLTI showed a similar improvement pattern (pinteraction=0.181). Distribution of Rutherford category improved both in IC and in CLTI (each p<0.001). Three-year MACE rates were 20.4% and 42.3% and 3-year reintervention rates were 22.1% and 46.8% for patients with IC and CLTI, respectively (log-rank p<0.001). Elevated D-dimer (p=0.001), age (p=0.043), impaired functional status (p=0.018), and end-stage renal disease (p=0.019) were independently associated with MACE. After considering competing risks of death and major amputation for reintervention, elevated erythrocyte sedimentation rate (p=0.003) and infrainguinal intervention (p=0.002) were independently associated with reintervention. Patients with CLTI merely showed borderline significance for MACE (adjusted hazard ratio 1.700, 95% confidence interval 0.950-3.042, p=0.074) and reintervention (adjusted hazard ratio 1.976, 95% confidence interval 0.999-3.909, p=0.05)., Conclusions: The CLTI is characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared with IC. Also, CLTI has approximately twice MACE and reintervention rates than IC, and the underlying inflammatory coagulation disorder per se is associated with these outcomes., Clinical Impact: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study, JPASSION study found that CLTI was characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared to IC. Also, CLTI had approximately twice major adverse cardiovascular event (MACE) and reintervention rates than IC. Intriguingly, the underlying inflammatory coagulation disorder per se was independently associated with MACE and reintervention. Further studies to clarify the role of anticoagulation and anti-inflammatory therapies will contribute to the development of post-interventional therapeutics in the context of peripheral artery disease., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: O.K. has received a research grant and consulting fees from Terumo and has received lecture fees from Medicon, Otsuka Pharmaceutical, and Kowa Pharmaceutical. H.O. has received lecture fees from Bayer Pharmaceutical, Bristol-Meyers Squibb, Eisai, Novartis Pharma, Pfizer, Towa Pharmaceutical, and Toa Eiyo. S.Y. has received remuneration for lecture from Bristol-Meyers, Bayer, and Daiichi-Sankyo; has received trust research/joint research funds from Takeda, NEC, Daiichi-Sankyo, Bayer, and Abbott; and is affiliated with endowed department sponsored by Abbott, Terumo, Nihon-Kohden, Medtronic, Japan Lifeline, Otsuka, Ono, Boehringer Ingelheim, Takeda, Kowa, Zeon, Shionogi, Nippon-Shinyaku, Mochida, and Tesco. The remaining authors have nothing to disclose.

Background: Past research has suggested a cross-sectional association between COVID-19-related discrimination and PTSD symptom severity. However, no cohort study has examined the longitudinal association that better supports causal interpretation. Also, even if such an association genuinely exists, the specific pathway remains unclear., Methods: We conducted a two-year follow-up study, obtaining data from healthcare workers in a hospital setting. We first evaluated how COVID-19-related discrimination in 2021 was associated with subsequent PTSD symptom severity in 2023. Thereafter, we conducted causal mediation analysis to examine how this association was mediated by psychological distress in 2022, accounting for exposure-mediator interaction. Missing data were handled using random forest imputation., Results: A total of 660 hospital staff were included. The fully adjusted model showed greater PTSD symptom severity in individuals who experienced any COVID-19-related discrimination compared with those without such experiences (β, 0.44; 95% CI, 0.04-0.90). Regarding each type of discrimination, perceived discrimination was associated with greater PTSD symptom severity (β, 0.52; 95% CI, 0.08-0.96), whereas verbal discrimination did not reach statistical significance. Psychological distress mediated 28.1%-38.8% of the observed associations., Conclusions: COVID-19-related discrimination is associated with subsequent PTSD symptom severity in healthcare workers. Psychological distress may serve as an important mediator, underscoring the potential need for interventions targeting this factor., (© 2024. The Author(s).)

Aim: Patients with schizophrenia can have significant subjective difficulties in social cognition, but few undergo testing or treatment for social cognition. The Social Cognition Psychometric Evaluation (SCOPE) study recommends six social cognitive measures; however, the reliability and validity of these measures in different cultural and linguistic areas has not been adequately examined. We examined the psychometric properties of nine social cognitive measures and the relationship to social function, with the aim of determining the level of recommendation for social cognitive measures in clinical practice in Japan., Methods: For our test battery, an expert panel previously selected nine measures: the Bell Lysaker Emotion Recognition Task (BLERT); Facial Emotion Selection Test (FEST); Hinting Task (Hinting); Metaphor and Sarcasm Scenario Test (MSST); Intentionality Bias Task (IBT); Ambiguous Intentions and Hostility Questionnaire (AIHQ); Social Attribution Task-Multiple Choice (SAT-MC); SAT-MCII; and Biological Motion (BM) task. In total, 121 outpatients with schizophrenia and 70 healthy controls were included in the analysis, and the results were provided to an expert panel to determine the recommendations for each measure. The quantitative psychological indices of each measure were evaluated for practicality, tolerability, test-retest reliability, correlation with social function, and the incremental validity of social function., Results: Hinting and FEST received the highest recommendations for use in screening, severity assessment, and longitudinal assessment, followed by BLERT, MSST AIHQ, SAT-MC, and SAT-MCII, with IBT and BM receiving the lowest recommendations., Conclusion: This study provides a uniform assessment tool that can be used in future international clinical trials for social cognitive impairment., Competing Interests: Declaration of Competing Interest T.U. and T.N. belong to the Department of Psychiatry and Implementation Science, Toho University Faculty of Medicine, which is funded by the Nippon Life Insurance Company. The remaining authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The impact of FOXP3 single-nucleotide polymorphisms (SNP) on clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains poorly understood. We investigated the relationship between a FOXP3 SNP (rs3761548) and clinical outcomes in 91 patients with hematological malignancies after allo-HSCT. Multivariate analysis showed that risk of severe chronic graft-versus-host disease (cGVHD) was significantly higher in patients with the FOXP3-3279C/A or FOXP3-3279A/A genotype than those with the FOXP3-3279C/C genotype [hazard ratio (HR), 2.69; 95% confidence interval (CI) 1.14-6.31; p = 0.023]. Therefore, FOXP3 at SNP rs3761548 can be a useful marker for predicting the occurrence of severe cGVHD., (© 2024. Japanese Society of Hematology.)

Background: Coping refers to conscious responses to negative circumstances, with the intention of ameliorating these situations. Few studies have compared the differences between psychotherapy and medication treatment for coping strategies for depression. In this study, we investigated the differences in coping strategies between cognitive behavioral therapy (CBT) combined with medication (CBT group) and medication alone (pharmacotherapy group) among outpatients with depression., Methods: A prospective observational study was conducted among 50 patients with major depression (24 and 26 in the CBT and pharmacotherapy groups, respectively). Stress coping strategies (Coping Inventory for Stressful Situations [CISS]) and depression severity (Beck Depression Inventory-Second Edition [BDI-II]) were assessed at baseline and 16 weeks later. Changes in the CISS and BDI-II scores in both groups were tested using repeated analysis of variance. Inverse probability weighting with propensity score analysis was applied to address potential selection bias., Results: At 16 weeks, the CBT group exhibited increased CISS task-oriented coping, distraction, and social diversion scores, which differed from those of the pharmacotherapy group. The CBT group exhibited a significantly greater reduction in depressive symptoms than the pharmacotherapy group., Limitations: This study was not a randomized controlled trial and thus may have selection bias., Conclusion: Gaining adaptive coping skills, including task-oriented coping, distraction, and social diversion skills, by combining CBT with medication may lead to greater improvement in depression symptoms. These findings suggest that clinicians should evaluate coping strategies and facilitate the acquisition of adaptive coping strategies in patients with depression to reduce their symptoms., Competing Interests: The authors report the following conflicts of interest: AN has received speaker and/or consultant fees from Lundbeck, Otsuka, Sumitomo Pharma, Mitsubishi Tanabe Pharma, Viatris, Takeda, and MICIN. NK has received speaker and/or consultant fees from Lundbeck, Sumitomo Pharma, and Takeda. HU has received grants from Daiichi Sankyo, Eisai, Mochida, Otsuka, and Sumitomo Pharma; speaker’s fees from Eisai, Lundbeck, Meiji Seika Pharma, Otsuka, Boehringer Ingelheim Japan, MSD, and Sumitomo Pharma; and advisory board fees from Lundbeck, Sumitomo Pharma, Takeda Pharmaceutical Company, and Boehringer Ingelheim Japan for the past three years. 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 © 2024 Ihara, Katayama, Nogami, Amano, Noda, Kurata, Kobayashi, Sasaki, Mitsuda, Ozawa, Matsuoka, Takemura, Uchida and Nakagawa.)

Background: This study aimed to evaluate the association of COVID-19 preventive behavior and job-related stress with sleep quality among healthcare workers (HCWs). We conducted a cross-sectional survey using a questionnaire at the National Center of Neurology and Psychiatry, Tokyo, Japan., Methods: A total of 586 participants who completed the questionnaire were eligible for the study. The Pittsburgh Sleep Quality Index was used to evaluate sleep quality. We examined the level of engagement between poor sleep and COVID-19-related infection preventive behaviors, such as avoiding closed spaces, crowded places, and close contact (three Cs), a distance of at least one meter from others, wearing a face mask regularly, washing hands regularly, and working remotely, as well as job-related stress in the work environment, exposure to patients, potential risk of infection, fear of infecting others, need for social confinement, and financial instability. We conducted a hierarchical logistic regression analysis to examine the relationship between poor sleep and COVID-19 preventive behavior, job-related stress, and other covariates, including age, sex, and the Kessler Psychological Distress Scale (K6), which was used to measure non-specific psychological distress., Results: Poor sleep was observed in 223 (38.1%) participants. Adherence to COVID-19 preventive measures was relatively high: 84.1% of participants answered "always" for wearing a face mask regularly and 83.4% for washing hands regularly. In the multivariate logistic regression analysis, stress in the work environment (odds ratio [OR] = 2.09, 95% confidence interval [CI], 1.37-3.20; p < 0.001), financial instability (OR = 1.73, 95% CI, 1.12-2.67; p < 0.05), and low adherence to working remotely (OR = 1.65, 95% CI, 1.06-2.57; p < 0.05) were independently and significantly associated with poor sleep after controlling for the covariates., Conclusions: One year into the COVID-19 pandemic, the poor sleep rates of HCWs remained high. These results emphasize the need to protect HCWs from work environment stress and financial concerns., (© 2024. The Author(s).)

The patient was a 48-year-old man with relapsed acute myelogenous leukemia who underwent a second umbilical cord blood transplantation. Four months after the transplantation, he was admitted to our hospital due to immobility. Computed tomography and magnetic resonance imaging showed multiple nodules in the cerebrum and lungs, and blood tests revealed pancytopenia and hyperfibrinolysis, which suggested hemophagocytic syndrome. Antibacterial and antifungal therapy was started, but organ failure progressed. Due to progression of pancytopenia, hyperfibrinolysis, and fever, a bone marrow examination was performed on the 8th day of admission to assess for hemophagocytic syndrome. The bone marrow smear showed Toxoplasma gondii tachyzoites and cysts. The patient had not been given trimethoprim/sulfamethoxazole due to a drug allergy, and thus was administered trimethoprim/sulfamethoxazole immediately. However, he developed multiple organ failure and died on the 9th day of admission. We report a rare case of disseminated toxoplasmosis after allogeneic hematopoietic stem cell transplantation in which Toxoplasma gondii tachyzoites and cysts were identified in the bone marrow smear.

Immune checkpoint inhibitor (ICI)-induced thrombocytopenias are rare immune-related adverse events (irAE), but ICI-related thrombotic thrombocytopenic purpura (TTP) is extremely rare. A 79-year-old woman with non-small cell lung cancer received maintenance therapy with the anti-human PD-L1 monoclonal antibody durvalumab. Four weeks after the last infusion, she developed overt TTP. Remission was achieved by plasma exchange and prednisolone, and the patient has now been recurrence-free for over 12 months. To our knowledge, this is the first report of TTP occurring as an irAE of durvalumab.

Objective: Health anxiety (HA), defined as excessive worry about having a serious medical condition, may affect preventive behaviors during the coronavirus disease 2019 (COVID-19) pandemic. We examined the distinct role of two dimensions of HA-perceived likelihood (probability dimension) and awfulness of illness (awfulness dimension)-in self-protection, as reflected in preventive behaviors during the pandemic., Methods: Participants comprised 657 healthcare workers. Data were collected between February 24 and 26, 2021. The Short Health Anxiety Inventory determined the HA dimensions. Adherence to the government's recommendations for COVID-19 preventive behaviors was self-rated. An independent association between each HA dimension and participants' adherence to the recommendations was examined using multivariable regression., Results: Within the analyzed sample of 560 subjects, severe HA was observed in 9.1 %. The more the participants felt awful, the less frequently they engaged in the recommended preventive behaviors (adjusted odds ratio = 0.993, 95 % confidence interval: 0.989, 0.998, p = 0.003) regardless of their profession, working position, psychological distress, sleep disturbance, and current physical diseases. However, the probability dimension was not associated with their preventive behaviors., Conclusion: The awfulness dimension of HA could be a more sensitive marker of preventive behaviors than the probability dimension. Paying particular attention to the awfulness dimension may help optimize self-protection strategies during the COVID-19 pandemic. A two-dimensional understanding of HA may be useful for the maintenance of the healthcare system and public health as well as healthcare workers' own health., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Takeshi Miyama reports financial support was provided by Japan Health Research Promotion Bureau. Kentaro Nagao reports a relationship with 10.13039/501100002975Dainippon Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Kentaro Nagao reports a relationship with 10.13039/100008373Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Takuya Yoshiike reports a relationship with MSD that includes: speaking and lecture fees. Takuya Yoshiike reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with 10.13039/501100003769Eisai Co Ltd that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with 10.13039/501100004169Meiji Seika Pharma Co Ltd that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with MSD that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with 10.13039/501100007132Otsuka Pharmaceutical Co Ltd that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with 10.13039/100008373Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with Yoshitomi Pharmaceutical that includes: speaking and lecture fees. Aoi Kawamura reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: speaking and lecture fees. Aoi Kawamura reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Muneto Izuhara reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Tomohiro Utsumi reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Ayumi Tsuru reports a relationship with MSD that includes: speaking and lecture fees. Hideki Oi reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants. Hideki Oi reports a relationship with Sumitomo Pharma Co Ltd that includes: funding grants. Hideki Oi reports a relationship with Japan Society of Clinical Trials and Research that includes: board membership. Hideki Oi reports a relationship with Japanese Association of Pharmaceutical Medicine that includes: board membership. Kenichi Kuriyama reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants. Kenichi Kuriyama reports a relationship with 10.13039/501100005612Shionogi Pharma that includes: funding grants. Kenichi Kuriyama reports a relationship with 10.13039/501100004169Meiji Seika Pharma Co Ltd that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with Eisai Co Ltd that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with MSD that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with Takeda Pharmaceutical Company Limited that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with 10.13039/501100013420Tsumura & Co that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with Yoshitomi Pharmaceutical that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Igaku-Shoin Ltd that includes: consulting or advisory. Kazuyuki Nakagome reports a relationship with SHIONOGI that includes: funding grants. Kazuyuki Nakagome reports a relationship with Sumitomo Pharma Co Ltd that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with Meiji Seika Pharma Co Ltd that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with 10.13039/100008897Janssen Pharmaceuticals Inc that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with 10.13039/501100012351Mitsubishi Tanabe Pharma Corporation that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with Nippon Boehringer Ingelheim Co Ltd that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with Mochida Pharmaceutical Co Ltd that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees and travel reimbursement. Kazuyuki Nakagome reports a relationship with 10.13039/501100013327Lundbeck Japan that includes: speaking and lecture fees. Kazuyuki Nakagome reports a relationship with Viatris that includes: speaking and lecture fees. Kazuyuki Nakagome reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees., (© 2023 The Authors.)

Background: Recent studies have shown an association between psychological distress and emotion malleability beliefs, meaning mindsets about whether one's emotions are fixed or changeable. However, most studies have not examined the association between these beliefs and sociodemographic factors., Methods: A nationwide cross-sectional Internet survey of residents of Japan aged 15-79 years was conducted using sampling weights for national estimates to investigate the association between emotion malleability beliefs and sociodemographic factors and between fixed beliefs and severe psychological distress (SPD). SPD was defined as a Kessler 6 Scale score of ≥13. Adjusted odds ratios for SPD were calculated considering potential confounders. Further analyses were stratified by sex, age and presence of any psychiatric disorder., Results: The analysis included 23,142 participants (female, 48.64%). Fixed beliefs were associated with female sex, age < 45 years, and presence of psychiatric disorders. These beliefs were associated with SPD, and additional analysis showed stronger associations with SPD among female respondents, respondents aged 45-59 years, and those aged ≥60 years., Conclusion: Results indicate that female sex, age < 45 years, and current mental disorders were associated with fixed emotion malleability beliefs. Associations between fixed emotion malleability beliefs and SPD were particularly strong among female respondents and people aged ≥45 years compared with the general population. Our study extends the association between emotion malleability beliefs and psychological health to the general population. Future studies should explore mechanisms underlying individual differences in emotion beliefs., Competing Interests: SI has received honoraria for lectures from Boehringer Ingelheim Pharmaceuticals, Inc., H. Lundbeck A/S, Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., and Takeda Pharmaceutical Company Limited, has received support for attending meetings and/or travel from Boehringer Ingelheim Pharmaceuticals, Inc., H. Lundbeck A/S, and Takeda Pharmaceutical Company Limited, and has received consulting fees from Boehringer Ingelheim Pharmaceuticals, Inc. 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 Sasaki, Okubo, Takeda, Ikezawa, Tabuchi and Shirotsuki.)

Background: Discrimination is an important determinant of negative mental health outcomes. This study determined the association between the experience of COVID-19-related discrimination and psychological distress among healthcare workers (HCWs) in Japan., Methods: This cross-sectional study conducted a health survey among 5703 HCWs of six national medical and research centers in Japan from October 2020 to March 2021. COVID-19-related discrimination was defined either when participants or their family members were badmouthed or when they felt discriminated against in some way. We used the Kessler Psychological Distress Scale (K6) to assess the presence of severe psychological distress (≥ 13 points). We used logistic regression models to examine the association between discrimination and psychological distress. We also identified factors associated with discrimination., Results: Of the participants, 484 (8.4%) reported COVID-19-related discrimination and 486 (8.5%) had severe psychological distress. HCWs who were female vs. male (adjusted odds ratio [AOR] = 1.41, 95% confidence interval [CI] = 1.28-1.55), had high vs. low viral exposure (AOR = 2.31, 95% CI = 1.81-2.93), and worked for 11 or more hours/day vs. 8 or less hours/day (AOR = 1.42, 95% CI = 1.35-1.49) were more likely to have experienced COVID-19-related discrimination. The AOR (95% CI) of severe psychological distress was 1.83 (1.29-2.59) among those who experienced discrimination. In the stratified analysis by sociodemographic and job-related factors, all the interactions did not reach statistical significance (p for interaction > 0.20)., Conclusion: Experience of COVID-19-related discrimination was associated with severe psychological distress among HCWs. During the pandemic, effective measures should be taken to prevent the development of negative mental health outcomes in HCWs who experience discrimination., (© 2023. The Author(s).)

Background: Little evidence is available about the long-term safety of fractional flow reserve (FFR)-guided deferral of revascularization in infarct-related artery (IRA) lesions, especially when measuring FFR in the late setting after myocardial infarction (MI). This study aimed to assess the long-term outcomes after deferral of revascularization in IRA lesions based on FFR assessed in the late phase of post-MI., Methods: From the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), data on 1447 lesions (1263 patients) were divided into 2 groups: the IRA and non-IRA groups. The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), such as cardiac death, target vessel-related MI, and clinically driven target vessel revascularization., Results: Of the 1447 lesions, 138 (9.5%) were classified into the IRA group. The median duration of FFR measurement was 716 days after MI. The frequency of visual-functional mismatches (ie, FFR >0.80 and percent diameter stenosis ≥50% or FFR ≤0.80 and percent diameter stenosis <50%) was comparable between the IRA and non-IRA groups (31.9% vs 36.3%). The cumulative 5-year incidence of TVF did not differ between the groups (9.2% vs 11.8%; inverse probability-weighted hazard ratio, 1.18, 95% confidence intervals, 0.48-2.91, P = .71). Similar results were observed irrespective of regional wall motion assessed by ultrasonic cardiography and acute MI type., Conclusions: The 5-year TVF rate did not differ between the IRA and non-IRA lesions when deferring revascularization guided by FFR in the late setting of post-MI., (© 2023 The Authors.)

Previous cross-sectional studies showed that COVID-19-related discrimination against healthcare workers was linked to depression. However, no study has examined the longitudinal association that allows causal interpretations. This prospective cohort study aimed to examine whether COVID-19-related discrimination at baseline is associated with depression and suicidal ideation several months later. Data were collected from October 2020 to July 2021. Multivariable logistic regression was performed. Fixed effects models were used to control for the effect of hospitals (Level 2 variable). Adjustments also included age, sex, living alone, alcohol consumption, exercise, BMI, working hours, comorbidity, and frontline worker status (Level 1 variables). Multiple sensitivity analyses were conducted to examine if the results substantially changed and were robust to unmeasured confounding. Multiple imputation for missing data was conducted via chained equations. As the final sample, 2862 healthcare workers without depression at baseline were studied. A total of 269 individuals (9.4%) experienced COVID-19-related discrimination. Depression was suggested in 205 participants (7.2%), and suicidal ideation in 108 participants (3.8%). In the adjusted models, COVID-19-related discrimination was significantly associated with subsequent depression (OR = 2.18, 95% CI = 1.39 to 2.90) and suicidal ideation (OR = 2.07, 95% CI = 1.22 to 3.50). Multiple sensitivity analyses verified the results. COVID-19-related discrimination results in depression and suicidal ideation in healthcare workers. Interventions to prevent such discrimination against healthcare workers, e.g., anti-discrimination campaigns, are crucial during the COVID-19 pandemic., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The differences in rooting characteristics of cuttings prepared from E. sinica strains were investigated and found that cuttings prepared from strains with high rooting characteristics showed approximately 90% of the cuttings were rooted, whereas cuttings prepared from low rooting characteristics did not root. To understand the reason for this substantial difference, the anatomy of nodes was examined and found that adventitious roots were generated from the cortex and parenchyma in pith. Calculations of the correlation coefficients between the rooting rate and the value of anatomy indicated that the rooting rate was positively correlated with the parenchyma in pith in the node. On the basis of the positive correlation, it is possible to estimate the rooting characteristics of new strains without having to prepare cuttings. Next, we conducted a screening for E. sinica strains on the basis of total alkaloids content [ephedrine (E) + pseudoephedrine (PE)] and selected strains having no less than 0.7% total alkaloids content as defined by the Japanese Pharmacopoeia 18th edition. Strains having characteristic E or PE content were uncovered: E-rich strains had 100% E content and PE-rich strains had 99% PE content. We were able to select E. sinica strains on the basis of two factors: high rooting rate of cuttings and high or characteristic alkaloid content. These strains are valuable for breeding., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

To date, little effort has been made to examine if frontline workers who deal with COVID-19 patients are more likely to experience discrimination than second-line workers. Also, little information has appeared on how COVID-19-related discrimination affects PTSD symptoms in healthcare workers. We aimed to examine the association between COVID-19-related discrimination and frontline worker status. We further aimed to examine how COVID-19-related discrimination was associated with PTSD symptoms and psychological distress. We studied 647 healthcare workers. For the association between COVID-19-related discrimination and frontline worker status, we conducted multivariable logistic regression adjusting for age, sex and living alone. For the association of COVID-19-related discrimination with PTSD symptoms and psychological distress, we performed multivariable regression using hierarchical adjustments for age, sex, living alone, alcohol consumption, exercise and frontline worker status. Bias-corrected and accelerated bootstrap confidence intervals (CIs) were used. A total of 136 individuals worked on the frontline and the largest group were nurses (n = 81, 59.6%). Frontline workers had increased odds of COVID-19-related discrimination compared with second-line workers (odds ratio = 2.60, 95% CI = 1.37-4.96). COVID-19-related discrimination was associated with PTSD symptoms and psychological distress even at the highest level of adjustment (β = 0.67, 95% CI = 0.10-1.23; β = 2.43, 95% CI = 0.91-3.95, respectively). Frontline workers are more likely to experience COVID-19-related discrimination than second-line workers. Such discrimination may result in PTSD symptoms and psychological distress. Interventions to prevent COVID-19-related discrimination against healthcare workers, for example anti-discrimination campaigns, are important., (© 2022 John Wiley & Sons Australia, Ltd.)

Background: We focused on the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) and devised an inflammation-combined prognostic index (ICPI) as a prognostic marker of cancer-specific survival (CSS)., Methods: We reviewed the clinicopathological data of 480 patients with gastric cancer undergoing curative laparoscopic gastrectomy between 2009 and 2019. This study examined the significance of LMR, NLR, PLR, and ICPI as cancer-specific prognostic markers., Results: In univariate analysis, tumor diameter, histological differentiation, pathological tumor-node-metastasis (pTNM) stage, LMR, NLR, PLR, C-reactive protein (CRP) level, carcinoembryonic antigen (CEA), and postoperative chemotherapy were significantly associated with CSS. In multivariate analysis, pTNM stage and CEA were the independent risk factors for CSS, although LMR, NLR, and PLR were not the independent risk factors for CSS. The ICPI formula was constructed using hazard ratios for three inflammation-based biomarkers with worse prognosis identified in the univariate analysis: LMR <4.315, NLR ≥2.344, and PLR ≥212.01, which were each scored as 1, with all remaining values pointed at 0. ICPI was calculated as follows: ICPI = 2.9 × LMR + 2.8 × NLR + 2.8 × PLR. The optimal cutoff value of ICPII was 2.9. On multivariate analysis, pTNM stage, CEA, and ICPI were independent prognostic factors for CSS. In the Kaplan-Meier survival analysis, CSS in the high ICPI group was significantly worse than that in the low ICPI group., Conclusion: ICPI was devised as a novel predictive index for prognosis, and its usefulness was clarified.

A 75-year-old man who had lymphadenopathy was admitted to our hospital. Histopathological examination of cervical lymph node biopsy specimens showed diffuse proliferation of lymphoma cells with large nuclei. In immunohistochemistry, the lymphoma cells were positive for CD5, CD10, CD20, BCL2, BCL6, and MYC. The patient was diagnosed with CD5- and CD10-positive diffuse large B-cell lymphoma (DLBCL). MYD88 L265P mutations have been detected in DLBCL. Partial response was achieved after six courses of R-THP-COP therapy. However, the patient died because of disease progression 18 months after the diagnosis. On autopsy, lymphoma cells were found in the lymph nodes throughout the body, central nervous system, adrenals, and skin. CD5- and CD10-positive DLBCL account for 0.5-1% of DLBCL cases and have a very poor disease prognosis. This is a rare case of CD5- and CD10-positive DLBCL with MYC and BCL2 expressions harboring MYD88 L265P mutation.

Mast cells (MCs) play an important role in allergies, leading to the development of MC-targeted therapies. Ephedra herb (Mao) has potent anti-allergic activity, but contains ephedrine alkaloids (EAs); therefore, its hazardous effects are taken into consideration during its clinical use. We previously reported that Mao attenuates robust MC degranulation by an allergen through high-affinity immunoglobulin E (IgE) receptor (FcεRI) internalization, in which an EA-independent mechanism was suggested to be at play. This study aimed to deepen our understanding of the potential of Mao against FcεRI internalization using two strains with different EA contents. Mao extracts were administered to bone marrow-derived MCs (BMMCs), and their cellular responses, including FcεRI internalization, were analyzed. In addition, physiological events were evaluated using a passive cutaneous anaphylactic (PCA) reaction mouse model. BMMCs mediate the production of diverse inflammatory mediators. Among these, the potent chemokine CCL2 is thought to be differentially regulated from other pro-inflammatory mediators. We found that Mao significantly induces CCL2 expression in BMMCs despite suppressing robust degranulation through FcεRI internalization. Importantly, this was a distinctly EAs-independent response. In the PCA reaction, local MC activation following allergen challenge was suppressed by Mao treatment, which strengthened the view that Mao sufficiently decreased the rapid activation of MCs and promoted CCL2 secretion. Collectively, these observations provide additional insights into the mechanism of Mao-induced silent FcεRI internalization in MCs and the complex and heterogeneous secretory responses operating in MCs.

We investigated the seasonal variation of alkaloids (ephedrine and pseudoephedrine), total polyphenol, and sugar contents in Ephedra sinica cultivated in Japan and elucidated the controlling factors for the variation. In 2018, alkaloids and polyphenol contents increased dramatically from May to July, decreased to their lowest in October, and slightly increased again in November. The reduction of alkaloids and polyphenol contents in the autumn may be affected by precipitation in summer. In 2020, alkaloids and polyphenol contents started to decrease in late July when rainfall was abundant from July to August. In contrast, sucrose and starch contents continued to increase until September and remained high until October. Vascular bundles and fiber developed, and herbal stem weight increased from August to October. Alkaloids and total polyphenol contents tended to increase in November. At the same time, starch and sucrose contents decreased dramatically, whereas glucose and fructose contents increased. Sugar content decreased from October and was lowest in November. The seasonal variation of alkaloids and total polyphenol contents exhibited a contrasting tendency to the seasonal variation of sugar content and tissue development. The seasonal variation of alkaloids and total polyphenol contents was caused by the seasonal variation of sugar content and tissue development. In addition, it is suggested that anatomy may be used for alkaloids content estimation in Ephedra plants., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Context: The bulb of Lilium brownii F. E. Brown (Liliaceae) (LB) is a common Chinese medicine to relieve insomnia., Objective: To investigate the molecular mechanism of LB relieving insomnia., Materials and Methods: Insomnia model was induced by intraperitoneally injection p -chlorophenylalanine (PCPA) in Wistar rats. Rats were divided into three groups: Control, PCPA (400 mg/kg, i.p. 2 days), LB (598.64 mg/kg, oral 7 days). The levels of 5-hydroxytryptamine (5-HT), norepinephrine (NE), melatonin (MT), and the expression of GABA A , 5-HT1A and MT receptors, as well as pathological changes in hypothalamus, were evaluated. 16S rDNA sequencing and UPLC-MS/MS were used to reveal the change of the intestinal flora and metabolic profile., Results: The adverse changes in the abundance and diversity of intestinal flora and faecal metabolic phenotype altered by PCPA in rats were reversed after LB treatment, accompanied by the up-regulated levels of 5-HT as 8.14 ng/mL, MT as 16.16 pg/mL, 5-HT1A R and GABA A R, down-regulated level of NE as 0.47 ng/mL, and the improvement of pathological phenomena of cells in the hypothalamus. And the arachidonic acid metabolism and tryptophan metabolism pathway most significantly altered by PCPA were markedly regulated by LB. Besides, it was also found that LB reduced the levels of kynurenic acid related to psychiatric disorders and trimethylamine- N -oxide associated with cardiovascular disease., Conclusion: The mechanism of LB relieving insomnia involves regulating flora and metabolites to resemble the control group. As a medicinal and edible herb, LB could be considered for development as a health-care food to relieve increasing insomniacs in the future.

Purpose: Major depression is a heterogeneous disorder. Therefore, careful evaluation and comprehensive assessment are crucial elements for achieving remission. Personality traits influence prognosis and treatment outcomes, but there is not enough evidence on the association between personality traits and sustained remission (SR). Hence, the present study aimed to evaluate the relationship between personality traits and SR among patients with major depression., Patients and Methods: The 12-month prospective study evaluated 77 patients diagnosed with major depressive disorder. All patients underwent a comprehensive assessment, including the Temperament and Personality Questionnaire (T&P) at baseline, and depression severity was measured at baseline as well as six and 12 months. SR was defined as remission (the GRID-Hamilton Depression Rating Scale [GRID-HAMD 17 ] score ≦ 7) at both the 6- and 12-month follow-up. We compared eight T&P construct scores at baseline between the SR and non-SR groups. Multivariable logistic regression analyses were performed to determine the T&P personality traits related to SR., Results: Patients who achieved SR had a lower T&P personal reserve and lower T&P rejection sensitivity. Further, lower scores on the T&P personal reserve trait were independently associated with higher rates of SR among patients with major depression. Patients who achieved SR had a shorter duration of the current depressive episode and milder severity of depression at baseline., Conclusion: A lower level of personal reserve predicted a higher probability of SR in the treatment of depression. Extended observations in naturalistic follow-up settings with larger sample sizes are required to better understand the personality traits affecting SR in patients with depression., Competing Interests: Prof. Dr. Masaru Mimura reports personal fees from Biogen Japan, personal fees from Byer Pharmaceutical, grants, personal fees from Daiichi Sankyo, personal fees from Dainippon-Sumitomo Pharma, personal fees from Demant Japan, grants, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Fuji Film RI Pharma, personal fees from Hisamitsu Pharmaceutical, personal fees from H.U. Frontier, personal fees from Janssen Pharmaceutical, personal fees from Mochida Pharmaceutical, personal fees from MSD, personal fees from Mylan EPD, personal fees from Nippon Chemipher, personal fees from Novartis Pharma, personal fees from Ono Yakuhin, personal fees from Otsuka Pharmaceutical, personal fees from Pfizer, grants from Shionogi, grants from Takeda Yakuhin, personal fees from Teijin Pharma, personal fees from Viatris, personal fees from Fronteo, grants from Tanabe Mitsubishi, grants from Tsumura, outside the submitted work. All authors declare that they have no conflicts of interest regarding this study., (© 2022 Nogami et al.)

Background: Little evidence is available regarding the long-term outcome in elderly patients after deferral of revascularization based on fractional flow reserve (FFR)., Methods and results: From the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on fractional flow reserve in multicenter registry), 1,262 patients were divided into 2 groups according to age: elderly and younger patients (aged ≥75 or <75 years, respectively). The primary endpoint was the cumulative 5-year incidence of target vessel failure (TVF), defined as a composite of cardiac death, target vessel-related myocardial infarction (TVMI), and clinically driven target vessel revascularization (CDTVR). Cumulative 5-year incidence of TVF was not significantly different between elderly and younger patients (14.3% vs. 10.8%, P=0.12). Cardiac death occurred more frequently in elderly patients than younger patients (4.4% vs. 0.8%, P<0.001), whereas TVMI and CDTVR did not differ between groups (1.3% vs. 0.9%, P=0.80; 10.7% vs. 10.1%, P=0.80, respectively). FFR values in lesions with diameter stenosis <50% were significantly higher in elderly patients than in younger patients (0.88±0.07 vs. 0.85±0.07, P=0.01), whereas this relationship was not observed in those with diameter stenosis ≥50%., Conclusions: Elderly patients had no excess risk of ischemic events related to the deferred coronary lesions by FFR, although FFR values in mild coronary artery stenosis were modestly different between elderly and younger patients.

Background: Social cognitive impairments adversely affect social functioning (e.g., employment status) in patients with schizophrenia. Although pharmacological interventions have been suggested to provide some benefits on social cognition, little information is available on the comparative efficacy of pharmacotherapy. Thus, the aim of this planned systematic review and network meta-analysis is to perform a quantitative comparison of the effects of various psychotropic drugs, including supplements, on social cognition disturbances of schizophrenia., Methods: The literature search will be carried out using the PubMed, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, ClinicalTrials.gov, and International Clinical Trials Registry Platform databases from inception onward. Randomized controlled trials that examined the efficacy of drugs in social cognitive disturbances will be included, based on the most recent studies and the broader literature than previously searched. This protocol defines a priori the methods that will be used for study selection, data collection, quality assessment, and statistical syntheses., Discussion: The findings this work are expected to help promote the development of better therapeutics of social cognitive impairments in schizophrenia and related psychiatric conditions., Systematic Review Registration: [www.crd.york.ac.uk/prospero], identifier [CRD42021293224]., 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 Yamada, Okubo, Tachimori, Uchino, Kubota, Okano, Ishikawa, Horinouchi, Takanobu, Sawagashira, Hasegawa, Sasaki, Nishiuchi, Kawashima, Tomo, Hashimoto, Ikezawa, Nemoto, Watanabe and Sumiyoshi.)

Background: Despite advances in surgical techniques, long-term survival after esophagectomy for esophageal cancer remains unacceptably low, and more effective perioperative chemotherapy is expected. However, an important concern regarding the application of postoperative adjuvant chemotherapy is treatment toxicity. We aimed to evaluate the feasibility of adjuvant chemotherapy with S-1 in patients after esophagectomy., Methods: We investigated the tolerability of a 2-week administration followed by 1-week rest regimen of S1 as postoperative adjuvant therapy in 20 patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy (NAC) and 22 patients who did not receive NAC during 2011-2020., Results: In the non-NAC group, the mean and median relative dose intensity (RDI) were 78.7% and 99.4%, respectively, and 11 patients (50%) had altered treatment schedules. The corresponding rates in the NAC group were 77.9% and 100%, respectively, and nine patients (45%) had altered treatment schedules, with no significant difference among the groups. Moreover, 17 patients (77.2%) in the non-NAC group and 16 patients (80.0%) in the NAC group continued S-1 treatment as planned for one year postoperatively, with no significant difference in the S-1 continuation rate (p = 0.500). Seventeen of 22 patients (77.3%) and 15 of 20 patients (75.0%) experienced several adverse events in the non-NAC and NAC groups, respectively. The frequency, severity, and type of adverse events were consistent among patients with and without NAC., Conclusions: S-1 could be safely and continuously administered as adjuvant chemotherapy for patients with esophageal cancer regardless of NAC. Long-term prognosis should be evaluated for S-1 to become the standard treatment after esophagectomy., (© 2022. The Author(s).)

Remote cognitive and behavioral therapy (CBT) via videoconference has been garnering attention as a means of improving access to CBT for depression, in particular during the coronavirus disease 2019 pandemic. However, there is a lack of evidence supporting its implementation in Japanese clinical settings. This case series aimed to establish preliminary evidence of whether remote CBT can be an effective therapy for major depression in Japanese clinical settings. Five patients who met the diagnostic criteria for major depressive disorder were enrolled and underwent remote CBT via videoconference and face-to-face assessment interviews. The results showed that remote CBT via videoconference improved depressive symptoms, enabling a relatively high level of patient satisfaction and working alliance. Moreover, detailed feedback from our patients showed that continuous monitoring was preferable for increasing treatment engagement. Further research is warranted to test the efficacy and acceptability of remote CBT via videoconference for treating major depression., (© 2022 Association for Behavioral and Cognitive Therapies. Published by Elsevier Ltd.)

Introduction: Few people can access psychotherapy for irritable bowel syndrome (IBS). Group cognitive-behavioral therapy (GCBT) may be efficient, but the evidence for its efficacy is weak and limited. We aimed to assess the efficacy and safety of GCBT with interoceptive exposure (GCBT-IE), a novel form of GCBT for drug-refractory IBS., Methods: A single-center, open-label, randomized, controlled trial was conducted in Japan among people aged 18-75 years with moderate-to-severe drug-refractory IBS. Participants were stratified by IBS severity and allocated 1:1 to 10-week GCBT-IE or waiting list (WL) in a blockwise randomization by independent staff. Both arms practiced self-monitoring and received treatment as usual. Multiple primary outcomes were changes from baseline to week 13 in the IBS Symptom Severity Score and the IBS Quality of Life Measure (IBS-QOL), assessed in the intention-to-treat sample., Results: A total of 114 people with drug-refractory IBS were randomized to GCBT-IE (n = 54) or WL (n = 60). Forty-nine participants (90.7%) in the GCBT-IE arm and 58 (96.7%) in the WL arm completed the week 13 assessment. Participants in the GCBT-IE arm reported greater improvements in both IBS symptom severity and quality of life compared with the WL arm, with -115.8 vs -29.7 on the IBS Symptom Severity Score (a difference of -86.1, 95% confidence interval -117.3 to -55.0), and 20.1 vs -0.2 on the IBS-QOL (a difference of 20.3, 95% confidence interval 15.2-25.3), respectively. Six unexpected serious adverse events were reported but were judged as unrelated to the interventions., Discussion: GCBT-IE is an efficacious, safe, and efficient treatment option for people with drug-refractory IBS., (Copyright © 2022 by The American College of Gastroenterology.)

It is said that Rehmannia glutinosa is grouped into two types, Akaya and Kaikei, in Japan. However, previous reports of genetic analysis of R. glutinosa in commercial products suggest the existence of varieties other than these two, and therefore, it is inappropriate to simply classify them into these two varieties. In this study, we clarified the diversity of R. glutinosa cultivated in Japan on the basis of morphological observation and genetic analysis. We conducted principal component analysis (PCA) of R. glutinosa morphology, including leaf surface color, leaf undersurface anthocyanin coloration, root shape, and the ratio of string root. We also performed (1) sequence-related amplified polymorphism (SRAP) analysis and (2) polymorphism analysis of the TEOSINTE BRANCHED1, CYCLOIDEA, and PCF (TCP) gene region. We were able to separate Akaya type from Kaikei type, and to divide Kaikei type into three small groups. These two gene analysis methods were also useful in estimating the patrilineal and matrilineal strains of a hybrid origin. Our findings revealed that Akaya type and Kaikei type can be distinguished on the basis of morphological and genetic analyses, and that Kaikei type cultivated in Japan exhibited morphological and genetic diversity., (© 2021. The Japanese Society of Pharmacognosy.)

Background: Despite the importance of Beck's theoretical cognitive model of psychopathology, the neural mechanisms underlying future thinking in cognitive behavioral therapy (CBT) remain elusive. Recent neuroimaging studies have shown that the function of the frontopolar cortex (Brodmann area 10 [BA10]) is associated with future thinking. We hypothesized that, compared with unstructured psychotherapy (talking control: TC), CBT may involve different neural responses in BA10 associated with future thinking., Methods: This randomized clinical trial included 38 adult patients with moderate-to-severe major depressive disorder who underwent up to 16 weeks of CBT or TC with a 6-month follow-up period. We evaluated changes in BA10 activation during distant future thinking using functional magnetic resonance imaging with a future-thinking task. We assessed frontal neurocognitive function and clinical symptoms at baseline and post-treatment. Depression severity and automatic thoughts were assessed at the 6-month follow-up., Results: We found decreased activation in the frontopolar cortex during distant future thinking after CBT (t = 3.00, df=15, p = 0.009) and no changes after TC. Further, the reduction in BA10 activity significantly correlated with changes in frontal cognitive function after the treatment (r = 0.48, p = 0.007), and in positive automatic thought after 6 months of treatments (r = 0.39; p = 0.03)., Limitations: Relatively small sample size and homogenous clinical profile could limit the generalizability. Patients received pharmacotherapy including antidepressant., Conclusions: CBT appears to improve frontopolar cortex function during future thinking in a manner distinct from TC. Larger clinical trials are necessary to provide firm evidence whether BA10 activity may serve as a neuro-marker for monitoring successful depression treatment with CBT., (Copyright © 2021. Published by Elsevier B.V.)

Background: Augmented mindfulness-based cognitive therapy (MBCT) with treatment as usual (mainly pharmacotherapy) is reported to be effective after treatment for anxiety disorders. However, whether its effectiveness persists in the long term is unclear., Objective: This study aims to examine the feasibility, acceptability, and effectiveness of a follow-up program by conducting a feasibility randomized controlled trial (RCT) that compares augmented MBCT with follow-up sessions and that without follow-up sessions in preparation for a definitive RCT., Methods: The study involves an 8-week MBCT with a 10-month follow-up. Patients aged 20 to 65 years who meet the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for panic disorder, agoraphobia, or social anxiety disorder, which is not remitted with usual treatment for at least 4 weeks, will be included in the study and randomly allocated to receive augmented MBCT with follow-up sessions or augmented MBCT without follow-up sessions. For this feasibility RCT, the primary outcomes are (1) study inclusion rate, (2) dropout rate, (3) attendance rate, and (4) mean and standard deviation of several clinical measures at 8 weeks and 5, 8, and 12 months., Results: We started recruiting participants in January 2020, and 43 participants have been enrolled up to January 2021. The study is ongoing, and data collection will be completed by May 2022., Conclusions: This study is novel in terms of its design, which compares augmented MBCT with and without follow-up sessions. The limitations of the trial are as follows: (1) mixed participants in terms of the delivery mode of the intervention, and (2) lack of a pharmacotherapy-alone arm. Owing to its novelty and significance, this study will provide fruitful knowledge for future definitive RCTs., Trial Registration: UMIN Clinical Trials Registry UMIN000038626; https://tinyurl.com/2p9dtxzh., International Registered Report Identifier (irrid): DERR1-10.2196/33776., (©Mitsuhiro Sado, Akira Ninomiya, Maki Nagaoka, Akihiro Koreki, Naho Goto, Yohei Sasaki, Chie Takamori, Teppei Kosugi, Masashi Yamada, Sunre Park, Yasunori Sato, Daisuke Fujisawa, Atsuo Nakagawa, Masaru Mimura. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 21.01.2022.)

Background: We assessed the relationship between preoperative prognostic nutritional index (PNI) and short- and long-term outcomes among gastric cancer patients because the clinical significance of PNI in these patients remains controversial., Materials and Methods: We retrospectively reviewed the medical records of 434 consecutive patients who underwent curative laparoscopic gastrectomy for gastric cancer., Results: Patients with postoperative complications had a significantly poorer overall survival (OS) than those without. On multivariate analyses, postoperative complications were independently associated with PNI value and operative procedure type. In the low PNI group ( n = 118), those with postoperative complications experienced significantly poorer OS than those without complications. Among the low PNI group with pTNM stage I and II disease, those with postoperative complications experienced significantly worse OS than those without complications. However, among the high PNI group and patients with stage II and III disease in the low PNI group, OS was similar with respect to postoperative complications., Conclusions: The present study confirmed that long-term prognosis was unaffected by postoperative complications in well-nourished gastric cancer patients. In addition, preoperative nutritional status and postoperative complications, may be crucial in determining the prognosis of gastric cancer, especially in early-stage cancer., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest., (Copyright: © 2022 Hirahara et al.)

Rehmannia glutinosa is an important medicinal plant in Asia, and its roots are used as an ingredient in herbal medicine. However, the roots exhibit different medicinal effects depending on the processing conditions. Since the catalpol content differs greatly during the process, the catalpol content is an essential index for quality evaluation. R. glutinosa roots have various weights, diameters, and lengths, and there are differences between individuals and within an individual immediately after harvest. We found that, catalpol content in the roots tended to increase as root diameter increased. Furthermore, it has been reported that catalpol content decreased with drying, and our results also supported this phenomenon. To clarify the reason for the decrease in catalpol content, we investigated the effect of β-glucosidase in R. glutinosa cells. An in situ assay for β-glucosidase activity revealed that the activity in the tissue inside the cambium disappeared one month after drying under natural conditions, and the activity in the tissue outside the cambium completely disappeared after two months. Because catalpol content remained almost unchanged even after drying for two months, it was clarified that β-glucosidase activity had minimal involvement in the decrease in catalpol content in R. glutinosa roots. Based on the above results, we proposed that slicing the roots and rapidly removing water by natural drying is best to obtain dry root with little loss of catalpol content.

Paeoniae Radix, the dried root of Paeonia lactiflora, is one of the most important ingredients in Kampo medicine. It is known that Paeoniae Radix is derived from various P. lactiflora cultivars, including medicinal and horticultural cultivars, and that cultivar identification by DNA analysis has been unsuccessful. We attempted to develop sequence characterized amplified region (SCAR) markers as useful DNA markers for the identification and herbal medicine authentication of two cultivars developed in Japan, 'Bonten' and 'Kitasaisho,' which are two superior medicinal strains of P. lactiflora. Sequence-related amplified polymorphism (SRAP) analysis was conducted on fourteen P. lactiflora cultivars, and polymorphic fragments specific to 'Bonten' or 'Kitasaisho' were detected. Then, SCAR markers for 'Bonten' and 'Kitasaisho' were developed from the sequence information of these polymorphic fragments. Thirty cultivars of P. lactiflora and five herbal medicine samples were used to validate the specificity of the developed SCAR markers. As a result, we confirmed that our SCAR markers can identify 'Bonten' or 'Kitasaisho' from the plant samples and the herbal medicine samples. Thus, we have successfully designed two highly specific DNA markers and established an easy, rapid, and cost-efficient method to identify specific cultivars of P. lactiflora. Our SCAR markers are expected to contribute to the maintenance of P. lactiflora cultivars such as 'Bonten' as superior medicinal strains, the development of more elite cultivars in the future, and the deterrence of outflow of original cultivars to foreign countries.

We have developed a simple and accurate method for quantifying sugars in herbal medicines, which have hitherto been difficult to quantify. Using ultra performance liquid chromatography-quadrupole-time-of-flight (UPLC-Q-TOF)-MS and two types of columns with different chemical properties, we determined the optimum conditions for separating nine sugars (fructose, galactose, glucose, mannitol, sucrose, melibiose, raffinose, manninotriose, and stachyose) commonly found in herbal medicines. Separation was completed within 10 min when an apHera NH 2 HPLC column was used, although galactose and glucose could not be separated. On the other hand, the nine sugars were completely separated within 16 min when a hydrophilic interaction chromatography (HILIC)pak VG-50 2D column was used. The calibration curves obtained using those two columns gave good linearity for the sugar standards, and the coefficient of determination was 0.995 or higher. Both columns showed excellent performance with short analysis time and high sensitivity. Using our developed method, we were able to quantify sugars in galactose-free herbal medicines within 10 min and in herbal medicines containing galactose within 16 min. We revealed that our method could be used for the analysis of sugars in Angelica acutiloba and Rehmannia glutinosa roots.

Inflammatory cytokines play a role in hematopoiesis and development of myelodysplastic syndromes (MDS). Although increased serum levels of inflammatory cytokines are associated with poor survival in MDS patients, clinical management does not include assessment of inflammation. We investigated the significance of inflammation in MDS using serum C-reactive protein (CRP) levels, an indicator of the degree of systemic inflammation that can be used in routine practice. We hypothesized that serum CRP levels can be used to further classify low-risk MDS. We conducted a retrospective analysis of 90 patients with low-risk MDS, defined by the international prognostic scoring system (IPSS). We examined the prognostic relevance of CRP and known prognostic factors at diagnosis. Increased serum CRP (≥ 0.58 mg/dL) was associated with poor survival (hazard ratio [HR]: 17.63, 95% confidence interval [CI] 5.83-53.28, P < 0.001) both overall and among the 73 patients with low-risk MDS as defined by the revised IPSS (HR: 28.05, 95% CI 6.15-128.04, P < 0.001). Increased CRP might predict poor prognosis and serum CRP levels can indicate clonal hematopoiesis and non-hematological comorbidity in patients with low-risk MDS., (© 2021. Japanese Society of Hematology.)

We attempted to conduct an intraspecific analysis of 30 peony cultivars in Japan and to authenticate five herbal medicine samples derived from Paeoniae Radix by polymorphism analysis of the TEOSINTE BRANCHED1, CYCLOIDEA, and PCF (TCP) gene region. We focused on cultivar-dependent differences in leaf margin undulation and analyzed the sequence of the related TCP gene region. As a result, we found that the nucleotide sequences of 29 cultivars of Paeonia lactiflora except 'America' exhibit interspecific variations compared with the nucleotide sequences of Paeonia suffruticosa and Paeonia tenuifolia. Therefore, in the dendrogram constructed on the basis of the sequence similarity in the TCP gene region, the 29 cultivars of P. lactiflora were separated from P. suffruticosa, P. tenuifolia, and 'America', and clustered into three subgroups. There were 16 variations containing heterogenous DNA sequences within P. lactiflora species, and two characteristic variations in subgroup I. Some P. lactiflora cultivars showed the same nucleotide sequence in the TCP gene region, whereas the five herbal medicine samples showed different sequences, although all of them could be authenticated. The results suggest that Paeoniae Radix in the Japanese crude drug market can be authenticated by analysis of the TCP gene region., (© 2021. The Japanese Society of Pharmacognosy.)

In schizophrenia, social cognitive impairment is considered one of the greatest obstacles to social participation. Although numerous measures have been developed to assess social cognition, only a limited number of them have become available in Japan. We are therefore planning this evaluation study for social cognition measures in Japan (ESCoM) to confirm their psychometric characteristics and to promote research focused on social cognition. Participants in the cross-sectional observational study will be 140 patients with schizophrenia recruited from three Japanese facilities and 70 healthy individuals. In our primary analysis, we will calculate several psychometric indicators with a focus on whether they can independently predict social functioning. In secondary analyses, we will assess the reliability and validity of the Japanese translations of each measure and conduct an exploratory investigation of patient background, psychiatric symptoms, defeatist performance belief, and gut microbiota as determinants of social cognition. The protocol for this study is registered in UMIN-CTR, unique ID UMIN000043777.

The fear of cancer recurrence (FCR) is the most common and most severe unmet need among cancer survivors. Safe treatments for the FCR that are easily disseminated are greatly needed. Our primary aim is a preliminary evaluation of the efficacy and effect size of perilla oil, which is rich in omega-3 fatty acids, and Bifidobacterium , a probiotic, on FCR in breast cancer survivors after the completion of chemotherapy. This study has been planned as an exploratory clinical study (phase II) and will be conducted as a three-arm, 12-week parallel group, masked-rater randomized controlled trial. Fifteen participants will be randomized with 1:1:1 allocation to receive Bifidobacterium plus perilla oil, Bifidobacterium alone, or no intervention (control). Interventions will end within 12 weeks after the random allocation of each participant. The participants will be outpatients with invasive breast cancer aged 20 years or older whose chemotherapy was completed at least 6 months before registration; hormone therapy may be ongoing. The primary outcome will be severity of FCR at 12 weeks assessed by masked raters using the 4-item Concerns about Recurrence Scale concerning overall fear of recurrence. The study protocol for the current study is registered in the Japan Registry of Clinical Trials (jRCTs031200029).

By using Angelica acutiloba seedlings produced by short-period raising in paper pot (PP), we investigated the effect of taproot base diameter on the growth after planting and evaluated the quality of toki (, Angelicae Acutilobae Radix) produced from PP-grown seedlings (PT). In this study, PP-grown seedlings of seven classes which are sorted difference taproot base diameter (P1-P7) were transplanted. As a result, the survival rates were not less than 90% for P6 (taproot base diameter: 10.0-12.7 cm) and P7 (taproot base diameter: 12.8-17.3 cm), and the bolting rates were 20.5% and 24.1% for P6 and P7, respectively. The traditionally grown seedling (TS) showed the highest available harvest rate of 82.3%, followed by P6 (71.8%) and P7 (69.0%). P7 showed the highest fresh weight and dry weight per 1a (100 m 2 ), followed by P6 and TS. However, PP-grown seedlings are prone to bolting, and it is expected the yield can be increased by preventing bolting. In addition, PT satisfied the regulations of JP17 in terms of, for example, dilute ethanol-soluble extract content, total ash content, and acid-insoluble ash content. It was also found that PT has a higher proportion of lateral roots with respect to the total weight than toki produced from traditionally grown seedlings (TT). The total (Z)-ligustilide contents were 0.07% in PT and 0.12% in TT. It was revealed that it is possible to produce toki that satisfies JP17 regulations; moreover, the period required for toki production was shortened by 6 months with PP-grown seedlings.

Hemophagocytic lymphohistiocytosis (HLH) is an uncontrolled hyperinflammatory disorder driven by an overactive immune system that results in high mortality. Post-transplant-associated hemophagocytic lymphohistiocytosis (PT-HLH) is a type of secondary HLH that occurs following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical features of PT-HLH remain unclear and diagnostic and prognostic tools have not yet been established. Here, we retrospectively evaluated the clinical manifestations and outcomes of PT-HLH in 94 patients who underwent allo-HSCT. According to our PT-HLH criteria (hyperferritinemia and increased macrophage count in bone marrow), PT-HLH occurred in 12 patients (12.8%). The PT-HLH patients showed splenomegaly (P = .001), a higher risk of engraftment failure (P = .013), and an increased percentage of macrophages and hemophagocytes in bone marrow aspirates (P = .0009 and P = .0006, respectively). Moreover, univariate and multivariate analyses revealed that the survival rate was lower in PT-HLH patients than non-PT-HLH patients (P = .0017 and P = .034, respectively). This study defines the clinical features of PT-HLH and PT-HLH criteria that could be useful tools for diagnosing PT-HLH.

Social cognition is strongly linked to social functioning outcomes, making it a promising treatment target. Because social cognition measures tend to be sensitive to linguistic and cultural differences, existing measures should be evaluated based on their relevance for Japanese populations. We aimed to establish an expert consensus on the use of social cognition measures in Japanese populations to provide grounds for clinical use and future treatment development. We assembled a panel of experts in the fields of schizophrenia, social psychology, social neuroscience, and developmental disorders. The panel engaged in a modified Delphi process to (1) affirm expert consensus on the definition of social cognition and its constituent domains, (2) determine criteria to evaluate measures, and (3) identify measures appropriate for Japanese patients with a view toward future quantitative research. Through two online voting rounds and two online video conferences, the panel agreed upon a definition and four-domain framework for social cognition consistent with recent literature. Evaluation criteria for measures included feasibility and tolerability, reliability, clinical effectiveness, validity, and international comparability. The panel finally identified nine promising measures, including one task originally developed in Japan. In conclusion, we established an expert consensus on key discussion points in social cognition and arrived at an expert-selected set of measures. We hope that this work facilitates the use of these measures in Japanese clinical scenarios. We plan to further examine these measures in a psychometric evaluation study.

Purpose: Ephedra herb (Mao) exerts potent anti-allergic effects. This study aimed to examine the underlying mechanisms of Mao on allergic inflammation using in vitro cultured mast cells (MCs) and an in vivo model of MC-dependent anaphylaxis., Methods: Bone marrow-derived MCs (BMMCs) were presensitized with anti-2,4-dinitrophenol (DNP) immunoglobulin E (IgE) and challenged with antigens (Ag; DNP-human serum albumin). Degranulation responses and cell surface high-affinity receptor for IgE (FcεRI) expression were assessed with/without Mao treatment. Passive systemic anaphylaxis (PSA)-treated mice were administered Mao and the pathophysiological responses were evaluated., Results: Mao inhibited Ag-induced BMMC degranulation, but not polyclonal activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, indicating that Mao inhibits IgE-dependent activation of BMMCs. Mao-treated BMMCs exhibited significant reductions in expression of surface IgE and its receptor FcεRI. Analysis of subcellular localization revealed that Mao induces FcεRI internalization in BMMCs without degranulation. In the PSA mouse model, Mao administration prevented antigen-induced hypothermia. Mao administration significantly reduced cell surface expression of IgE-bound FcεRI on peritoneal MCs., Conclusions: Mao induced FcεRI internalization in MCs, thereby inhibiting Ag-induced IgE-dependent degranulation. The inhibitory effects of Mao on MC degranulation may offer a novel therapeutic approach for allergic diseases.