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With the rapid growth of the elderly population, dementia has become a global challenge that governments must address. Given the incurable nature of dementia, rehabilitation interventions starting in the mild cognitive impairment (MCI) stage may offer a solution. For a rehabilitation intervention to be implemented as early as possible, existing problems of identification of MCI and development of MCI-specific forms of rehabilitation must be addressed. Use of computer technologies such as virtual reality and artificial intelligence might be helpful in overcoming these problems. Multi-disciplinary integrated approaches to rehabilitation should be the direction that dementia-related rehabilitation takes in the future. In addition to early rehabilitation, prevention of cognitive decline through the development of public community-based services for the elderly might be a more reasonable approach.

This study was conducted to investigate the value of Synechococcus 7942 (Syne) as a sensitizer for photo-sonodynamic therapy (PSDT). Syne was characterized. The efficacy of Syne-mediated PSDT were verified in vitro (in 4T1 breast cancer cells) and in vivo (in a breast tumor-bearing mouse model). The safety of Syne-mediated PSDT was verified in vivo. Results indicated that Syne triggered the generation of oxygen and ROS during PSDT, thereby inducing cell death in 4T1 cells. Syne-mediated PSDT induced the death of tumor cells both in vitro and in vivo. The speed of tumor growth was delayed in animals receiving PSDT. Syne-mediated PSDT was more effective than photodynamic therapy or sonodynamic therapy alone. In addition, administration of a Syne monomer resulted in satisfactory tumor targeting. Syne-mediated PSDT affected neither the animal body weight nor the major organs, indicating satisfactory safety. Accordingly, Syne is an efficient, safe, and readily available sensitizer that is ideal for potential clinical use of PSDT to treat breast cancer. The findings of this study are useful for exploration of a novel sensitizer for PSDT, which might be a promising alternative therapy against breast cancer.

Aerobic exercise may be an effective treatment for knee osteoarthritis and central sensitization, but no interventional studies have examined its effects. In this study, the patient showed improvement in central sensitization, pain, and autonomic nervous system activity after aerobic exercise using an arm ergometer., Competing Interests: The authors declare no conflict of interest and the funders had no role in any of the procedures in this report., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

A T217M heterozygous mutation in the SLC22A12 gene caused renal hypouricemia; this patient with IgA nephropathy had no findings other than IgA nephropathy on renal biopsy. Hypouricemia was susceptible to oxidative stress, but IgA nephropathy in the patient with hypouricemia could be treated with steroid pulse therapy without adverse events., Competing Interests: None of the author and co‐authors has any conflicts of interest or any financial ties to disclose., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Non-ST-elevation myocardial infarction (NSTEMI) carries a poor prognosis, and accurately prognostication has significant clinical importance. In this study, we analyzed the predictive value of the CHADS 2 , CHA 2 DS 2 -VASc, and R 2 -CHADS 2 scores for major adverse cardiac events (MACE) following percutaneous coronary intervention (PCI) in patients with NSTEMI using data from a prospective multicenter registry., Methods and results: The registry included 440 consecutive patients with NSTEMI and coronary artery disease who underwent successful PCI. Patients were clinically followed for up to 3 years or until the occurrence of MACE. MACE was defined as a composite of all-cause death and nonfatal MI. During the follow-up period, 55 patients (12.5%) experienced MACE. Risk analysis of MACE occurrence, adjusted for the multivariable model, demonstrated a significant increase in risk with higher CHADS 2 , CHA 2 DS 2 -VASc, and R 2 -CHADS 2 scores. Kaplan-Meier analysis showed a higher incidence of MACE in patients with higher CHADS 2 , CHA 2 DS 2 -VASc, and R 2 -CHADS 2 scores, both in the short- and long-term periods., Conclusions: Patients with NSTEMI and higher CHADS 2 , CHA 2 DS 2 -VASc, and R 2 -CHADS 2 scores displayed a greater incidence of MACE.

The aim of this study was to investigate trends in suicide rates (SRs) among the elderly in China. Annual data on SRs among Chinese people ≥ the age of 65 were collected from China's Health Statistics Yearbook from 2002 to 2020. Then, data were stratified by age, region, and sex. Standardized SRs were calculated and analyzed using a conventional joinpoint regression model. Results revealed that overall, SRs among the elderly in China tended to decline from 2002-2020. Fluctuations in SRs, including in 2004-2005 due to the SARS epidemic, in 2009-2010 due to the economic crisis, and in 2019-2020 due to the COVID-19 pandemic, were also observed. Data suggested a relatively greater crude SR among the elderly ( vs. young people), in males ( vs. females), and in people living in a rural area ( vs. those living in an urban area). SRs tended to rise with age. Joinpoint regression analysis identified joinpoints only for males ages 65-69 and over the age of 85 living in a rural area, suggesting that individuals in these groups are more sensitive to negative stimuli and more likely to commit suicide, necessitating closer attention. The findings from this study should help to make policy and devise measures against suicide in the future., Competing Interests: The authors have no conflicts of interest to disclose., (2024, National Center for Global Health and Medicine.)

The reactivity of an isolable 2-germapropadiene with acids, ketones, and amines was investigated. The reactions of 2-germapropagiene 1 with hydrogen chloride and acetic acid afforded the corresponding dichlorogermane (2) and diacetoxygermane (3), respectively, indicating that the central germanium atom of 1 is electrophilic. The reaction of 1 with benzaldehyde proceeds via a formal [2+2] cycloaddition to afford the corresponding spiro compound (4). Moreover, 1 reacts smoothly with acetone to furnish germane 5, which contains a six-membered ring involving two acetone molecules. Furthermore, 1 undergoes N-H bond insertion with methylamine or aniline to afford diamino germanes 7 and 8, respectively. The reaction of 1 with urea selectively afforded the corresponding N-H-insertion product (8)., (© 2024 Wiley-VCH GmbH.)

This study was designed to investigate the state quo of the appropriateness of alerts overrides of the medication-related clinical decision support system (MRCDSS) in China. The medication-related alerts in one hospital from Jan 2022 to Dec 2022 were acquired and sampled. Rates of alert overrides, appropriateness of alert generation and physicians' responses were observed. Total 14,612 medication-related alerts (≤ level 3) were recorded, of those, 12,659 (86.6%) alerts were overridden. The top 3 alert types were: drug and diagnosis contraindications (23.8%), drug and test value contraindications (23.3%), and compatibility issues (17.7%). Of all sampled 1,501 alerts, 80.2% of them were appropriately overridden by the physicians. The appropriate rate of alert generation was 57.9% and the inappropriate rate was 42.1%. The inappropriate rate of physicians' responses was 17.8%, and 2.0% physicians' responses were undetermined. A few medications accounted for over 10% of overrides, 88.3% of "overridden reasons" inputted by the physicians were meaningless characters or values, indicating an obvious "alert fatigue" in these physicians. Our results indicated that the overridden rate of MRCDSS in China was still high, and appropriateness of generation of alert was quite low. These data indicated that the MRCDSS currently using in China still needs constantly optimization and timely maintenance. Proper sensitivity to reduce triggering of useless alerts and generation of alert fatigue might play a vital role. We believed that these findings are helpful for better understanding the state quo of MRCDSS in China and providing useful insights for future developing and improving MRCDSS.

Aim: C-reactive protein (CRP) is both an inflammatory and prognostic marker in various cancers. This study aimed to elucidate the characteristics of CRP and the prognostic factors in patients who were administered with atezolizumab plus bevacizumab (ATZ + BEV) for unresectable hepatocellular carcinoma (HCC)., Methods: A total of 213 patients who received ATZ + BEV for HCC from November 2020 to March 2023 at 15 hospitals were enrolled in this retrospective study. The prognosis was analyzed by subdividing the patients based on baseline characteristics, radiologic response, and treatment lines. Accuracy of survival prediction was assessed using CRP, alpha fetoprotein (AFP), C-reactive protein and alpha fetoprotein in immunotherapy (CRAFITY), and Glasgow Prognostic Score., Results: Compared with patients with baseline CRP <1 mg/dL, those with baseline CRP ≥1 mg/dL (n = 45) had a significantly higher baseline albumin-bilirubin score and AFP levels, significantly lower disease control rate (62.2%), and significantly shorter median overall survival (hazards ratios 2.292; 95% confidence interval 1.313-5.107; log-rank test, p < 0.001). Multivariate analysis identified CRP ≥1 mg/dL, AFP ≥100 ng/mL, and modified albumin-bilirubin grade as the significant prognostic factors. The baseline CRP, AFP, CRAFITY, and Glasgow Prognostic Score demonstrated higher discrimination for 1-year survival prediction after first-line ATZ + BEV administration, compared with beyond second line, with area under the receiver operating characteristic curves of 0.759, 0.761, 0.805, and 0.717, respectively., Conclusions: CRP was a significant biomarker in patients treated with ATZ + BEV for HCC. Elevated CRP levels may indicate aggressive cancer progression and potential resistance to ATZ + BEV therapy., (© 2023 Japan Society of Hepatology.)

Background: The anatomical approach for the management of para-Hisian ventricular arrhythmias (VAs) with QRS morphological changes after catheter ablation (CA) has not been well investigated., Objective: We aimed to evaluate the electrocardiographic and electrophysiological findings and ablation outcomes of para-Hisian VAs with QRS morphological changes after CA., Methods: Of the 30 patients who underwent CA for para-Hisian VAs at 4 institutions, 10 (33%) had QRS morphological changes after ablation. All 10 patients underwent an anatomical approach, targeting the site anatomically opposite to the site where the QRS morphology had been changed by ablation. We investigated the safety and efficacy of the anatomical approach., Results: Of the 10 patients evaluated, the approach was switched from the right ventricular septum to the left ventricular septum/aortic root in 7 (70%) (RL group) whereas 3 (30%) underwent left-to-right switches (LR group). After CA, the precordial transition zone tended to be earlier in the RL group and later in the LR group. In the RL group, successful VA suppression was achieved, despite suboptimal pace map concordance from the left side or a relatively delayed earliest activation time. Of the 10 patients who underwent an anatomical approach, 8 (80%) had procedural success, and ablation was discontinued in 1 (10%) because of the risk of atrioventricular block., Conclusion: The anatomical approach showed promising results regarding safety and efficacy. Therefore, it should be considered when QRS morphological changes are observed during or after CA of para-Hisian VAs., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

To further our understanding of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guideline and promote effective implementation, a public workshop was held in Japan by regulatory agency and industry representatives. In this workshop, important concepts explained in the ICH E17 guideline, such as intrinsic/extrinsic ethnic factors that influence treatment effects ("effect modifiers") and the holistic evaluation of consistency of treatment effect were actively discussed through case studies. The importance of holistic evaluation of consistency was recognized, and it was concluded that the evaluation and relevant discussion should be shared with regulatory authorities, sponsors, and broader stakeholders., (© 2024 The Authors. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Long COVID (LC)-related health problems are highly concerned. Many patients seem to have "recovered" from an acute SARS-CoV-2 infection, however, they might experience various symptoms, almost involving all organs and systems. Of those, neuropsychiatric symptoms like depression, anxiety, and post-traumatic stress disorder (PTSD) are not rare. These problems significantly impact the quality of life (QOL) of patients, family, and caregivers, even lead a tragic suicide outcome. Other than the conventional psychological and medical approaches, here, we proposal a positive emotion, engagement, relationships, meaning, and accomplishment (PERMA)-based approach to fight against these COVID-19-related mental health problems (CRMHPs). This approach is characterized by positive psychological interventions and self-achievements, which has been proved to be a powerful tool against mood disorders in common people. Nowadays, abolishment of certain prophylactic measures (such as isolation, lockdown, compulsorily wearing a mask and maintaining social distance, measures to avoid crowding) enables us to have more opportunities to contact patients and implement the PERMA-based approach to the patients with CRMHPs. We believe that application of PERMA-based approach is conducive to alleviate the influence of the CRMHPs and improve their QOL., Competing Interests: The authors have no conflicts of interest to disclose., (2024, National Center for Global Health and Medicine.)

The synthesis, structure, and properties of a stable, linear 2-stannapropadiene are reported. The identical C[double bond, length as m-dash]Sn bonds in this 2-stannapropadiene are the shortest hitherto reported C-Sn bonds. This 2-stannapropadiene features a 119 Sn NMR signal at 507 ppm for the central tin atom, indicative of an unsaturated Sn 4+ oxidation state. Due to the inert-pair effect, the tin atom displays a pronounced preference for the +2 oxidation state over the +4 oxidation state. Nevertheless, by employing silyl substituents, it is possible to disrupt the inert-pair effect, leading to the formation of an isolable 2-stannapropadiene with a linear structure centered on a Sn 4+ atom. Treatment of this 2-stannapropadiene with SnBr 2 ·dioxane resulted in the formation of a novel four-membered cyclic 1,1-dibromo-1,3-distannetane, which was subsequently reduced to afford the corresponding stable four-membered cyclic bis(stannylene)., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The etiology of Parkinson's disease (PD) is characterized by the death of dopamine neurons in the substantia nigra pars compacta, while misfolding and abnormal aggregation of α-synuclein (α-syn) are core pathological features. Previous studies have suggested that damage to dopamine neurons may be related to cell cycle dysregulation, but the specific mechanisms remain unclear. In this study, a PD mouse model was induced by stereotactic injection of α-syn into the nucleus, and treated with the cell cycle inhibitor, roscovitine (Rosc). The results demonstrated that Rosc improved behavioral disorders caused by α-syn, increased TH protein expression, inhibited α-syn and p-α-syn protein expression, and reduced the expression levels of G1/S phase cell cycle genes Cyclin D1, Cyclin E, CDK2, CDK4, E2F and pRB. Additionally, Rosc decreased Bax and Caspase-3 expression caused by α-syn, while increasing Bcl-2 protein expression. Meanwhile, we observed that α-syn can influence neuronal cell autophagy by decreasing the expression level of Beclin 1 and increasing the expression level of P62. However, Rosc can improve this phenomenon. In a cell model induced by α-syn in dopamine neuron injury cells, knockdown of Cyclin D1 led to similar results as those observed in animal experiments: Knocking down Cyclin D1 improved the abnormal initiation of the cell cycle caused by α-syn and regulated cellular autophagy, resulting in a reduction of apoptosis in dopamine neurons. In summary, exogenous α-syn can lead to the accumulation of α-syn and phosphorylated α-syn in dopamine neurons, increase key factors of the G1/S phase cell cycle such as Cyclin D1, and regulate downstream related indicators, causing the cell cycle to restart and leading to apoptosis of dopamine neurons. This exacerbates PD symptoms. However, knockdown of Cyclin D1 inhibits the progression of the cell cycle and can reverse this situation. These findings suggest that a Cyclin D inhibitor may be a novel therapeutic target for treating PD., 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 © 2024. Published by Elsevier Masson SAS.)

Competing Interests: Kenji Kuroki and Akira Sato received research grants from Abbott Medical Japan, Inc. The remaining authors have no conflicts of interest to declare.

Tuberculosis (TB) is one of the top ten causes of death worldwide, taking the lives of over a million people annually. In addition to being a serious health issue, TB is also closely linked to eradicating poverty according to the Sustainable Development Goals (SDGs) of the United Nations (UN). All UN members have committed to ending the TB epidemic by 2030. China has one of the highest TB loads worldwide, ranking third in the world on many TB burden indices. The national strategy for TB control is aimed at creating a collaborative network and integrating TB treatment into the medical system. According to the WHO's global TB report, China is expected to have 748,000 new cases of TB in 2022 and an incidence of 52 cases per 100,000 people. Ending TB remains a huge challenge and requires comprehensive control strategies in China. In this work, we have discussed the challenges of TB prevention and control in China and proposed specific measures to end TB.

The main technological difficulties of developing an intracellular (transmembrane) transport system for protein drugs lie in two points: i) overcoming the barriers in the cellular membrane, and ii) loading enough protein drugs, and particularly high-dose proteins, into particles. To address these two technological problems, we recently developed a novel cholesterol tag (C-Tag)-based transmembrane transport system. This pilot study found that the C-Tag dramatically improved the cellular uptake of Fab (902-fold, vs. Fab alone) into living cells, indicating that it successfully achieved transmembrane transport. Moreover, C-Tag-mediated membrane transport was verified using micron-scale large unilamellar vesicles (LUVs, approximately 1.5 μm)-based particles. The C-Tagged Fab was able to permeate the liposomal bilayer and it greatly enhanced (a 10.1-fold increase vs. Fab alone) internalization of proteins into the LUV-based particles, indicating that the C-Tag loaded enough proteins into particles for use of high-dose proteins. Accordingly, we established a novel C-Tag-based transport system that has overcome the known technological difficulties of protein transmembrane delivery, and this might be a useful technology for drug development in the future.

Background Cognition is a vital sign and its deterioration is a major concern in clinical medicine. It is usually evaluated using neuropsychological assessments, which have innate limitations such as the practice effect. To compensate for these assessments, the oscillatory power of resting-state brain activity has recently become available. The power is obtained noninvasively using magnetoencephalography and is summarized by spectral parameters such as the median frequency (MF), individual alpha frequency (IAF), spectral edge frequency 95 (SEF95), and Shannon's spectral entropy (SSE). As these parameters are less sensitive to practice effects, they are suitable for longitudinal studies. However, their reliability remains unestablished, hindering their proactive use in clinical practice. Therefore, we aimed to quantify the within-participant reliability of these parameters using repeated measurements of healthy participants to facilitate their clinical use and to evaluate the observed changes/differences in these parameters reported in previous studies. Methodology Resting-state brain activity with eyes closed was recorded using magnetoencephalography for five minutes from 15 healthy individuals (29.3 ± 4.6 years old: ranging from 23 to 28 years old). The following four spectral parameters were calculated: MF, IAF, SEF95, and SSE. To quantify reliability, the minimal detectable change (MDC) and intraclass correlation coefficient (ICC) were computed for each parameter. In addition, we used MDCs to evaluate the changes and differences in the spectral parameters reported in previous longitudinal and cross-sectional studies. Results The MDC at 95% confidence interval (MDC95) of MF, IAF, SEF95, and SSE were 0.61 Hz, 0.44 Hz, 2.91 Hz, and 0.028, respectively. The ICCs of these parameters were 0.96, 0.92, 0.94, and 0.83, respectively. The MDC95 of these parameters was smaller than the mean difference in the parameters between cognitively healthy individuals and patients with dementia, as reported in previous studies. Conclusions The spectral parameter changes/differences observed in prior studies were not attributed to measurement errors but rather reflected genuine effects. Furthermore, all spectral parameters exhibited high ICCs (>0.8), underscoring their robust within-participant reliability. Our results support the clinical use of these parameters, especially in the longitudinal monitoring and evaluation of the outcomes of interventions., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Okumura et al.)

We report the first total synthesis of silybin A (1). Key synthetic steps include the construction of the 1,4-benzodioxane neolignan skeleton, a modified Julia-Kocienski olefination reaction between m-nitrophenyltetrazole sulfone (m-NPT sulfone) 10 and aldehyde 21, the formation of the flavanol lignan skeleton 28 via a quinomethide intermediate under acidic conditions, and stepwise oxidation of the benzylic position of flavanol 29.

The relationship between age-related hearing loss (ARHL) and cognitive impairment (CI) remains intricate. However, there is no robust evidence from experimental or clinical studies to elucidate their relationship. The key unaddressed questions are (a) whether there is a causal effect of ARHL on CI and (b) whether efficacious treatment of ARHL (such as hearing-aid use) ameliorates CI and dementia-related behavioral symptoms. Because of several methodological and systematic flaws/challenges, rigorous verification has not been conducted. Addressing these stumbling blocks is essential to unraveling the relationship between ARHL and CI, which motivated us to undertake this review. Here, we discuss the methodological problems from the perspectives of potential confounding bias, assessments of CI and ARHL, hearing-aid use, functional-imaging studies, and animal models based on the latest information and our experiences. We also identify potential solutions for each problem from the viewpoints of clinical epidemiology. We believe that "objectivity," specifically the use of more objective behavioral assessments and new computerized technologies, may be the key to improving experimental designs for studying the relationship between ARHL and CI.

Background: Patients who undergo percutaneous coronary intervention (PCI) with rotational atherectomy (RA) are at high risk of adverse clinical outcomes, and there are few clinical risk stratification tools for these patients., Methods: We conducted a study with 196 patients who underwent PCI with RA out of 7391 patients who underwent PCI using a multicenter, prospective cohort registry. Patients were divided into three groups according to the tertiles of the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P): 65 patients in the T1 group (TRS 2°P < 3), 66 patients in the T2 group (TRS 2°P = 3), and 65 patients in the T3 group (TRS 2°P > 3). The primary endpoint was the cumulative 2-year incidence of major adverse cardiovascular and cerebrovascular events (MACCE), defined as a composite of cardiac death, acute coronary syndrome, and ischemic stroke., Results: Cumulative 2-year MACCE occurred in 41 patients (24 %) during the follow-up period. The cumulative incidence of MACCE was significantly higher in the T3 group than in the T1 group (log-rank test, p = 0.02). Multivariate Cox analyses revealed that the T3 group was associated with an increased risk of MACCE compared to that of the T1 group (adjusted hazard ratio, 2.66; 95 % confidence interval, 1.04-6.77; p = 0.04). The addition of TRS 2°P to conventional risk factors, including male sex, number of diseased vessels, and low-density lipoprotein cholesterol levels, improved the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.39, p = 0.027; IDI 0.072, p < 0.001)., Conclusions: Atherothrombotic risk stratification using TRS 2°P was useful in identifying high-risk patients with heavily calcified lesions following RA., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The human gastrointestinal tract is inhabited by a diverse range of microorganisms, collectively known as the gut microbiota, which form a vast and complex ecosystem. It has been reported that the microbiota-gut-brain axis plays a crucial role in regulating host neuroprotective function. Studies have shown that patients with Parkinson's disease (PD) have dysbiosis of the gut microbiota, and experiments involving germ-free mice and fecal microbiota transplantation from PD patients have revealed the pathogenic role of the gut microbiota in PD. Interventions targeting the gut microbiota in PD, including the use of prebiotics, probiotics, and fecal microbiota transplantation, have also shown efficacy in treating PD. However, the causal relationship between the gut microbiota and Parkinson's disease remains intricate. This study reviewed the association between the microbiota-gut-brain axis and PD from the perspectives of humoral pathway, cellular immune pathway and neuronal pathway. We found that the interactions among gut microbiota and PD are very complex, which should be "multidirectional", rather than conventionally regarded "bidirectional". To realize application of the gut microbiota-related mechanisms in the clinical setting, we propose several problems which should be addressed in the future study., 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 © 2023 Jia, Chen, Zhang and Asakawa.)

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs)., Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated., Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis., Discussion/conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab., Competing Interests: Masatoshi Kudo reports the following conflicts of interest: honoraria payment to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eli Lilly, Eisai, and Takeda; research funding to institution from AbbVie, Chugai Pharmaceutical Co. Ltd., EA Pharma, Eisai, F. Hoffmann-La Roche Ltd, GE HealthCare, Gilead Sciences, Otsuka, Sumitomo Dainippon Pharma, Taiho, and Takeda; and Editor in Chief of Liver Cancer. Kaoru Tsuchiya reports the following conflicts of interest: advisory/consultancy fees to self from Chugai Pharmaceutical Co. Ltd. and Eisai; speakers bureau participation for Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, and Takeda; and research funding to institution from F. Hoffmann-La Roche Ltd. Yu-Yun Shao reports the following conflicts of interest: honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd, Ipsen, Merck, and Ono. Richard S. Finn reports the following conflicts of interest: consulting fees to self from AstraZeneca, Bayer, CStone Pharmaceuticals, Eisai, Eli Lilly, Exelixis, F. Hoffmann-La Roche Ltd., Hengrui, Merck, and Pfizer; research funding to institution from Adaptimmune, Bristol Myers Squibb, Eisai, Eli Lilly, Merck, Pfizer, and F. Hoffmann-La Roche Ltd.; and Editorial Board Member of Liver Cancer. Peter R. Galle reports the following conflicts of interest: consulting fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; honoraria payment to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; advisory fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; and research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Michel Ducreux reports the following conflicts of interest: honoraria, consulting fees, or advisory fees to self from Amgen, AstraZeneca, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Serono, Pierre Fabre, and Servier; travel support from Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Sharp & Dohme, and Servier; speakers bureau participation for Amgen, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, and Merck Serono; and research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Ann-Lii Cheng reports the following conflicts of interest: research funding to institution from F. Hoffmann-La Roche Ltd. Tatsuya Yamashita reports the following conflicts of interest: speakers bureau participation for Bayer and Chugai Pharmaceutical Co. Ltd. and research funding to institution from F. Hoffmann-La Roche Ltd. Hironori Koga reports the following conflicts of interest: research funding to institution from AbbVie, Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo, and F. Hoffmann-La Roche Ltd. Ryosuke Take, Kyoko Yamada, Takashi Asakawa, and Yuki Nakagawa reports the following conflicts of interest: employment by Chugai Pharmaceutical Co. Ltd. Masafumi Ikeda reports the following conflicts of interest: honoraria to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, and Takeda; advisory/consulting fees to self from Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, Merck Sharp & Dohme, and Takeda; and research funding to institution from Bayer, Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Merck Sharp & Dohme, and Takeda., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Disinfection of dental unit waterlines (DUWLs) plays a key role in control and prevention of nosocomial infection in a dental clinic. The most conventional disinfectant is hydrogen peroxide (H 2 O 2 ), while chlorine dioxide (ClO 2 ) has been considered however was limited by the "activation" procedures. With the availability of commercialized stable ClO 2 solution (free of activation), direct application of ClO 2 in the dental practice became possible. This study was designed to compare the disinfecting effects of stable 5 ppm of ClO 2 solution with conventional 0.24% of H 2 O 2 on DUWLs in dental practice. Studies of colony-forming units (CFUs), confocal laser scanning microscopy (CLSM) and scanning electron microscope (SEM) were employed for evaluation. In CFUs studies, we found that the efficiency of ClO 2 was no less than those of H 2 O 2. In the morphological studies, the stronger disinfecting effects of ClO 2 was verified by both CLSM and SEM studies for removal and prevention of biofilm. Importantly, ClO 2 solution achieved a better disinfecting efficiency not only at the surface of bacterial biofilm, but also, it has penetrating effects, presented disinfecting effects from the surface to the bottom of the biofilm. This pilot study provided evidence regarding the efficiency of stable ClO 2 solution on disinfection of DUWLs in the dental practice setting. Application of stable ClO 2 solution in dental practice is therefore become possible.

The tuberculosis (TB)-related caregiver burden (CB), and particularly the multidrug and extensively drug-resistant tuberculosis (M/XDR-TB)-related CB, is not rare in caregivers caring for TB patients, especially when a family member is the caregiver. However, the existing studies on this topic are insufficient. This study briefly summarized the risk factors for the imposition of a TB-related CB and reasons why caregivers for patients with M/XDR-TB are more susceptible to a CB. We propose that special measures should be implemented to alleviate the TB-related CB based on our clinical experience and insights from China. This may improve the situation of caregivers for TB patients and ultimately improve the quality of life of TB patients.

This work describes a novel artificial intelligence-based training and monitoring system (AITMS) that was used to control and prevent nosocomial infections (NIs) by improving the skills of donning/removing personal protective equipment (PPE). The AITMS has two working modes, namely an AI-based protective equipment surveillance mode and an AI-based training mode, that were used for routine surveillance and training, respectively. Data revealed that the accuracy rate of donning/removing PPE improved as a result of the AITMS. Interestingly, the frequency of NIs decreased with the use of the AITMS. This study suggested the key role of using PPE in controlling and preventing NIs. Data preliminarily proved that appropriate donning/removing PPE may help to reduce the risk of NIs. In addition, the newest computerized technologies, such as AI, have proven to be useful in controlling and preventing NIs. These findings should helpful to formulate a better strategy against NIs in the future.

Aim: The present study aimed to conduct a meta-analysis to evaluate the methods and effects of interventions to increase life-space mobility among community-dwelling older adults., Methods: Records were identified through nine databases. Eligible study designs for inclusion in the review were randomized controlled trials of interventions on life-space mobility for community-dwelling older adults. The risk of bias was assessed using the Risk of Bias 2 tool. We followed the Grading of Recommendations, Assessment, Development, and Evaluation approach to summarize the evidence., Results: Four studies (558 participants) identified via search strategies were included. Two studies involved individualized exercise and lifestyle interventions. In three out of the four studies, individual interventions were applied. Overall, when compared with a control group, the intervention group was more likely to positively affect increasing life-space mobility (standardized mean difference 0.47, 95% confidence interval [0.020 to 0.92]). The heterogeneity statistic indicated considerable heterogeneity (I 2  = 84%). The evidence was downgraded one step owing to imprecision., Conclusions: Interventions on increasing life-space mobility for community-dwelling older adults have a positive effect. Combination interventions may be more effective than single interventions, and individual interventions may be more effective than group interventions. However, owing to the limited number of studies, conducting further research to enhance the generalizability of results is crucial. Additionally, subgroup analysis should be conducted to clarify differences in intervention methods and effects. Geriatr Gerontol Int 2023; 23: 842-848., (© 2023 Japan Geriatrics Society.)

Background: Symptomatic gastric hypomotility (SGH) is a rare but major complication of atrial fibrillation (AF) ablation, but data on this are scarce., Objective: We compared the clinical course of SGH occurring with different energy sources., Methods: This multicenter study retrospectively collected the characteristics and clinical outcomes of patients with SGH after AF ablation., Results: The data of 93 patients (67.0 ± 11.2 years, 68 men, 52 paroxysmal AF) with SGH after AF ablation were collected from 23 cardiovascular centers. Left atrial (LA) ablation sets included pulmonary vein isolation (PVI) alone, a PVI plus a roof-line, and an LA posterior wall isolation in 42 (45.2%), 11 (11.8%), and 40 (43.0%) patients, respectively. LA ablation was performed by radiofrequency ablation, cryoballoon ablation, or both in 38 (40.8%), 38 (40.8%), and 17 (18.3%) patients, respectively. SGH diagnoses were confirmed at 2 (1-4) days post-procedure, and 28 (30.1%) patients required re-hospitalizations. Fasting was required in 81 (92.0%) patients for 4 (2.5-5) days; the total hospitalization duration was 11 [7-19.8] days. After conservative treatment, symptoms disappeared in 22.3% of patients at 1 month, 48.9% at 2 months, 57.6% at 3 months, 84.6% at 6 months, and 89.7% at 12 months, however, one patient required surgery after radiofrequency ablation. Symptoms persisted for >1-year post-procedure in 7 patients. The outcomes were similar regardless of the energy source and LA lesion set., Conclusions: The clinical course of SGH was similar regardless of the energy source. The diagnosis was often delayed, and most recovered within 6 months, yet could persist for over 1 year in 10%., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Miyazaki, Kobori, Jo, Keida, Yoshitani, Mukai, Sagawa, Asakawa, Sato, Yamao, Horie, Manita, Fukaya, Hayashi, Tanimoto, Iwayama, Chiba, Sato, Sekiguchi, Sugiura, Iwai, Isonaga, Miwa, Kato, Inaba, Hirota, Nagata, Ono, Hachiya, Yamauchi, Goya, Nitta, Tada and Sasano.)

Cancer cell resistance arises when tyrosine kinase inhibitor (TKI)-targeted therapies induce a drug-tolerant persister (DTP) state with growth via genetic aberrations, making DTP cells potential therapeutic targets. We screened an anti-cancer compound library and identified fibroblast growth factor receptor 1 (FGFR1) promoting alectinib-induced anaplastic lymphoma kinase (ALK) fusion-positive DTP cell's survival. FGFR1 signaling promoted DTP cell survival generated from basal FGFR1- and fibroblast growth factor 2 (FGF2)-high protein expressing cells, following alectinib treatment, which is blocked by FGFR inhibition. The hazard ratio for progression-free survival of ALK-TKIs increased in patients with ALK fusion-positive non-small cell lung cancer with FGFR1- and FGF2-high mRNA expression at baseline. The combination of FGFR and targeted TKIs enhanced cell growth inhibition and apoptosis induction in basal FGFR1- and FGF2-high protein expressing cells with ALK-rearranged and epidermal growth factor receptor (EGFR)-mutated NSCLC, human epidermal growth factor receptor 2 (HER2)-amplified breast cancer, or v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma by preventing compensatory extracellular signal-regulated kinase (ERK) reactivation. These results suggest that a targeted TKI-induced DTP state results from an oncogenic switch from activated oncogenic driver signaling to the FGFR1 pathway in basal FGFR1- and FGF2-high expressing cancers and initial dual blockade of FGFR and driver oncogenes based on FGFR1 and FGF2 expression levels at baseline is a potent treatment strategy to prevent acquired drug resistance to targeted TKIs through DTP cells regardless of types of driver oncogenes., (© 2023. Nature Publishing Group UK.)

Bipolar radiofrequency catheter ablation (RFCA) is a novel strategy for refractory or recurrent ventricular arrhythmias (VAs) resistant to conventional ablation methods. Lesions created during bipolar RFCA are larger than those created during sequential unipolar ablation. We present a case of refractory LV summit VAs, which identified the origin using a 2.7-F over-the-wire microelectrodes catheter, and it was successfully treated with bipolar RFCA in the acute phase., Competing Interests: Kenji Kuroki and Akira Sato have received research grant and honoraria from Abbott Medical Japan, LLC. All other authors have no conflicts to disclose., (© 2023 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Objectives: One of the causes of death in patients with multiple system atrophy (MSA) is aspiration pneumonia caused by cough dysfunction. This study aimed to identify an effective approach to improve coughing and to explore the establishment of criteria for the use of gastrostomy based on cough and respiratory dysfunctions., Methods: Eighteen probable MSA patients participated in the study. They were categorized into air stacking and non-air stacking groups. First, we investigated how the inspiration volume changes by applying maximum insufflation capacity (MIC). Second, peak cough flow (PCF) was measured by different cough augmentation methods: 1) spontaneous coughing (SpC); 2) SpC with MIC (SpC + MIC); 3) SpC with manually assisted cough (MAC) (SpC + MAC); and 4) SpC with MIC and MAC (SpC + MIC + MAC). Among these four conditions, PCF values were compared to determine the most effective approach for cough augmentation. Receiver operating characteristic analysis was performed on percent forced vital capacity (%FVC) to determine an index for discriminating PCF below160 L/min, which indicates a high risk of suffocation, involving SpC and SpC + MIC., Results: Inspiration volume increased significantly with MIC in both groups (P < 0.05), and PCF increased significantly with MIC in the air stacking group (P < 0.01). PCF could not be maintained at 160 L/min when %FVC fell below 59%, even when MIC was applied., Conclusions: PCF increases with MIC in patients with MSA. It may be meaningful to consider the timing of gastrostomy introduction based on the severity of cough and respiratory dysfunction., Competing Interests: CONFLICTS OF INTEREST: Mieko Ogino received honoraria for lecturing from Takeda Pharmaceutical. The remaining authors declare no conflict of interest., (2023 The Japanese Association of Rehabilitation Medicine.)

The purpose of this study was to clarify changes in cough function in patients with multiple system atrophy (MSA). Seventeen probable patients with MSA were studied. Peak cough flow (PCF), respiratory function (percentage of vital capacity, percentage of forced vital capacity, and percentage of predicted forced expiratory volume in one second), respiratory muscle strength (percentage of maximal inspiratory mouth pressure and percentage of maximal expiratory mouth pressure), and maximum phonation time (MPT) were assessed. Walking ability, disease duration, possibility of air stacking, Unified MSA Rating Scale (UMSARS), and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III were also assessed. Data were separately analyzed for ambulatory and non-ambulatory groups categorized by Functional Ambulation Categories. PCF, respiratory function, respiratory muscle strength, and MPT were significantly lower in the non-ambulatory group than in the ambulatory group. On the other hand, no correlation between PCF and disease duration was observed. A significant number of patients in the non-ambulatory group were unable to hold their breath. The UMSARS and MDS-UPDRS Part III in the non-ambulatory group were significantly higher than in the ambulatory group. It was concluded that ambulatory dysfunction is associated with the decline of cough function and respiratory-related function in patients with MSA.

The granulocyte-colony-stimulating factor (G-CSF) glycoprotein stimulates precursor cell proliferation and differentiation in the bone marrow. Various G-CSF-producing tumors have been reported; they showed early progression and an extremely poor prognosis. Here, we report a case of G-CSF-producing gallbladder cancer with lymph node metastasis. In addition, we reviewed 30 previous case reports of G-CSF-producing gallbladder cancers to elucidate the characteristics and most appropriate treatment. During a routine visit to her local doctor for monitoring of diabetes and hypertension, a 68-year-old female was found to have an elevated white-blood-cell (WBC) count and C-reactive protein (CRP) level, and a gallbladder mass. Laboratory tests revealed a high serum G-CSF level, and imaging revealed a tumor of the gallbladder with regional lymphadenopathy. We diagnosed a G-CSF-producing gallbladder cancer and performed liver resection of segment IVa/V: regional lymph node dissection with extrahepatic bile duct resection. Pathologically, the tumor was a poorly differentiated squamous cell carcinoma. G-CSF immunostaining for tumor cells was positive. She is alive without recurrence at 16 months after surgery. If a patient exhibits a gallbladder tumor, with an elevated WBC count and CRP level but no symptoms of infection, a G-CSF-producing gallbladder cancer should be suspected; radical resection should be performed immediately after diagnosis., (© 2023. Japanese Society of Gastroenterology.)

Purpose: The purpose was to review relevant clinical data and formulate recommendations supporting the use of saline as a simple rinse for an early reassuring intervention to reduce the occurrence of re-positive COVID-19 patients., Methods: We conducted a single-centre retrospective cohort study, which enrolled patients with confirmed re-testing positive COVID-19 during 7-60 days after discharge from Third People's Hospital of Shenzhen. By one-to-two propensity score matching for age and sex, the control group of those not re-testing positive during the same period served as matched control., Results: A total of 223 patients were included in our study, 94 in re-positive group and 129 in non-re-positive group. The result shows that the rates of nasal douche treatment in the non-re-positive group were considerably higher than that of the re-positive group. And the Ct value of nasal douche group increased faster than that of non-nasal douche group after the Ct value reaching ≥35. Further analysis revealed that the higher the Ct value at the time of readmission, the shorter the time of average Ct values to reach ≥35., Conclusion: These findings suggest that nasal douche is beneficial to shorten the time of virus nucleic acid turning negative, thereby reducing the incidence of re-positive. The prevention and control of epidemics focuses on re-positive patients with Ct values <35., Competing Interests: The authors have no conflicts of interest to disclose for this work., (© 2023 Liao et al.)

By far, there is no general consensus concerning the definition of frailty even though it may be a global public health concern with aging of the population. It is regarded as a pathophysiological state before development of a severe illness that is associated with many adverse outcomes. Although previous studies attempted to verify its clinical value to prevent the development of serious illness, robust evidence is lacking. Based on previous studies of frailty, the current study analyzed the problems with existing investigations of frailty and it puts forward future strategies to improve those investigations. Finalizing the definition of frailty is the first step. Next, development of objective tools to identify/measure frailty based on the newest biological and computerized technologies is indispensable. Finally, well-designed clinical trials also need to be conducted to yield compelling evidence regarding the clinical value of medical interventions in frailty.

Background: SIM0417 (SSD8432) is an orally administered coronavirus main proteinase (3CL pro ) inhibitor with potential anti-SARS-CoV-2 activity. This study aimed to evaluate the efficacy and safety of SIM0417 plus ritonavir (a pharmacokinetic enhancer) in adults with COVID-19., Methods: This was a randomised, double-blind, placebo-controlled, phase 1b study in China. Adults with asymptomatic infection, mild or moderate COVID-19 were randomly assigned (3:3:2) to receive either 750 mg SIM0417 plus 100 mg ritonavir, 300 mg SIM0417 plus 100 mg ritonavir or placebo every 12 h for 10 doses. The main efficacy endpoints included SARS-CoV-2 viral load, proportion of participants with positive SARS-CoV-2 nucleic acid test and time to alleviation of COVID-19 symptoms. This trial is registered with ClinicalTrials.gov, NCT05369676., Findings: Between May 12 and August 29, 2022, 32 participants were enrolled and randomised to high dose group (n = 12), low dose group (n = 12) or placebo (n = 8). The viral load change from baseline in high dose group was statistically lower compared with placebo, with a maximum mean difference of -2.16 ± 0.761 log 10 copies/mL (p = 0.0124) on Day 4. The proportion of positive SARS-CoV-2 in both active groups were lower than the placebo. The median time to sustained alleviation of COVID-19 symptoms was 2.0 days in high dose group versus 6.0 days in the placebo group (HR = 3.08, 95% CI 0.968-9.818). SIM0417 plus ritonavir were well tolerated with all adverse events in grade 1., Interpretation: SIM0417 plus ritonavir was generally well tolerated. The efficacy of SIM0417 showed a monotonic dose-response relationship, and the 750 mg SIM0417 plus 100 mg ritonavir was selected as the recommended clinical dose., Funding: The study was funded by Jiangsu Simcere Pharmaceutical Co., Ltd., Competing Interests: RHT, YMY, WW, JXT, YSH and YY are employees of Jiangsu Simcere Pharmaceutical Co., Ltd., (© 2023 Published by Elsevier Ltd.)

Detecting and appropriately diagnosing a Mycobacterium tuberculosis infection remains technologically difficult because the pathogen commonly hides in macrophages in a dormant state. Described here is novel near-infrared aggregation-induced-emission luminogen (AIEgen) labeling developed by the current authors' laboratory for point-of-care (POC) diagnosis of an M. tuberculosis infection. The selectivity of AIEgen labeling, the labeling of intracellular M. tuberculosis by AIEgen, and the labeling of M. tuberculosis in sputum samples by AIEgen, along with its accuracy, sensitivity, and specificity, were preliminarily evaluated. Results indicated that this near-infrared AIEgen labeling had satisfactory selectivity and it labeled intracellular M. tuberculosis and M. tuberculosis in sputum samples. It had a satisfactory accuracy (95.7%), sensitivity (95.5%), and specificity (100%) for diagnosis of an M. tuberculosis infection in sputum samples. The current results indicated that near-infrared AIEgen labeling might be a promising novel diagnostic tool for POC diagnosis of M. tuberculosis infection, though further rigorous verification of these findings is required.

Allenes (>C=C=C<) are classified as cumulated dienes with a linear structure and an sp-hybridized central carbon atom. We have synthesized and isolated a stable 2-germapropadiene with bulky silyl substituents. The 2-germapropadiene allene moiety adopts a linear structure both in the solid state and in solution. An X-ray diffraction electron-density-distribution (EDD) analysis of this 2-germapropadiene confirmed the linear C=Ge=C geometry with a formally sp-hybridized germanium atom that bears two orthogonal C=Ge π-bonds. Based on detailed structural and computational studies, we concluded that the linear geometry of the isolated 2-germapropadiene most likely arises from the negative hyperconjugation of the silyl substituents at the terminal carbon atoms. The 2-germapropadiene reacts rapidly with nucleophiles, indicating that the linearly oriented germanium atom is highly electrophilic., (© 2023 Wiley-VCH GmbH.)

In this study, we constructed a prediction formula for unbound valproic acid (VPA) concentration that was more accurate and widely applicable than previously reported formulae. A total of 136 datasets from 75 patients were analyzed retrospectively. The median of free fraction of VPA was 0.16 (interquartile range: 0.07; range: 0.07-0.45). The parameter that combined total VPA concentration (C tVPA ) and serum albumin (SA), (C tVPA [μM] - 2 × SA [μM]), was significantly related to the free fraction of VPA (r = 0.76, p < 0.001). We constructed a combined parameter-based prediction formula for unbound VPA concentration. Analysis using external datasets from patients without severe renal failure showed that the prediction errors of the unbound VPA concentration were lower than those of previously reported formulae. Although the previous formulae showed large prediction errors, especially in the specific range of C tVPA values, the constructed formula showed a weak trend with C tVPA or SA. The formula based on (C tVPA [μM] - 2 × SA [μM]) had high prediction accuracy and wide applicability in predicting the unbound VPA concentration in patients without severe renal failure., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Over three years have passed since the COVID-19 pandemic started. The dangerousness and impact of COVID-19 should definitely not be ignored or underestimated. Other than the symptoms of acute infection, the long-term symptoms associated with SARS-CoV-2 infection, which are referred to here as "sequelae of long COVID (LC)", are also a conspicuous global public health concern. Although such sequelae were well-documented, the understanding of and insights regarding LC-related sequelae remain inadequate due to the limitations of previous studies (the follow-up, methodological flaws, heterogeneity among studies, etc.). Notably, robust evidence regarding diagnosis and treatment of certain LC sequelae remain insufficient and has been a stumbling block to better management of these patients. This awkward situation motivated us to conduct this review. Here, we comprehensively reviewed the updated information, particularly focusing on clinical issues. We attempt to provide the latest information regarding LC-related sequelae by systematically reviewing the involvement of main organ systems. We also propose paths for future exploration based on available knowledge and the authors' clinical experience. We believe that these take-home messages will be helpful to gain insights into LC and ultimately benefit clinical practice in treating LC-related sequelae.

Aims: The relationship between low body mass index (BMI) and prognostic factors for patients with coronary artery disease, commonly observed in elderly individuals in Japan, is important. Few studies have evaluated the prognosis for patients with low BMI after percutaneous coronary intervention (PCI). Using a multivariable-adjusted model and data from a prospective cohort registry, we analyzed the risk associated with low BMI for patients after PCI., Methods: This prospective, multicenter registry included 5965 consecutive patients with coronary artery disease who underwent successful PCI. The patients were followed-up clinically for up to 3 years or until the occurrence of major adverse cardiac events. The primary endpoint was all-cause death and nonfatal myocardial infarction composite., Results: Primary events occurred in 639 (10.7%) patients during the follow-up period. A risk analysis of the primary endpoint adjusted for the multivariable model showed a significant increase in risk for elderly individuals, underweight individuals [HR 1.43 (95% confidence interval (CI), 1.10-1.85), P＜0.001], those with diabetes mellitus (DM), peripheral artery disease, low left ventricular ejection fraction or acute coronary syndrome (ACS), and smokers. A stratified adjusted risk analysis based on BMI levels showed that the risk associated with underweight status was significantly pronounced for male patients, those aged 60-74 years, and those with DM or ACS., Conclusion: Underweight patients with several risk factors significantly increased risk after PCI. Furthermore, the risk associated with low BMI was significantly more pronounced for men, individuals aged 60-74 years, and patients with DM or ACS.

Recently, the morbidity of acute severe hepatitis of unknown origin in children (SHIC) has tended to decrease, but this condition should not be ignored because of its uncertain but severe nature. The current study briefly summarizes updated information regarding the epidemiological, clinical, and etiological aspects of SHIC based on the newest information available. Opinions from pediatricians are also presented. In light of the status quo of SHIC and COVID-19 globally, several suggestions are proposed to improve future studies, which could help to further explore the underlying mechanisms of SHIC in the context of COVID-19.

Apelin (APL), an endogenous ligand for APJ, has been reported to be upregulated in a murine model of acute colitis induced by sodium dextran sulfate, as well as inflammatory bowel diseases (IBD) in humans. However, the mechanisms and functions of APL/APJ axis in the pathogenesis of IBD are unclear. We herein analyzed CD4 + T cells to determine the functions of APL in a murine model of chronic colitis induced in Rag deficient mice (Rag -/- ). In colonic tissues of wild-type mice (WT), we found that APL was expressed especially in the lamina propria lymphocytes, where CD4 + T cells are dominant, rather than the epithelial cells. Unexpectedly, the APL expression was rather downregulated in the colonic tissue of the chronic colitis group compared to the control groups (Rag -/- before colitis induction and WT). The APL expression was downregulated when naïve T cells were differentiated into effecter T cells. A lack of APL resulted in decreased naïve T cells and increased effecter T cells in secondary lymphoid organs. A synthetic APL peptide, [Pyr 1 ]-APL-13, increased IL-10 and decreased IFN-γ productions by effecter T cells. Administration of [Pyr 1 ]-APL-13 improved survival rate in association with lessened colitis severity and decreased pro-inflammatory cytokine production. This is the first report showing immunological function of APL specifically on T cells, and these results indicate that APL/APJ axis may be a novel therapeutic target for IBD., 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 Inc. All rights reserved.)

The stereo-controlled total synthesis of (-)-domoic acid is described. The critical construction of the C1'-C2' Z -configuration was accomplished by taking advantage of an unsaturated lactam structure. The side chain fragment was introduced in the final stages of synthesis through a modified Julia-Kocieński reaction, aiming for its efficient derivatization.

In Japan in 2004, 59 people who had consumed angel-wing mushroom, Pleurocybella porrigens, experienced acute encephalopathy, and of these 17 died. We purified a lethal protein to mice, pleurocybelline (PC), from P. porrigens. Although PC caused no damage to the brain, PC formed a complex with a lectin (PPL) and showed exo-protease activity, degrading substrates from both N- and C-termini. In addition, the presence of an unstable toxic compound, pleurocybellaziridine (PA), in the mushroom was demonstrated. We hypothesized that the complex and PA are involved in disease development and verified that apoptotic cells in the hippocampus were significantly increased by injection of the mixture of PC, PPL, and PA, indicating that these substances might be involved in acute encephalopathy., 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 © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A saline gargle (SG) has proven to be an efficient method of sampling to detect SARS-CoV-2. The aim of this pilot study was to verify the efficiency of SG sampling in detecting the Omicron variant of SARS-CoV-2. Subjects were a total of 68 patients with COVID-19 (Omicron variant), and 167 pairs of samples were collected. A conventional oropharyngeal swab (OPS) was obtained and SG sampling was performed immediately afterward; both were subjected to RT-qPCR. A subgroup analysis of symptomatic and asymptomatic patients was performed. Results revealed no significant differences in the distribution of patients and cycle threshold (CT) values between the SG and OPS in overall data and data on days 1-3, 4-7, and 8-14. The subgroup analysis revealed no significant differences between the SG and OPS results in symptomatic patients. In asymptomatic patients, the CT values for the SG were significantly lower than those for the OPS, implying that SG sampling had better sensitivity in the context of the Omicron variant. These data indicate that the SG had satisfactory efficiency (vs. the OPS). An SG is a simple and less invasive method of sampling that is suited to mass, frequent, and repeated sampling to detect SARS-CoV-2.