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Abstract Background Local recurrence is a major problem after surgery for rectal cancer. Precision of the circumferential resection margin (CRM) has been shown to be an independent predictor of local recurrence. The purpose of this study is to evaluate the usefulness of robotic surgery for defining the CRM. Methods A retrospective cohort study of patients with rectal cancer who underwent radical surgery at Tokushima University Hospital from January 2012 to April 2023 was included in this study to evaluate risk factors for CRM involvement. Short-term outcomes, including CRM rates, as well as long-term outcomes, were compared between patients who had undergone robot-assisted versus laparoscopic surgery following propensity score analysis. Results A total of 223 patients were analyzed in this study. Multivariate analysis demonstrated that lymph node metastasis was the most significant predictive factor for CRM involvement (p = 0.030), and that robot-assisted surgery tended to lead to less CRM involvement (p = 0.085). The CRM involvement rate for robotic and laparoscopic surgery before propensity score matching was 4.7% and 11.7%, respectively. Following propensity score matching, the CRM involvement rate for robotic surgery was 4.5% versus 11.4% for laparoscopic surgery. Disease-free survival (DFS) and overall survival (OS) rates for patients who had undergone robot-assisted and laparoscopic surgery were not significantly different before or after matching (DFS before matching: p = 0.876, DFS after matching: p = 0.805, OS before matching: p = 0.511, OS after matching: p = 0.458). Conclusion Robot-assisted surgery may be useful in defining the CRM for rectal cancer.

We investigated whether soticlestat (TAK-935), a newly discovered cholesterol 24-hydroxylase (CH24H) inhibitor now in phase 3 clinical trials for Dravet and Lennox-Gastaut syndromes, has effects on neurodegeneration in both chronic and acute animal models associated with glutamate hyperexcitation. Soticlestat was administered at doses that approximately halve 24S-hydroxycholesterol in both experiments. In the kainic acid (KA)-induced acute hippocampal degeneration model, soticlestat ameliorated inflammatory cytokine expression, hippocampal degeneration, and memory impairment. We ruled out the possibility that soticlestat directly interferes with KA binding to the KA receptor, or that 24S-hydroxycholesterol modulates KA receptor signaling, by conducting receptor binding and cell death assays. In the PS19 chronic degeneration model of tauopathy, treatment effects were observed in neurodegeneration markers. Notably, there was a significant correlation between the levels of brain 24S-hydroxycholesterol and a proinflammatory cytokine, tumor necrosis factor-α, which is implicated in cognitive decline and lowering of seizure threshold. This is the first study demonstrating that CH24H inhibition can alleviate neurodegeneration concomitant with neuroinflammation. Herein, we discuss the interplay among 24S-hydroxycholesterol production, neuroinflammation, and excitotoxicity. Effects on neurodegeneration and neuroinflammation demonstrated in two preclinical models suggest that soticlestat is effective in ameliorating seizures and addressing cognitive dysfunction in seizure disorders.

Abstract A subset of oropharyngeal squamous cell carcinoma (OPSCC) is caused by the high-risk human papilloma virus (HPV), which expresses p16INK4a immunoreactivity. Dual-color immunofluorescence (IF) analysis of TP53 binding protein-1 (53BP1) and a proliferative indicator, Ki-67, to elucidate genomic instability (GIN) in tumor tissues revealed that abnormal 53BP1 expression is closely associated with carcinogenesis in diverse organs. We have previously demonstrated that the number of 53BP1 nuclear foci (NF) in cervical cells increases with cancer progression. The distribution of 53BP1 NF was similar to that of punctate HPV signals, as determined by in situ hybridization, and the pattern of p16INK4a overexpression. The present study aimed to confirm the type of 53BP1 expression using dual-color IF as an indicator of GIN in oropharyngeal squamous epithelial lesions, including HPV-dependent and -independent OPSCC. This study identified significant differences in the nuclear expression of 53BP1 between benign oropharyngeal epithelial lesions and OPSCC, and between HPV-dependent and HPV-independent OPSCC. We concluded that the incidence of abnormal 53BP1 expression in OPSCC is significantly associated with stage classification and overall survival. Therefore, double IF analysis of 53BP1 and Ki-67 expression may be a useful tool for estimating the malignant potential and prognosis of OPSCC.

Abstract This retrospective study compared postoperative prediction errors of recent formulas using standard- or total keratometry (K or TK) for intraocular lens (IOL) power calculation in post-myopic LASIK patients. It included 56 eyes of 56 patients who underwent uncomplicated cataract surgery, with at least 1-month follow-up at Keio University Hospital in Tokyo or Hayashi Eye Hospital in Yokohama, Japan. Prediction errors, absolute errors, and percentage of eyes with prediction errors within ± 0.25 D, ± 0.50 D, and ± 1.00 D were calculated using nine formulas: Barrett True-K, Barrett True-K TK, Haigis-L, Haigis TK, Pearl-DGS, Hoffer QST, Hoffer QST PK, EVO K, and EVO PK. Statistical comparisons utilized Friedman test, Conover’s all-pairs post-hoc, Cochran’s Q, and McNemar post-hoc testing. Root-Mean-Square Error (RMSE) was compared with heteroscedastic testing. Barrett True-K TK had the lowest median predicted refractive error (-0.01). EVO PK had the smallest median absolute error (0.20). EVO PK had the highest percentage of eyes within ± 0.25 D of the predicted value (58.9%), significantly better than Haigis-L (p = 0.047). EVO PK had the lowest mean RMSE value (0.499). The EVO PK formula yielded the most accurate IOL power calculation in post-myopic LASIK eyes, with TK/PK values enhancing accuracy.

Abstract This systematic review focused on the benefits of invasive alien plant species (IAPS) for human well-being. It examines the intellectual structure of knowledge of these benefits to identify knowledge gaps for future research and explore sustainable management practices to manage IAPS. The screening of bibliometric data from 1601 publications in Scopus based on the PRISMA protocol resulted in the identification of 69 publications for detailed review. The findings show an increasing trend in studies on IAPS benefits for human well-being since 2009. These benefits include provisioning services (food, medicines, fodder, bioenergy, and construction materials), regulating services (bioagents and shades), cultural services (aesthetics and ornamentals) and supporting services (soil and land reclamation). Additionally, the findings reveal geographical disparity in the distribution of research produced by researchers from different regions, with most research produced in Europe and limited to Africa, the Americas, and Oceania. The findings also show skewness in the management practices of IAPS, though some of them enhance IAPS benefits. Furthermore, there are limited applications of interdisciplinary approaches to investigate the benefits of IAPS for human well-being. Employing interdisciplinary mixed methodologies may help to generate new knowledge with a better understanding of complex interactions between IAPS and human well-being. Given the unique sociocultural, economic, and ecological settings of the IAPS, future research is expected to include comparative perspectives on how different countries and regions use the IAPS for their benefit while considering both the positive and negative impacts of the IAPS on human well-being to develop sustainable management practices.

Abstract Seismological observations indicate the presence of chemical heterogeneities at the lowermost mantle, just above the core–mantle boundary (CMB), sparking debate over their origins. A plausible explanation for the enigmatic seismic wave velocities observed in ultra-low-velocity zones (ULVZs) is the process of iron enrichment from the core to the silicate mantle. However, traditional models based on diffusion of atoms and penetration of molten iron fail to account for the significant iron enrichment observed in ULVZs. Here, we show that the chemical reaction between silicate bridgmanite and iron under hydrous conditions leads to profound iron enrichment within silicate, a process not seen in anhydrous conditions. Our findings suggest that the interaction between the core and mantle facilitates deep iron enrichment over a few kilometres at the bottom of the mantle when water is present. We propose that the seismic signatures observed in ULVZs indicate whole mantle convection, accompanied by deep water cycles from the crust to the core through Earth’s history.

Abstract Exercise capacity is a strong independent predictor of cardiovascular and all-cause mortality. The utilization of well-established submaximal tests of exercise capacity such as the 6-min walk test (6MWT), 3-min step test (3MST) and 10-chair rise test (10CRT) in the community would improve patient care but requires remote monitoring technology. Consumer grade smartwatches provide such an opportunity, however, their accuracy in measuring physiological responses to these tests is unclear. The aim of this study was to determine the accuracy of consumer grade smartwatches in assessing exercise capacity to develop a framework for remote, unsupervised testing. 16 healthy adults (7 male (44%), age median 27 [interquartile range (IQR) 26,29] years) performed 6MWTs using two protocols: (1) standard—straight 30 m laps (6MWT-standard) and 2) continuous lap—circular 240 m laps around a park (6MWT-continuous lap), 3MSTs and 10CRTs. Each one of these four tests was performed three times across two clinic visits. Each participant was fitted with a Garmin Vivoactive4 and Fitbit Sense smartwatch to measure three parameters: distance, step counts and heart rate (HR) response. Reference measures were a meter-wheel, hand tally counter and ECG, respectively. Mean HR was measured at rest, peak exercise and recovery. Agreement was measured using Bland–Altman analysis for repeated measures and summarized as median absolute percentage errors (MAPE). Distance during 6MWT-continuous lap had better agreement than during 6MWT-standard for both Garmin (MAPE: 6.4% [3.0, 10.4%] versus 20.1% [13.9, 28.4%], p

Abstract Punishment serves as a balancing force that dissuades people from acting selfishly, which complements cooperation as an essential characteristic for the prosperity of human societies. Past studies using economic games with two options (cooperation and defection) reported that cooperation decisions are generally faster than defection decisions and that time pressure possibly induces human players to be more intuitive and thus cooperative. However, it is unclear where punishment decisions sit on this time spectrum. Therefore, we recruited human players and implemented two series of online network games with cooperation, defection, and punishment options. First, we find that punishment decisions are slower than cooperation or defection decisions across both game series. Second, we find that imposing experimental time pressure on in-game decisions neither reduces nor increases the frequency of punishment decisions, suggesting that time pressure may not directly interact with the mechanisms that drive players to choose to punish.

Manidipine (MP) is widely used for reducing high blood pressure. Calslot® (CALS) tablets, which are the original MP medicines, and their generic medicines have been used for patients in clinical situations. The authors hypothesized that the photodegradability of MP drug substance in CALS tablets might be enhanced when the tablets were photo-exposed after the change of the dosage form by the presence of riboflavin (RF), which is utilized as a coloring agent and a well-known photosensitizer. The present study clarified that RF enhanced the photodegradation of MP when the powders and the suspensions of CALS tablets were ultraviolet light (UV) irradiated. The addition of RF to the suspension of MP standard substances also promoted MP photodegradation along with the increase of the generation rate of its main photoproduct, benzophenone. Finally, the authors performed the photostabilization of MP suspensions based on the addition of quercetin (QU), which is one of polyphenols and has both the antioxidative potency and the UV filtering potency. It is summarized that QU has a protective potency for MP’s own photodegradation, and it partially suppresses the photocatalytic effect of RF. Further studies focused on the photochemical behaviors of utilized additives for medicines are needed for their safe use.

Abstract Previous studies have shown that rapid on-site evaluation (ROSE) improves the diagnostic yield of bronchoscopy using endobronchial ultrasound with a guide sheath (EBUS-GS) for peripheral pulmonary lesions (PPL). While ROSE of imprint cytology from forceps biopsy has been widely discussed, there are few reports on ROSE of brush cytology. This study investigated the utility of ROSE of brush cytology during bronchoscopy. We retrospectively analyzed data from 214 patients who underwent bronchoscopy with EBUS-GS for PPL. The patients in the ROSE group had significantly higher diagnostic sensitivity through the entire bronchoscopy process than in the non-ROSE group (96.8% vs. 83.3%, P = 0.002). The use of ROSE significantly increased the sensitivity of brush cytology with Papanicolaou staining (92.9% vs. 75.0%, P

Abstract Background Long-term deterioration in the mental health of healthcare workers (HCWs) has been reported during and after the COVID-19 pandemic. Determining the impact of COVID-19 incidence and mortality rates on the mental health of HCWs is essential to prepare for potential new pandemics. This study aimed to investigate the association of COVID-19 incidence and mortality rates with depressive symptoms over 2 years among HCWs in 20 countries during and after the COVID-19 pandemic. Methods This was a multi-country serial cross-sectional study using data from the first and second survey waves of the COVID-19 HEalth caRe wOrkErS (HEROES) global study. The HEROES study prospectively collected data from HCWs at various health facilities. The target population included HCWs with both clinical and non-clinical roles. In most countries, healthcare centers were recruited based on convenience sampling. As an independent variable, daily COVID-19 incidence and mortality rates were calculated using confirmed cases and deaths reported by Johns Hopkins University. These rates represent the average for the 7 days preceding the participants’ response date. The primary outcome was depressive symptoms, assessed by the Patient Health Questionnaire-9. A multilevel linear mixed model (LMM) was conducted to investigate the association of depressive symptoms with the average incidence and mortality rates. Results A total of 32,223 responses from the participants who responded to all measures used in this study on either the first or second survey, and on both the first and second surveys in 20 countries were included in the analysis. The mean age was 40.1 (SD = 11.1), and 23,619 responses (73.3%) were from females. The 9323 responses (28.9%) were nurses and 9119 (28.3%) were physicians. LMM showed that the incidence rate was significantly and positively associated with depressive symptoms (coefficient = 0.008, standard error 0.003, p = 0.003). The mortality rate was significantly and positively associated with depressive symptoms (coefficient = 0.049, se = 0.020, p = 0.017). Conclusions This is the first study to show an association between COVID-19 incidence and mortality rates with depressive symptoms among HCWs during the first 2 years of the outbreak in multiple countries. This study’s findings indicate that additional mental health support for HCWs was needed when the COVID-19 incidence and mortality rates increase during and after the early phase of the pandemic, and these findings may apply to future pandemics. Trial registration Clinicaltrials.gov, NCT04352634.

Abstract Background Nonresectable gastric cancer develops rapidly; thus, monitoring disease progression especially in patients receiving nivolumab as late-line therapy is important. Biomarkers may facilitate the evaluation of nivolumab treatment response. Herein, we assessed the utility of serum-based inflammatory indicators for evaluating tumor response to nivolumab. Methods This multicenter retrospective cohort study included 111 patients treated with nivolumab monotherapy for nonresectable advanced or recurrent gastric cancer from October 2017 to October 2021. We measured changes in the C-reactive protein (CRP)-to-albumin ratio (CAR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) in serum from baseline to after the fourth administration of nivolumab. Furthermore, we calculated the area under the receiver operating characteristic curves (AUC ROCs) for CAR, PLR, and NLR to identify the optimal cutoff values for treatment response. We also investigated the relationship between clinicopathologic factors and disease control (complete response, partial response, and stable disease) using the chi-squared test. Results The overall response rate (complete and partial response) was 11.7%, and the disease control rate was 44.1%. The median overall survival (OS) was 14.0 (95% CI 10.7‒19.2) months, and the median progression-free survival (PFS) was 4.1 (95% CI 3.0‒5.9) months. The AUC ROCs for CAR, PLR, and NLR before nivolumab monotherapy for patients with progressive disease (PD) were 0.574 (95% CI, 0.461‒0.687), 0.528 (95% CI, 0.418‒0.637), and 0.511 (95% CI, 0.401‒0.620), respectively. The values for changes in CAR, PLR, and NLR were 0.766 (95% CI, 0.666‒0.865), 0.707 (95% CI, 0.607‒0.807), and 0.660 (95% CI 0.556‒0.765), respectively. The cutoff values for the treatment response were 3.0, 1.3, and 1.4 for CAR, PLR, and NLR, respectively. The PFS and OS were significantly longer when the treatment response values for changes in CAR, PLR, and NLR were below these cutoff values (CAR: OS, p

Abstract Objective This study validates a direct multiplex real-time reverse transcription polymerase chain reaction (rRT-PCR) assay which was previously established for enabling rapid and simultaneous detection of African swine fever (ASF) virus (ASFV) and classical swine fever virus. The assay eliminates the need for viral nucleic acid purification using a buffer system for crude extraction and an impurity-tolerant enzyme. However, the assay had not yet been validated using field samples of ASFV-infected pigs. Therefore, to address this gap, we tested 101 samples collected from pigs in Vietnam during 2018 and 2021 for validation. Results The rRT-PCR assay demonstrated a diagnostic sensitivity of 98.8% and a specificity of 100%. Remarkably, crude samples yielded results comparable to those of purified samples, indicating the feasibility of using crude samples without compromising accuracy in ASFV detection. Our findings emphasize the effectiveness of the rRT-PCR assay for the prompt and accurate diagnosis of both swine fever viruses, which is essential for effective disease prevention and control in swine populations.

Sozo Kurahashi's (1882-1955) theories, formed from his profound respect for children, have influenced Japanese early childhood education and care (ECEC) practitioners for a long time. They also have influenced the national ECEC curriculum in Japan, which emphasizes the need for a rich environment where children can actively learn and play rather than being led by an adult. However, the uniqueness of Kurahashi's ECEC philosophy is not limited to the learning environment. More than his methods and theories, Kurahashi's spirit of education and care has supported the daily work of many Japanese practitioners to this day. In this article, the author highlights Kurahashi's originality and spirit through a reinterpretation of his kindergarten practice from nearly a century ago and offers fresh insight applicable to the future of ECEC.