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Sampling reference data is crucial in machine learning potential (MLP) construction. Inadequate coverage of local configurations in reference data may lead to unphysical behaviors in MLP-based molecular dynamics (MLP-MD) simulations. To address this problem, this study proposes a new on-the-fly reference data sampling method called radial distribution function (RDF)-based data sampling for MLP construction. This method detects and extracts anomalous structures from the trajectories of MLP-MD simulations by focusing on the shapes of RDFs. The detected structures are added to the reference data to improve the accuracy of the MLP. This method allows us to realize a reasonable MLP construction for liquid water with minimal additional data. We prepare data from an H 2 O molecular cluster system and verify whether the constructed MLPs are practical for bulk water systems. MLP-MD simulations without RDF-based data sampling show unphysical behaviors, such as atomic collisions. In contrast, after applying this method, we obtain MLP-MD trajectories with features, such as RDF shapes and angle distributions, that are comparable to those of ab initio MD simulations. Our simulation results demonstrate that the RDF-based data sampling approach is useful for constructing MLPs that are robust to extrapolations from molecular cluster systems to bulk systems without any specialized know-how., (© 2024 The Author(s). Journal of Computational Chemistry published by Wiley Periodicals LLC.)

Enantioenrichment of amino acids is essential during the early chemical evolution leading to the origin of life. However, the detailed molecular mechanisms remain unsolved. Dimerization of enantiomers is the first molecular process in the nucleation of deposition and crystallization, which are both essential for enantioenrichment. Here, we report the enantioselective interactions of dimers of chiral intermediates, i.e. , aminonitriles, in both gas and water environments based on density functional theory (DFT) and more accurate coupled-cluster (CC) calculations. We show that all the aminonitriles stabilize the homochiral dimer preferentially to the heterochiral dimer in the gas phase, while this trend was not observed in water. The energies of the enantioselective interactions in aminonitriles are substantially lower compared to those in amino acids, especially isovaline. These results suggest that prebiotic enhancements of enantiomeric excess are more likely to occur in amino acids than in the aminonitrile intermediates.

Thalamic pain can be understood as a network reorganization disorder. This study aimed to investigate functional connectivity (FC) in human patients and a macaque model of thalamic pain. In humans, resting-state FC was compared between patients with thalamic pain and healthy individuals. Furthermore, resting-state FC was compared in macaques, before and after the induction of thalamic pain in the same individuals. FC between the amygdala of the unaffected hemisphere and the brainstem was significantly higher in patients with thalamic pain. More specifically, a significantly higher FC was observed between the basolateral amygdala and the ventral tegmental area, which also significantly predicted the value of a visual analog scale of pain intensity in individual patients. The macaque model of thalamic pain also exhibited a significantly higher FC between the amygdala of the unaffected hemisphere and the brainstem, particularly between the basolateral amygdala and the midbrain. Furthermore, the previously reported significantly higher FC between the amygdala and the mediodorsal nucleus of the thalamus in macaques with thalamic pain was also reproduced in the human patients. Therefore, the present results suggest that the FC changes in the regions associated with emotion, memory, motivation, and reward are part of the underlying mechanisms of thalamic pain onset present in both human patients and model macaques. This cross-species convergence provides new insights into the neurological mechanisms underlying thalamic pain, paving the way for further studies and the development of therapeutic strategies. PERSPECTIVE: This article presents that the FC changes in the regions associated with emotion, motivation, and reward are part of the underlying mechanisms of thalamic pain in humans and macaques., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Open thoracic aortic surgery is believed to necessitate more intensive rehabilitation. This study aimed to compare the progress of postoperative rehabilitation between standard and delayed mobilization. A retrospective review was conducted on 199 patients who underwent isolated total aortic arch replacement via median sternotomy. Cases of in-hospital mortality and postoperative stroke were excluded. Based on the current guidelines for cardiovascular rehabilitation of the Japanese Circulation Society, patients were categorized into standard mobilization (could sit on the edge of bed within 2 days) and delayed mobilization (could not do so) groups. Rehabilitation progress was compared among both groups. Initial mobilization was delayed in 100 patients (delayed mobilization group), primarily because of respiratory failure (46.0%). Preoperative risk characteristics, including EuroSCORE II (median, 2.9 versus 3.5), were similar between the standard and delayed mobilization groups. The delayed mobilization group had longer operation (median, 6.1 versus 8.0 hours, P < 0.001) and cardiopulmonary bypass (median, 3.2 versus 4.1 hours, P < 0.001) times. Independent ambulation occurred earlier in the standard mobilization group (median, 6.0 versus 8.0 days, P < 0.001).In conclusion, early initiation of sitting on the edge of the bed within 2 days was associated with earlier independent ambulation during postoperative rehabilitation, which supports the current guidelines. Longer operation and cardiopulmonary bypass times were associated with delayed mobilization initiation, suggesting the need for more tailored approaches in such cases.

Background and study aims Endoscopic sphincterotomy can be challenging especially in patients with surgically altered anatomy. Although a rotatable sphincterotome (r-sphincterotome) may be useful, its rotational function is often inadequate. We evaluated the feasibility of a newly designed r-sphincterotome equipped with a well-conceived cutting wire. Methods We measured the movement and dynamics of both the newly designed r-sphincterotome and two existing r-sphincterotomes using in-house equipment. Ideally, the rotational force exerted at the proximal end should transmit directly to the distal end. But it is often challenging, particularly within the constraints of a bent endoscope and working channel. We collected data regarding deviation from the ideal value 10 times for each sphincterotome. Results The deviation from the ideal value was significantly lower with the newly designed r-sphincterotome than with the conventional r-sphincterotomes (44.9 ± 27.8 vs. 73.7 ± 44.6 and 130.1 ± 71.4 degrees, respectively; P < 0.001). The newly designed r-sphincterotome rotated smoothly and consistently at a constant speed, mirroring the input rotation. Conclusions We evaluated the feasibility of the newly designed r-sphincterotome using an experimental model. We believe that the findings from these experiments may contribute to easier and more precise sphincterotomies., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objective: Numerous studies have reported that corrective surgery improves postoperative health-related quality of life (HRQOL) in patients with adult spinal deformity (ASD), and postoperative HRQOL is maintained over 5-year follow-up. However, few studies have investigated factors associated with mid-term patient satisfaction. This study aimed to examine the factors contributing to 5-year patient satisfaction in patients with ASD following corrective surgery., Methods: This study included 51 patients who underwent corrective surgery and were followed up for > 5 years postoperatively. We investigated radiographic parameters and patient-reported outcomes using the Scoliosis Research Society 22r (SRS-22r) questionnaire and 36-item Short-Form Health Survey (SF-36) preoperatively and at two postoperative time points: two years (PO2Y) and five years (PO5Y). Spearman's rank correlation analysis was used to assess the relationship between patient satisfaction at PO5Y and both radiographic parameters and HRQOL scores at PO2Y and PO5Y. Correlation between patient satisfaction at PO5Y and improvement of both radiographic parameters and HRQOL scores were also assessed., Results: Patient satisfaction at PO5Y was significantly correlated with thoracic kyphosis, thoracolumbar kyphosis, and the distance between the C7-plumb line and the center of the sacral vertical line at PO2Y and PO5Y. Notably, the improvement of the function and social function domains of the SRS-22r and the SF-36, respectively, both at PO2Y and PO5Y, demonstrated a significantly weak correlation with patient satisfaction at PO5Y., Conclusion: These findings underscore the significance of functional and social function improvements following corrective surgery, as they contribute to higher levels of satisfaction among patients with ASD., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no conflict of interest. Ethical approval: The study protocol was approved by the institutional review board of Osaka City General Hospital (number 1305011)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Aplastic anemia (AA) is a life-threatening disease, and drug-induced AA is rare. Recently, studies on cases that possibly developed AA following osimertinib treatment have been conducted. This study evaluated the association of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including osimertinib, with AA and characterized such registered patients using a large spontaneous adverse event reporting database., Materials and Methods: Data from the Food and Drug Administration's Adverse Event Reporting System spanning from the first quarter of 2015 to the second quarter of 2023 were used. Disproportionality analyses with reporting odds ratio (ROR) and information component (IC) were performed for signal detection. Furthermore, we described a case series of patients who experienced AA during osimertinib treatment., Results: A signal was detected with osimertinib (ROR: 4.16, 95% confidence interval (CI): 2.54 - 6.80; IC: 1.80, 95% CI: 1.10 - 2.51); however, no signals were detected with other EGFR-TKIs. 16 individuals treated with osimertinib had AA, of whom 14 (87.5%) were registered as suspected drugs. The median age of these individuals was 70.5 years (interquartile range (IQR), 64.8 - 78.3 years), with varying time to onset (IQR, 4 - 210 days) and outcomes, including 3 (18.8%) deaths., Conclusion: Our analyses generated a safety signal for the association between osimertinib and AA. Further studies are required to understand and confirm the role of osimertinib administration in the development of AA.

Purpose: To investigate the incidence of microbial keratitis among Japanese patients wearing orthokeratology (ortho-k) lenses STUDY DESIGN: Retrospective multicenter study METHOD: This study was conducted at 4 hospitals in Japan and involved 1438 patients who had been prescribed ortho-k lenses and had worn them for at least 3 months. Data on patient demographics, lens characteristics, lens care systems, and presence of microbial keratitis were extracted from the medical records. Duration of ortho-k lens wear was calculated from the original fitting date to the patient's last visit, with the total years of lens wear used as person-years of lens wear. The incidence of microbial keratitis was calculated by dividing the number of infected cases by the total person-years of lens wear for all enrolled participants., Results: Among the 1438 patients, 753 were male and 685 were female, with a mean age of 12.7 ± 5.4 years. The mean duration of ortho-k lens wear was 5.2 ± 4.5 years, and the mean lens power was -3.52 ± 1.41 D. The total person-years of lens wear for all enrolled patients was 7415. Four cases of microbial keratitis were identified, resulting in an overall incidence of microbial keratitis of 5.4 (95% CI: 1.0-9.8) per 10,000 patient-years among ortho-k lens wearers., Conclusion: This study represents the largest sample size to date for estimating the incidence of microbial keratitis associated with ortho-k lenses. The incidence was similar to or slightly lower than that of previous studies on ortho-k-related microbial keratitis and also comparable to that of daily wear soft contact lenses., Competing Interests: Declarations Conflict of interest T. Hiraoka, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (Topcon, SEED, Menicon, Johnson & Johnson, Alpha corporation, Alcon, Santen, Senju); S. Matsumura, Consulting fees (Cooper Vision), Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (Menicon, Cooper Vision, Santen, Welch Allyn, Nikon, Senju, Ophtecs); Y. Hori, Grants or contracts to the author’s institution (Alcon, Novoxel), Consulting fees (Cooper Vision), Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (Santen, Senju, Johnson & Johnson, Menicon, Ophtecs, Alcon, Lumenis, HOYA); K. Kamiya, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (Alcon, Johnson & Johnson, STAAR Surgical, HOYA, ZEISS, Santen, Senju, Otsuka, Kowa, Nikon, SEED, Cooper Vision); K. Miyata, None; T. Oshika, Consulting fees (Santen, Alcon, HOYA, Johnson & Johnson), Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (Topcon, HOYA, TOMEY, Johnson & Johnson, Novartis, Alcon, Santen, Senju)., (© 2024. Japanese Ophthalmological Society.)

Artepillin C is a diprenylated phenylpropanoid with various pharmacological benefits for human health. Its natural occurrence is limited to a few Asteraceae plants, such as Baccharis species, necessitating a stable supply through synthetic biology. In Saccharomyces cerevisiae , the utilization of aromatic substrates within the cell was limited, resulting in very low production of artepillin C. In this study, we used AcPT1, a p -coumaric acid ( p -CA)-specific diprenyltransferase, in Komagataella phaffii to produce artepillin C. Detailed studies revealed that the critical bottleneck in K. phaffii was the supply of prenyl diphosphates, not phenylpropanoid flux. By enhancing the prenyl substrate pathway through overexpression of isopentenyl diphosphate isomerase and a truncated HMG-CoA reductase, we achieved a strong increase in artepillin C production. A major part of artepillin C was accumulated in yeast cells. One of the advantages of K. phaffii is its superior growth and ability to achieve high cell density cultivation compared to that of S. cerevisiae . Therefore, fed-batch cultivation with glycerol was performed. As a result, the dry cell weight (DCW) reached 61.0 g/L, and the intracellular amount of de novo produced artepillin C reached 187.3 μg/DCW. Analysis of intermediates revealed that the supply of p -CA constituted a bottleneck in artepillin C production in the engineered strain. By enhancing the p -CA supply, the intracellular accumulation of artepillin C reached 1200 μg/DCW even in batch cultivation. Moreover, the total intra- and extracellular amounts of artepillin C reached 12.5 mg/L, marking the highest de novo synthesis amount of artepillin C reported thus far, even under batch cultivation conditions.

Background/objectives: On-site diagnosis of infection in their early stages requires assays with high sensitivities that are compact and easy to operate out of the laboratory and hospital environments. However, current assay technologies fall short of these requirements and require highly skilled technicians to set up, operate, and interpret the results., Methods: To address these challenges, we developed and evaluated a Point-of-Care-Testing (PoCT) immunoassay platform called the D-strip. The D-strip platform combines the capabilities of a digital enzyme-linked immunoassay (ELISA) with a lateral flow assay (LFA). The D-strip sample flow cell is composed of the same components found in conventional LFAs, and its high sensitivity is due to its efficient implementation of ELISA. The fully integrated platform is simple and requires minimal user intervention to operate., Results: The D-strip exhibited a sample-to-result time of 15 min with a limit of detection (LOD) of 1.7 × 10 3 copies/mL for severe acute respiratory syndrome coronavirus 2 (SARS-2-CoV) antigen. The LOD of the D-strip is 488-fold higher than that for conventional LFAs and is comparable to a clinical laboratory test., Conclusions: The D-strip is a compact and highly sensitive immunoassay platform with a strong potential for application as a confirmatory assay outside the clinical laboratory.

Background: This study aimed to assess the feasibility and safety of a problem-solving exercise program based on the items in the short physical performance battery (SPPB) for older patients with chronic respiratory diseases (CRDs) to inform future randomized controlled trials., Methods: This was a multicenter, prospective, non-randomized feasibility study. Participants with CRD received an enhancement program based on the SPPB decline items (balance, walk, and/or chair stand) for 4 weeks. The feasibility, safety, and efficacy of the problem-solving exercise program in improving the SPPB score, physical function, and step count (measured using a pedometer) were assessed., Results: Overall, 36 patients were enrolled in this study, and adherence to the exercise program was high (100%). No exercise program-related adverse events were observed. The implementation of the exercise program ranged from 70 to 100%. The mean daily step count increased from 2152 ± 1498 steps during the first week to 2899 ± 1865 steps in the last week (p<0.01). Additionally, the SPPB total score increased from 8.9 ± 1.8 points to 10.7 ± 1.3 points at the end of the program (p<0.001)., Conclusions: The problem-solving exercise program based on SPPB is feasible and safe for older patients with CRDs. However, the effectiveness of this exercise program should be validated in large-scale, randomized-controlled trials in the future., Trial Registration: University Hospital Medical Information Network Center (UMIN-CTR) UMIN: approval number: UMIN000048761., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Rikkunshito (RKT), a traditional Japanese medicine, can relieve epigastric discomfort and anorexia in patients with functional dyspepsia. RKT enhances the orexigenic hormone, ghrelin. Ghrelin regulates food motivation by stimulating the appetite control center in the hypothalamus and the brain mesolimbic dopaminergic pathway (MDPW). However, the effect of RKT on MDPW remains unclear. Here, we aimed to investigate the central neural mechanisms underlying the orexigenic effects of RKT, focusing on the MDPW., Methods: We examined the effects of RKT on food intake and neuronal c-Fos expression in restraint stress- and cholecystokinin octapeptide-induced anorexia in male rats., Key Results: RKT treatment significantly restored stress- and cholecystokinin octapeptide-induced decreased food intake. RKT increased c-Fos expression in the ventral tegmental area (VTA), especially in tyrosine hydroxylase-immunoreactive neurons, and nucleus accumbens (NAc). The effects of RKT were suppressed by the ghrelin receptor antagonist [D-Lys 3 ]-GHRP-6. RKT increased the number of c-Fos/orexin-double-positive neurons in the lateral hypothalamus (LH), which project to the VTA. The orexin receptor antagonist, SB334867, suppressed RKT-induced increase in food intake and c-Fos expression in the LH, VTA, and NAc. RKT increased c-Fos expression in the arcuate nucleus and nucleus of the solitary tract of the medulla, which was inhibited by [D-Lys 3 ]-GHRP-6., Conclusions & Inferences: RKT may restore appetite in subjects with anorexia through ghrelin- and orexin-dependent activation of neurons regulating the brain appetite control network, including the hypothalamus and MDPW., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Aim: We aimed to determine whether baseline high-density lipoprotein (HDL) cholesterol efflux capacity (CEC) at the time of coronary angiography (CAG) could serve as a prognostic marker for future major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) through a systematic review and meta-analysis., Methods: The MEDLINE, Cochrane, and Embase databases were used for data collection. As of April 2024, 2,871 studies have been identified. Clinical studies comparing MACEs over an observational interval exceeding 12 months in patients with angiographically defined CAD with estimated hazard ratios (HRs) of MACEs in the higher or top-quartile HDL-CEC (H-HDL-CEC) group compared with the lower or bottom-quartile HDL-CEC (L-HDL-CEC) group, after adjusting for six confounding variables, including HDL-C, were included. HRs of 1) overall cardiovascular outcomes, composite of cardiovascular mortality, myocardial infarction, any coronary revascularization, and all-cause mortality (Model-1), and 2) cardiovascular outcomes excluding all-cause mortality from Model-1 (Model-2), compared between the L-HDL-CEC and H-HDL-CEC groups, were estimated using a random-effects model, respectively., Results: In five studies, 5,725 patients with CAD with a mean observational interval of 4.9 years were included. The H-HDL-CEC group had significantly lower risks for both estimates (Model-1: HR: 0.34, 95% confidence interval [CI]: 0.18-0.63 [p=0.0005], and I 2 =59.8% [p=0.04]; Model-2: HR: 0.28, 95% CI: 0.13-0.60 [p=0.0013], and I 2 =64% [p=0.04])., Conclusion: This is the first systematic review and meta-analysis to demonstrate a significant inverse relationship between the baseline HDL-CECs on CAG and long-term MACEs in CAD patients.

The photochemical reactivity of 1-bromo-2-oxo-1,2-dihydronaphthalene-1-carboxylates (BODNs) was demonstrated. They are inert in the dark under physiological conditions but become active as brominating reagents for tyrosine modification under visible light irradiation in the presence of a photocatalyst. The BODNs can be applied to protein labeling with bromo groups as sensitive mass tags.

Competing Interests: Disclosures The authors have no conflicts of interest to disclose.

Protein immobilization using water-soluble ionic metal-organic polyhedra (MOPs) acting as porous spacers has recently been demonstrated as a potent strategy for the preparation of biocatalysts. In this article, we describe a mixed-protein approach to achieve biocomposites with adjustable enzyme contents and excellent immobilization efficiencies, in a systematic and well-controlled manner. Self-assembly of either cationic or anionic MOPs with bovine serum albumin or egg white lysozyme combined with enzymes (alkaline phosphatase, laccase or cytochrome c) led to solid-state catalysts with a high retention of enzyme activity. Furthermore, for all these systems, the dilution of enzymes within the solid-state composite led to noticeably improved catalytic performances, with both higher specific activity and affinity for substrate.

Background: Although the prognosis of follicular lymphoma (FL) has improved, some patients experience early disease progression, including progression of disease within 24 months (POD24). Histological transformation is a critical event in FL. However, the heterogeneity of FL tumors makes it challenging to diagnose transformation accurately. We retrospectively applied the clinical transformation criteria used for FL transformation assessments at relapse or disease progression to conduct transformation assessments before the initial immunochemotherapy., Methods: Sixty-six FL patients who first received immunochemotherapy between January 2009 and February 2023 at our institution were selected. Twenty-three were clinical-transformation-positive (CLT+)., Results: The progression-free survival (PFS) rate of the CLT+ patients was significantly lower than that of the clinical-transformation-negative (CLT-) patients. In the POD24 assessment subgroup, the CLT+ patients had a higher incidence of POD24 than the CLT- patients. There was no significant difference in PFS between the patients treated with CHOP-like regimens and those treated with bendamustine regimens. In the CHOP-like group, the CLT+ patients exhibited significantly lower PFS than the CLT- patients. In the bendamustine group, the clinical transformation did not affect PFS., Conclusion: Clinical transformation criteria may be useful for the prognostic stratification of FL prior to immunochemotherapy. Additionally, they may serve as predictors of POD24.

Background: Although several reports have compared the outcomes of self-expandable metallic stent (SEMSs) and transanal decompression tube (TDT) placement for malignant colorectal obstruction (MCO), few studies have compared the radiation exposure (RE) associated with these two procedures. Consequently, we aimed to compare the RE of SEMS and TDT placements for MCO using propensity score matching (PSM) in a multi-center, prospective observational study. Methods: This study investigated the clinical data of 236 patients who underwent SEMS or TDT placement. The air kerma at the patient entrance reference point (K a,r : mGy) and air kerma-area product (P KA ; Gycm 2 ) were measured and compared between SEMS and TDT groups after PSM. Results: After PSM, 61 patients were identified in each group. The median K a,r in the SEMS group was significantly greater than that in the TDT group (77.4 vs. 55.6 mGy; p = 0.025) across the entire cohort. With respect to subgroup analyses by location, in the rectum, the median K a, r and P KA were significantly greater in the SEMS group than in the TDT group (172.9 vs. 34.6 mGy; p = 0.001; and 46.0 vs. 18.1 Gycm 2 ; p = 0.006, respectively). However, in the colon, the RE parameters did not significantly differ between the two groups. Conclusions: TDT might be a more suitable option for decompression in patients with malignant rectal obstruction due to its lower RE and technical advantages. Conversely, SEMS placement is recommended as the first decompression method to treat malignant colonic obstruction, in line with the current guidelines.

Aims: This study aimed to investigate the association between the time to achieve walkability after cardiac surgery and the risk of cardiovascular disease after hospital discharge., Methods: We conducted a prospective cohort study involving 553 ambulatory patients aged 71.5 (range, 64.0-77.0) years who underwent cardiac surgery. All patients were divided into five groups based on the time to achieve walkability ≥100 m within 1, 2, 3, 4 or 5 days after cardiac surgery. We examined the risk of post-cardiovascular disease outcomes, including readmission due to heart failure, ischaemic heart disease and other cardiovascular disease, according to the time to achieve walkability with reference to 5 days using the Fine and Gray regression model, considering competing risks., Results: In the survival curve analysis, we examined the time to experience post-cardiovascular disease incidence after hospital discharge. During a median of 3.3 years of follow-up, 118 patients developed cardiovascular disease. We observed a positive association between the time to achieve walkability and cardiovascular disease risk, particularly heart failure. The multivariate hazard ratios (95% confidence intervals) for heart failure readmission were N/A (not assessed due to the sample size being too small) for 1 day, 0.31 (0.10-0.99) for 2 days, 0.60 (0.21-1.79) for 3 days and 0.76 (0.22-2.72) for 4 days (P for trend = 0.032)., Conclusions: The shorter walkability achievement time was associated with a lower risk of cardiovascular diseases, more specifically heart failure readmission, among patients who underwent cardiac surgery. The time required to achieve walkability is a useful predictor for cardiovascular diseases after hospital discharge., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: To evaluate the organ-specific therapeutic effect of enfortumab vedotin (EV) after chemotherapy and immunotherapy failed for advanced urothelial carcinoma., Materials Methods: At 6 institutions between December 2021 and July 2023, we retrospectively analyzed patients with metastatic upper and lower urinary tract cancer who received EV monotherapy after platinum-based chemotherapy and immune checkpoint blockade therapy. Objective response rate (ORR) and organ-specific response rate (OSRR) were evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1., Results: This study analyzed 58 patients with 210 tumor lesions, of which 24% were females and 48% had upper urinary tract cancer. The ORR and disease control rate were 53.5% and 74.1%. Moreover, we found 15 target lesions in the primary site, 7 in local recurrence, 93 in the lymph nodes, 46 in the lung, 29 in the liver, and 20 in the bone, with OSRRs of 40%, 71.4%, 61.1%, 70.6%, 90.9%, and 18.2%, respectively. Over time from baseline, the reduction rate (median) in tumor burden was 50% or more in the lymph node, lung, and liver metastases., Conclusion: The organ-specific tumor response to EV in patients with metastatic urothelial carcinoma was almost favorable. The antitumor activity of EV monotherapy may be less in bone metastasis than in other organ sites. Conversely, EV showed remarkably high efficacy against liver metastasis., Competing Interests: Disclosure The authors declare that they have no competing interests in relation to this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To assess the incidence of postoperative shoulder imbalance (PSI) following posterior spinal fusion surgeries in adolescent idiopathic scoliosis (AIS) with Lenke2 and calculate the risk factors for PSI., Methods: Sixty patients who underwent surgery for Lenke2 AIS with more than 2-year follow-up were selected. Radiographic parameters were measured before and after surgery, and at the latest follow-up. The patients were divided into PSI and non-PSI groups, with PSI defined as a radiographic shoulder height >15 mm on postoperative radiography. The factors were compared between the PSI and non-PSI groups using the Mann-Whitney U test or chi-squared test. Finally, explanatory variables were chosen for multivariate analysis based on previous studies., Results: The PSI group comprised 17 patients. Most PSI cases spontaneously improved, and four patients (6.7%) showed PSI at the final follow-up. Univariate analysis indicated significant differences between postoperative T1 tilt (9.00 ± 5.17 vs. 5.67 ± 4.02, P = 0.029), UIV tilt (1.94 ± 4.49 vs. -1.00 ± 5.04, P = 0.039), and ΔT1 tilt (4.82 ± 3.99 vs. 2.12 ± 3.77, P = 0.026). Multivariate logistic regression analysis indicated that ΔT1 tilt had a significant positive relationship with PSI occurrence (coefficient = 0.2541, 95% confidence interval [CI]: 0.023 to 0.485, P = 0.0310). This study found no significant differences in the SRS-22 scores at the final follow-up., Conclusions: The incidence of PSI for Lenke2 AIS was 28.3% at 1 week postoperatively and 6.7% at the final follow-up. ΔT1 tilt was a risk factor for PSI. Adjustment of the T1 tilt during surgery was considered useful for the prevention of PSI., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gilteritinib is a tyrosine kinase inhibitor (TKI) that treats acute myeloid leukemia (AML) by inhibiting FMS-like tyrosine kinase 3 (FLT3). This is a report on hypopituitarism induced by gilteritinib and its resolution following withdrawal. A 54-year-old woman was treated with gilteritinib for AML. She subsequently developed general fatigue. Blood tests showed low levels of anterior pituitary hormone. After 10 months of gilteritinib withdrawal, the levels of anterior pituitary hormones returned to normal values. When nonspecific symptoms such as fatigue in patients treated with gilteritinib are coupled with electrolyte abnormalities, a close checkup for hypopituitarism is recommended., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hori et al.)

Introduction: The surgical management of severe scoliosis in patients with osteogenesis imperfecta (OI) is challenging because of curve rigidity, small stature, and inherent bone fragility. This study evaluated the midterm outcomes of our multimodal approach to address these issues, integrating perioperative bisphosphonate therapy, preoperative/intraoperative traction, various osteotomies, segmental pedicle screw instrumentation with cement augmentation, and bone morphogenetic protein-2 application., Methods: A single-center retrospective review of 30 patients (average age 14.1 ± 2.2 years; 18 were female) diagnosed with OI and scoliosis was conducted. These patients underwent posterior spinal fusion between 2008 and 2020 and completed a minimum follow-up of 2 years. We measured radiographic parameters at each visit and reviewed the incidence of complications. A mixed-effects model was used to evaluate changes in radiographic parameters from preoperative measurements to the first and latest follow-ups., Results: The patient cohort consisted of 2 individuals with type I OI, 20 with type III, 6 with type IV, and 2 with other types (types V and VIII). Surgical intervention led to a notable improvement in the major curve magnitude from 76° to 36°, with no notable correction loss. In addition, the minor curve, apical vertical translation, lowest instrumented vertebra tilt, and pelvic obliquity were also improved. In the sagittal plane, thoracic kyphosis and lumbar lordosis remained unchanged while thoracolumbar kyphosis markedly improved. Two patients experienced proximal junctional kyphosis with screw pullout, one of whom required revision surgery. One patient developed a superficial infection that was successfully treated with oral antibiotics. No instances of neurologic deficits or cement extravasation were observed., Discussion: This study demonstrated the effectiveness and safety of our multimodal approach to treating scoliosis in patients with OI, achieving a 53% major curve correction with minimal complications over 2-year follow-up. These findings provide notable insights into managing scoliosis in this population., Level of Evidence: Level IV (case series)., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

Introduction: The neck-shaft angle and head-shaft angle in children with varying levels of neurological disability were evaluated to define change over different ages., Methods: Children aged 1-12 years with spastic cerebral palsy, spinal muscular atrophy types 1 and 2, or typical development were reviewed to evaluate the neck-shaft angle and head-shaft angle. Patients were divided into five groups: Gross Motor Function Classification System levels I and II, Gross Motor Function Classification System level III, Gross Motor Function Classification System levels IV and V, spinal muscular atrophy types 1 and 2, and typical development. A linear mixed model was utilized to evaluate neck-shaft angle and head-shaft angle., Results: Data from 196 children (mean age 4.8 ± 4.5 years) were included. Gross Motor Function Classification System levels I and II: 22 children, 130 hip radiographs measured, neck-shaft angle 143.7 ± 7.4, and head-shaft angle 160.0 ± 7.1. Gross Motor Function Classification System level III: 8 children, 33 hips evaluated, neck-shaft angle 153.1 ± 4.3, and head-shaft angle 163.4 ± 4.2. Gross Motor Function Classification System levels IV and V: 30 children, 137 hip radiographs measured, neck-shaft angle 156.4 ± 5.6, and head-shaft angle 167.9 ± 6.8. Spinal muscular atrophy types 1 and 2: 32 children, 83 hip radiographs measured, neck-shaft angle 161.9 ± 9.7, and head-shaft angle 173.4 ± 7.4. Typical development: 104 children, 222 hip radiographs measured, neck-shaft angle 138.6 ± 7.0, and head-shaft angle 156.4 ± 5.9. There were significant statistical differences when comparing neck-shaft angle and head-shaft angle., Conclusion: As children grow, neck-shaft angle and head-shaft angle tend to decrease in typical development and Gross Motor Function Classification System levels I and II groups. However, in low-tone (spinal muscular atrophy types 1 and 2) and high-tone groups (Gross Motor Function Classification System levels IV and V), neck-shaft angle and head-shaft angle tend to increase with age. In both low-tone and high-tone groups, coxa valga is observed. When evaluating the effect of proximal femur-guided growth, these defined normal growth patterns should be considered., Level of Evidence: Level III Retrospective comparative study., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Mega-aortic syndrome including aortic arch and descending aortic aneurysm is a challenging surgical case. Because the aorta continuously dilates, creating the distal anastomosis sites becomes an issue. Despite the developments in endovascular techniques including frozen elephant trunk, in the case of mega-aortic syndrome or mycotic aneurysm, extensive surgical repair is still a strong armamentarium. Our patient had a mega-aorta with chronic aortic dissection. Herein, we show tips regarding concurrent ascending, aortic arch, and descending aortic replacement via posterolateral thoracotomy for this relatively young patient., Case Presentation: A 46-year-old man with chronic kidney disease had chronic type A aortic dissection with an extensively dilated thoracic aorta from the distal ascending to the descending aorta measuring 63 mm in diameter and abdominal aorta measuring 50 mm. The short segment of the distal descending aorta was narrowed to 36 mm. The patient underwent a concurrent replacement of the distal ascending aorta, aortic arch, and descending aorta via a posterolateral thoracotomy. The patient was extubated on postoperative day (POD) 1 and discharged home without serious complications such as stroke, respiratory failure, or renal failure on POD 18. The 1-year follow-up computed tomography did not find issues in the anastomosis sites; however, the abdominal aorta enlarged from 50 to 58 mm. The patient underwent a thoracoabdominal aortic replacement and recovered well without any complications., Conclusions: Good exposure and meticulous organ protection methods are key to a safe concurrent replacement of the ascending, aortic arch, and descending aorta via posterolateral thoracotomy., (© 2024. The Author(s).)

Primates must adapt to changing environments by optimizing their behavior to make beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which two male macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task's rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate dissociable contributions of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates., (© 2024. The Author(s).)

Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of the serotonin 5-HT 4 receptor (5-HT 4 R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT 4 R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT 4 R in the dCDh. We then examined the effects of a specific 5-HT 4 R antagonist infused into the dCDh. Blockade of 5-HT 4 R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT 4 R blockade because saline controls showed no such effect. The results demonstrate that 5-HT 4 Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT 4 R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms., (© 2024. The Author(s).)

Most mechanochromic luminescent compounds are crystalline and highly hydrophobic; however, mechanochromic luminescent molecular assemblies comprising amphiphilic molecules have rarely been explored. This study investigated mechanochromic luminescent supramolecular fibers composed of dumbbell-shaped 9,10-bis(phenylethynyl)anthracene-based amphiphiles without any tetraethylene glycol (TEG) substituents or with two TEG substituents. Both amphiphiles formed water-insoluble supramolecular fibers via linear hydrogen bond formation. Both compounds acquired water solubility when solid samples composed of supramolecular fibers are ground. Grinding induces the conversion of 1D supramolecular fibers into micellar assemblies where fluorophores can form excimers, thereby resulting in a large redshift in the fluorescence spectra. Excimer emission from the ground amphiphile without TEG chains is retained after dissolution in water. The micelles are stable in water because hydrophilic dendrons surround the hydrophobic luminophores. By contrast, when water is added to a ground amphiphile having TEG substituents, fragmented supramolecular fibers with the same molecular arrangement as the initial supramolecular fibers are observed, because fragmented fibers are thermodynamically preferable to micelles as the hydrophobic arrays of fluorophores are covered with hydrophilic TEG chains. This leads to the recovery of the initial fluorescent properties for the latter amphiphile. These supramolecular fibers can be used as practical mechanosensors to detect forces at the mesoscale., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

Background: A pallor optic nerve head (ONH) is one of the three features of retinitis pigmentosa (RP). This study aimed to assess the ONH prospectively by color tone, presence of hyper-reflective tissue, blood flow, retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC) and investigate the change in these parameters with and without ONH pallor., Methods: The presence of ONH pallor was assessed by three independent examiners through careful examination using fundus photographs. The presence of a hyper-reflective structure on the ONH was carefully evaluated using a volume scan optical coherence tomography (OCT). RNFL thickness and ellipsoid zone (EZ) width around the macula were also evaluated by OCT. Laser speckle flowgraphy was used to measure the mean blur rate of the entire ONH area, which was subsequently divided into the vessel area (MV) and tissue area (MT)., Results: Twenty-eight eyes of 28 patients with RP (55.4 ± 16.23 years of age) were included. The pale ONH was observed in 10 (35%) eyes. Hyper-reflective structures were observed in seven (25%) eyes. No significant correlation was found between the pale ONH and the presence of a hyper-reflective structure (Pearson's chi-squared test, p  = .364). The average of the ONH area, MV, and MT was 8.65 ± 3.08 AU, 17.81 ± 7.54 AU, and 6.4 ± 2.66 AU, respectively, which significantly decreased in patients with pallor ONH (all p  < .05). The global RNFL thickness was 73.54 ± 18.82 μm. The nasal and superior quadrants and global RNFL thickness in patients with a pale ONH were significantly thinner than in patients without a pale ONH (all p  < .05). The global and superior and inferior GCC thickness in patients with a pale ONH were significantly thinner than in patients without a pale ONH(all p  < .05).There was no difference in the EZ width between patients with and without a pale ONH ( p  = .107)., Conclusion: We conducted multiple assessments of the ONH in RP patients and investigated its clinical significance. Our findings suggest that ONH pallor may indicate a comprehensive change that emerges alongside the progression of retinal degeneration in RP., Trial Registration: This trial was retrospectively registered in the UMIN Clinical Trial Registry (UMIN ID: 000048168).

Histological assessment of centroblasts is an important evaluation in the diagnosis of follicular lymphoma, but there is substantial observer variation in assessment among hematopathologists. We aimed to perform quantitative morphological analysis of centroblasts in follicular lymphoma using new artificial intelligence technology in relation to the clinical prognosis. Hematoxylin and eosin slides of lesions were prepared from 36 cases of follicular lymphoma before initial chemotherapy. Cases were classified into three groups by clinical course after initial treatment. The 'excellent prognosis' group were without recurrence or progression of follicular lymphoma within 60 months, the 'poor prognosis' group were those that had relapse, exacerbation, or who died due to the follicular lymphoma within 60 months, and the 'indeterminate prognosis' group were those without recurrence or progression but before the passage of 60 months. We created whole slide images and image patches of hematoxylin and eosin sections for all cases. We designed an object detection model specialized for centroblasts by fine-tuning YOLOv5 and segmented all centroblasts in whole slide images. The morphological characteristics of centroblasts in relation to the clinical prognosis of follicular lymphoma were analyzed. Centroblasts in follicular lymphoma of the poor prognosis group were significantly smaller in nuclear size than those in follicular lymphoma of the excellent prognosis group in the following points: median of nuclear area (p = 0.013), long length (p = 0.042), short length (p = 0.007), nuclear area of top 10 % cells (p = 0.024) and short length of top 10 % cells (p = 0.020). Cases with a mean nuclear area of <55 μm 2 had poorer event-free survival than those with a mean nuclear area of ≥55 μm 2 (p < 0.0123). AI methodology is suggested to be able to surpass pathologist's observation in capturing morphological features. Small-sized centroblasts will likely become a new prognostic factor of follicular lymphoma., Competing Interests: Declaration of competing interest None Declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Killip classification has been used to stratify the risk of patients with acute myocardial infarction (AMI). There were many reports that Killip class 3 or 4 is closely associated with poor clinical outcomes. In other words, Killip class 1 or 2 is associated with favorable clinical outcomes in patients with AMI, especially when patients received primary percutaneous coronary intervention (PCI). However, some patients with Killip class 1/2 suffer from serious in-hospital complications. This study aimed to identify factors associated with serious in-hospital complications of ST-segment elevation myocardial infarction (STEMI) in patients with Killip class 1/2. The primary endpoint was serious in-hospital complications defined as the composite of in-hospital death and mechanical complications. We included 809 patients with STEMI, and divided them into the non-complication group (n = 791) and the complication group (n = 18). In-hospital death was observed in 14 patients (1.7%), and mechanical complications were observed in 4 patients (0.5%). Final TIMI flow ≤ 2 was more frequently observed in the complication group (33.3%) than in the non-complication group (5.4%) (p < 0.001). Multivariate logistic regression analysis revealed that serious in-hospital complication was associated with final TIMI flow grade ≤ 2 (Odds ratio 6.040, 95% confidence interval 2.042-17.870, p = 0.001). In conclusion, serious in-hospital complication of STEMI was associated with insufficient final TIMI flow grade in patients with Killip class 1/2. If final TIMI flow grade is suboptimal after primary PCI, we may recognize the potential risk of serious complications even when patients presented as Killip class 1/2., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Background/aim: This study retrospectively evaluated whether enfortumab vedotin (EV) monotherapy is effective as a late-line treatment according to prior treatment type in patients with advanced urothelial carcinoma (UC)., Patients and Methods: We assessed consecutive patients from the Uro-Oncology Group in the Kyushu study population with lower and upper urinary tract cancer treated with EV monotherapy after platinum-based chemotherapy and immune checkpoint inhibitor therapy failure between December 2021 and March 2024. In particular, patients receiving avelumab maintenance or pembrolizumab therapy before EV for advanced UC were analyzed and compared according to the response rate, progression-free survival (PFS), and overall survival (OS)., Results: Of the 80 enrolled patients, 31 and 49 received avelumab and pembrolizumab before EV therapy, respectively. The avelumab and pembrolizumab groups had comparable objective response rates (48.4% vs. 44.9%, p=0.820) and disease control rates (77.4% vs. 67.3%, p=0.448). These two groups showed no significant difference in PFS from the initiation of EV (median: 6.4 months vs. 4.2 months, p=0.184); meanwhile, the avelumab group had better OS from the initiation of EV than the pembrolizumab group (median: 16.0 months vs. 10.2 months, p=0.019). Moreover, the median OS after first-line chemotherapy initiation was longer in the avelumab group than in the pembrolizumab group (40.3 months vs. 24.7 months, p=0.054). On multivariate analysis, avelumab maintenance therapy before EV reduced the mortality risk by 47% (95% confidence interval=0.27-1.03; p=0.059)., Conclusion: EV monotherapy after avelumab maintenance therapy provides favorable survival outcomes in patients with advanced UC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The efficacy, safety, and liver toxicity of enfortumab vedotin (EV) for elderly advanced urothelial carcinoma (UC) patients and patients with a poor performance status (PS) are unclear., Patients and Methods: We retrospectively analyzed the efficacy, safety, and liver toxicity of EV in elderly patients and patients with a poor PS between December 2021 and August 2023., Results: Sixty-two patients (≥75 years old, n=22; PS≥2, n=10) were enrolled. Patients with PS≥2 had significantly lower albumin levels than those with PS<2 (p=0.023). The objective response and disease control rates did not differ significantly between patients <75 and ≥75 years old (p=0.598 and p=0.769, respectively) or between those with PS<2 and PS≥2 (p>0.99 and p=0.178, respectively). Progression-free survival (PFS) and overall survival (OS) were not significantly different in patients <75 years and ≥75 years (p=0984, 0.368). A significant difference in PFS (p=0.047) but not OS (p=0.086) was observed between the PS<2 and PS≥2 groups. The rates of any-grade and severe (grade ≥3) adverse events did not differ significantly between patients <75 and ≥75 years (p=0.471, p=0.136) or between PS<2 and PS≥2 groups (p>0.99, 0.99). Aspartate aminotransferase (AST) levels significantly increased, but alanine aminotransferase levels did not, following EV treatment (p<0.001). Multivariate analyses revealed that the albumin level was an independent prognostic factor (hazard ratio=0.159; p<0.001)., Conclusion: EV demonstrated similar efficacy and safety in elderly and younger patients with advanced UC. In patients with a poor PS, although the safety was similar, survival was significantly worse in terms of PFS, while the AST levels were significantly elevated., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The subtype of urothelial carcinoma (SUC) has been known to possess morphological diversity for histologic subtype or divergent differentiation. However, the efficacy of avelumab against SUC remains unclear. Therefore, the effect of the treatment as well as the survival results of avelumab monotherapy were evaluated as a first-line therapeutic maintenance in patients with advanced SUC., Methods: A retrospective analysis was conducted on consecutive patients from the Uro-Oncology Group in Kyushu study population with advanced lower and upper urinary tract cancer who underwent avelumab maintenance therapy without progression after first-line platinum-based chemotherapy. Patients with pure urothelial carcinoma (PUC) and SUC were comparatively analyzed based on objective response rate (ORR), disease control rate, progression-free survival (PFS), and overall survival (OS)., Results: Out of 49 recorded patients, 38 and 11 had PUC and SUC, respectively. The most common subtype element was glandular differentiation (n=5), followed by squamous differentiation (n=3), micropapillary (n=1), and plasmacytoid subtypes (n=1). The SUC and PUC groups had comparable ORR (0% vs. 2.6%, P>0.99) and disease control rates (54.5% vs. 44.7%, P=0.73). These patient groups also showed no significant difference in PFS (median 3.9 vs. 3.1 months, P=0.33) or OS (median 16.7 vs. 22.1 months, P=0.47)., Conclusions: The response of SUC and PUC to avelumab was comparable in patients with advanced lower and upper urinary tract cancer, indicating that avelumab maintenance therapy is also effective for SUC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-53/coif). The authors have no conflicts of interest to declare., (2024 Translational Andrology and Urology. All rights reserved.)

The intermuscular technique for subcutaneous implantable cardioverter-defibrillator (S-ICD) implantations is a technique for implanting the device between the anterior serratus muscle and latissimus dorsi (LD) muscle. A 70-year-old hypertrophic cardiomyopathy patient underwent a surgical repositioning of an S-ICD due to a moved device with skin thinning from mechanical stress. The patient had an S-ICD implantation 4 years prior to the reimplantation and the intermuscular technique was not expected to be achieved. The locational relationship of the S-ICD and LD was visually confirmed by computed tomography (CT), which was useful for planning the reimplantation. The device was reimplanted under the LD, with a position slightly cranial to the apex, and the defibrillation test was successful at 65 J. Our case suggested that preoperative CT imaging detailing the location of the implanted device and LD was practical for an optimal repositioning of an S-ICD., Learning Objective: The traditional technique for subcutaneous implantable cardioverter-defibrillator (S-ICD) implantations is associated with pocket-related skin problems in patients who lack sufficient subcutaneous tissue to adequately cover the device. Therefore, the submuscular approach has been used as an alternative technique for safety. In the event of an S-ICD malposition during the long-term follow-up, computed tomography imaging is helpful in identifying the detailed anatomy of the latissimus dorsi muscle and determining the optimal device reimplantation site., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 Japanese College of Cardiology. Published by Elsevier Ltd.)

Cholangiocarcinoma (CCA) is a cancer with a poor prognosis due to difficulties in diagnosis and limited treatment options, highlighting the urgent need for new targeted therapies. In a clinical setting, we found that leukotriene levels in bile were higher than in serum. Immunohistochemical analysis of surgically resected samples also revealed that CysLT receptor 1 (CysLTR1) was more highly expressed in CCA than in normal bile duct tissue, prompting us to investigate leukotriene as a potential therapeutic target in CCA. In vitro studies using CCA cell lines expressing CysLTR1 showed that leukotriene D4, a major ligand of CysLTR1, promoted cell proliferation, with increased phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Additionally, treatment with two clinically available anti-allergic drugs-zileuton, an inhibitor of CysLT formation, and montelukast, a CysLTR1 inhibitor-had inhibitory effects on cell proliferation and migratory capacity, accompanied by the reduced phosphorylation of AKT and ERK1/2. Furthermore, the simultaneous administration of both drugs synergistically enhanced the inhibitory effect on cell proliferation. Our study suggests that use of these drugs may represent a novel approach to treat CCA through drug repositioning.

The membrane raft accommodates the key enzymes synthesizing amyloid β (Aβ). One of the two characteristic components of the membrane raft, cholesterol, is well known to promote the key enzymes that produce amyloid-β (Aβ) and exacerbate Alzheimer's disease (AD) pathogenesis. Given that the raft is a physicochemical platform for the sound functioning of embedded bioactive proteins, the other major lipid component sphingomyelin may also be involved in AD. Here we knocked out the sphingomyelin synthase 2 gene (SMS2) in 3xTg AD model mice by hybridization, yielding SMS2KO mice (4S mice). The novel object recognition test in 9/10-month-old 4S mice showed that cognitive impairment in 3xTg mice was alleviated by SMS2KO, though performance in the Morris water maze (MWM) was not improved. The tail suspension test detected a depressive trait in 4S mice, which may have hindered the manifestation of performance in the wet, stressful environment of MWM. In the hippocampal CA1, hyperexcitability in 3xTg was also found alleviated by SMS2KO. In the hippocampal dentate gyrus of 4S mice, the number of neurons positive with intracellular Aβ or its precursor proteins, the hallmark of young 3xTg mice, is reduced to one-third, suggesting an SMS2KO-led suppression of syntheses of those peptides in the dentate gyrus. Although we previously reported that large-conductance calcium-activated potassium (BK) channels are suppressed in 3xTg mice and their recovery relates to cognitive amelioration, no changes occurred by hybridization. Sphingomyelin in the membrane raft may serve as a novel target for AD drugs., 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 Elsevier B.V. All rights reserved.)

Objective Testing for the Janus activating kinase 2 (JAK2) V617F mutation is important for diagnosing and treating myeloproliferative neoplasms (MPNs). Recently, urine cell-free DNA (ucfDNA) was reported to be useful for detecting tumor-specific gene mutations in several solid tumors. However, its utility in detecting such mutations in hematological malignancies has not yet been assessed. In this study, we assessed whether or not the JAK2 V617F mutation could be detected in ucfDNA and whether or not its positivity rate in ucfDNA was associated with the JAK2 V617F allele ratio of peripheral blood cells in patients with MPN. Methods The JAK2 V617F allele ratio of genomic DNA from peripheral blood cells was determined using quantitative polymerase chain reaction (qPCR) or droplet digital PCR (ddPCR). ucfDNA was subjected to ddPCR. The correlation between the JAK2 V617F mutation positivity rates of blood-derived DNA and those of ucfDNA was assessed. Materials Twelve patients with polycythemia vera and 12 patients with essential thrombocythemia were enrolled. Ethylenediaminetetraacetic acid-treated peripheral blood (100 mL) and 15-30 mL of fresh urine were used. Results The JAK2 V617F mutation was detected in the ucfDNA from all 20 JAK2 V617F mutation-positive patients. In addition, the JAK2 V617F mutation positivity rate of ucfDNA was correlated with the JAK2 V617F allele ratio of blood-derived DNA, including in both estimated glomerular filtration rate (eGFR) groups (patients with an eGFR ≥50 or <50 mL/min/1.73 m 2 ). Conclusion Our results indicate that ucfDNA is a valuable tool for diagnosing and monitoring MPN. Given these findings, other disease-specific gene mutations in hematological malignancies may also be detectable in ucfDNA.

Visual object memory is a fundamental element of various cognitive abilities, and the underlying neural mechanisms have been extensively examined especially in the anterior temporal cortex of primates. However, both macroscopic large-scale functional network in which this region is embedded and microscopic neuron-level dynamics of top-down regulation it receives for object memory remains elusive. Here, we identified the orbitofrontal node as a critical partner of the anterior temporal node for object memory by combining whole-brain functional imaging during rest and a short-term object memory task in male macaques. Focal chemogenetic silencing of the identified orbitofrontal node downregulated both the local orbitofrontal and remote anterior temporal nodes during the task, in association with deteriorated mnemonic, but not perceptual, performance. Furthermore, imaging-guided neuronal recordings in the same monkeys during the same task causally revealed that orbitofrontal top-down modulation enhanced stimulus-selective mnemonic signal in individual anterior temporal neurons while leaving bottom-up perceptual signal unchanged. Furthermore, similar activity difference was also observed between correct and mnemonic error trials before silencing, suggesting its behavioral relevance. These multifaceted but convergent results provide a multiscale causal understanding of dynamic top-down regulation of the anterior temporal cortex along the ventral fronto-temporal network underpinning short-term object memory in primates., (© 2024. The Author(s).)

Background: Appropriate prognostic indicators are required for patients with stage IV colorectal cancer (CRC). Lymph node metastasis mainly involves four histological types of CRC. Some metastatic lymph nodes (mLNs) showing cribriform carcinoma are associated with distant metastasis in patients with node-positive CRC and are correlated with recurrence and survival in stage III disease. However, the significance of mLN histology in the prognosis of patients with node-positive stage IV disease remains unclear., Methods: We enrolled 449 consecutive patients with CRC who underwent primary tumor resection with lymph node dissection between January 2011 and November 2018. This study included 88 patients with node-positive stage IV CRC and synchronous or metachronous distant metastases. We retrospectively investigated the association between cancer histology in the mLNs based on our classification and cancer-specific survival (CSS) in patients with node-positive stage IV CRC., Results: Kaplan-Meier analysis showed that CSS was better in patients with CRC and all the mLNs showing tubular-type carcinoma. In contrast, patients with at least some mLNs showing poorly differentiated-type carcinoma had poor prognosis. Multivariate analysis showed that "all mLNs showing tubular-type carcinoma" was an independent good prognostic factor for CSS in patients with node-positive stage IV CRC. In addition, "at least some mLNs showing poorly differentiated-type carcinoma" was an independent poor prognostic factor for CSS in patients with node-positive stage IV disease., Conclusions: The histological type of the mLN may indicate a better or poor prognosis for patients with stage IV CRC., Competing Interests: The authors declare that they have no competing interests., (© 2024 Yokoyama et al.)