Search

Pao-Wen Yen,1 Hsing-Yu Lin,2 Chien-Chih Wu,2 Tai-Chung Huang,3 Shang-Ju Wu,3 Szu-Yu Pan,1,4 Kuan-Yu Hung1,5 1Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan; 2Department of Pharmacy, National Taiwan University Hospital, Taipei City, Taiwan; 3Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan; 4Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei City, Taiwan; 5Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanCorrespondence: Chien-Chih Wu, Department of Pharmacy, National Taiwan University Hospital, Taipei City, Taiwan, Tel +886-2-23123456, Email r93451011@gmail.com Kuan-Yu Hung, Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan, Tel +886-2-23123456, Email kyhung@ntu.edu.twBackground: Acute kidney injury (AKI) is a serious complication following high-dose methotrexate (HD-MTX) treatment, despite established preventive measures. This study presents a case report and a retrospective review of patients treated with HD-MTX, aiming to identify risk factors for AKI and propose a modified treatment protocol.Methods: We report a case of a 43-year-old man with diffuse large B-cell lymphoma who developed severe AKI after HD-MTX therapy. Additionally, a retrospective review of 70 patients receiving HD-MTX at our institution was conducted to identify predictors of AKI. Serum methotrexate levels were analyzed to determine their significance in predicting AKI.Results: The index patient developed methotrexate intoxication and severe AKI despite receiving standard prophylactic measures, requiring temporary hemodialysis. The retrospective review identified serum methotrexate levels as a significant predictor of AKI (OR 11.84, 95% CI: 2.62– 53.53, p = 0.001). Higher initial serum methotrexate levels correlated with the development of AKI.Conclusion: Timely measurement of serum methotrexate levels is crucial in managing and preventing AKI in patients undergoing HD-MTX therapy. Based on our findings, we propose a modified HD-MTX treatment protocol to reduce the incidence of AKI. This includes earlier serum methotrexate level monitoring and adjustments in urine alkalization and leucovorin dosing strategies.Keywords: methotrexate, acute kidney injury

This roadmap includes the perspectives and visions of leading researchers in the key areas of flexible and printable electronics. The covered topics are broadly organized by the device technologies (sections 1–9), fabrication techniques (sections 10–12), and design and modeling approaches (sections 13 and 14) essential to the future development of new applications leveraging flexible electronics (FE). The interdisciplinary nature of this field involves everything from fundamental scientific discoveries to engineering challenges; from design and synthesis of new materials via novel device design to modelling and digital manufacturing of integrated systems. As such, this roadmap aims to serve as a resource on the current status and future challenges in the areas covered by the roadmap and to highlight the breadth and wide-ranging opportunities made available by FE technologies.

Flexible electronics are emerging as an alternative to conventional Si electronics for smart sensors, disposable RFID tags, and solar cells. By utilizing inexpensive manufacturing methods such as ink-jet printing and roll-to-roll imprinting, flexible electronics can be made on low-cost plastic films just like printing newspapers. However, the key elements of flexible electronics, thin-film transistors (TFTs), have slower operating speeds and are less reliable than their Si electronics counterparts. Furthermore, TFTs are usually mono-type - either p- or n-type - devices. Making air-stable complementary TFT circuits is very challenging or sometimes not feasible to most TFT technologies. Existing design methodologies for Si electronics, therefore, cannot be directly applied to flexible electronics. Other factors such as high supply voltage, large process variation, and lack of trustworthy device modeling also make designing larger-scale and robust TFT circuits a significant challenge. The objective of this article is to provide an in-depth overview of flexible electronics from their applications, manufacturing processes, device characteristics, to circuit and system design solutions. We first introduce the low-cost fabrication methods for flexible electronics, including ink-jet printing, screen printing, and gravure printing. The device characteristics and compact modeling of several major TFT technologies will be illustrated. We will then give an overview of digital and analog circuit design from basic logic gates to a microprocessor, as well as design automation tools and methods, for designing flexible electronics. We also describe a reliability simulation framework that can predict TFT circuits' performance degradation under bias-stress. This framework has been validated using the amorphous-silicon (a-Si) TFT scan driver for TFT-LCD displays. Finally, we will give an overview of flexible thin-film photovoltaics using different materials including amorphous silicon, CdTe, CIGS, and organic solar cells.

The repair of injured or transected nerves is frequently encountered in head and neck surgery. Recently, CO2 lasers with milliwatt capability and micrometer spot sizes have been developed that may be used in nerve anastomosis. A comparative study was performed between microsuture and CO2 laser repair of transected sciatic nerves in rats. Nerve regeneration was measured in terms of morphology, electrophysiology, and function. Histologic studies revealed no difference in the size and number of regenerated axons, although there was less scar tissue formation at the anastomotic site with the laser repair. EMG and nerve conduction velocity were similar for the two repair methods. Functional recovery, as determined objectively using measurements of gait footprints, showed no difference between suture and laser repair. Laser-repaired nerves did have a higher dehiscence rate, although this problem can probably be prevented by splinting the rats postoperatively. However, laser repair was faster and simpler than suture repair and required less manipulation of the nerve. This study shows laser repair of peripheral nerves is possible with results comparable to conventional microsuture neurorrhaphy. Laser nerve anastomosis may be an effective alternative to suture nerve repair.

Background: The conventional FEV(1)/FVC test is the "gold standard" to quantitate airway obstruction, but elderly subjects or patients with severe respiratory diseases quite frequently cannot make such an effort. Many studies have investigated the usefulness of FEV(1)/forced expired volume in 6 s (FEV(6)) measurements as an alternative for FEV(1)/FVC for diagnosis of airway obstruction. We conducted a meta-analysis to determine the FEV(1)/FEV(6) substitute for FEV(1)/FVC in the diagnosis of airway obstruction.Methods: After a systematic review of all-language studies, sensitivity, specificity, and other measures of accuracy of FEV(1)/FEV(6) in the diagnosis of airway obstruction were pooled using random-effects models. Summary receiver operating characteristic curves were used to summarize overall test performance.Results: Eleven studies met our inclusion criteria. The summary estimates for FEV(1)/FEV(6) in the diagnosis of airway obstruction in the studies included were as follows: sensitivity, 0.89 (95% confidence interval [CI], 0.83 to 0.93); specificity, 0.98 (95% CI, 0.95 to 0.99); positive likelihood ratio, 45.46 (95% CI, 18.26 to 113.21); negative likelihood ratio, 0.11 (95% CI, 0.08 to 0.17); diagnostic odds ratio, 396.02 (95% CI, 167.32 to 937.31); and diagnostic score, 5.98 (95% CI, 5.12 to 6.84).Conclusions: FEV(1)/FEV(6) is a sensitive and specific test for the diagnosis of airway obstruction. FEV(1)/FEV(6) can be used as a valid alternative for FEV(1)/FVC in the diagnosis of airway obstruction. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a chronic condition characterized by joint pain and disability, driven by excessive oxidative stress and inflammatory cytokine production in chondrocytes, resulting in cell death and cartilage matrix breakdown. Our previous study showed that in monosodium iodoacetate (MIA)-induced OA rats, oral administration of heat-killed Lactobacillus delbrueckii subsp. lactis 557 (LDL557) could significantly decrease OA progression., Methods: Accordingly, we designed an in vitro cell culture study aimed at investigating the effects of heat-killed LDL557 extracts on chondrocytes using SW1353 cells (a human chondrosarcoma cell line) challenged with 5 μM MIA to mimic OA conditions., Results: The results showed that the 10 μg/mL LDL557 extracts protected SW1353 cells from MIA-induced death and reduced extracellular matrix (ECM) loss, as evaluated by toluidine blue O staining and extracellular matrix component synthesis with RT-qPCR measurement. This was achieved by decreasing the expression of MIA-induced pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, while slightly increasing the MIA-suppressed expression of the anti-inflammatory cytokine IL-10, which were evidenced by RT-qPCR analysis. Moreover, the RT-qPCR evaluation also indicated that the LDL557 extracts slightly reduced the expression of COX-2 compared with the control, while it did not reduce the MIA-increased expression of microsomal prostaglandin E synthase-1 (mPGES-1). In addition, the LDL557 extracts influenced neither the matrix-degrading protease expressions measured via RT-qPCR nor the oxidative stress measured via fluorescence flow cytometry in the cells with or without the MIA challenge., Conclusions: This study demonstrates that LDL557 extracts may protect chondrocytes from OA damage by reducing inflammation-related factors and thus mitigating cartilage matrix loss, suggesting LDL557 extracts are attractive alternatives for OA applications.

Background: The effectiveness of statin use in preventing adverse cardiovascular events in individuals with atrial fibrillation (AF) has remained uncertain. This study aimed to assess whether statin use could lead to better outcomes among individuals with AF., Methods and Results: We enrolled 397 787 patients with AF from January 1, 2012 to December 31, 2020. Patients with AF were divided into 2 groups (statin user and statin nonuser), and the risks of composite outcomes (including ischemic stroke, hemorrhagic stroke, and transient ischemic attack), all-cause death, and major adverse cardiovascular events (which encompassed cardiovascular death, myocardial infarction, stroke, and heart failure hospitalization) were analyzed. We analyzed 288 958 patients with newly diagnosed AF (mean age, 73 years; 44% women; mean CHA 2 DS 2 -VASc score, 3.5). Compared with patients without statin use, statin users had lower risks of composite end points (adjusted hazard ratio [HR], 0.91 [95% CI, 0.87-0.94]; P <0.01). In regard to all-cause death, statin users exhibited a 67% risk reduction compared with statin nonusers (adjusted HR, 0.33 [95% CI, 0.32-0.33]; P <0.01). Statin use was also associated with reduced incidence of major adverse cardiovascular events (adjusted HR, 0.64 [95% CI, 0.63-0.66]; P <0.01). In the subgroups stratified by CHA 2 DS 2 -VASc score, statin therapy was particularly effective for patients with CHA 2 DS 2 -VASc scores 0 to 3 for composite end points but consistently reduced all-cause mortality and major adverse cardiovascular events across all score categories., Conclusions: Among patients with newly diagnosed AF, statin use was associated with lower risk of ischemic stroke, hemorrhagic stroke, transient ischemic attack, all-cause mortality, and major adverse cardiovascular events.

Background: Moxidectin is an active pharmaceutical ingredient (API) extensively used in various drug products within the pharmaceutical and animal health sectors. Despite its widespread use, the analytical methods prescribed by the United States Pharmacopeia (USP) and European Pharmacopoeia (EP, Ph. Eur.) exhibit significant limitations. These methods fail to adequately separate key impurities of (23Z)-moxidectin (EP impurity L) and 3,4-epoxy-moxidectin, potentially affecting the quality control, purity assessment, and safety of moxidectin-containing products., Objective: The objective was to develop and validate an alternative, improved stability-indicating HPLC method for the identification, assay, and quantification of related substances in the moxidectin drug substance, along with the analysis of its degradation pathways., Methods: High-Resolution Mass Spectrometry (HRMS) and Nuclear Magnetic Resonance (NMR) were employed to comprehensively examine moxidectin and its two degradation products under specified acidic conditions. The degradation products were isolated and identified using a range of analytical techniques, including HRMS, NMR, and other relevant methods., Results: The epoxy derivative of moxidectin (RRT = 1.2) was not identified under the studied acidic degradation conditions. HRMS data indicated that the degradant at RRT = 1.2 is an isomer of moxidectin, as it exhibited an identical molecular ion. Detailed NMR studies on moxidectin and its impurity at RRT-1.2 revealed differences in carbon and proton chemical shifts at positions C-22 and C-24, strongly supporting the identification of the structure as an oxime geometric isomer of moxidectin, ie, (23Z)-moxidectin., Conclusions: The findings revealed specific degradation products formed under acidic conditions, offering valuable insights into the chemical transformations of moxidectin. This information is crucial for assessing the drug's stability profile and ensuring the quality and safety of moxidectin-containing products., Highlights: The HPLC method developed in this study significantly improves upon existing USP/EP methods with regard to a separation of key impurities of (23Z)-moxidectin and 3,4-epoxy-moxidectin, offering robust performance for routine analysis of bulk moxidectin API batches and stability samples in quality control (QC) laboratories., (© The Author(s) 2024. Published by Oxford University Press on behalf of AOAC INTERNATIONAL. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

SPINT1, a membrane-anchored serine protease inhibitor, regulates cascades of pericellular proteolysis while its tissue-specific functions remain incompletely characterized. In this study, we generate Spint1-lacZ knock-in mice and observe Spint1 expression in embryonic pancreatic epithelium. Pancreas-specific Spint1 disruption significantly diminishes islet size and mass, causing glucose intolerance and downregulation of MAFA and insulin. Mechanistically, the serine protease HEPSIN interacts with SPINT1 in β cells, and Hepsin silencing counteracts the downregulation of Mafa and Ins1 caused by Spint1 depletion. Furthermore, we demonstrate a potential interaction between HEPSIN and GLP1R in β cells. Spint1 silencing or Hepsin overexpression reduces GLP1R-related cyclic AMP levels and Mafa expression. Spint1-disrupted mice also exhibit a significant reduction in Exendin-4-induced insulin secretion. Moreover, SPINT1 expression increases in islets of prediabetic humans compared to non-prediabetic groups. The results unveil a role for SPINT1 in β cells, modulating glucose homeostasis and insulin production via HEPSIN/MAFA signaling., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Uterine leiomyoma (UL), commonly referred to as benign tumors, is characterized by excessive cell proliferation, extracellular matrix (ECM) accumulation, and the presence of stem cell-like properties. Nicotinamide adenine dinucleotide (NAD + ) metabolism, regulated in part by nicotinamide phosphoribosyltransferase (NAMPT), plays a crucial role in these pathological processes and has emerged as a potential therapeutic target. Additionally, redox signaling pathways are integral to the pathogenesis of UL, influencing the dynamics of NAD + metabolism. This study sought to elucidate the regulatory functions of NAMPT and NAD + metabolism, in conjunction with redox signaling, in the progression of UL, and to explore potential therapeutic strategies targeting these pathways. Evaluation of NAMPT expression in human UL tissues revealed a positive correlation between elevated NAMPT levels and increased ECM deposition, as well as the expression of stemness markers. The use of FK866 and nicotinamide (NAM), to inhibit NAMPT significantly suppressed UL cell viability and attenuated stem cell-like characteristics. Redox signaling pathways, including those associated with DNA damage, lysosomal function homeostasis, and redox-sensitive phagophore formation, were implicated in the regulation of ECM dynamics, particularly through ECM-targeted inhibition. This study highlights the pivotal roles of NAMPT, NAD + metabolism, and redox signaling in the pathophysiology of UL. Targeting NAMPT, particularly through the use of inhibitors FK866 and NAM, represents a promising therapeutic approach for mitigating UL progression by modulating redox and ECM dynamics. These findings offer novel insights into UL pathogenesis and establish NAMPT as a compelling target for future clinical investigation., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The diagnostic challenges in early mycosis fungoides (MF) and other cutaneous T-cell lymphomas (CTCL) persist despite advancements in molecular methods., Aim: The study aims to provide a preliminary assessment of next-generation sequencing in analyzing T-cell receptor gamma (TRG) sequences for distinguishing CTCL from benign inflammatory disorders., Methods: Skin samples from CTCL and benign inflammatory skin disorders proven clinicopathologically were assessed for TRG by NGS., Results: Our study analyzed skin samples from a total of 36 subjects, comprising 22 cases of CTCL, including 14 MF and 8 other CTCLs, alongside 14 cases of benign inflammatory skin disorders. According to the LymphoTrack criteria, monoclonality was detected in 75.0 % of the overall 24 CTCL patients. Specifically, in MF cases, 10 out of 14 were identified as monoclonality, with all four non-monoclonal cases being in the patch stage. For the other CTCL, 6 out of 8 cases displayed monoclonality. Among the overall 22 CTCL patients, 11 had multiple biopsies, with 9 displaying the same dominant clone across different sites. Among the 14 benign cases, only the case with erythrodermic psoriasis exhibited monoclonality. Our decision tree analysis suggests that a high frequency of the most abundant clone, its ratio to the third most abundant clone, and TRG V-I segment usage are effective markers aiding in diagnosing CTCL., Conclusion: Combination of the clone frequencies, and TRG V segment usage may enhance diagnosis for MF and other CTCLs, aiding in differentiating them from benign conditions. However, molecular diagnosis for patch-stage MF remains challenging., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cutaneous T cell lymphomas (CTCLs), with mycosis fungoides (MF) and Sézary syndrome (SS) as the classic types, are the commonest group of primary cutaneous lymphomas. The diverse clinical manifestation and non-specific histologic findings of early lesions in CTCLs render diagnosis challenging. Treatment modalities also vary and include topical and oral medications, chemotherapy, phototherapy, and radiation therapies. Local dermatological, hemato-oncologic and radiotherapeutical experts in Taiwan convened meetings in 2023 to review and discuss the latest evidence and updates regarding diagnosis and management of CTCLs. A consensus was developed with the aim to raise awareness and understanding, provide practical guidance for early diagnosis and appropriate management, and ultimately optimize care to maximize benefits of patients., Competing Interests: Declaration of competing interest See separate submission of “Authorship & conflicts of Interest Statement Form”, (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

This study investigates predictors of unsatisfactory outcomes in female overactive bladder (OAB) patients treated with oral monotherapy by analyzing skin sympathetic nerve activity (SKNA) using a novel "neuECG" method. The study included 55 newly diagnosed female patients with idiopathic OAB, autonomic function was evaluated using neuECG before treatment initiation, and validated OAB questionnaires and urodynamic studies were administered. Initial monotherapy was administered for the first 4 weeks, with non-responders defined as patients not achieving satisfactory symptom relief and requiring further treatment. Responders (n = 32) and non-responders (n = 23) had no significant differences in baseline characteristics or urodynamic parameters; however, non-responders exhibited significantly higher baseline average SKNA (aSKNA) (1.36 ± 0.49 vs. 0.97 ± 0.29 μV, p = 0.001), higher recovery aSKNA (1.28 ± 0.46 vs. 0.97 ± 0.35 μV, p = 0.007), and a lower stress/baseline ratio of aSKNA (1.05 ± 0.42 vs. 1.26 ± 0.26, p = 0.029). Baseline aSKNA had the highest predictive value for monotherapy refractoriness in OAB (AUROC = 0.759, p = 0.001), with an optimal cut-off point of >1.032 μV. These findings suggest that elevated pre-treatment aSKNA can predict resistance to oral monotherapy in OAB, warranting close monitoring and proactive treatment strategies for patients with high aSKNA., (© 2024 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignant tumor, and it ranks 2nd in terms of mortality rate among all malignancies in Taiwan. Sorafenib is a multiple tyrosine kinase inhibitor that suppresses tumor cell proliferation and angiogenesis around tumors via different pathways. However, the survival outcome of advanced HCC patients treated with sorafenib is still unsatisfactory. Unfortunately, there are no clinically applicable biomarkers to predict sorafenib therapeutic efficiency in HCC thus far. We found that serpin peptidase inhibitor, clade G, member 1 (SERPING1) is highly associated with overall and recurrence-free survival rates in HCC patients and is also highly correlated with several clinical parameters. SERPING1 expression was increased with sorafenib in both the HCC cell extract and conditioned medium, which was also observed in sorafenib-resistant HepG2 and Huh7 cells. Sorafenib decreased cell viability and migration, which was similar to the effect of SERPING1 in HCC progression. Moreover, sorafenib inhibited both MMP-2 and MMP-9 activity and enhanced the expression of p-ERK in HCC cells. In summary, sorafenib reduces HCC cancer progression might through the p-ERK-MMP-2-MMP-9 cascade via upregulation of SERPING1. In the present study, the roles and molecular mechanisms of SERPING1 and its value as a marker for predicting sorafenib resistance and progression in HCC patients were examined. The results of the present study provide a deep understanding of the roles of SERPING1 in HCC sorafenib resistance, which can be applied to develop early diagnosis and prognosis evaluation methods and establish novel therapeutic targets for specifically treating HCC., (© 2024 The Author(s). Environmental Toxicology published by Wiley Periodicals LLC.)

Recurrences are frequent in nasopharyngeal carcinoma (NPC) despite high remission rates with treatment, leading to considerable morbidity. This study aimed to develop a prediction model for NPC survival by harnessing both pre- and post-treatment magnetic resonance imaging (MRI) radiomics in conjunction with clinical data, focusing on 3-year progression-free survival (PFS) as the primary outcome. Our comprehensive approach involved retrospective clinical and MRI data collection of 276 eligible NPC patients from three independent hospitals (180 in the training cohort, 46 in the validation cohort, and 50 in the external cohort) who underwent MRI scans twice, once within 2 months prior to treatment and once within 10 months after treatment. From the contrast-enhanced T1-weighted images before and after treatment, 3404 radiomics features were extracted. These features were not only derived from the primary lesion but also from the adjacent lymph nodes surrounding the tumor. We conducted appropriate feature selection pipelines, followed by Cox proportional hazards models for survival analysis. Model evaluation was performed using receiver operating characteristic (ROC) analysis, the Kaplan-Meier method, and nomogram construction. Our study unveiled several crucial predictors of NPC survival, notably highlighting the synergistic combination of pre- and post-treatment data in both clinical and radiomics assessments. Our prediction model demonstrated robust performance, with an accuracy of AUCs of 0.66 (95% CI: 0.536-0.779) in the training cohort, 0.717 (95% CI: 0.536-0.883) in the testing cohort, and 0.827 (95% CI: 0.684-0.948) in validation cohort in prognosticating patient outcomes. Our study presented a novel and effective prediction model for NPC survival, leveraging both pre- and post-treatment clinical data in conjunction with MRI features. Its constructed nomogram provides potentially significant implications for NPC research, offering clinicians a valuable tool for individualized treatment planning and patient counseling., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Reflectin is an intrinsically disordered protein known for its ability to modulate the biophotonic camouflage of cephalopods based on its assembly-induced osmotic properties. Its reversible self-assembly into discrete, size-controlled clusters and condensed droplets are known to depend sensitively on the net protein charge, making reflectin stimuli-responsive to pH, phosphorylation, and electric fields. Despite considerable efforts to characterize this behavior, the detailed physical mechanisms of reflectin's assembly are not yet fully understood. Here, we pursue a coarse-grained molecular understanding of reflectin assembly using a combination of experiments and simulations. We hypothesize that reflectin assembly and phase behavior can be explained from a remarkably simple colloidal model whereby individual protein monomers effectively interact via a short-range attractive and long-range repulsive (SA-LR) pair potential. We parameterize a coarse-grained SA-LR interaction potential for reflectin A1 from small-angle x-ray scattering measurements, and then extend it to a range of pH values using Gouy-Chapman theory to model monomer-monomer electrostatic interactions. The pH-dependent SA-LR interaction is then used in molecular dynamics simulations of reflectin assembly, which successfully capture a number of qualitative features of reflectin, including pH-dependent formation of discrete-sized nanoclusters and liquid-liquid phase separation at high pH, resulting in a putative phase diagram for reflectin. Importantly, we find that at low pH size-controlled reflectin clusters are equilibrium assemblies, which dynamically exchange protein monomers to maintain an equilibrium size distribution. These findings provide a mechanistic understanding of the equilibrium assembly of reflectin, and suggest that colloidal-scale models capture key driving forces and interactions to explain thermodynamic aspects of native reflectin behavior. Furthermore, the success of SA-LR interactions presented in this study demonstrates the potential of a colloidal interpretation of interactions and phenomena in a range of intrinsically disordered proteins., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Adjuvant nivolumab reduces recurrence in patients with locoregional esophageal cancer who had pathological residual disease after neoadjuvant chemoradiotherapy and R0 resection. However, the efficacy of adjuvant anti-PD-1 therapy in patients at higher risk of recurrence remains unclear., Methods: This phase II trial (ClinicalTrials.gov identifier: NCT03322267) enrolled patients with locally advanced esophageal squamous cell carcinoma (ESCC) received neoadjuvant chemoradiotherapy plus esophagectomy but still had various risk factors for recurrence, such as involved or close margins (≤ 1 mm), extranodal extension of the involved lymph nodes, and the ypN2-3 stage. Patients received adjuvant therapy composed of a course of cisplatin-based chemoradiotherapy and pembrolizumab (200 mg, IV every 3 weeks) for 18 cycles. The primary endpoint was 1-year relapse-free survival (RFS) rate., Results: Twenty-five patients were enrolled. The risk factors were tumor margins of ≤ 1 mm (18 patients), extranodal extension of the involved lymph nodes (9 patients), and the ypN2-3 stage (9 patients). The median follow-up duration was 21.6 months (95% CI: 18.7-33.2). The rate of 1-year RFS was 60.0%. The median duration of RFS and overall survival was 14.3 (95% CI: 9.0-19.5) and 21.6 (95% CI: 0.0-45.5) months, respectively. Treatment-emergent adverse events of any grade and those of ≥ 3 grade occurred in 56% and 8% of all patients receiving cisplatin-based chemoradiotherapy and in 79.2% and 12.5% of those receiving pembrolizumab., Conclusions: Adjuvant chemoradiotherapy followed by pembrolizumab is feasible and may be associated with improved 1-year RFS rate in patients at high risk of recurrence after trimodality therapy for locally advanced ESCC. Trial registration number ClinicalTrials.gov (No. NCT03322267)., (© 2024. The Author(s).)

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

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for around 30-60% of all cases. The management of DLBCL in Asia has several unmet needs due to the diversity of the population, the heterogeneity of local clinical guidelines for DLBCL and the wide disparity in resources and healthcare systems across different regions. Rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) is widely recognized as the standard first-line treatment for DLBCL; however, alternative regimens are required to improve patient outcomes in challenging subtypes, such as patients with high International Prognostic Index scores, old/frail patients, and patients with double-hit and double-expressor DLBCL or concurrent central nervous system disease. This review article draws from the expertise of practicing hematologists/oncologists in the region, with the aim of integrating data from current scientific evidence to address the unmet needs and unique socioeconomic challenges faced by challenging high risk patient groups in the Asia-Pacific region., Competing Interests: Disclosure Daryl Tan: Grant/Research support: Novartis, Janssen. Speaker's bureau: BMS, Novartis, Pfizer, Roche, Takeda, Janssen. Consultant: Amgen, AstraZeneca, BMS, GSK, Takeda, Pfizer, Roche. Jason Yongsheng Chan: Consultant/Speaker's Bureau: Antengene, Takeda, AstraZeneca, Novartis, Roche, MSD, Specialised Therapeutics, DKSH/Beigene, Janssen, AbbVie. Grant/Research support: SymBio Pharmaceuticals, Scinnohub Pharmaceuticals, ArcherDX/Invitae, Miltenyi Biotec, STEMCELL Technologies, MGI Technologies, BGI Research, Twist Biosciences, Agilent Technologies, Illumina, BioSyngen, NovogeneAIT. Travel support: AstraZeneca, Janssen, Amgen. Kitsada Wudhikarn: Advisory with honorarium: Beigene. Raymond Siu Ming Wong: Grant/Research support: AbbVie, Acerta, Alexion, Amgen, Apellis, Astella, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Celgene, Daiichi-Sankyo, GSK, Janssen, Kartos, Morphosys, MSD, Novartis, Pfizer, Regeneron, Roche. Speaker's bureau: Astella, Amgen, Bayer, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, Novartis, Pfizer, Roche. Consultant: Alexion, Amgen, Astella, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche. Limei Poon: Research support: Regeneron. Lalita Norasetthada: This author has no COIs to declare. Tai-Chung Huang: Honoraria: HOPE Foundation for Cancer Care, Janssen, MundiPharma, Novartis, Roche. Consulting or advisory role: AbbVie, Antengene, AstraZeneca, Beigene, Roche, Takeda. Research funding: NTUH Hematology Clinical Research Grant, Yonglin Foundation. Speakers’ bureau: AbbVie, Antengene, Bristol-Myers Squibb, Celltrion, Hematology Society of Taiwan, MundiPharma, Novartis, Roche, Takeda, TTY. Travel, accommodations, expenses: Janssen, MundiPharma, Roche, Takeda. Eric Tse: Consultant and research support: MSD. Research support from AstraZeneca and Janssen. Advisory with honorarium: Abbvie, Beigene, Janssen, Pfizer, Roche., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Low-grade body inflammation is a major cause of osteoarthritis (OA), a common joint disease. Gut dysbiosis may lead to systemic inflammation which can be prevented by probiotic administration. The Lactobacillus delbrueckii subsp. lactis 557 (LDL557) has been demonstrated to have beneficial effects for anti-inflammation. This study investigated the effects of LDL557 on OA progress using monosodium iodoacetate (MIA)-induced OA of rats. Live or heat-killed (HK)-LDL557 of a low or high dose was administrated for two weeks before MIA-induced OA, and then continuously administrated for another six weeks. After taking supplements for eight weeks, OA progress was analyzed. Results showed that MIA induced knee joint swelling, chondrocyte damage, and cartilage degradation, and supplementation with a high dose of LDL557 reduced MIA-induced knee joint swelling, chondrocyte damage, and cartilage degradation. Additionally, MIA increased serum levels of the matrix-degrading enzyme MMP-13, while a high dose of HK-LDL557 decreased it for the controls. Simultaneously, bone turnover markers and inflammatory cytokines of serum were assayed, but no significant differences were found except for a TNF-α decrease from a low dose of live LDL557. These results demonstrated that supplementation with high doses of live LDL557 or HK-LDL557 can reduce the progression of MIA-induced OA in rats.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have a variety of cardiovascular and renoprotective effects and have been developed as novel agents for the treatment of heart failure. However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1/3/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA , EPAS1 , AGTRAP , etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.

Background: Prevention measures for palliative care and the provision of discharge planning services for inpatients in Taiwan before and during the COVID-19 pandemic had not been investigated. This study was aimed to investigate the factors associated with heightened palliative care needs and increased mortality rates., Methods: This research adopts a retrospective case-control study design. The investigation encompasses patients admitted before the pandemic (from January 1, 2019, to May 31, 2019) and during the COVID-19 pandemic (from January 1, 2020, to May 31, 2020). The case group consisted of 231 end-of-life inpatients during the pandemic, control group was composed of the pool of inpatients with pre-pandemic and matched with cases by sex and age in a 1:1 ratio., Results: The results showed that the prevalence of respiratory failure symptoms ( p  = 0.004), residing in long-term care facilities ( p  = 0.017), palliative care needs assessment scores ( p  = 0.010), as well as the provision of guidance for nasogastric tube feeding ( p  = 0.002), steam inhalation ( p  = 0.003), turning and positioning ( p  < 0.001), percussion ( p  < 0.001), passive range of motion ( p  < 0.001), and blood pressure measurement ( p  < 0.001). Furthermore, the assessment of the necessity for assistive devices, including hospital beds, also exhibited statistically significant variations ( p  < 0.001). Further investigation of the factors associated with high palliative care needs and the risk of mortality for both the case and control groups. Risk factors for high palliative care needs encompassed assessments of daily activities of living, the presence of pressure ulcers, and the receipt of guidance for ambulation. Risk factors for mortality encompassed age, a diagnosis of cancer, palliative care needs assessment scores, and the provision of guidance for disease awareness., Conclusion: This research highlights the heightened risk of COVID-19 infection among end-of-life inpatients during the COVID-19 pandemic. The findings of this study may advance care planning to alleviate avoidable suffering. To meet the needs of inpatients during pandemic, healthcare professionals should undergo comprehensive palliative care training and receive policy support., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Hsiaog, Huang, Chu and Liu.)

Osteoarthritis (OA) is a chronic degenerative disease leading to articular cartilage destruction. Menopausal and postmenopausal women are susceptible to both OA and osteoporosis. S-equol, a soy isoflavone-derived molecule, is known to reduce osteoporosis in estrogen-deficient mice, but its role in OA remains unknown. This study aimed to explore the effect of S-equol on different degrees of menopausal OA in female Sprague-Dawley (SD) rats induced by estrogen deficiency caused by bilateral ovariectomy (OVX) combined with intra-articular injection of mono-iodoacetate (MIA). Knee joint histopathological change; serum biomarkers of bone turnover, including N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (CTX-I) and N-terminal telopeptide of type I collagen (NTX-I); the cartilage degradation biomarkers hyaluronic acid (HA) and N-terminal propeptide of type II procollagen (PIINP); and the matrix-degrading enzymes matrix metalloproteinases (MMP)-1, MMP-3 and MMP-13, as well as the oxidative stress-inducing molecules nitric oxide (NO) and hydrogen peroxide (H 2 O 2 ), were assessed for evaluation of OA progression after S-equol supplementation for 8 weeks. The results showed that OVX without or with MIA injection induced various severity levels of menopausal OA by increasing pathological damage, oxidative stress, and cartilage matrix degradation to various degrees. Moreover, S-equol supplementation could significantly reduce these increased biomarkers in different severity levels of OA. This indicates that S-equol can lessen menopausal OA progression by reducing oxidative stress and the matrix-degrading enzymes involved in cartilage degradation.

Background: Atrial arrhythmia, particularly atrial fibrillation (AF), is known to be associated with renal function decline and increased risk of end-stage kidney disease. In recent years, premature atrial complexes (PACs) as subclinical arrhythmia have been proposed to be a marker of atrial cardiomyopathy and associated with poor clinical outcomes. However, the relationship between excessive daily PAC burden and renal outcomes remains unexplored., Methods: This retrospective, all-comers cohort study analyzed 30 488 consecutive Holter monitoring records obtained from a validated Holter databank at a referral medical center in Taiwan between 2011 and 2018. After exclusion, 10 981 patients were categorized into three groups: high daily PAC burden (≥100 beats per day), low PAC burden (<100 beats per day) and the AF group. We used parallel propensity score matching to balance confounding factors between groups. The primary study interest was major adverse kidney events, including an estimated glomerular filtration rate (eGFR) decline of 40%, eGFR <15 mL/min/1.73 m 2 or the initiation of hemodialysis., Results: After a mean follow-up of 4.07 ± 3.03 years, patients with high PAC burden had a 1.24-fold higher incidence of major adverse kidney events compared with the low PAC burden group [95% confidence interval (CI) 1.03-1.50]. The risk of major adverse kidney events was similar between patients with AF and those with high PAC burden [adjusted hazard ratio (HR) 1.05, 95% CI 0.87-1.25], but significantly higher in the AF group than in the low PAC burden group (adjusted HR 1.29, 95% CI 1.07-1.56)., Conclusion: Excessive daily PAC burden is associated with a higher risk of major adverse kidney events and has a comparable impact as AF., Competing Interests: All authors do not have any conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Purpose of Review: To provide an update on comorbidity of vestibular symptoms and migraine., Recent Findings: Multisensory processing and integration is a key concept for understanding mixed presentation of migraine and vestibular symptoms. Here, we discuss how vestibular migraine should be distinguished from a secondary migraine phenomenon in which migraine symptoms may coincide with or triggered by another vestibular disorder. We also have some updates on the diagnostic criteria of vestibular migraine, its pathophysiology, and common approaches used for its treatment. As a common clinical presentation of migraine and vestibular symptoms, vestibular migraine should be distinguished from a secondary migraine phenomenon, in which migraine symptoms may be triggered by or coincide with another vestibular disorder. Recent experimental evidence suggests vestibular symptoms in vestibular migraine are linked to multisensory mechanisms that control body motion and orientation in space., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: The authors declared no potential conflict of interest.