Search

BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODSSixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTSCommon adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5-14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton's tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.

Aims: MicroRNA-126 (miR-126), one of the most abundant microRNAs in platelets, is involved in the regulation of platelet activity and the circulating miR-126 is reduced during antiplatelet therapy. However, whether intraplatelet miR-126 plays a role in thrombosis and platelet inhibition remains unclear., Methods and Results: Here, using tissue-specific knockout mice, we reported that the deficiency of miR-126 in platelets and vascular endothelial cells significantly prevented thrombosis and prolonged bleeding time. Using chimeric mice, we identified that the lack of intraplatelet miR-126 significantly prevented thrombosis. Ex vivo experiments further demonstrated that miR-126-deficient platelets displayed impaired platelet aggregation, spreading, and secretory functions. Next, miR-126 was confirmed to target phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) in platelet, which encodes a negative regulator of the phosphoinositide 3-kinase/protein kinase B pathway, enhancing platelet activation through activating the integrin αIIbβ3-mediated outside-in signalling. After undergoing myocardial infarction (MI), chimeric mice lacking intraplatelet miR-126 displayed reduced microvascular obstruction and prevented MI expansion in vivo. In contrast, overexpression of miR-126 by the administration of miR-126 agonist (agomiR-126) in wild-type mice aggravated microvascular obstruction and promoted MI expansion, which can be almost abolished by aspirin administration. In patients with cardiovascular diseases, antiplatelet therapies, either aspirin alone or combined with clopidogrel, decreased the level of intraplatelet miR-126. The reduction of intraplatelet miR-126 level was associated with the decrease in platelet activity., Conclusion: Our murine and human data reveal that (i) intraplatelet miR-126 contributes to platelet activity and promotes thrombus formation, and (ii) the reduction of intraplatelet miR-126 contributes to platelet inhibition during antiplatelet therapy., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. 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.)

Although the biogeographical pattern and mechanisms underlying microbial assembly have been well-explored in lentic ecosystems, the relevant scenarios in lotic ecosystems remain poorly understood. By sequencing the bacterial communities in bacterioplankton and biofilm, our study detected their distance-decay relationship (DDR), and the balance between deterministic and stochastic processes, along the Kaidu river in an arid and semi-arid region of northwest China. Our results revealed that bacterioplankton and biofilm had significantly contrasting community structures. The bacterioplankton communities showed a gradually decreasing trend in alpha-diversity from the headwater to the river mouth, contrasting with the alpha-diversity of biofilm communities which was constant along the river length. Both bacterioplankton and biofilm showed significant DDRs along the 500-km river corridor with the slope of the bacterioplankton DDR being steeper than that of the biofilm DDR, which implies a stronger biogeography of bacterioplankton than biofilm. Relative to biofilm communities, the species interactions formed a denser and more complex network in the bacterioplankton communities than in the biofilm communities. Our results also revealed that there was a transition of community assembly from deterministic to stochastic processes upstream to downstream, although both the bacterioplankton and biofilm communities were mainly regulated by deterministic processes within the entire river. All these empirical results expand our knowledge of microbial ecology in an arid and semi-arid lotic ecosystem., Competing Interests: Declaration of Competing Interest ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Guang Gao reports financial support was provided by Nanjing Institute of Geography and Limnology Chinese Academy of Sciences. Guang Gao reports a relationship with Nanjing Institute of Geography and Limnology Chinese Academy of Sciences that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024. Published by Elsevier Inc.)

Silver carp steak is a rarely utilized silver carp processing byproduct. This study aimed to optimize a dual enzymatic method to extract antioxidant peptide components from silver carp steak and characterize their structure and in vitro antioxidant activity through ultrafiltration purification, response surface methodology, molecular docking, and radical scavenging activity analysis. The optimal extraction conditions for silver carp steak antioxidant peptides (SCSAP) were determined as 1:6 solid-liquid ratio, 1500 U/g alkaline protease addition, 4 h alkaline protease hydrolysis time, 1946 U/g flavor enzyme addition, and 2.5 h flavor enzyme hydrolysis time. The <3 kDa SCSAP component (SCSAP-3kDa) showed the strongest antioxidant activity, with its 1,1-diphenyl-2-trinitrophenyl hydrazine (DPPH) radical scavenging rate, ABTS radical scavenging rate, hydroxyl radical scavenging rate, metal ion chelating rate, and reducing capacity reaching 88.75%, 91.21%, 67.02%, 69.07%, and 0.985, respectively. Moreover, the three peptides (PF-7, GP-8, and YF-10) of 100 µg/mL could protect HepG2 cells from oxidative stress damage by reducing the oxidative damage level and activating Keap1-Nrf2-ARE pathways, enabling an increase of superoxide dismutases (SOD) activity, and a decrease of malondialdehyde (MDA) content and reactive oxygen species (ROS) level. The integrated results indicate the enormous potential of SCSAP-3kDa as a functional food ingredient in the food industry. PRACTICAL APPLICATION: This study selected the antioxidant capacity of silver carp steak peptides as the index and developed a facile dual enzymatic hydrolysis method to obtain three antioxidant peptides (PF-7, GP-8, and YF-10) with biological activity, providing a theoretical basis for bioavailability of antioxidant peptides from silver carp steak and contributing to their application in new functional foods., (© 2024 Institute of Food Technologists.)

B-box zinc-finger transcription factor (BBX) plays important regulatory roles in plant secondary metabolism. Here, we identified 21 BBXs that could be further categorized into five subfamilies from Cerasus humilis. Two segmentally duplicated Subfamily IV members, ChBBX6 and ChBBX18, were found to share high homology with reported anthocyanin-related BBXs and express highly in fruits with high anthocyanins but low carotenoids contents. Their transient overexpression in apple and C. humilis fruits both led to significantly increased anthocyanins accumulation and significantly upregulated expression of anthocyanins-related genes. However, their overexpression resulted in decreased carotenoids accumulation and greatly upregulated the expression of carotenoids-related genes especially degradation-related genes. Additionally, their overexpression both greatly improved the ABA content in C. humilis fruits. Through yeast one-hybrid and dual-luciferase reporter assays, we found that both ChBBX6 and ChBBX18 could bind to and activate the promoters of chalcone synthase (ChCHS), flavanone 3-hydroxylase (ChF3H), and 9-cis-epoxycarotenoid dioxygenase 5 (ChNCED5). Our study demonstrates that ChBBX6 and ChBBX18 are positive regulators of anthocyanins biosynthesis and carotenoids degradation and can provide basis for understanding the roles of BBX genes in C. humilis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interests., (Copyright © 2024. Published by Elsevier B.V.)

With the rapid advancements in nutrition and dietary management, infant formulas for special medical purposes (IFSMPs) have been developed to cater to the unique nutraceutical requirements of infants with specific medical conditions or physiological features. However, there are various challenges in effectively preserving and maximizing the health benefits of the specific nutraceuticals incorporated in IFSMPs. This review provides an overview of the nutritional compositions of various IFSMPs and highlights the challenges associated with the effective supplementation of specific nutraceuticals for infants. In addition, it emphasizes the promising potential of emulsion delivery systems, which possess both encapsulation and delivery features, to significantly improve the solubility, stability, oral acceptance, and bioavailability (BA) of nutraceutical bioactives. Based on this information, this work proposes detailed strategies for designing and developing model IFSMP emulsions to enhance the BA of specially required nutraceuticals. Key areas covered include emulsion stabilization, selective release mechanisms, and effective absorption of nutraceuticals. By following these proposals, researchers and industry professionals can design and optimize emulsion-based IFSMPs with enhanced health benefits. This review not only outlines the developmental states of IFSMP formulations but also identifies future research directions aimed at improving the physiological health benefits of IFSMPs. This effort lays the theoretical groundwork for the further development of emulsion-type IFSMP in infant formula (IF) industry, positioning the IF industry to better meet the complex needs of infants requiring specialized nutrition., (© 2024 Institute of Food Technologists®.)

The white spot syndrome virus (WSSV) causes white spot disease (WSD), a severe condition in crustacean aquaculture, leading to significant economic losses. Our previous study demonstrated that C7 is an effective therapeutic agent against WSSV infection in aquaculture. It specifically blocked viral horizontal transmission and reduced shrimp mortality in a dose- and time-dependent manner. Here, we report the potential antiviral mechanism of C7 in shrimp. C7 regulated abnormal glycerophospholipid metabolism caused by WSSV and inhibited phosphatidylcholine (PC) synthesis by more than twofold, potentially enhancing shrimp resistance to viral infection. As the primary phospholipid in the cell membrane, PC is one of the main reactants in lipid peroxidation. Our results indicated that C7 significantly reduced the levels of lipid peroxidation products 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) induced by WSSV, whereas PC had the opposite effect. Accumulation of lipid peroxidation products inhibits stimulator of interferon genes (STING) signaling. Further evidence showed that C7 promoted STING transport from the endoplasmic reticulum to the Golgi apparatus, significantly activating the expression of the shrimp interferon analogue Vago4 gene. In contrast, PC suppressed Vago4 expression. Our results demonstrated that C7 inhibited PC synthesis, reduced the degree of lipid peroxidation, promoted STING translocation, activated Vago4 expression, and ultimately exerted antiviral effects. Therefore, C7 exhibits immunoregulatory activity as a preventative agent for enhancing the innate immunity of shrimp, making it potentially useful for future immunomodulatory approaches., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Volatile organic compounds (VOCs) are crucial precursors in the formation of ozone (O 3 ). The sources of pollution are complex and significantly impact O 3 generation. Long-term exposure to high-concentration O 3 environments causes serious damage to organisms. High-altitude areas experience continuous high temperatures and strong solar radiation, which can easily produce O 3 through photochemical reactions, making these areas prone to frequent air pollution. This study utilizes the National Positioning Station of the Yinchuan Urban Ecosystem in Ningxia to conduct field synchronous observations, gathering data on VOCs, meteorological variables, and O 3 . By employing machine learning algorithms, we examined the seasonal distribution characteristics of VOCs, their pollution sources, and their impact on O 3 . The results show that the seasonal distribution of VOCs areas is low in spring and autumn and high in summer and winter. The components with higher volume fraction contribution are m-tolualdehyde in spring and summer, ethane in autumn, and acetylene in winter. The main emission sources of VOCs pollution are hydrocarbon volatile emission in spring and winter, solvent volatilization emission in summer, and industrial sources in autumn. VOCs have a negative effect on O 3 , with a greater impact in winter and spring, evidenced by standardized effect values of -0.26 and -0.24. The key components affecting O 3 in VOCs vary by season. Aromatic hydrocarbons are the key components in spring and winter, with contribution rates of 22 % and 21.3 %. Alkenes are the key components in summer and autumn (24.5 % and 26.8 %). Among meteorological variables, temperature is the key factor affecting O 3 , while wind speed is the key factor affecting O 3 only in winter. This study aims to clarify the sources of VOCs pollution in different seasons and their impact on O 3 , providing a theoretical basis and technical support for the prevention and control of VOCs and O 3 pollution in high-altitude areas., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Micropterus salmoides rhabdovirus (MSRV) poses a significant threat to aquaculture, causing substantial economic losses. In this study, we evaluated the antiviral efficacy and immunomodulatory potential of palmatine, a plant-derived monomer, against MSRV infection in largemouth bass. Our results demonstrated that palmatine significantly inhibited MSRV replication, with a reduction in viral nucleoprotein expression by 85 % at a safe concentration. Additionally, palmatine pre-treatment of EPC cells enhanced their antiviral capacity, with a maximum inhibition rate of 82 % following 24 h pre-incubation. Palmatine also effectively reduced MSRV-induced cytopathic effects, protecting cellular integrity and maintaining mitochondrial membrane potential. In vivo studies revealed that palmatine immersion at 80 mg/L was non-toxic and significantly suppressed MSRV replication in largemouth bass, increasing survival rates by 53 % over 15 d. Furthermore, palmatine pre-treatment enhanced the fish's resistance to MSRV, with a 78 % inhibition rate of viral replication and a 46 % increase in survival rate. Mechanistically, palmatine activated key immune genes, including IRF3, IRF7, and IFN, indicating its role in boosting innate immune responses. The compound also reduced horizontal transmission of MSRV in a cohabitation model, decreasing viral spread by up to 78 % over nine days. These findings highlight palmatine's potential as a small-molecule immunomodulator in aquaculture, offering a sustainable approach to disease management and enhancing fish health and welfare. Integrating palmatine into fish diets as an immunostimulant could provide a continuous, proactive defense against viral outbreaks, promoting more resilient and sustainable aquaculture practices., 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 Ltd. All rights reserved.)

Upon chemotherapy, excessive reactive oxygen species (ROS) often lead to the production of massive lipid peroxides in cancer cells and induce cell death, namely ferroptosis. The elimination of ROS is pivotal for tumor cells to escape from ferroptosis and acquire drug resistance. Nevertheless, the precise functions of long non-coding RNAs (lncRNAs) in ROS metabolism and tumor drug-resistance remain elusive. In this study, we identify LncRNA-HMG as a chemoresistance-related lncRNA in colorectal cancer (CRC) by high-throughput screening. Abnormally high expression of LncRNA-HMG predicts poorer prognosis in CRC patients. Concurrently, we found that LncRNA-HMG protects CRC cells from ferroptosis upon chemotherapy, thus enhancing drug resistance of CRC cells. LncRNA-HMG binds to p53 and facilitates MDM2-mediated degradation of p53. Decreased p53 induces upregulation of SLC7A11 and VKORC1L1, which contribute to increase the supply of reducing agents and eliminate excessive ROS. Consequently, CRC cells escape from ferroptosis and acquire chemoresistance. Importantly, inhibition of LncRNA-HMG by anti-sense oligo (ASO) dramatically sensitizes CRC cells to chemotherapy in patient-derived xenograft (PDX) model. LncRNA-HMG is also a transcriptional target of β-catenin/TCF and activated Wnt signals trigger the marked upregulation of LncRNA-HMG. Collectively, these findings demonstrate that LncRNA-HMG promotes CRC chemoresistance and might be a prognostic or therapeutic target for CRC., 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.)

Spring viraemia of carp virus (SVCV) is a major threat to the aquaculture industry, causing severe economic losses and significantly impacting fish health. Despite this, no approved antiviral treatments are currently available for use in aquaculture, underscoring the urgent need for effective interventions. This study evaluated the antiviral and immunomodulatory potential of Schisandrin A (SA), a bioactive compound derived from the traditional Chinese medicinal herb Schisandra chinensis, against SVCV. Through a combination of in vitro and in vivo experiments, SA was found to significantly inhibit SVCV replication, lower the viral titer, and improve survival rates in infected juvenile carp. Mechanistically, SA enhanced the host's innate immune response, as demonstrated by the upregulation of key antiviral genes including interferon-alpha1 (ifna1), interferon-gamma (ifnγ), interferon-stimulated gene 15 (isg15), and myxovirus resistance 1 (mx1). Additionally, SA exhibited potent antioxidative properties, preserving mitochondrial integrity and reducing oxidative stress in SVCV-infected cells. These findings showed the dual role of SA in both directly suppressing viral replication and modulating the immune response, offering a multifaceted approach to managing SVCV infection. Given its low toxicity and biodegradability, SA emerges as a promising, sustainable antiviral agent for aquaculture. This study highlights the potential of SA to enhance biosecurity and promote sustainability in the industry, paving the way for the development of eco-friendly antivirals that could improve the management of viral diseases, ensuring healthier fish populations and greater economic stability., 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 Ltd. All rights reserved.)

The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618-482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = -0.309, 95% CI: -0.38 to -0.24, p = 1.51E-19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10, 95% CI: -0.188 to -0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Soluble carbohydrates and organic acids are critical determinants of fruit flavor and consumer preference, both of which are susceptible to postharvest treatments and storage conditions. While the individual effectiveness of 1-methylcyclopropene (1-MCP) and non-chilling temperature storage in delaying fruit ripening and influencing flavor development has been established, their combined effects on peach storage traits remain unexplored. This study investigated the impact of 1-MCP combined with non-chilling temperature storage on the quality and flavor attributes of yellow peach. Our results revealed that 1-MCP treatment reduced ethylene production during storage and delayed ripening and softening by down-regulating ethylene biosynthesis and signaling genes. Transcriptomic analysis indicated that 1-MCP maintained higher levels of soluble carbohydrates by up-regulating sucrose phosphate synthase (PpSPS1/2) and sorbitol dehydrogenase (PpSDH1) while down-regulating hexokinase (PpHXK1). Concurrently, 1-MCP preserved citric and malic acid levels by suppressing aconitate hydratase (PpACO1) and inducing malate dehydrogenase (PpMDH1), thereby delaying flavor degradation. Co-expression network analysis implicated ethylene response factors (PpERFs) as major regulators of sugar and acid metabolisms genes, with PpERF19 potentially functioning as a key transcriptional controller. Overall, this study verified the efficacy of combined 1-MCP and non-chilling storage for yellow peach preservation, identified key 1-MCP-modulated genes involved in sugar and acid metabolisms, and provided insights into regulating peach flavor development via postharvest approaches., 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 Masson SAS. All rights reserved.)

Introduction: Past studies suggested that Parkinson's disease (PD) patients who engage in physical activity (PA) after diagnosis have slower motor progression. Here, we examine the influence of lifetime PA prior to PD onset on motor, cognitive, and overall functional decline among PD patients., Methods: For 495 participants in the Parkinson's Environment and Gene (PEG) studies, we collected PA-related measures through interviews and quantified these using metabolic equivalents (MET) scores. PD progression was defined as time to a Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) conversion to ≥ 35 points, Hoehn and Yahr (H&Y) ≥ 3, and a 4-point decline in Mini-Mental State Examination (MMSE). We used Cox frailty models to estimate hazard ratios and inverse probability weights to account for heterogeneity by enrollment wave and censoring., Results: For PD patients reporting the highest lifetime strenuous MET-h/wk (highest quartile), we estimated a lower HR for time-to-UPDRS-III-conversion (Q4 vs. Q1: HR = 0.56, 95 % CI = [0.36, 0.87]). Additionally, having engaged in any competitive sport also reduced the risk of reaching a UPDRS-III ≥ 35 points (low vs. none: HR = 0.61, 95 % CI = [0.44, 0.86]; high vs. none: HR = 0.63; 95 % CI = [0.44,0.86]); high levels of sports activities also affected progression on the H&Y scale (high vs. none: HR = 0.73; 95 % CI = [0.46,1.00]). Lifetime PA measures did not affect time-to-MMSE decline., Conclusion: Our study suggests that PD patients who engaged in higher levels of lifetime strenuous PA and competitive sports prior to PD diagnosis experience slower motor and overall functional decline, suggesting that lifetime PA may contribute to a physical reserve advantageous for PD patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Study Objective: Computed tomography pulmonary angiogram (CTPA) is overused during pulmonary embolism (PE) testing in the emergency department (ED), whereas prediction rules and D-dimer are underused. We report the adherence, clinical benefit, and safety of a D-dimer-only strategy to guide need for PE imaging in the ED., Methods: This was a prospective multicenter implementation study in 2 EDs with historical and external controls. Patients with suspected PE underwent D-dimer testing and imaging (CTPA or ventilation-perfusion scan) when D-dimer levels were 500 ng/mL or more. PE was ruled out if D-dimer was less than 500 ng/mL or with negative imaging. The primary implementation outcome was the proportion of patients tested for PE in adherence with the pathway. The primary clinical benefit outcome was the proportion of patients tested for PE who received pulmonary imaging. The primary safety outcome was diagnosis of PE in the 30 days following negative PE testing postimplementation., Results: Between January 2018 and June 2021, 16,155 patients were tested for PE, including 33.4% postimplementation, 30.7% preimplementation, and 35.9% in an external control site. Adherence with the D-dimer-only pathway was 97.6% (adjusted odds ratio (aOR) post- versus preimplementation 5.26 (95% confidence interval 1.70 to 16.26). There was no effect on the proportion undergoing PE imaging. Imaging yield increased aOR 4.89 (1.17 to 20.53). Two cases of PE (0.04%; 0.01% to 0.16%) were diagnosed within 30 days., Conclusion: In this Canadian ED study, the uptake of a D-dimer-only PE testing strategy was high. Implementation was associated with higher imaging yield and a D-dimer level of less than 500 ng/mL safely excluded PE., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Glyphosate, a commonly used organophosphorus herbicide in rice-crayfish cropping regions, may alter regional phosphorus cycle processes while affecting the structure of microbial communities. However, the effects of glyphosate residues on rice-crayfish systems remain unclear. In this study, we assessed the spatial and temporal distribution characteristics of glyphosate and its primary degradation products, as well as the impact mechanisms of glyphosate on microbial communities and the phosphorus cycle in rice-crayfish systems such as paddy fields, breeding ditches and recharge rivers. The detection rates of glyphosate and aminomethylphosphonic acid (AMPA) were 100% in rice-crayfish systems. Concentrations of glyphosate in the water phase and soil/sediment were as high as 0.012 μg/L and 7.480 μg/kg, respectively, and concentrations of AMPA were as high as 17.435 μg/L and 13.200 μg/kg, respectively. Glyphosate concentrations were not affected by rainfall or sampling site, but concentrations of AMPA in the water phase of recharge rivers were affected by rainfall. The glyphosate concentration was significantly and positively correlated with RBG-16-58-14 abundance, and the AMPA concentration was significantly and positively correlated with Actinobacteria and Lysobacter abundance, and negatively correlated with Cyanobacteria abundance (P < 0.05). The highest abundances of phoD, phnK, and ppx genes were found in all soils/sediments. Glyphosate concentration in soil/sediment was significantly and positively correlated with the abundance of phoD gene encoding an organophosphorus-degrading enzyme and ppx gene encoding poly inorganic phosphate (Pi) hydrolase (P < 0.05). In addition, the glyphosate concentration was significantly and positively correlated with the Ca-bonded Pi content (P < 0.05). This implies that glyphosate may promote the production of stable Pi in rice-crayfish systems by increasing the abundance of phoD and ppx genes. The results of this study reveal the impact mechanism of glyphosate on the phosphorus cycle in rice-crayfish systems and provide a basis for the risk assessment of glyphosate., 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 Inc. All rights reserved.)

The study aimed to describe the prevalence of lymph node metastases per lymph node station for esophageal squamous cell carcinoma (ESCC) after neoadjuvant treatment. Clinicopathological variables of ESCC patients were retrieved from the prospective database of the Surgical Esophageal Cancer Patient Registry in West China Hospital, Sichuan University. A two-field lymphadenectomy was routinely performed, and an extensive three-field lymphadenectomy was performed if cervical lymph node metastasis was suspected. According to AJCC/UICC 8, lymph node stations were investigated separately. The number of patients with metastatic lymph nodes divided by those who underwent lymph node dissection at that station was used to define the percentage of patients with lymph node metastases. Data are also separately analyzed according to the pathological response of the primary tumor, neoadjuvant treatment regimens, pretreatment tumor length, and tumor location. Between January 2019 and March 2023, 623 patients who underwent neoadjuvant therapy followed by transthoracic esophagectomy were enrolled. Lymph node metastases were found in 212 patients (34.0%) and most frequently seen in lymph nodes along the right recurrent nerve (10.1%, 58/575), paracardial station (11.4%, 67/587), and lymph nodes along the left gastric artery (10.9%, 65/597). For patients with pretreatment tumor length of >4 cm and non-pathological complete response of the primary tumor, the metastatic rate of the right lower cervical paratracheal lymph nodes is 10.9% (10/92) and 10.6% (11/104), respectively. For patients with an upper thoracic tumor, metastatic lymph nodes were most frequently seen along the right recurrent nerve (14.2%, 8/56). For patients with a middle thoracic tumor, metastatic lymph nodes were most commonly seen in the right lower cervical paratracheal lymph nodes (10.3%, 8/78), paracardial lymph nodes (10.2%, 29/285), and lymph nodes along the left gastric artery (10.4%, 30/289). For patients with a lower thoracic tumor, metastatic lymph nodes were most frequently seen in the paracardial station (14.2%, 35/247) and lymph nodes along the left gastric artery (13.1%, 33/252). The study precisely determined the distribution of lymph node metastases in ESCC after neoadjuvant treatment, which may help to optimize the extent of lymphadenectomy in the surgical management of ESCC patients after neoadjuvant therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ethnopharmacological Relevance: Dendrobium crepidatum Lindl. ex Paxton is a perennial epiphyte of Dendrobium genus, distributed in southern China, and utilized as the traditional Chinese medicine "Shihu" in Yunnan Province. Due to its heat-clearing and detoxicating properties, it is formulated as the "XiaoCuoWan" as recorded in the China Pharmacopoeia, and specially used to treat chronic skin inflammatory diseases, such as acne., Aim of the Study: This research aimed to estimate impact of the octahydroindoline alkaloid Homocrepidine A (HCA), isolated from D. crepidatum, on acne inflammation using both human THP-1 cells and mouse models. Furthermore, the potential anti-inflammatory mechanism of HCA has been analyzed through molecular biology methods and computer simulation., Materials and Methods: THP-1 cells and mouse models induced by live Propionibacterium acnes (P. acnes) were employed to evaluate the anti-inflammatory properties of crude extract of D. crepidatum (DCE) and HCA. ELISA was utilized to detect the release of inflammatory cytokines in both cellular and murine ear tissues. RNAseq was used to screen the pathways associated with HCA-mediated inflammatory inhibition, while Western blot, RT-qPCR, and immunofluorescence were utilized to detect the expression of relevant proteins. Additionally, molecular docking simulations and cellular thermal shift assays were employed to confirm the target of HCA., Results: Our research shows that DCE and HCA can effectively alleviate acne inflammation. HCA inhibits TLR2 expression by interacting with amino acid residues in the TIR domain of hTLR2, including Pro-681, Asn-688, Trp-684, and Ile-685. Moreover, HCA disrupts inflammatory signal transduction mediated by MAPK and NF-κB pathways through MyD88-dependent pathway. Additionally, HCA treatment facilitates Nrf2 nuclear translocation and upregulates HO-1 expression, thereby inhibiting NLRP3 inflammasomes activation. In vivo experiments further revealed that HCA markedly attenuated erythema and swelling caused by P. acnes in mice ears, while also decreasing the expression of pro-inflammatory cytokines IL-1β and IL-8., Conclusions: Our research highlights the protective effects of D. crepidatum and its bioactive compound HCA against acne inflammation, marking the first exploration of its potential in this context. The discoveries indicate that HCA treatment may represent a promising functional approach for acne therapy., 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.)

Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Short-term exposure to ozone (O 3 ) has been associated with higher stroke mortality, but it is unclear whether this association differs between urban and rural areas. The study aimed to compare the association between short-term exposure to O 3 and ischaemic and haemorrhagic stroke mortality across rural and urban areas and further investigate the potential impacts of modifiers, such as greenness, on this association., Methods: A multi-county time-series analysis was carried out in 19 counties of Shandong Province from 2013 to 2019. First, we employed generalized additive models (GAMs) to assess the effects of O 3 on stroke mortality in each county. We performed random-effects meta-analyses to pool estimates to counties and compare differences in rural and urban areas. Furthermore, a meta-regression model was utilized to assess the moderating effects of county-level features., Results: Short-term O 3 exposure was found to be associated with increased mortality for both stroke subtypes. For each 10-µg/m 3 (lag0-3) rise in O 3 , ischaemic stroke mortality rose by 1.472% in rural areas and 1.279% in urban areas. For each 0.1-unit increase in the Enhanced Vegetation Index (EVI) per county, the ischaemic stroke mortality caused by a 10-µg/m 3 rise in O 3 decreased by 0.60% overall and 1.50% in urban areas., Conclusions: Our findings add to the evidence that short-term O 3 exposure increases ischaemic and haemorrhagic stroke mortality and has adverse effects in urban and rural areas. However, improving greenness levels may contribute to mitigating the detrimental effects of O 3 on ischaemic stroke mortality., (© 2024. The Author(s).)

The use of deep learning techniques to identify grape leaf diseases relies on large, high-quality datasets. However, a large number of images occupy more computing resources and are prone to pattern collapse during training. In this paper, a depth-separable multifeature generative adversarial network (DMFGAN) was proposed to enhance grape leaf disease data. First, a multifeature extraction block (MFEB) based on the four-channel feature fusion strategy is designed to improve the quality of the generated image and avoid the problem of poor feature learning ability of the adversarial generation network caused by the single-channel feature extraction method. Second, a depth-based D-discriminator is designed to improve the discriminator capability and reduce the number of model parameters. Third, SeLU activation function was substituted for DCGAN activation function to overcome the problem that DCGAN activation function was not enough to fit grape leaf disease image data. Finally, an MFLoss function with a gradient penalty term is proposed to reduce the mode collapse during the training of generative adversarial networks. By comparing the visual indicators and evaluation indicators of the images generated by different models, and using the recognition network to verify the enhanced grape disease data, the results show that the method is effective in enhancing grape leaf disease data. Under the same experimental conditions, DMFGAN generates higher quality and more diverse images with fewer parameters than other generative adversarial networks. The mode breakdown times of generative adversarial networks in training process are reduced, which is more effective in practical application., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

The optoelectronic, electrocatalytic, and photocatalytic properties of new tin selenides are of great significance for various energy applications. Herein, a facile solvothermal reaction of Sn, Se, and MnCl 2 in 1,3-propodiamine (1,3-dap) solution at 150 °C for 7 days was used to achieve a new type of one-dimensional (1D) organic hybrid manganese-tin selenide [Mn 2 (1,3-dap) 4 (μ-1,3-dap)Sn 2 Se 6 ] n ( MnSnSe-1 ), whose 1D framework is built up from the linkage of rare unsaturated binuclear [Mn 2 (1,3-dap) 4 (μ-1,3-dap)] 2+ cations and dimeric [Sn 2 Se 6 ] 4- anions. The combination of MnSnSe-1 and Ni nanoparticle is first applied for the preparation of a Ni/ MnSnSe-1 /NF electrode (NF = porous Ni foam) as the efficient electrocatalyst for the hydrogen evolution reaction (HER), indicating excellent HER electrocatalytic property with an overpotential of 117 mV at 10 mA·cm -2 in a neutral medium. Owing to its narrow absorption edge of 1.65 eV, implying prominent harvesting ability in the visible-light region, MnSnSe-1 shows a remarkable photocurrent response and excellent visible-light-driven photocatalytic property for the degradation of methylene blue in aqueous solution.

L-Boronophenylalanine (BPA), a widely used 10 B carrier for clinical boron neutron capture therapy (BNCT), was quantified in rat plasma through a simple, effective and stable ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Chromatographic separation was performed on an ACQUITY UPLC HSS T3 (100 mm × 2.1 mm, 1.8 μm) column with the mobile phase of 0.5 % formic acid aqueous solution and acetonitrile. For the detector, the m/z ion pairs used for quantification were 209.1→120.1 for BPA and 210.1→120.1 for internal standard in a positive mode by electrospray ionization (ESI) using multiple reaction monitoring (MRM). The method is specific and robust with rare affection by endogenous substances in the matrix. A good linear relationship was observed over 80-80000 ng/mL (r 2 = 0.9993). The values of inter- and intra-day accuracy and precision were within the acceptance criteria of ±15 %. BPA was found to be stable under different experimental conditions. This developed method was successfully applied on a pharmacokinetic experiment on Sprague-Dawley rats (intravenous injection, 125 mg/kg) and a comparation between UHPLC-MS/MS and ICP-MS for BPA was carried out., 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.)

Phosphatidylserine (PS), a rare phospholipid in Antarctic krill oil (AKO) critical for brain development, can be produced from the abundant phosphatidylcholine (PC) using phospholipase D (PLD) in Pickering emulsion interfacial catalysis (PIC) systems. However, the exposure of PLD to organic solvent around the emulsion interface diminished PLD activity, limiting the conversion efficiency of PS. In this study, we proposed a strategy to fabricate a PIC system with high efficiency and stability by immobilizing PLD in a specific phase on the emulsion interface, based on investigating the effect of the interfacial microenvironment on PLD activity. Janus-poly(acrylic acid)/polystyrene (JPP) and Janus-polyethylenimine/octadecane (JPO) particles were fabricated as carriers to realize the specific-phase immobilization of PLD. The highest activity was observed when PLD was immobilized on the hydrophilic side of JPP (PLD@JPP(W)), 1.9-fold that of free PLD. The catalytic efficiency of PLD@JPP(W) was 1.7-fold that of free PLD, confirmed by the k cat / K m value enhancement. Immobilization on the hydrophilic side also enhanced the thermal stability of PLD. The half-lives of PLD were extended from 4 to 36 h at 40 °C and from 6 to 28 days at 4 °C. Importantly, PLD@JPP(W) showed excellent catalytic efficiency as a PIC system, achieving a PS productivity of 93% within a short time of 2 h at an enzyme dosage of 0.05 mg. PLD@JPP(W) exhibited a 3.6 times higher yield than free PLD in the production of PS from PC rich in Antarctic krill oil. The strategy in this work could also be applied to other lipases, providing a promising method for the efficient conversion of functional lipids.

There is still little research on the consistency among the subcortical volume estimates of different software packages. It is also unclear whether there are age-related differences in the inter-software consistency. The current study aimed to examine the consistency of three commonly used automated software packages and the effect of age on inter-software consistency. We analyzed T1-weighted structural images from two public datasets, in which the subjects were divided into four age groups ranging from childhood and adolescence to late adulthood. We chose three mainstream automated software packages including FreeSurfer, CAT, and FSL, to estimate the volumes of seven subcortical structures, including thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and accumbens. We used the intraclass correlation coefficient (ICC) and Pearson correlation coefficient (PCC) to quantify inter-software consistency and compared the consistency measures among the age groups. As a measure of validity, we additionally evaluated the predictive power of each software package's estimates for predicting age. The results showed good inter-software consistency in the thalamus, caudate, putamen, and hippocampus, moderate consistency in the pallidum, and poor consistency in the amygdala and accumbens. Significant differences in the inter-software consistency were not observed among the age groups in most cases. FreeSurfer exhibited higher age prediction accuracy than CAT and FSL. The current study showed that the inter-software consistency on the subcortical volume estimation varies with structures but generally not with age groups, which has important implications for the interpretation and reproducibility of neuroimaging findings., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Eucalyptus urophylla S.T. Blake, an important economic tree species, is widely cultivated as a raw material source for pulpwood, veneer plywood, and sawlog timber in southern China. As a tree in multiple environments, tree-breeding programs can assess genotype by environment (G × E) interactions and identify the suitable genotype for a specific environment. G × E interactions related to growth traits and soil factors have not been adequately studied for clones of Eucalyptus urophylla and its hybrids. To examine this important question, trials containing 20 clones of E. urophylla and its hybrids were established at three sites in southern China: Shankou (SK), Tiantang (TT), and Xiniujiao (XNJ). These sites each have different soil conditions but similar geographical and climatic conditions. With the data across nearly eight years, average phenotypic trends and broad sense repeatability (H 2 ) were modeled, G×E interactions between clones and diverse soil environments were estimated, genetic gains of clones were calculated, and the adaptabilities of E. urophylla clones in different soil environments were compared. Average survival trends for clones tended to show a moderate decrease while growth traits tended to show sharp increases with age. At the same age, sites were ordered for average survival and growth traits as TT>SK>XNJ while H 2 values for growth traits by site followed the basic order TT>SK>XNJ. The H 2 values for growth traits at SK tended to increase at first, platform, and then smooth with age. The H 2 values for growth traits at TT were high and stable across ages, and those at XNJ tended to undulate largely at a relatively low level across ages. Genetic correlations for growth traits between any pair of sites tended to increase at first and then decrease. A genetic correlation was strong between SK and TT, intermediate between SK and XNJ, and weak between TT and XNJ. It was concluded that: (1) clones tended to be adapted better to an environment with acidic and loamy soil with a clay content of about 45.6%, the soil depth from the surface to parent material about 1.5 m, and the previous vegetation of Eucalypts . (2) The G×E interactions between clones and sites are weaker if the environmental conditions between the sites are similar, and which are stronger if the environmental conditions between the sites are different. (3) The optimum selection age for clones ranged from 1.5 to 3.5 years old, while the optimum selection growth trait is individual tree volume., Competing Interests: The authors declare there are no competing interests., (©2024 Li et al.)

Introduction: This systematic review aimed to determine the effect of therapeutic drug monitoring (TDM) for tumor necrosis factor-α inhibitors (TNF-αI) in immune-mediated inflammatory diseases (IMIDs) based on real-world evidence, as results from published meta-analyses based on randomized controlled trials (RCTs) may not fully capture the nuances of clinical practice due to strict criteria., Methods: We searched PubMed, Embase, and the Cochrane Library up to 1 August 2023. Cohort studies comparing TDM (proactive and reactive) with empirical management were included. Primary outcome was effectiveness [for IBDs: clinical remission; for rheumatic diseases: clinical remission or low disease activity], with certainty of evidence appraised using the GRADE approach. Secondary outcomes included treatment failure, serious adverse events (SAEs), IMIDs-related surgeries or hospitalizations, and anti-drug antibodies (ADAs) development risk., Results: Twenty-four cohort studies were included and almost all were on infliximab. For IBDs, compared with empirical management, proactive TDM significantly improved clinical remission (RR = 1.15, 95% CI = 1.04-1.28), reduced IBDs-related surgeries (RR = 0.46, 95% CI = 0.26-0.81), hospitalizations (RR = 0.60, 95% CI = 0.43-0.83), SAEs (RR = 0.23, 95% CI = 0.07-0.76), and ADAs development risk (RR = 0.34, 95% CI = 0.19-0.60). Reactive TDM significantly lowered hospitalization rates and might be cost-effective. Proactive TDM outperformed reactive TDM in secondary outcomes. For rheumatic diseases, benefits of TDM were inconclusive due to limited evidence., Conclusions: Real-world evidence supports proactive TDM of TNF-αI (particularly infliximab) in IBDs to improve effectiveness, safety, and immunogenicity. However, benefits of TDM for different TNF-αI in other IMIDs remain uncertain., Protocol Registration: www.crd.york.ac.uk/ PROSPERO identifier is CRD42022370846.

Background: Neoadjuvant immunotherapy is under intensive investigation for esophageal squamous cell carcinoma (ESCC). This study assesses the efficacy and immune response of neoadjuvant immunochemotherapy (nICT) in ESCC., Methods: In this phase II trial (ChiCTR2100045722), locally advanced ESCC patients receiving nICT were enrolled. The primary endpoint was the pathological complete response (pCR) rate. Multiplexed immunofluorescence, RNA-seq and TCR-seq were conducted to explore the immune response underlying nICT., Results: Totally 42 patients were enrolled, achieving a 27.0% pCR rate. The 1-year, 2-year DFS and OS rates were 89.2%, 64.4% and 97.3%, 89.2%, respectively. RNA-seq analysis highlighted T-cell activation as the most significantly enriched pathway. The tumour immune microenvironment (TIME) was characterised by high CD4, CD8, Foxp3, and PD-L1 levels, associating with better pathological regression (TRS0/1). TIME was categorised into immune-infiltrating, immune-tolerant, and immune-desert types. Notably, the immune-infiltrating type and tertiary lymphoid structures correlated with improved outcomes. In the context of nICT, TIM-3 negatively influenced treatment efficacy, while elevated TIGIT/PD-1 expression post-nICT correlated positively with CD8+ T cell levels. TCR-seq identified three TCR rearrangements, underscoring the specificity of T-cell responses., Conclusions: Neoadjuvant camrelizumab plus chemotherapy is effective for locally advanced, resectable ESCC, eliciting profound immune response that closely associated with clinical outcomes., (© 2024. The Author(s).)

Background: Despite the widespread adoption of video-assisted thoracoscopic surgery (VATS) for major lung resection, the 10-year long-term survival outcomes of non-small cell lung cancer (NSCLC) treated with VATS compared with open major lung resection is lacking. The purpose of this study was to analyze the short- and long-term outcomes of VATS vs. open major lung resection for NSCLC., Methods: The perioperative outcomes and long-term survival of p-stage I-III NSCLC patients who underwent major lung resection via VATS vs. open major lung resection in the Western China Lung Cancer Database (WCLCD) between May 2006 and June 2018 were studied using propensity score matching (PSM)., Results: Of the 10,167 patients who underwent surgery for lung malignancies, 6,405 patients with stage I-III NSCLC were included in the study, including 4,224 in the VATS group and 2,181 in the open group. PSM resulted in 1,487 patients in both the VATS and open groups. The patients were matched by patient demographics, Charlson comorbidity index (CCI), tumor histology and TNM stage. Compared with open surgery, major lung resection via VATS resulted in less blood loss (median: 50 vs. 100 mL, P<0.001) and a shorter postoperative hospital stay (7.6±6.0 vs. 8.6±4.9 days, P<0.001) but higher total hospital costs (52.5±21.2 vs. 45.0±16.4 kRMB, P<0.001). The matched cohort showed that patients who underwent major lung resection via VATS had better overall survival (OS) and recurrence-free survival (RFS) than did patients who underwent major lung resection via open surgery (5-year survival: 64.9% vs. 57.7%, P<0.001; 5-year RFS: 50.3% vs. 45.3%, P=0.003). Patients who underwent VATS had a better 10-year OS rate (47.8% vs. 42.6%). According to the subgroup analysis, patients with stage II NSCLC who underwent major lung resection via VATS had better OS and RFS (OS: P<0.001; RFS: P=0.004), while there were no significant differences in OS or RFS between stage I and III NSCLC patients., Conclusions: Major lung resection via the VATS should be the preferred surgical option for stage I-III NSCLC patients due to its superior long-term survival outcome and advantages of less blood loss and shorter postoperative hospital stays., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-150/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

This study aimed to develop a satisfactory essential oil (EO) nano-emulsion through high pressure microjet technology and explore its physiochemical properties and synergistic coating effects on grass carp fillets. The optimal conditions for oregano/litsea cubeba (6:4, wt%/wt%) nano-emulsion were shown to be 80 s high pressure microjet pretreatment time, 9000 lb per square inch pretreatment pressure, 6 % oil phase, and 3:2 Km (mass ratio of surfactant to co-surfactant). The obtained nano-emulsion exhibited 100.42 ± 0.96 nm oil diameter at 4 °C after 15-day storage, coupled with high stability after centrifugation, freeze-thaw and heating treatment. Compared with untreated samples at day 6 storage, the nano-emulsion-treated grass carp fillets exhibited improved textural properties, higher water-holding capacity (74.23 % ± 0.80 %), lower total volatile basic nitrogen (TVB-N, 13.46 ± 0.30 mg/100g)/thiobaric acid (TBA,0.43 ± 0.02 mgMDA/100g), and lower total viable spoilage bacteria count (4.98 ± 0.21 lgCFU/g). This study facilitates understanding the combined EOs nano-emulsion on improving the shelf life of grass carp fillets., 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 Ltd. All rights reserved.)

Objective: Numerous observational studies have found a relationship between systemic lupus erythematosus (SLE) and epilepsy; however, their causal relationship remains unclear. This study aimed to investigate the causal role of SLE in epilepsy or any of its subtypes using a two-sample Mendelian randomization (MR) analysis., Methods: Single nucleotide polymorphisms (SNPs) linked to SLE were utilized as instrumental variables in MR analysis to assess their causal impact on epilepsy. The primary MR findings were derived using the inverse variance weighted (IVW) method, which was further supported by the weighted median and MR-Egger regression techniques. Additionally, sensitivity analyses, including Cochran's Q test and pleiotropy tests, were conducted to evaluate the influence of these SNPs on epilepsy, particularly looking for signs of horizontal pleiotropy and heterogeneity., Results: We selected 43 SNPs that reached genome-wide significance from genome-wide association studies (GWASs) on SLE to serve as instrumental variables in this study. The IVW method showed no evidence to support a causal association between SLE and epilepsy (all epilepsy: odds ratio (OR) = 1.006, 95% confidence interval (CI) = 0.994-1.018; focal epilepsy: OR = 1.006, 95% CI = 0.994-1.019; generalized epilepsy: OR = 1.015, 95% CI = 0.996-1.035). Other MR complementary methods revealed consistent results. Furthermore, there was no evidence indicating heterogeneity or horizontal pleiotropy., Significance: The findings of MR analysis did not support a genetically predicted causal relationship between SLE and epilepsy, but emphasized the need for further research on shared pathophysiological mechanisms, particularly the role of immune system abnormalities and potential influences such as chronic inflammation and therapeutic interventions., Plain Language Summary: The etiology of epilepsy is complex and diverse, including immune factors. Through a Mendelian randomization analysis, we did not find evidence of a genetic causal relationship between systemic lupus erythematosus and epilepsy. However, this does not invalidate epidemiological evidence, and further exploration is needed to investigate factors influencing the relationship between the two., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Fermentation has been identified as an effective strategy to alter the chemical makeup of tobacco, thereby enhancing its quality. The deliberate introduction of microorganisms can hasten the fermentation process. In this research, microbial consortia harvested from the tobacco surface were utilized to enhance the tobacco quality. This enhancement also elevated several sensory attributes of HnB cigarettes, such as aroma richness, moisture, strength, and reduced irritation, achieving a sensory quality rating of 84.5. This marks a notable improvement compared to the 82 rating of the original, unfermented cigarettes. Untargeted metabolomics analysis revealed a decrease in total polyphenols and unsaturated fatty acids, while the levels of polyacids, alcohols, ketones, furans, and other compounds increased in the fermented tobacco. Additionally, KEGG pathway enrichment analysis indicated that the enhancement in tobacco quality through microbial consortia fermentation is linked to various biological pathways, with pathways related to fatty acid and amino acid degradation playing pivotal roles. The findings of this study will serve as a reference for the commercial production of HnB cigarettes, and the elucidated mechanism offers a theoretical basis for exploring microbial fermentation as a means to improve tobacco quality.

This research aimed to investigate the pharmacological components for liver stagnation and spleen deficiency syndrome (LSSDS) of Evodia rutaecarpa (also called Yu HuangLian [YHL]) by exploring the spectrum-effect relationship between fingerprints and pharmacological actions. The fingerprints of 17 batches of YHL with different preparation conditions according to Box-Behnken Design were generated and analyzed to identify the common peaks by HPLC and FT-IR. Vasoactive intestinal peptide (vip), substance P, and 5-HT levels in colon sample were measured by ELISA. Gray degree correlation and orthogonal partial least squares were employed to explore the correlation degree between components and pharmacologic activity. The presumed pharmacological components were further confirmed by network pharmacology, molecular docking, and qRT-PCR. The columbamine, jatrorrhizine, coptisine, berberine, rutecarpine, and evodiamine of the 14 common peaks in HPLC fingerprints were significantly correlated with the pharmacological indexes. Similarly, there was a strong correlation with -OH, δNC-H, and νC-O-C of the 10 common peaks in FT-IR fingerprints. PTGS2 and CHRM3 were the main targets intervening LSSDS, and the presumed pharmacological components could markedly increase the expression of CHRM3 and obviously reduce the expression of PTGS2 compared with the model group., (© 2024 John Wiley & Sons, Ltd.)

Adaptor proteins play crucial roles in signal transduction across diverse signaling pathways. Src-homology 2 domain-containing E (SH2E) is the adaptor protein highly expressed in vascular endothelial cells and myocardium during zebrafish embryogenesis. In this study we investigated the function and mechanisms of SH2E in cardiogenesis. We first analyzed the spatiotemporal expression of SH2E and then constructed zebrafish lines with SH2E deficiency using the CRISPR-Cas9 system. We showed that homozygous mutants developed progressive pericardial edema (PCE), dilated atrium, abnormal atrioventricular looping and thickened atrioventricular wall from 3 days post fertilization (dpf) until death; inducible overexpression of SH2E was able to partially rescue the PCE phenotype. Using transcriptome sequencing analysis, we demonstrated that the MAPK/ERK and NF-κB signaling pathways might be involved in SH2E-deficiency-caused PCE. This study underscores the pivotal role of SH2E in cardiogenesis, and might help to identify innovative diagnostic techniques and therapeutic strategies for congenital heart disease., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Introduction: This systematic review aimed to determine the effect of therapeutic drug monitoring (TDM) for tumor necrosis factor-α inhibitors (TNF-αI) in immune-mediated inflammatory diseases (IMIDs) based on real-world evidence, as results from published meta-analyses based on randomized controlled trials (RCTs) may not fully capture the nuances of clinical practice due to strict criteria., Methods: We searched PubMed, Embase, and the Cochrane Library up to 1 August 2023. Cohort studies comparing TDM (proactive and reactive) with empirical management were included. Primary outcome was effectiveness [for IBDs: clinical remission; for rheumatic diseases: clinical remission or low disease activity], with certainty of evidence appraised using the GRADE approach. Secondary outcomes included treatment failure, serious adverse events (SAEs), IMIDs-related surgeries or hospitalizations, and anti-drug antibodies (ADAs) development risk., Results: Twenty-four cohort studies were included and almost all were on infliximab. For IBDs, compared with empirical management, proactive TDM significantly improved clinical remission (RR = 1.15, 95% CI = 1.04-1.28), reduced IBDs-related surgeries (RR = 0.46, 95% CI = 0.26-0.81), hospitalizations (RR = 0.60, 95% CI = 0.43-0.83), SAEs (RR = 0.23, 95% CI = 0.07-0.76), and ADAs development risk (RR = 0.34, 95% CI = 0.19-0.60). Reactive TDM significantly lowered hospitalization rates and might be cost-effective. Proactive TDM outperformed reactive TDM in secondary outcomes. For rheumatic diseases, benefits of TDM were inconclusive due to limited evidence., Conclusions: Real-world evidence supports proactive TDM of TNF-αI (particularly infliximab) in IBDs to improve effectiveness, safety, and immunogenicity. However, benefits of TDM for different TNF-αI in other IMIDs remain uncertain., Protocol Registration: www.crd.york.ac.uk/ PROSPERO identifier is CRD42022370846.

The Loess Plateau is renowned for its deep soil layer and rich in organic carbon (C). In recent years, numerous ecological restoration projects have been undertaken on the Loess Plateau, with consequence on the stability of soil organic carbon (SOC). The SOC stability is pivotal for its capacity to sequestrate and store C. However, comprehensive review on the characteristics of SOC stability and its mechanisms during vegetation restoration on the Loess Plateau is scarce. Therefore, we summarized the dynamics of SOC stability during vegetation restoration on the Loess Plateau, discussed the mechanisms of SOC stabilization, including mineral protection, physical protection, and biological mechanisms. Furthermore, we prospected the future development directions and research focus of SOC stability research during vegetation restoration on the Loess Plateau to provide scientific support for theory and technology of soil C sequestration and stabilization during vegetation restoration, and to provide scientific reference for achieving the "double-carbon" goals.

Introduction: Carotenoids are important precursors of various aroma components in tobacco and play an important role in the sensory quality of tobacco. Phaffia rhodozyma is a species of Xanthophyllomyces capable of synthesizing a highly valuable carotenoid-astaxanthin, but has not yet been used in improving tobacco quality., Methods: The dynamic changes of microbial community and metabolites during tobacco fermentation were analyzed in combination with microbiome and metabolome, and the quality of tobacco after fermentation was evaluated by sensory scores., Results: P. rhodozyma could grow and produce carotenoids in tobacco extract, with a maximum biomass of 6.50 g/L and a maximum carotenoid production of 36.13 mg/L at 100 g/L tobacco extract. Meanwhile, the correlation analysis combined with microbiome and metabolomics showed that P. rhodozyma was significantly positively correlated with 11 metabolites such as 6-hydroxyluteolin and quercetin. Furthermore, the contents of alcohols, ketones and esters, which were important aromatic components in fermented tobacco, reached 77.57 μg/g, 58.28 μg/g and 73.51 μg/g, increasing 37.39%, 265.39% and 266.27% compared to the control group, respectively. Therefore, the aroma and flavor, and taste scores of fermented tobacco increased by 0.5 and 1.0 points respectively., Discussion: This study confirmed that P. rhodozyma fermentation could effectively improve the sensory evaluation of tobacco, and provided a novel microbial fermentation method to improve tobacco quality., 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 Mai, Zhu, Hu, Zhang, Liu, Sun, Hu and Zhao.)

Objective: To investigate the clinical feasibility and effectiveness of the modified grafted tubularized incised plate urethroplasty (G-TIP), namely "glans G-TIP (GG-TIP) ", in treatment of hypospadias., Methods: A clinical data of 137 children with hypospadias qualified by the selection criteria between January 2021 and June 2023 was retrospectively analyzed. Among them, 75 children were treated with GG-TIP (GG-TIP group) and 62 with G-TIP (G-TIP group). There was no significant difference ( P >0.05) between the two groups in terms of age, hypospadias type, penile length, penile head width, penile head height, penile curvature, meatus-apex distance, urethral plate width, and distance from the distal endpoint of navicular groove to the dorsal or ventral midline point of the glans corona, and the difference between the two. The operation time, reconstructed urethral length, distance from meatus to ventral glans corona, postoperative complications, maximum urinary flow rate at 2 weeks after operation, and the hypospadias objective scoring evaluation (HOSE) score at 6 months after operation in the two groups were recorded and analyzed., Results: The operation time was significantly shorter in GG-TIP group than in G-TIP group ( P <0.05); but there was no significant difference ( P >0.05) between the two groups in terms of reconstructed urethral length and distance from meatus to ventral glans corona. All urinary meatus located at the tip of glans with vertical fissure shape. All children in the two groups were followed up 6-35 months (median, 26 months). During follow-up, there were 3 cases of urethral fistula, 2 cases of urethral stricture, and 1 case of glans separation in GG-TIP group, and 3, 3, and 1 cases in the G-TIP group, respectively. There was no significant difference in the incidence of complications between the two groups ( P >0.05). The maximum urinary flow rate at 2 weeks and the HOSE score at 6 months after operation were significantly higher in GG-TIP group than in G-TIP group ( P <0.05)., Conclusion: GG-TIP is safe and effective for repairing hypospadias in children. Compared with G-TIP, it has the advantages of relatively simple operation, shortened operation time, significant improvement in urinary flow rate, and better cosmetic results.

T cells suffer from long-term antigen stimulation and insufficient energy supply, leading to a decline in their effector functions, memory capabilities, and proliferative capacity, ultimately resulting in T cell exhaustion and an inability to perform normal immune functions in the tumor microenvironment. Therefore, exploring how to restore these exhausted T cells to a state with effector functions is of great significance. Exhausted T cells exhibit a spectrum of molecular alterations, such as heightened expression of inhibitory receptors, shifts in transcription factor profiles, and modifications across epigenetic, metabolic, and transcriptional landscapes. This review provides a comprehensive overview of various strategies to reverse T cell exhaustion, including immune checkpoint blockade, and explores the potential synergistic effects of combining multiple approaches to reverse T cell exhaustion. It offers new insights and methods for achieving more durable and effective reversal of T cell exhaustion., 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.)

Lithium (Li) metal is regarded as the most promising anode for next-generation batteries with high energy density. However, the uncontrolled dendrite growth and infinite volume expansion during cycling seriously hinder the application of Li metal batteries (LMBs). Herein, an inorganic/organic protective layer (labeled as BPH), composed of in situ formed inorganic constituents and PVDF-HFP, is designed on the 3D carbon paper (CP) surface by hot-dipping method. The BPH layer can effectively improve the mechanical strength and ionic conductivity of the SEI layer, which is beneficial to expedite the Li-ion transfer of the entire framework and achieve stable Li plating/stripping behavior. As a result, the modified 3D CP (BPH-CP) exhibits an ultrahigh average Coulombic efficiency (CE) of ≈99.7% over 400 cycles. Further, the Li||LiFePO 4 (LFP) cell exhibits an extremely long-term cycle life of over 3000 cycles at 5 C. Importantly, the full cell with high mass loading LiFePO 4 (20 mg cm -2 ) or LiNi 0.8 Co 0.1 Mn 0.1 O 2 (NCM, 16 mg cm -2 ) cathode exhibits stable cycling for 100 or 150 cycles at 0.5 C with high-capacity retention of 86.5% or 82.0% even at extremely low N/P ratio of 0.88 or 0.94. believe that this work enlightens a simple and effective strategy for the application of high-energy-density and high-rate-C LMBs., (© 2024 Wiley‐VCH GmbH.)

Tai Chi (TC) practice has been shown to improve both cognitive and physical function in older adults. However, the neural mechanisms underlying the benefits of TC remain unclear. Our primary aims are to explore whether distinct age-related and TC-practice-related relationships can be identified with respect to either temporal or spatial (within/between-network connectivity) differences. This cross-sectional study examined recurrent neural network dynamics, employing an adaptive, data-driven thresholding approach to source-localized resting-state EEG data in order to identify meaningful connections across time-varying graphs, using both temporal and spatial features derived from a hidden Markov model (HMM). Mann-Whitney U tests assessed between-group differences in temporal and spatial features by age and TC practice using either healthy younger adult controls (YACs, n = 15), healthy older adult controls (OACs, n = 15), or Tai Chi older adult practitioners (TCOAs, n = 15). Our results showed that aging is associated with decreased within-network and between-network functional connectivity (FC) across most brain networks. Conversely, TC practice appears to mitigate these age-related declines, showing increased FC within and between networks in older adults who practice TC compared to non-practicing older adults. These findings suggest that TC practice may abate age-related declines in neural network efficiency and stability, highlighting its potential as a non-pharmacological intervention for promoting healthy brain aging. This study furthers the triple-network model, showing that a balancing and reorientation of attention might be engaged not only through higher-order and top-down mechanisms (i.e., FPN/DAN) but also via the coupling of bottom-up, sensory-motor (i.e., SMN/VIN) networks.

Memristive computing system (MCS), with the feature of in-memory computing capability, for artificial neural networks (ANNs) deployment showing low power and massive parallelism, is a promising alternative for traditional Von-Neumann architecture computing system. However, because of the various non-idealities of both peripheral circuits and memristor array, the performance of the practical MCS tends to be significantly reduced. In this work, a linear compensation method (LCM) is proposed for the performance improvement of MCS under the effect of non-idealities. By considering the effects of various non-ideal states in the MCS as a whole, the output error of the MCS under different conditions is investigated. Then, a mathematic model for the output error is established based on the experimental data. Furthermore, the MCS is researched at the physical circuit level as well, in order to analyze the specific way in which the non-idealities affect the output current. Finally, based on the established mathematical model, the LCM output current is compensated in real time to improve the system performance. The effectiveness of LCM is verified and showing outstanding performance in the residual neural network-34 network architecture, which is easily affected by the non-idealities in hardware. The proposed LCM can be naturally integrated into the operation processes of MCS, paving the way for optimizing the deployment on generic ANN hardware based on the memristor., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

NLRP3 inflammasome activation, essential for cytokine secretion and pyroptosis in response to diverse stimuli, is closely associated with various diseases. Upon stimulation, NLRP3 undergoes subcellular membrane trafficking and conformational rearrangements, preparing itself for inflammasome assembly at the microtubule-organizing center (MTOC). Here, we elucidate an orchestrated mechanism underlying these ordered processes using human and murine cells. Specifically, NLRP3 undergoes palmitoylation at two sites by palmitoyl transferase zDHHC1, facilitating its trafficking between subcellular membranes, including the mitochondria, trans-Golgi network (TGN), and endosome. This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. Consistently, Zdhhc1-deficiency mitigated LPS-induced inflammation and conferred protection against mortality in mice. Altogether, our findings provide valuable insights into the regulation of NLRP3 membrane trafficking and inflammasome activation, governed by palmitoylation and phosphorylation events., Competing Interests: Declaration of interests W.W. is a co-founder and consultant for ReKindle Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Many potential use cases for machine learning in chemistry and materials science suffer from small dataset sizes, which demands special care for the model design in order to deliver reliable predictions. Hence, feature selection as the key determinant for dataset design is essential here. We propose a practical and efficient feature filter strategy to determine the best input feature candidates. We illustrate this strategy for the prediction of adsorption energies based on a public dataset and sublimation enthalpies using an in-house training dataset. The input of adsorption energies reduces the feature space from 12 dimensions to two and still delivers accurate results. For the sublimation enthalpies, three input configurations are filtered from 14 possible configurations with different dimensions for further productive predictions as being most relevant by using our feature filter strategy. The best extreme gradient boosting regression model possesses a good performance and is evaluated from statistical and theoretical perspectives, reaching a level of accuracy comparable to density functional theory computations and allowing for physical interpretations of the predictions. Overall, the results indicate that the feature filter strategy can help interdisciplinary scientists without rich professional AI knowledge and limited computational resources to establish a reliable small training dataset first, which may make the final machine learning model training easier and more accurate, avoiding time-consuming hyperparameter explorations and improper feature selection., (© 2024. The Author(s).)

The performance of Li-ion batteries (LIBs) at sub-ambient temperatures is limited by the resistive interphases due to electrolyte decomposition, particularly on the anode surface. In this study, lithium fluorosulfonate (LFS) was added to commercial electrolytes to enhance the low-temperature electrochemical performance of LiFePO 4 (LFP)/graphite (Gr) pouch cells. The addition of LFS significantly reduced the charge transfer resistance of the anode, substantially extending the cycle life and discharge capacity of commercial LFP/Gr pouch cells at -10 and -30 °C. Compared with the capacity retention rate of the baseline electrolyte at -10 °C (80 % after 25cycles), the capacity retention rate of the LFS electrolyte after 100 cycles under 0.5 C/0.5 C was retained at 94 %. Further mechanistic studies showed that the LFS additive induced the formation of a solid electrolyte interphase (SEI) film comprising inorganic-rich LiF, Li 2 SO 4 , and additional organic fluorides and sulfides to maintain good stability at the Gr/electrolyte interface during low-temperature operation. LFS suppressed electrolyte decomposition by forming a robust and low-resistance SEI film on the anode. These results demonstrate that LFS is a promising electrolyte additive for low-temperature LFP/Gr pouch cells., 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 Inc. All rights reserved.)

Background: Although mesh-based implant breast reconstruction surgery is emerging as the primary surgical procedure for breast reconstruction, mesh use remains controversial in implant breast reconstruction surgery, especially in terms of how to select the ideal mesh. Our aim is to elaborate relevant prognosis in the mesh-based implant breast reconstruction surgery., Methods: Relevant studies were identified from PubMed, Web of Science, EMBASE, and Cochrane library searches. Extracted data included study type, basic characteristics, mesh information, complications, etc. We analyzed the included cohort studies and randomized controlled trials that reported mesh-related implant breast reconstruction complications and breast quality scale scores., Results: A total of 32 studies including 7475 subjects were included. The results showed that the overall complication rate was 2.07 times higher in the biological mesh group than in the synthetic mesh group (risk ratio [RR]: 2.07, 95% CI 1.14-3.78). The risk of seroma was 4.50 times higher in the biological mesh group than in the synthetic mesh group (RR: 4.50, 95% CI 2.27-8.95). In terms of comparing breast quality scale scores, the mesh group had scores that were 1.49 (95% CI 0.19-2.78) higher than the non-mesh group for "physical well-being" and 2.05 (95% CI 0.08-4.02) higher for "sexual well-being.", Conclusions: Our study found that the risk of total complications was higher with biological mesh than with synthetic mesh in implant breast reconstruction surgery. Based on short-term cost, healthcare burden, and healthcare benefits, synthetic meshes are superior to biological meshes., Level of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Objective: To develop an Artificial Intelligence (AI)-based anomaly detection model as a complement of an "astute physician" in detecting novel disease cases in a hospital and preventing emerging outbreaks., Methods: Data included hospitalized patients (n = 120,714) at a safety-net hospital in Massachusetts. A novel Generative Pre-trained Transformer (GPT)-based clinical anomaly detection system was designed and further trained using Empirical Risk Minimization (ERM), which can model a hospitalized patient's Electronic Health Records (EHR) and detect atypical patients. Methods and performance metrics, similar to the ones behind the recent Large Language Models (LLMs), were leveraged to capture the dynamic evolution of the patient's clinical variables and compute an Out-Of-Distribution (OOD) anomaly score., Results: In a completely unsupervised setting, hospitalizations for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection could have been predicted by our GPT model at the beginning of the COVID-19 pandemic, with an Area Under the Receiver Operating Characteristic Curve (AUC) of 92.2 %, using 31 extracted clinical variables and a 3-day detection window. Our GPT achieves individual patient-level anomaly detection and mortality prediction AUC of 78.3 % and 94.7 %, outperforming traditional linear models by 6.6 % and 9 %, respectively. Different types of clinical trajectories of a SARS-CoV-2 infection are captured by our model to make interpretable detections, while a trend of over-pessimistic outcome prediction yields a more effective detection pathway. Furthermore, our comprehensive GPT model can potentially assist clinicians with forecasting patient clinical variables and developing personalized treatment plans., Conclusion: This study demonstrates that an emerging outbreak can be accurately detected within a hospital, by using a GPT to model patient EHR time sequences and labeling them as anomalous when actual outcomes are not supported by the model. Such a GPT is also a comprehensive model with the functionality of generating future patient clinical variables, which can potentially assist clinicians in developing personalized treatment plans., 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 Inc. All rights reserved.)