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Vladislav Berdunov,1 Gebra Cuyun Carter,2 Ewan Laws,1 Roger Luo,2 Christy A Russell,2 Sara Campbell,2 Yara Abdou,3 Jeremy Force4 1Putnam, London, UK; 2Exact Sciences, Madison, WI, USA; 3School of Medicine, UNC, Chapel Hill, NC, USA; 4School of Medicine, Duke University, Durham, NC, USACorrespondence: Vladislav Berdunov, Putnam, 22-24 Torrington Place, Fitzrovia, London, WC1E 7HJ, UK, Tel +44 7542947557, Email vlad.berdunov@putassoc.comBackground and Objectives: The 21-gene assay (the Oncotype DX Breast Recurrence Score® test) estimates the 10-year risk of distant recurrence in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) early-stage breast cancer to inform adjuvant chemotherapy decisions. The cost-effectiveness of the 21-gene assay compared against standard clinical-pathological risk tools alone for HR+/HER2- early-stage breast cancer was assessed using an economic model informed by evidence from randomized controlled trials.Materials and Methods: A cost-effectiveness model consisted of a decision-tree to stratify patients according to their Recurrence Score (RS) results and the use of adjuvant chemotherapy, followed by a Markov component to estimate the long-term costs and outcomes of the chosen treatment. Distributions of patients and distant recurrence probabilities were derived from the TAILORx (N0) and RxPONDER (N1) trials. The model was evaluated from a healthcare payer and societal perspective. Endocrine therapy and chemotherapy use were informed using clinical expert opinion to reflect US clinical practice and were combined with Medicare drug costs (2021) to estimate the cost of treatment. Societal costs included lost productivity and patient out-of-pocket costs obtained from literature.Results: The Oncotype DX test generated more quality-adjusted life-years (QALYs) (N0: 0.25; N1: 0.08) at a lower cost (N0: -$13,395; N1: -$2526) compared to clinical-pathological risk alone from a societal cost perspective. The overall conclusions from the model did not change when considering a payer perspective. The main cost drivers were avoidance of distant recurrence for N0 (-$12,578), and the cost of adjuvant chemotherapy for N1 (-$2133). Lost productivity had a major impact in the societal perspective analysis (N0: -$4607; N1: -$1586).Conclusion: Adjuvant chemotherapy decisions based on the RS result led to more life year gains and lower healthcare costs (dominant) compared to using clinical-pathological risk factors alone among patients with HR+/HER2- N0 and N1 early-stage breast cancer.Keywords: cost-effectiveness, tumour profiling test, breast cancer, chemotherapy, the Oncotype DX test

Zhengqin Tian,1,* Qihang Man,1,* Yixin Yang,1,* Xiaomei Zhang,2,* Hexian Guan,1 Wenjing Gu,2 Ying Wang,1 Dandan Song,2 Rongmu Luo,1,2 Jingbo Wang1 1Department of Hematology, Aerospace Center Hospital, Beijing, People’s Republic of China; 2Department of Hematology, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongmu Luo; Jingbo Wang, Email luorongmu@163.com; wangjingbo721@126.comAbstract: Engraftment syndrome (ES) is an early complication of hematopoietic stem cell transplantation (HSCT) characterized by fever and additional clinical manifestations including rash, diarrhea, lung infiltrates, weight gain, and neurological symptoms. Steroid-resistant ES following HSCT significantly affects the efficacy of transplantation and may even result in patient mortality. As ES essentially represents a cytokine storm induced by engrafted donor cells with interferon-gamma (IFN-γ) playing a central role, we hypothesized that emapalumab (an anti-IFN-γ monoclonal antibody) may be an effective approach to treat steroid-resistant ES. Here, we present a case report of a 14-year-old female patient who received a second haploidentical HSCT due to a relapse of acute myeloid leukemia. Nine days after the transplantation, the patient developed a fever and exhibited a poor response to antimicrobials (ceftazidime/avibactam). A few days later, the patient presented with a new-onset rash, weight gain, and impaired liver function, leading to a diagnosis of ES. Initial immunosuppressive (tacrolimus and mycophenolate mofetil) treatment failed to control the disease. On day 16 post-transplantation, the patient received two infusions of 50 mg of emapalumab. Following the initiation of emapalumab treatment, the patient’s fever returned to normal and ES was effectively controlled. This case report demonstrated that emapalumab had a possible efficacy for steroid-resistant ES and provided a novel therapeutic strategy to treat this clinical complication.Keywords: haploidentical hematopoietic stem cell transplantation, engraftment syndrome, emapalumab, acute myeloid leukemia

Siyi Zhang,1,2,* Yue Zhou,1,* Jinghui Wang,2 Qingan Fu,1 Tianzhou Shen,2 Guanrui Pan,2 Renfei Luo,1 Xinlei Yang,3 Long Jiang,1 Hui Hu4 1Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 2Department of Clinical Medicine, Queen Mary School of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 3Department of Biobank Center, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 4Department of Medical Big Data Center, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Long Jiang, Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China, Tel +86-13767026990, Email skyiadx@hotmail.com Hui Hu, Department of Medical Big Data Center, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China, Tel +86-13576978125, Email huhuillz@sina.comBackground: Lipoprotein(a) [Lp(a)] is a well-established risk factor for ischaemic stroke (IS). It is unclear whether Lp(a) is associated with IS in patients with atrial fibrillation (AF). The aim of this study is to explore the association between the concentration of Lp(a) and the risk of IS in AF patients, hope to find the potential risk factor for the IS in AF patients.Methods: This study is a retrospective cohort study. The screened AF patients between January 2017 and July 2021 were matched at 1:1 by the propensity score matching (PSM) method in the Second Affiliated Hospital of Nanchang University. Associations between Lp(a) and ischaemic stroke were analysed using logistic regression models, stratified analysis and sensitivity analysis. Statistical analyses were conducted using IBM SPSS software.Results: The number of enrolled participates is 2258, which contains 1129 non-AF patients and 1129 AF patients. Among IS patients, the median Lp(a) concentration was higher than that of controls (17.03 vs. 15.36 mg/dL, P = 0.032). The Spearman rank-order correlation coefficients revealed significant positive relationships between IS and Lp(a) (P = 0.032). In addition, a significant increase in IS risk was associated with Lp(a) levels > 30.00 mg/dL in unadjusted model [OR:1.263, 95% CI(1.046– 1.523), P = 0.015], model 1 [OR:1.284, 95% CI(1.062,1.552), P = 0.010], model 2 [OR: 1.297, 95% CI(1.07,1.573). P = 0.008], and model 3 [OR: 1.290, 95% CI (1.064, 1.562). P = 0.009]. The stratified analysis indicated that this correlation was not affected by female sex [1.484 (1.117, 1.972), P = 0.006], age ≤ 60 [1.864 (1.067-3.254), P=0.029], hypertension [1.359 (1.074, 1.721), P = 0.011], or non-coronary heart disease (CHD) [1.388 (1.108, 1.738), P = 0.004].Conclusion: High levels of Lp(a) were significantly related to IS in AF patients and may be a potential risk factor in the onset of an IS in AF patients. Keywords: ischaemic stroke, Lipoprotein(a), atrial fibrillation, risk factor, retrospective cohort study

Background: Insomnia, a prevalent sleep disorder in contemporary society, frequently coexists with other mental health conditions such as depression, schizophrenia, and obsessive-compulsive disorder. Sleep disorders can compromise daytime functioning and overall quality of life. While music has been explored as an adjunct therapy for insomnia, its efficacy in improving insomnia among students remains unclear., Methods: Seventy-five students, aged between 18 and 30 years with an average age of 20.97 years (SD: 1.92), presenting sleep issues were randomly allocated to one of three groups: the classical music group, the jazz music group, and the control group, each with 25 participants. Participants in the classical and jazz music group were instructed to listen to classical or jazz music for a minimum of 30 min preceding bedtime. This was paired with deep breathing and relaxation techniques, practiced two consecutive nights per week from 23:00 to 01:00 over a five-week intervention period. Conversely, participants in the control group were only directed to follow the deep breathing and relaxation techniques before sleep on two consecutive nights weekly. Insomnia severity with the Insomnia Severity Index (ISI), sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), depressive symptoms with the Beck Depression Inventory-II (BDI- II), and anxiety symptoms with the Self-rating Anxiety Scale (SAS). Measurements were taken at baseline, after the second week of intervention, at the intervention's conclusion (five weeks), and two months post-intervention (follow-up)., Results: 1. The music groups showed a significant difference in insomnia severity compared with the control group after five weeks of intervention(p < .05). 2. music groups exhibited significant enhancements in sleep quality relative to the control group after a five-week intervention (p < .05). 3. Regarding mood enhancement, music groups showed significant improvements in depression and anxiety symptoms compared to the baseline after the five-week intervention. Notably, the control group also displayed improvements in these symptoms post-intervention., Conclusion: 1. Integrating music into a consistent bedtime routine ameliorates sleep quality and insomnia severity. However, no specific genre of music emerged as the superior choice for pre-sleep listening. 2. While music can considerably enhance mood indicators like depression and anxiety, techniques such as deep breathing and mindfulness also contribute positively. 3. Incorporating music before sleep tangibly elevates overall quality of life and daytime functioning., Trial Registration: ChiCTR2300073953., Competing Interests: Declaration of competing interest This manuscript has not been published or presented elsewhere in part or in entirely and is not under consideration by another journal. We have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The use of hyperscanning technology has revealed the neural mechanisms underlying multi-person interaction in musical activities. However, there is currently a lack of integration among various research findings. This systematic review aims to provide a comprehensive understanding of the social dynamics and brain synchronization in music activities through the analysis of 32 studies. The findings illustrate a strong correlation between inter-brain synchronization (IBS) and various musical activities, with the frontal, central, parietal, and temporal lobes as the primary regions involved. The application of hyperscanning not only advances theoretical research but also holds practical significance in enhancing the effectiveness of music-based interventions in therapy and education. The review also utilizes Predictive Coding Models (PCM) to provide a new perspective for interpreting neural synchronization in music activities. To address the limitations of current research, future studies could integrate multimodal data, adopt novel technologies, use non-invasive techniques, and explore additional research directions., Competing Interests: Declaration of interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Insufficient lighting poses challenges to both human and machine visual analytics. While existing low-light enhancement methods prioritize human visual perception, they often neglect machine vision and high-level semantics. In this paper, we make pioneering efforts to build an illumination enhancement model for high-level vision. Drawing inspiration from camera response functions, our model could enhance images from the machine vision perspective despite being lightweight in architecture and simple in formulation. We also introduce two approaches that leverage knowledge from base enhancement curves and self-supervised pretext tasks to train for different downstream normal-to-low-light adaptation scenarios. Our proposed framework overcomes the limitations of existing algorithms without requiring access to labeled data in low-light conditions. It facilitates more effective illumination restoration and feature alignment, significantly improving the performance of downstream tasks in a plug-and-play manner. This research advances the field of low-light machine analytics and broadly applies to various high-level vision tasks, including classification, face detection, optical flow estimation, and video action recognition.

Aurantii Fructus Immaturus (AFI) was structurally divided into two parts named "peel" and "pulp". The exocarp and mesocarp of materials named "peel". The endocarp separated into multiple compartments and the cystic hair attached to it named "pulp". In order to explore the distribution and content of constituents in AFI, an efficient method to explore the distribution of constituents was developed based on matrix assisted laser desorption/ionization fourier transform ion cyclotron resonance mass spectrometry imaging (MALDI-FTICR-MSI). After simple processing, thirty-two constituents with distinct localization in the mass range of 101-1200 Da were identified by MALDI-FTICR-MSI. In addition, the identified four flavnoids (poncirin, sinensetin, 3,5,6,7,8,3',4'-heptemthoxyflavone, and tangeritin) were analyzed for differences between using LC-MS. Quantitative analysis results supported the quantitative results from MALDI-FT-ICR-MSI. The results implied that different parts had different constituents in AFI, and demonstrated MALDI-MSI have high potential in the direct analysis of constituents., Competing Interests: Declaration of competing interest The authors do not have any conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Large language models (LLMs) offer transformative opportunities in bioinformatics education for medical students by creating interactive experiences. The integration of LLMs enhances educational outcomes through providing accessible code templates, clarifying the function of coding elements, and assisting in error troubleshooting. Here, we demonstrate the practical applications of LLMs with a case study on transcriptome sequencing data processing, a vital component of medical research. However, the reliability of the content that LLMs generate requires rigorous validation. Ensuring the accuracy and appropriateness of the LLM-generated information requires integrating innovative LLMs with traditional educational methods to prepare medical students effectively for future challenges in bioinformatics., (© 2024. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Objective: Echocardiographic videos are commonly used for automatic semantic segmentation of endocardium, which is crucial in evaluating cardiac function and assisting doctors to make accurate diagnoses of heart disease. However, this task faces two distinct challenges: one is the edge blurring, which is caused by the presence of speckle noise or excessive de-noising operation, and the other is the lack of an effective feature fusion approach for multilevel features for obtaining accurate endocardium., Methods: In this study, a deep learning model, based on multilevel edge perception and calibration fusion is proposed to improve the segmentation performance. First, a multilevel edge perception module is proposed to comprehensively extract edge features through both a detail branch and a semantic branch to alleviate the adverse impact of noise. Second, a calibration fusion module is proposed that calibrates and integrates various features, including semantic and detailed information, to maximize segmentation performance. Furthermore, the features obtained from the calibration fusion module are stored by using a memory architecture to achieve semi-supervised segmentation through both labeled and unlabeled data., Results: Our method is evaluated on two public echocardiography video data sets, achieving average Dice coefficients of 93.05% and 93.93%, respectively. Additionally, we validated our method on a local hospital clinical data set, achieving a Pearson correlation of 0.765 for predicting left ventricular ejection fraction., Conclusion: The proposed model effectively solves the challenges encountered in echocardiography by using semi-supervised networks, thereby improving the segmentation accuracy of the ventricles. This indicates that the proposed model can assist cardiologists in obtaining accurate and effective research and diagnostic results., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Protein-based subunit vaccines like RBD-Fc are promising tools to fight COVID-19. RBD-Fc fuses the receptor-binding domain (RBD) of the SARS-CoV-2 virus spike protein with the Fc region of human IgG1, making it more immunogenic than RBD alone. Earlier work showed that combining RBD-Fc with iNKT cell agonists as adjuvants improved neutralizing antibodies but did not sufficiently enhance T cell responses, a limitation RBD-Fc vaccines share with common adjuvants. Here we demonstrate that aluminum hydroxide combined with α-C-GC, a C-glycoside iNKT cell agonist, significantly improved the RBD-Fc vaccine's induction of RBD-specific T-cell responses. Additionally, aluminum hydroxide with α-GC-CPOEt, a phosphonate diester derivative, synergistically elicited more robust neutralizing antibodies. Remarkably, modifying αGC with phosphate (OPO 3 H 2 ) or phosphonate (CPO 3 H 2 ) to potentially enhance aluminum hydroxide interaction did not improve efficacy over unmodified αGC with aluminum hydroxide. These findings underscore the straightforward yet potent potential of this approach in advancing COVID-19 vaccine development and provide insights for iNKT cell-based immunotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rui Luo, Zheng Liu, Ya-Qian Li, and Cheng Yan are listed as inventors on a pending patent application about αGC-CPOEt. All other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no cure except transplantation. Abnormal alveolar epithelial regeneration is a key driver of IPF development. The function of Yes1 Associated Transcriptional Regulator (YAP) in alveolar regeneration and IPF pathogenesis remains elusive. Here, we first revealed the activation of YAP in alveolar epithelium 2 cells (AEC2s) from human IPF lungs and fibrotic mouse lungs. Notably, conditional deletion of YAP in mouse AEC2s exacerbated bleomycin-induced pulmonary fibrosis. Intriguingly, we showed in both conditional knockout mice and alveolar organoids that YAP deficiency impaired AEC2 proliferation and differentiation into alveolar epithelium 1 cells (AEC1s). Mechanistically, YAP regulated expression levels of genes associated with cell cycle progression and AEC1 differentiation. Furthermore, overexpression of YAP in vitro promoted cell proliferation. These results indicate the critical role of YAP in alveolar regeneration and IPF pathogenesis. Our findings provide new insights into the regulation of alveolar regeneration and IPF pathogenesis, paving the road for developing novel treatment strategies.

Background: Although the concept of the intrarenal renin-angiotensin system (RAS) in renal disease is well-described in the literature, the precise pathogenic role and mechanism of this local system have not been directly assessed in the absence of confounding influence from the systemic RAS. The present study used novel mouse models of collecting duct (CD)-specific deletion of (pro)renin receptor (PRR) or renin together with pharmacological inhibition of soluble PRR production to unravel the precise contribution of the intrarenal RAS to renal injury induced by unilateral ureteral obstruction., Methods: We examined the impact of CD-specific deletion of PRR, CD-specific deletion of renin, and S1P (site-1 protease) inhibitor PF429242 treatment on renal fibrosis and inflammation and the indices of the intrarenal RAS in a mouse model of unilateral ureteral obstruction., Results: After 3 days of unilateral ureteral obstruction, the indices of the intrarenal RAS including the renal medullary renin content, activity and mRNA expression, and Ang (angiotensin) II content in obstructed kidneys of floxed mice were all increased. That effect was reversed with CD-specific deletion of PRR, CD-specific deletion of renin, and PF429242 treatment, accompanied by consistent improvement in renal fibrosis and inflammation. On the other hand, renal cortical renin levels were unaffected by unilateral ureteral obstruction, irrespective of the genotype. Similar results were obtained via pharmacological inhibition of S1P, the key protease for the generation of soluble PRR., Conclusions: Our results reveal that PRR-dependent/soluble PRR-dependent activation of CD renin represents a key determinant of the intrarenal RAS and, thus, obstruction-induced renal inflammation and fibrosis.

Ethnopharmacological Relevance: Hepatic ischemia/reperfusion injury (HIRI) is a common occurrence during or after liver surgery, representing a major cause for postoperative complications or increased morbidity and mortality in liver diseases. Rehmanniae Radix Praeparata (RRP) is a traditional Chinese medicine frequently used and has garnered extensive attention for its therapeutic potential treating cardiovascular and hepatic ailments. Recent studies have indicated the possibility of RRP in regulating lipid accumulation and apoptosis in hepatocytes., Aim of the Study: This study aimed to investigate the specific mechanisms by which RRP may impede the progression of HIRI through the regulation of lipid metabolism., Materials and Methods: High-performance liquid chromatography (HPLC) was used to identify the major components of RRP water extract. C57BL/6J mice were orally given RRP at doses of 2.5 g/kg, 5 g/kg, and 10 g/kg for a duration of 7 days before undergoing HIRI surgery. Furthermore, we established a lipid-loaded in vitro model by exposing hepatocytes to oleic acid and palmitic acid (OAPA). The anti-HIRI effect of RRP was determined through transcriptomics and various molecular biology experiments., Results: After identifying active ingredients in RRP, we observed that RRP exerted lipid-lowering and hepatoprotective effects on HIRI mice and OAPA-treated hepatocytes. RRP activated AMP-activated protein kinase (AMPK) and inhibited mammalian target of rapamycin (mTOR), which further on the one hand, inhibited the cleavage and activation of sterol regulatory element binding protein 2 (SREBP2) by limiting the movement of SREBPs cleavage-activating protein (SCAP)-SREBP2 complex with the help of endoplasmic reticulum lipid raft-associated protein 1 (ERLIN1) and insulin-induced gene 1 (INSIG1), and on the other hand, promoted liver X receptor α (LXRα) nuclear transportation and subsequent cholesterol efflux. Meanwhile, the anti-lipotoxic effect of RRP can be partly reversed by an LXRα inhibitor but largely blocked by the application of compound C, an AMPK inhibitor., Conclusion: Our study elucidated that RRP served as a potential AMPK activator to alleviate HIRI by blocking SREBP2 activation and cholesterol synthesis, while also activating LXRα to facilitate cholesterol efflux. These findings shed new light on the potential therapeutic use of RRP for improving HIRI., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: An mHealth-based school health education platform (EduSaltS) was promoted in real-world China to reduce salt intake among children and their families. This progress evaluation explores its implementation process and influencing factors using mixed methods., Methods: The mixed-methods process evaluation employed the RE-AIM framework. Quantitative data were collected from a management website monitoring 54,435 third-grade students across two cities. Questionnaire surveys (n = 27,542) assessed pre- and post-education effectiveness. Mixed-effects models were used to control cluster effects. Qualitative interviews (23 individuals and 8 focus groups) identified program performance, facilitators, and barriers. Findings were triangulated using the RE-AIM framework., Results: The program achieved 100% participation among all the third-grade classes of the 208 invited primary schools, with a 97.7% registration rate among all the 54,435 families, indicating high "Reach." Qualitative interviews revealed positive engagement from children and parents through the "small hands leading big hands" strategy. The high completion rate of 84.9% for each health cloud lesson and the significant improvement in salt reduction knowledge and behaviors scores from 75.0 (95%CI: 74.7-75.3) to 80.9 (95%CI: 80.6-81.2) out of 100 demonstrated the "Effect" of EduSaltS. The program's "Adoption" and "Implementation" were supported by attractive materials, reduced workload via auto-delivered lessons/activities and performance evaluation, and high fidelity to recommended activities, with medians 3.0 (IQR: 2.0-8.0)/class and 9.0 (IQR: 5.0-14.0)/school. Stable course completion rates (79.4%-93.4%) over one year indicated promising "Maintenance." Apart from the facilitating features praised by the interviewees, government support was the basis for the scaling up of EduSaltS. Barriers included the lack of smartphone skills among some parents and competing priorities for schools. Unhealthy off-campus environments, such as excessive use of salt in pre-packaged and restaurant foods, also hindered salt reduction efforts. The program's scalability was evident through its integration into existing health education, engagement of local governments and adaptation across various mobile devices., Conclusions: The mHealth-based school health education program is scalable and effective for public salt reduction in China. Identified barriers and facilitators can inform future health program scale-ups. The program's successful implementation demonstrates its potential for broader application in public health initiatives aimed at reducing dietary salt intake., (© 2024. The Author(s).)

Functional enhancer annotation is critical for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants. However, unbiased enhancer discovery in disease-relevant contexts remains challenging. To identify enhancers pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers identified, we focused on an enhancer we named ONECUT1e-664kb, ∼664 kb from the ONECUT1 promoter. Previous studies have linked ONECUT1 coding mutations to pancreatic hypoplasia and neonatal diabetes. We found that homozygous deletion of ONECUT1e-664kb in hPSCs leads to a near-complete loss of ONECUT1 expression and impaired pancreatic differentiation. ONECUT1e-664kb contains a type 2 diabetes-associated variant (rs528350911) disrupting a GATA motif. Introducing the risk variant into hPSCs reduced binding of key pancreatic transcription factors (GATA4, GATA6, and FOXA2), supporting its causal role in diabetes. This work highlights the utility of unbiased enhancer discovery in disease-relevant settings for understanding monogenic and complex disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tea polyphenols (TPs), prominent constituents of green tea, possess remarkable antioxidant and anti-inflammatory properties. However, their therapeutic potential is limited due to low absorption and poor bioavailability. To address this limitation and enhance their efficacy, we developed a biomimetic nanoplatform by coating platelet membrane (PM) onto poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) to create targeted delivery vehicles for TPs (PM@TP/NPs) to the inflamed tissues in asthma., Methods: After synthesizing and characterizing PM@TP/NPs, we assessed their biocompatibility and biosafety through cell viability assays, hemolysis tests, and inflammation analysis in vivo and in vitro. The therapeutic effect of PM@TP/NPs on asthma was then evaluated using a mouse model of HDM-induced asthma. Additionally, PM@TP/NPs-mediated reactive oxygen species (ROS) scavenging capacity, as well as the activation of signaling pathways, were analyzed in HBE cells and asthmatic mice via flow cytometry, RT-qPCR, and western blotting., Results: Compared with free TPs, PM@TP/NPs demonstrated excellent biocompatibility and safety profiles in both in vitro and in vivo, as well as enhanced retention in inflamed lungs. In HDM-induced mouse asthma model, inhaled PM@TP/NPs largely attenuated lung inflammation and reduced the secretion of type 2 pro-inflammatory cytokines in the lungs compared to free TPs. The therapeutic effects of PM@TP/NPs on asthma might be associated with an enhanced ROS scavenging capacity, increased activation of the Nrf2/HO-1 pathway, and decreased activation of the CCL2/MAPK and TLR4/NF-κB pathway in the lungs., Conclusions: Our findings demonstrate that inhalation of PM@TP/NPs largely attenuated lung inflammation in HDM-induced asthmatic mice. These results suggest that PM@TP/NPs might be a novel therapeutic strategy for asthma., (© 2024. The Author(s).)

Macroautophagy/autophagy plays a crucial role in inhibiting viral replication and regulating the host's immune response. The autophagy receptor SQSTM1/p62 (sequestosome 1) restricts viral replication by directing specific viral proteins to phagophores for degradation. In this study, we investigate the reciprocal relationship between Zika virus (ZIKV) and selective autophagy mediated by SQSTM1/p62. We show that NS2B3 protease encoded by ZIKV cleaves human SQSTM1/p62 at arginine 265 (R265). This cleavage also occurs with endogenous SQSTM1 in ZIKV-infected cells. Furthermore, overexpression of SQSTM1 inhibits ZIKV replication in A549 cells, while its absence increases viral titer. We have also shown that SQSTM1 impedes ZIKV replication by interacting with NS3 and NS5 and directing them to autophagic degradation, and that NS2B3-mediated cleavage could potentially alter this antiviral function of SQSTM1. Taken together, our study highlights the role of SQSTM1-mediated selective autophagy in the host's antiviral defense against ZIKV and uncovers potential viral evasion strategies that exploit the host's autophagic machinery to ensure successful infection. Abbreviation: Cas9: CRISPR-associated protein 9; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DENV: dengue virus; GFP: green fluorescent protein; IFA: indirect immunofluorescence assay; KIR: KEAP1-interacting region; KO: knockout; LIR: MAP1LC3/LC3-interacting region; mAb: monoclonal antibody; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; pAb: polyclonal antibody; PB1: Phox/BEM1 domain; R265A, a SQSTM1 construct with the arginine (R) residue at position 265 replaced with glutamic acid (A); SQSTM1: sequestosome 1; SQSTM1-C, C-terminal fragment of SQSTM1; SQSTM1-N, N-terminal fragment of SQSTM1; SVV: Seneca Valley virus; TAX1BP1: Tax1 binding protein 1; TBD: TRAF6-binding domain; TCID 50 : 50% tissue culture infective dose; UBA: ubiquitin-associated domain; Ub: ubiquitin; WT: wild type; ZIKV: Zika virus; ZZ: ZZ-type zinc finger domain.

Background: Irritable bowel syndrome (IBS) significantly impacts individuals due to its prevalence and negative effect on quality of life. Current genome-wide association studies (GWAS) have only identified a small number of crucial single nucleotide polymorphisms (SNPs), not fully elucidating IBS's pathogenesis., Objective: To identify genomic loci at which common genetic variation influence IBS susceptibility., Methods: Combining independent cohorts that in total comprise 65,840 cases of IBS and 788,652 controls, we performed a meta-analysis of genome-wide association studies (GWAS) of IBS. We also carried out gene mapping and pathway enrichment to gain insights into the underlying genes and pathways through which the associated loci contribute to disease susceptibility. Furthermore, we performed transcriptome analysis to deepen our understanding. IBS risk models were developed by combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. We detect the phenotype association for IBS utilizing PRS-based phenome-wide association (PheWAS) analyses, linkage disequilibrium score regression, and Mendelian randomization., Results: The GWAS meta-analysis identified 10 IBS risk loci, seven of which were novel (rs12755507, rs34209273, rs34365748, rs67427799, rs2587363, rs13321176, rs1546559). Multiple methods identified nine promising IBS candidate gene (PRRC2A, COP1, CADM2, LRP1B, SUGT1, MED12L, P2RY14, PHF2, SHISA6) at 10 GWAS loci. Transcriptome validation also revealed differential expression of these genes. Phenome-wide associations between PRS-IBS and nine traits (neuroticism, diaphragmatic hernia, asthma, diverticulosis, cholelithiasis, depression, insomnia, COPD, and BMI) were identified. The six diseases (asthma, diaphragmatic hernia, diverticulosis, insomnia major depressive disorder and neuroticism) were found to show genetic association with IBS and only major depressive disorder and neuroticism were found to show causality with IBS., Conclusion: We identified seven novel risk loci for IBS and highlight the substantial influence on genetic risk harboured. Our findings offer novel insights into aetiology and phenotypic association of IBS and lay the foundation for therapeutic targets and interventional strategies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hydrogen bonds profoundly influence the fundamental chemical, physical and biological properties of molecules and materials. Owing to their relatively weaker interactions compared to other chemical bonds, hydrogen bonds alone are generally insufficient to induce substantial changes in electrical properties, thus imposing severe constraints on their applications in related devices. Here we report a metal-insulator transition controlled by hydrogen bonds for an organic-inorganic (1,3-diaminopropane) 0.5 SnSe 2 superlattice that exhibits a colossal on-off ratio of 10 7 in electrical resistivity. The key to inducing the transition is a change in the amino group's hydrogen-bonding structure from dynamic to static. In the dynamic state, thermally activated free rotation continuously breaks and forms transient hydrogen bonds with adjacent Se anions. In the static state, the amino group forms three fixed-angle positions, each separated by 120°. Our findings contribute to the understanding of electrical phenomena in organic-inorganic hybrid materials and may be used for the design of future molecule-based electronic materials., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Nature's two redox cofactors, nicotinamide adenine dinucleotide (NAD + ) and nicotinamide adenine dinucleotide phosphate (NADP + ), are held at different reduction potentials, driving catabolism and anabolism in opposite directions. In biomanufacturing, there is a need to flexibly control redox reaction direction decoupled from catabolism and anabolism. We established nicotinamide mononucleotide (NMN + ) as a noncanonical cofactor orthogonal to NAD(P) + . Here we present the development of Nox Ortho, a reduced NMN + (NMNH)-specific oxidase, that completes the toolkit to modulate NMNH:NMN + ratio together with an NMN + -specific glucose dehydrogenase (GDH Ortho). The design principle discovered from Nox Ortho engineering and modeling is facilely translated onto six different enzymes to create NMN(H)-orthogonal biocatalysts with a consistent ~10 3 -10 6 -fold cofactor specificity switch from NAD(P) + to NMN + . We assemble these enzymes to produce stereo-pure 2,3-butanediol in cell-free systems and in Escherichia coli, enabled by NMN(H)'s distinct redox ratio firmly set by its designated driving forces, decoupled from both NAD(H) and NADP(H)., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

What Is Already Known About This Topic?: Fractures are a common and serious injury among children. While many studies have utilized clinical data, there is a lack of large-scale community-based research in China., What Is Added by This Report?: This cross-sectional study provides national and regionally representative data on the prevalence of fractures among Chinese children aged 6-17 years (6.93%), with higher rates observed in males than in females (8.13% vs . 5.71%) and in rural areas compared to urban areas (7.22% vs . 6.62%). The most common site of fracture was the upper limbs (4.24%, accounting for 63.0% of fractures)., What Are the Implications for Public Health Practice?: The need to enhance awareness of fracture prevention is critical, particularly for children in rural areas and males in middle childhood. We recommend that local authorities increase investments in educational programs and child safety oversight. Additionally, promoting balanced diets for children, training in proper exercise techniques, and reinforcing participation in outdoor sports are essential., Competing Interests: No conflicts of interest., (Copyright and License information: Editorial Office of CCDCW, Chinese Center for Disease Control and Prevention 2024.)

Diarrhea is a common issue in domestic yaks (Bos grunniens) that can occur with pasture alterations and significantly impacts growth performance. Previous research has examined the microbiota of diarrhetic yaks; however, the structural changes in gut bacterial community and microbial interactions in yaks with grassland alteration-induced diarrhea remain poorly understood. To explore variations in gut microbiota homeostasis among yaks suffering from diarrhea, fecal microbiota diversity and composition were analyzed using 16 S rRNA amplicon sequencing. Gut fecal microbiota diversity was lower in diarrhetic yaks than in non-diarrhetic yaks. Furthermore, the bacterial community composition (including that of Proteobacteria and Actinobacteria) in the feces of diarrhetic yaks displayed significant alterations. Co-occurrence network analysis further underscored the compromised intestinal flora stability in yaks with diarrhea relative to that in non-diarrhetic yaks. Interestingly, the abundance of beneficial bacteria, such as Lachnospiraceae&#95;AC2044&#95;group and Lachnospiraceae&#95;NK4A136&#95;group, were decreased in yaks with diarrhea, and the reductions were negatively correlated with the fecal water content. Collectively, these findings indicate that diminished microbial stability and increased abundance of certain bacteria in the gut may contribute to diarrhea occurrence in yaks., (© 2024. The Author(s).)

G band, originating from the in-plane vibrations of carbon atoms, is the main signature in Raman spectroscopy of graphene-based systems. It is often used to characterize the sample quality and obtain molecular vibration information. Here we investigate the Raman spectroscopy of ABt-twisted trilayer graphene (ABt-TTG) and observe two enhancement centers for the G band across samples with different twist angles. To understand the origin of these two enhancement centers, we theoretically calculate the G band intensity of ABt-TTG based on the continuum model. We find that the theoretical calculations exhibit two prominent peaks corresponding to the experimental observations after Fermi velocity corrections. We also investigated the real and imaginary parts of Raman resonances, respectively, and explained the origins of two enhancements of ABt-TTG. By using Raman spectroscopy, evolutions of band structures of ABt-TTG with respect to the twist angles can be characterized, which extends the potential applications of the Raman method in the investigation of electronic structures of graphene-based systems., (© 2024 IOP Publishing Ltd.)

Background: Multimorbidity has become a major public health problem among Chinese middle-aged and older adults, and the most costly to the health care system. However, most previous population-based studies of multimorbidity have focused on a limited number of chronic diseases, and diagnosis was based on participants' self-report, which may oversimplify the problem. At the same time, there were few reports on the relationship between multimorbidity patterns and health care costs. This study analyzed the multimorbidity patterns and changes among middle-aged and older people in China over the past decade, and their association with medical costs, based on representative hospital electronic medical record data., Methods: Two cross-sectional surveys based on representative hospital data were used to obtain adults aged 45 years and older in Xiangyang in 2013 ( n  = 20,218) and 2023 ( n  = 63,517). Latent Class Analysis was used to analyze changes in the patterns of multimorbidity, gray correlation analysis and ordered logistics model were used to assess the association of multimorbidity patterns with medical expenses. The diagnosis and classification of chronic diseases were based on the International Classification of Diseases, Tenth Revision codes (ICD-10)., Results: The detection rate of chronic disease multimorbidity has increased (70.74 vs. 76.63%, p  < 0.001), and multimorbidity patterns have increased from 6 to 9 (2013: Malignant tumors pattern, non-specific multimorbidity pattern, ischemic heart disease + hypertension pattern, cerebral infarction + hypertension pattern, kidney disease + hypertension pattern, lens disease + hypertension pattern; new in 2023: Nutritional metabolism disorders + hypertension pattern, chronic lower respiratory diseases + malignant tumors pattern, and gastrointestinal diseases pattern) in China. The medical cost of all multimorbidity patients have been reduced between 2013 and 2023 (RMB: 8216.74 vs. 7247.96, IQR: 5802.28-15,737 vs. 5014.63-15434.06). The top three specific multimorbidity patterns in both surveys were malignancy tumor pattern, ischemic heart disease + hypertension pattern, and cerebral infarction + hypertension pattern. Hypertension and type 2 diabetes are important components of multimorbidity patterns. Compared with patients with a single disease, only lens disorders + hypertension pattern were at risk of higher medical costs in 2013 (aOR:1.23, 95% CI: 1.03, 1.47), whereas all multimorbidity patterns were significantly associated with increased medical costs in 2023, except for lens disorders + hypertension (aOR:0.35, 95% CI: 0.32, 0.39). Moreover, the odds of higher medical costs were not consistent across multimorbidity patterns. Among them, ischemic heart disease + hypertension pattern [adjusted odds ratio (aOR):4.66, 95%CI: 4.31, 5.05] and cerebral infarction + hypertension pattern (aOR: 3.63, 95% CI: 3.35, 3.92) were the two patterns with the highest risk. Meanwhile, men (aOR:1.12, 95CI:1.09, 1.16), no spouse (aOR:1.09, 95CI: 1.03, 1.16) had a positive effect on medical costs, while patients with total self-pay (aOR: 0.45, 95CI: 0.29, 0.70), no surgery (aOR: 0.05, 95CI: 0.05, 0.05), rural residence (aOR: 0.92, 95CI: 0.89, 0.95), hospitalization days 1-5 (aOR: 0.04, 95CI: 0.04, 0.04), and hospitalization days 6-9 (aOR: 0.15, 95CI: 0.15, 0.16) had a negative impact on medical costs., Conclusion: Multimorbidity patterns among middle-aged and older adults in China have diversified over the past decade and are associated with rising health care costs in China. Smart, decisive and comprehensive policy and care interventions are needed to effectively manage NCDS and their risk factors and to reduce the economic burden of multimorbidity on patients and the country., 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 Ju, Liu, Gong, Guo, Ge, Liu, Luo, Yang, Li, Liu, Li, He, Liu, Huang, Xu and Liu.)

Background: While low body mass index (BMI) is associated with poor tuberculosis (TB) treatment outcomes, the impact of weight gain during TB treatment is unclear. To address this knowledge gap, we assessed if lack of weight gain is associated with all-cause mortality during and after TB treatment., Methods: We conducted a retrospective cohort study among adults with newly diagnosed multi- or extensively drug-resistant (M/XDR) pulmonary TB in Georgia between 2009-2020. The exposure was a change in BMI during the first 3-6 months of TB treatment. All-cause mortality during and after TB treatment was assessed using the National Death Registry. We used competing-risk Cox proportional hazard models to estimate adjusted hazard ratios (aHR) between BMI change and all-cause mortality., Results: Among 720 adult participants, 21% had low BMI (<18.5 kg/m 2 ) at treatment initiation and 9% died either during (n=16) or after treatment (n=50). During the first 3-6 months of TB treatment, 17% lost weight and 14% had no weight change. Among 479 adults with normal baseline BMI ( ≥18.5-24.9 kg/m 2 ), weight loss was associated with an increased risk of death during TB treatment (aHR=5.25; 95%CI: 1.31-21.10). Among 149 adults with a low baseline BMI, no change in BMI was associated with increased post-TB treatment mortality (aHR=4.99; 95%CI: 1.25-19.94)., Conclusions: Weight loss during TB treatment (among those with normal baseline BMI) or no weight gain (among those with low baseline BMI) was associated with increased rates of all-cause mortality. Our findings suggest that scaling up weight management interventions among those with M/XDR TB may be beneficial., Summary: Among a cohort of persons with drug resistant tuberculosis (TB), failure to gain weight during TB treatment was associated with an increased risk of all-cause mortality during and after completion of treatment.

Pancreatic cancer (PC) is a common gastrointestinal cancer with high invasiveness and high mortality. Curcumin is a natural polyphenol with anti-tumor activity against different cancers, including PC. Curcumin has been verified to mediate the expression of circular RNAs (circRNAs) to inhibit tumor development. This study aimed to explore the function and regulatory mechanism of curcumin on circ&#95;0079440 in PC. PC cells were treated with different concentrations of curcumin (0, 5, 10 or 15 μM) for 24 h. Gene expression in PC cells and tissues was detected using RT-qPCR. Cell malignant phenotypes were determined by functional assays. The levels of EMT-related proteins were tested using western blot. RNA interaction was determined using RNA pulldown assay, luciferase reporter assay and RIP assay. The results showed that curcumin suppressed cell proliferative, migratory, and invasive capabilities, and weakened epithelial-mesenchymal transition (EMT) in a concentration-dependent way. Circ&#95;0079440 was expressed at a high level in PC and its level was reduced via curcumin administration in PC cells. Rescue assays showed that circ&#95;0079440 overexpression reversed the suppressive effects of curcumin on PC cell malignant phenotypes. Furthermore, in the xenograft mouse models, curcumin treatment inhibited tumor growth and metastasis, and circ&#95;0079440 upregulation reversed the function of curcumin. Additionally, circ&#95;0079440 was revealed to bind to miR-522-3p to upregulate eukaryotic initiation factor 4A1 (EIF4A1) expression in PC cells. EIF4A1 expression was also downregulated by curcumin, and EIF4A1 overexpression abolished the suppressive functions of curcumin. Moreover, EIF4A overexpression or miR-522-3p inhibition counteracted the anti-tumor effects of circ&#95;0079440 depletion on PC development. To sum up, curcumin suppresses PC development by targeting the circ&#95;0079440/miR-522-3p/EIF4A1 pathway, which might provide novel therapeutic targets for treatment of PC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The aim of this present work was to investigate the mechanism of the microRNA (miR)-216a-5p/FASL axis in mice with acute kidney injury (AKI)., Methods: Mice kidney ischemia/reperfusion (I/R) injury was used as AKI models in this study. I/R mice were injected with miR-216a-5p- and FASL-related constructs to investigate potential mechanisms of kidney protection. kidney function, inflammation, oxidative stress, and kidney cell apoptosis were assessed after 24 h of reperfusion. In vitro, the hypoxia-reoxygenation (H/R) model was used with kidney tubular epithelial cells (TECs) to mimic kidney I/R injury. H/R-treated TECs were transfected with miR-216a-5p- and FASL-related constructs to detect cell viability, inflammation, and oxidative stress. miR-216a-5p and FASL expression levels in mouse kidney tissues and in H/R-treated TECs were detected., Results: miR-216a-5p was downregulated and FASL was upregulated in kidney tissues of I/R mice and H/R-treated TECs. Upregulating miR-216a-5p attenuated kidney cell apoptosis and the damage of kidney function, and reduced inflammatory factor levels and oxidative stress response in kidney tissues of I/R mice. Upregulating miR-216a-5p advanced cell viability and reduced inflammatory factor levels and oxidative stress response in H/R-treated TECs. Downregulation of FASL effectively reversed the influences of downregulation of miR-216a-5p on kidney injury in mice and kidney TEC survival., Conclusion: Our study reveals that miR-216a-5p reduces I/R-induced pathological kidney damage in AKI via suppressing FASL., (The Author(s). Published by S. Karger AG, Basel.)

Background: COVID-19 can cause cardiac complications and the latter are associated with poor prognosis and increased mortality. SARS-CoV-2 variants differ in their infectivity and pathogenicity, but how they affect cardiomyocytes (CMs) is unclear., Methods: The effects of SARS-CoV-2 variants were investigated using human induced pluripotent stem cell-derived (hiPSC-) CMs in vitro and Golden Syrian hamsters in vivo., Results: Different variants exhibited distinct tropism, mechanism of viral entry and pathology in the heart. Omicron BA.2 most efficiently infected and injured CMs in vitro and in vivo, and induced expression changes consistent with increased cardiac dysfunction, compared to other variants tested. Bioinformatics and upstream regulator analyses identified transcription factors and network predicted to control the unique transcriptome of Omicron BA.2 infected CMs. Increased infectivity of Omicron BA.2 is attributed to its ability to infect via endocytosis, independently of TMPRSS2, which is absent in CMs., Conclusions: In this study, we reveal previously unknown differences in how different SARS-CoV-2 variants affect CMs. Omicron BA.2, which is generally thought to cause mild disease, can damage CMs in vitro and in vivo. Our study highlights the need for further investigations to define the pathogenesis of cardiac complications arising from different SARS-CoV-2 variants., (© 2024. The Author(s).)

Aim: To explore the correlations between examination tolerance and anxiety, knowledge needs and examination cooperation in sedation-free gastroscopy examinees., Design: Cross-sectional survey using convenience sampling., Methods: A total of 170 healthy adults who underwent sedation-free gastroenteroscopy were asked to complete a visual analogue scale (VAS) to rate their examination tolerance, the state anxiety questionnaire (S-AI), a newly designed knowledge needs questionnaire and a cooperation questionnaire., Results: The VAS score was 4.47 ± 1.96, the state anxiety score was 39.46 ± 9.81, the total score for knowledge needs was 44.89 ± 11.02, and the average cooperation score was 2.47 ± 0.38. The VAS score during the examination positively correlated with the pretest state anxiety score and pretest knowledge needs score and negatively correlated with the examination cooperation score. The results of multiple linear regression analysis showed that after undergoing the examination for the first time, anxiety, body position and swallowing control were the main factors influencing the examination tolerance of sedation-free gastroscopy examinees., Patient or Public Contribution: We would like to thank the staff and patients of the participating hospital for their assistance and cooperation in performing the current study., (© 2024 The Author(s). Nursing Open published by John Wiley & Sons Ltd.)

Background: The escalating global burden of diabetes and its associated cognitive impairment underscores the urgency for effective interventions. Bergenin shows promise in regulating glucose metabolism, mitigating inflammation, and improving cognitive function. Zebrafish models offer a unique platform for assessing drug efficacy and exploring pharmacological mechanisms, complemented by subsequent investigations in cell and rat models., Methods: The experimental subjects included zebrafish larvae (CZ98: Tg (mpeg1:EGFP) ihb20Tg/+ ), adult zebrafish (immersed in 2% glucose), BV2 cell line (50 mM glucose + 10 μm Aβ 1-42 ), and a streptozotocin (STZ) bilateral intracerebroventricular injection rat model. Bergenin's effects on the toxicity, behavior, and cognitive function of zebrafish larvae and adults were evaluated. The Morris water maze assessed cognitive function in rats. Neuronal histopathological changes were evaluated using HE and Nissl staining. qPCR and Western blot detected the expression of glycolysis enzymes, inflammatory factors, and Bergenin's regulation of PPAR/NF-κB pathway in these three models., Results: 1) In zebrafish larvae, Bergenin interventions significantly reduced glucose levels and increased survival rates while decreasing teratogenicity rates. Microglial cell fluorescence in the brain notably decreased, and altered swimming behavior tended to normalize. 2) In adult zebrafish, Bergenin administration reduced BMI and blood glucose levels, altered swimming behavior to slower speeds and more regular trajectories, enhanced recognition ability, decreased brain glucose and lactate levels, weakened glycolytic enzyme activities, improved pathological changes in the telencephalon and gills, reduced expression of pro-inflammatory cytokines, decreased ins expression and increased expression of irs1 , irs2a , and irs2b , suggesting a reduction in insulin resistance. It also altered the expression of pparg and rela . 3) In BV2 cell line, Bergenin significantly reduced the protein expression of glycolytic enzymes (GLUT1, HK2, PKFKB3, and PKM2), lowered IL-1β, IL-6, and TNF-α mRNA expression, elevated PPAR-γ protein expression, and decreased P-NF-κB-p65 protein expression. 4) In the rat model, Bergenin improves learning and memory abilities in STZ-induced rats, mitigates neuronal damage in the hippocampal region, and reduces the expression of inflammatory factors IL-1β, IL-6, and TNF-α. Bergenin decreases brain glucose and lactate levels, as well as glycolytic enzyme activity. Furthermore, Bergenin increases PPARγ expression and decreases p-NF-κB p65/NF-κB p65 expression in the hippocampus., Conclusion: Bergenin intervenes through the PPAR-γ/NF-κB pathway, redirecting glucose metabolism, alleviating inflammation, and preventing high glucose-induced neuronal damage., 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 Yu, Luo, He, Li, Yang, Zhou, He, Chen, Song and Cheng.)

Transcriptional regulation, critical for cellular differentiation and adaptation to environmental changes, involves coordinated interactions among DNA sequences, regulatory proteins, and chromatin architecture. Despite extensive data from consortia like ENCODE, understanding the dynamics of cis-regulatory elements (CREs) in gene expression remains challenging. Deep learning is a powerful tool for learning gene expression and epigenomic signals from DNA sequences, exhibiting superior performance compared to conventional machine learning approaches. However, even the most advanced deep learning-based methods may fall short in capturing the regulatory effects of distal elements such as enhancers, limiting their predictive accuracy. In addition, these methods may require significant resources to train or to adapt to newly generated data. To address these challenges, we present EPInformer, a scalable deep-learning framework for predicting gene expression by integrating promoter-enhancer interactions with their sequences, epigenomic signals, and chromatin contacts. Our model outperforms existing gene expression prediction models in rigorous cross-chromosome validation, accurately recapitulates enhancer-gene interactions validated by CRISPR perturbation experiments, and identifies crucial transcription factor motifs within regulatory sequences. EPInformer is available as open-source software at https://github.com/pinellolab/EPInformer.

Objective. Brain switches provide a tangible solution to asynchronized brain-computer interface, which decodes user intention without a pre-programmed structure. However, most brain switches based on electroencephalography signals have high false positive rates (FPRs), resulting in less practicality. This research aims to improve the operating mode and usability of the brain switch. Approach. Here, we propose a novel virtual physical model-based brain switch that leverages periodic active modulation. An optimization problem of minimizing the triggering time subject to a required FPR is formulated, numerical and analytical approximate solutions are obtained based on the model. Main results. Our motor imagery (MI)-based brain switch can reach 0.8FP/h FPR with a median triggering time of 58 s. We evaluated the proposed brain switch during online device control, and their average FPRs substantially outperformed the conventional brain switches in the literature. We further improved the proposed brain switch with the Common Spatial Pattern (CSP) and optimization method. An average FPR of 0.3 FPs/h was obtained for the MI-CSP-based brain switch, and the average triggering time improved to 21.6 s. Significance. This study provides a new approach that could significantly reduce the brain switch's FPR to less than 1 Fps/h, which was less than 10% of the FPR (decreasing by more than a magnitude of order) by other endogenous methods, and the reaction time was comparable to the state-of-the-art approaches. This represents a significant advancement over the current non-invasive asynchronous BCI and will open widespread avenues for translating BCI towards clinical applications., (© 2024 IOP Publishing Ltd.)

Objective: To evaluate the effectiveness and safety of nusinersen for the treatment of 5q-spinal muscular atrophy (SMA) among Chinese pediatric patients., Methods: Using a longitudinal, multi-center registry, both prospective and retrospective data were collected from pediatric patients with 5q-SMA receiving nusinersen treatment across 18 centers in China. All patients fulfilling the eligibility criteria were included consecutively. Motor function outcomes were assessed post-treatment by SMA type. Safety profile was evaluated among patients starting nusinersen treatment post-enrollment. Descriptive analyses were used to report baseline characteristics, effectiveness, and safety results., Results: As of March 2nd, 2023, 385 patients were included. Most patients demonstrated improvements or stability in motor function across all SMA types. Type II patients demonstrated mean changes [95% confidence interval (CI)] of 4.4 (3.4-5.4) and 4.1 (2.8-5.4) in Hammersmith Functional Motor Scale-Expanded (HFMSE), and 2.4 (1.7-3.1) and 2.3 (1.2-3.4) in Revised Upper Limb Module (RULM) scores at months 6 and 10. Type III patients exhibited mean changes (95% CI) of 3.9 (2.5-5.3) and 4.3 (2.6-6.0) in HFMSE, and 2.1 (1.2-3.0) and 1.5 (0.0-3.0) in RULM scores at months 6 and 10. Of the 132 patients, 62.9% experienced adverse events (AEs). Two patients experienced mild AEs (aseptic meningitis and myalgia) considered to be related to nusinersen by the investigator, with no sequelae., Conclusions: These data underscore the significance of nusinersen in Chinese pediatric patients with SMA regarding motor function improvement or stability, and support recommendations on nusinersen treatment by Chinese SMA guidelines and continuous coverage of nusinersen by basic medical insurance., (© 2024. The Author(s).)

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Patients often fail to recognize the early signs of CVDs, which display irregularities in cardiac contractility and may ultimately lead to heart failure. Therefore, continuously monitoring the abnormal changes in cardiac contractility may represent a novel approach to long-term CVD surveillance. Here, a zero-power consumption and implantable bias-free cardiac monitoring capsule (BCMC) is introduced based on the triboelectric effect for cardiac contractility monitoring in situ. The output performance of BCMC is improved over 10 times with nanoparticle self-adsorption method. This device can be implanted into the right ventricle of swine using catheter intervention to detect the change of cardiac contractility and the corresponding CVDs. The physiological signals can be wirelessly transmitted to a mobile terminal for analysis through the acquisition and transmission module. This work contributes to a new option for precise monitoring and early diagnosis of CVDs., (© 2024 Wiley‐VCH GmbH.)

Introduction: Intracerebral hemorrhage (ICH) is a severe manifestation of stroke, demonstrating notably elevated global mortality and morbidity. Thus far, effective therapeutic strategies for ICH have proven elusive. Currently, minimally invasive techniques are widely employed for ICH management, particularly using endoscopic hematoma evacuation in cases of deep ICH. Exploration of strategies to achieve meticulous surgery and diminish iatrogenic harm, especially to the corticospinal tract, with the objective of enhancing the neurological prognosis of patients, needs further efforts., Methods: We comprehensively collected detailed demographic, clinical, radiographic, surgical, and postoperative treatment and recovery data for patients who underwent endoscopic hematoma removal. This thorough inclusion of data intends to offer a comprehensive overview of our technical experience in this study., Results: One hundred fifty-four eligible patients with deep supratentorial intracerebral hemorrhage who underwent endoscopic hematoma removal were included in this study. The mean hematoma volume was 42 ml, with 74 instances of left-sided hematoma and 80 cases of right-sided hematoma. The median Glasgow Coma Scale (GCS) score at admission was 10 (range from 4 to 15), and the median time from symptom onset to surgery was 18 (range 2 to 96) h. The mean hematoma clearance rate was 89%. The rebleeding and mortality rates within 1 month after surgery were 3.2% and 7.8%, respectively. At the 6-month mark, the proportion of patients with modified Rankin Scale (mRS) scores of 0-3 was 58.4%., Conclusion: Both the reduction of surgery-related injury and the protection of the residual corticospinal tract through endoscopic hematoma removal may potentially enhance neurological functional outcomes in patients with deep ICH, warranting validation in a forthcoming multicenter clinical study., (© 2024. The Author(s).)

Objective: Our objective is to assess the oncologic outcomes of observation, elective neck dissection (END), and elective neck irradiation (ENI) in the neck management of head and neck cutaneous squamous cell carcinoma (HNcSCC) with parotid metastasis (P+) and to evaluate the quality of life (QoL) of patients who received END or ENI., Methods: Patients with P+ HNcSCC were retrospectively enrolled. The impact of observation, END, and ENI on regional control (RC) and overall survival (OS) was analyzed using Cox proportional hazards model with presentation via hazard ratio (HR) with a 95% confidence interval (CI). QoL was evaluated using the University of Washington Quality of Life questionnaire., Results: A total of 134 patients were included in our analysis. In the Cox model for RC, both END and ENI had decreased HRs of 0.27 (95% CI: 0.15-0.69) and 0.34 (95% CI: 0.18-0.86), respectively, in comparison with observation. In the Cox model for OS, both END (p = 0.001, HR: 0.22, 95% CI: 0.10-0.72) and ENI (p = 0.006, HR: 0.30, 95% CI: 0.17-0.83) were superior to observation. In patients with three or more positive parotid lymph nodes, END resulted in significantly better RC (p < 0.001) and OS (p = 0.001) compared with ENI. The two groups were found to be comparable in all 12 domains of the University of Washington Quality of Life questionnaire., Conclusion: In the neck management of P+ HNcSCC, observation is not recommended. END is the preferred option, but ENI is an alternative method without compromise to survival or QoL, except in cases with three or more metastatic parotid lymph nodes., (© 2024 Wiley Periodicals LLC.)

Background: The gut microbiota is crucial in human health and diseases. Traditional Chinese Medicine Constitution (TCMC) divides people into those with a balanced constitution (Ping-he [PH]) and those with an unbalanced constitution. Dampness-heat constitution (Shi-re [SR]) is a common unbalanced constitution in the Chinese population and is susceptible to diseases. However, unbalanced constitutions can be regulated by Chinese medicine and lifestyle interventions in clinical practice. Ermiao Pill (EMP) is a Chinese medicine known for clearing heat and draining dampness and improving SR. However, the efficacy and mechanism of EMP are unclear., Hypothesis/purpose: To determine alterations in the gut microbiota and metabolome in SR and any changes after EMP treatment combined with lifestyle intervention., Study Design: Randomized clinical trial., Methods: We enrolled 112 healthy SR individuals and evaluated the efficacy of EMP along with lifestyle interventions. We further assessed serum cytokine levels, serum and urinary metabolomes, and the gut microbiota by 16S rRNA gene sequencing analysis before and after the EMP and lifestyle interventions., Results: 107 SR individuals (55 in the intervention group and 52 in the control group) completed the 1-month-intervention and 1-year-follow-up. The intervention group significantly improved their health status within 1 month, with a reduced SR symptom score, and the efficacy lasted to the 1-year follow-up. The control group needed a further 6 months to reduce the SR symptom score. The gut microbiota of PH individuals was more diverse and had significantly higher proportions of many bacterial species than the SR. Microbiota co-occurrence network analysis showed that SR enriches metabolites correlating with microbial community structure, consistent with traits of healthy SR-enriched microbiota., Conclusion: EMP combined with lifestyle intervention produced health benefits in SR individuals. Our study indicates a pivotal role of gut microbiota and metabolome alterations in distinguishing between healthy SR and PH. Furthermore, the study reveals structural changes of gut microbiota and metabolites induced by EMP and lifestyle intervention. The treatment enriched the number of beneficial bacteria, such as Akkermansia muciniphila and Lactobacillus in the gut. Our findings provide a strong indication that several metabolite factors are associated with the gut microbiota. Moreover, the gut microbiome and metabolome might be powerful tools for TCMC diagnosis and personalized 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. Published by Elsevier GmbH.)

Purpose: Androgen receptors are expressed in the pelvic floor and lower urinary tract. However, the association between serum testosterone and overactive bladder (OAB) in women remains unclear. This study aimed to investigate their association in a nationally representative population., Methods: In this cross-sectional study, we collected data on female participants older than 20 years with serum total testosterone measurements and OAB questionnaires from the 2011-2016 National Health and Nutrition Examination Survey (NHANES). Survey-weighted logistic regression models were used to analyze the relationship between testosterone and OAB in women., Results: Data on 4991 women was analyzed in this study, of whom 25.9% had OAB symptoms. Women with lower serum testosterone had an increased frequency of urge urinary incontinence and nocturia compared to participants with enough testosterone. The multivariate logistic models showed that those women with a testosterone level less than 18.5 ng/dL had significantly higher odds of OAB compared to those with a testosterone level greater than 18.5 ng/dL [OR 95% CI = 1.271 (1.073-1.505), P = 0.0076]. Separate interaction analyses revealed no significant effect of age, BMI, diabetes, education, alcohol use and menopause on the association between serum testosterone and OAB. Sensitivity analyses demonstrated that additional variables (depression, stroke and stress urinary incontinence) had no significant effect on this relationship., Conclusions: Low serum testosterone is associated with an increased likelihood of OAB in women. This supports the potential therapeutic role of testosterone supplementation in women with OAB. Given the direct and indirect effects of testosterone on the pelvic floor and lower urinary tract, a potential mechanism for this relationship can be further explored in translational studies., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)