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Abstract Background Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice. Methods Open field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated. Results The research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction. Conclusions The decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery. Graphical Abstract

Abstract Objective The risk category of gastric gastrointestinal stromal tumors (GISTs) are closely related to the surgical method, the scope of resection, and the need for preoperative chemotherapy. We aimed to develop and validate convolutional neural network (CNN) models based on preoperative venous-phase CT images to predict the risk category of gastric GISTs. Method A total of 425 patients pathologically diagnosed with gastric GISTs at the authors’ medical centers between January 2012 and July 2021 were split into a training set (154, 84, and 59 with very low/low, intermediate, and high-risk, respectively) and a validation set (67, 35, and 26, respectively). Three CNN models were constructed by obtaining the upper and lower 1, 4, and 7 layers of the maximum tumour mask slice based on venous-phase CT Images and models of CNN_layer3, CNN_layer9, and CNN_layer15 established, respectively. The area under the receiver operating characteristics curve (AUROC) and the Obuchowski index were calculated to compare the diagnostic performance of the CNN models. Results In the validation set, CNN_layer3, CNN_layer9, and CNN_layer15 had AUROCs of 0.89, 0.90, and 0.90, respectively, for low-risk gastric GISTs; 0.82, 0.83, and 0.83 for intermediate-risk gastric GISTs; and 0.86, 0.86, and 0.85 for high-risk gastric GISTs. In the validation dataset, CNN_layer3 (Obuchowski index, 0.871) provided similar performance than CNN_layer9 and CNN_layer15 (Obuchowski index, 0.875 and 0.873, respectively) in prediction of the gastric GIST risk category (All P >.05). Conclusions The CNN based on preoperative venous-phase CT images showed good performance for predicting the risk category of gastric GISTs.

Abstract Background Remimazolam tosilate (RT) is a novel short-acting GABA (A) receptor agonist that has a rapid recovery from procedural sedation and can be fully reversed by flumazenil. To date, there have been relatively few articles comparing RT and propofol for general anesthesia. This study aimed to assess the efficacy and safety of RT with or without flumazenil compared with propofol in general anesthesia for day surgery. Methods 115 patients scheduled for day surgery were randomized into three groups: RT (n = 39), RT + flumazenil (n = 38) and propofol (n = 38). The primary endpoints were anesthesia induction time and time until fully alert. Anesthesia success rate, bispectral index (BIS) values, injection pain, opioid and vasopressor dosages, postoperative recovery profiles and perioperative inflammatory and cognitive changes were assessed. Any adverse events were recorded. Results Induction times were similar among the three groups (P = 0.437), but the median time until fully alert in patients treated with RT was longer than that of the propofol or RT + flumazenil groups (17.6 min vs. 12.3 min vs. 12.3 min, P 0.05). Smaller percentages of patients who received RT (26.3%) and RT + flumazenil (31.6%) developed hypotension during anesthesia maintenance compared with propofol (68.4%), and consequently less ephedrine (P

Abstract Background This study attempted to verify the potential of KCNJ14 as a biomarker in colorectal cancer (CRC). Methods Data on transcriptomics and DNA methylation and the clinical information of CRC patients were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Biological information analysis methods were conducted to determine the role of KCNJ14 in the prognosis, diagnosis, immune cell infiltration, and regulation mechanism of CRC patients. The effect of KCNJ14 on the proliferation and migration of HCT116 and SW480 CRC cell lines was verified by in vitro experiments (MTT, colony-forming, wound healing, and transwell assays). Western blotting was performed to detect the effect of KCNJ14 on the levels of mTOR signalling pathway-related proteins. Results KCNJ14 expression was remarkably increased in CRC tissues and cell lines, which reduced the overall survival time of patients. KCNJ14 mRNA was negatively regulated by its methylation site cg17660703, which can also endanger the prognosis of patients with CRC. Functional enrichment analysis suggested that KCNJ14 is involved in the mTOR, NOD-like receptor, and VEGF signalling pathways. KCNJ14 expression was positively correlated with the number of CD4 + T cells and negatively correlated with that of CD8 + T cells in the immune microenvironment. KCNJ14 knockdown significantly reduced not only the proliferation and migration of CRC cell lines but also the levels of mTOR signalling pathway-related proteins. Conclusions This study not only increases the molecular understanding of KCNJ14 but also provides a potentially valuable biological target for the treatment of colorectal cancer.

Abstract Background Postoperative cognitive dysfunction (POCD) is a very common complication that might increase the morbidity and mortality of elderly patients after surgery. However, the mechanism of POCD remains largely unknown. The NAD-dependent deacetylase protein Sirtuin 3 (SIRT3) is located in the mitochondria and regulates mitochondrial function. SIRT3 is the only sirtuin that specifically plays a role in extending lifespan in humans and is associated with neurodegenerative diseases. Therefore, the aim of this study was to evaluate the effect of SIRT3 on anesthesia/surgery-induced cognitive impairment in aged mice. Methods SIRT3 expression levels were decreased after surgery. For the interventional study, an adeno-associated virus (AAV)-SIRT3 vector or an empty vector was microinjected into hippocampal CA1 region before anesthesia/surgery. Western blotting, immunofluorescence staining, and enzyme-linked immune-sorbent assay (ELISA) were used to measure the oxidative stress response and downstream microglial activation and proinflammatory cytokines, and Golgi staining and long-term potentiation (LTP) recording were applied to evaluate synaptic plasticity. Results Overexpression of SIRT3 in the CA1 region attenuated anesthesia/surgery-induced learning and memory dysfunction as well as synaptic plasticity dysfunction and the oxidative stress response (superoxide dismutase [SOD] and malondialdehyde [MDA]) in aged mice with POCD. In addition, microglia activation (ionized calcium binding adapter molecule 1 [Iba1]) and neuroinflammatory cytokine levels (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β and IL-6) were regulated after anesthesia/surgery in a SIRT3-dependent manner. Conclusion The results of the current study demonstrate that SIRT3 has a critical effect in the mechanism of POCD in aged mice by suppressing hippocampal neuroinflammation and reveal that SIRT3 may be a promising therapeutic and diagnostic target for POCD.

Abstract Interleukin (IL)-9 belongs to the IL-2Rγc chain family and is a multifunctional cytokine that can regulate the function of many kinds of cells. It was originally identified as a growth factor of T cells and mast cells. In previous studies, IL-9 was mainly involved in the development of allergic diseases, autoimmune diseases and parasite infections. Recently, IL-9, as a double-edged sword in the development of cancers, has attracted extensive attention. Since T-helper 9 (Th9) cell-derived IL-9 was verified to play a powerful antitumor role in solid tumors, an increasing number of researchers have started to pay attention to the role of IL-9-skewed CD8+ T (Tc9) cells, mast cells and Vδ2 T cell-derived IL-9 in tumor immunity. Here, we review recent studies on IL-9 and several kinds of IL-9-producing cells in tumor immunity to provide useful insight into tumorigenesis and treatment. Video Abstract Graphical abstract

Abstract Background Macrophages are heterogenous phagocytic cells with an important role in the innate immunity. They are, also, significant contributors in the adaptive immune system. Macrophages are the most abundant immune cells in the lung during allergic asthma, which is the most common chronic respiratory disease of both adults and children. Macrophages activated by Th1 cells are known as M1 macrophages while those activated by IL-4 and IL-13 are called alternatively activated macrophages (AAM) or M2 cells. AAM are subdivided into four distinct subtypes (M2a, M2b, M2c and M2d), depending on the nature of inducing agent and the expressed markers. Body IL-4 is the major effector cytokine in both alternative activation of macrophages and pathogenesis of asthma. Thus, the role of M2a macrophages in asthma is a major concern. However, this is controversial. Therefore, further studies are required to improve our knowledge about the role of IL-4-induced macrophages in allergic asthma, through precisive elucidation of the roles of specific M2a proteins in the pathogenesis of asthma. In the current review, we try to illustrate the different functions of M2a macrophages (protective and pathogenic roles) in the pathogenesis of asthma, including explanation of how different M2a proteins and markers act during the pathogenesis of allergic asthma. These include surface markers, enzymes, secreted proteins, chemokines, cytokines, signal transduction proteins and transcription factors. Conclusions AAM is considered a double-edged sword in allergic asthma. Finally, we recommend further studies that focus on increased selective expression or suppression of protective and pathogenic M2a markers.

Abstract Both Gram-Positive and Gram-Negative bacteria can secrete outer membrane vesicles (OMVs) in their growth and metabolism process. Originally, OMVs were considered as a by-product of bacterial merisis. However, many scientists have reported the important role of OMVs in many fields recently. In this review, we briefly introduce OMVs biological functions and then summarize the findings about the OMVs interactions with host cells. At last, we will make an expectation about the prospects of the application of OMVs as vaccines.

Abstract Background To explore the current situation, existing problems and possible causes of said problems with regards to physician-nurse communication under an environment of increasingly widespread usage of Hospital Information Systems and to seek out new potential strategies in information technology to improve physician-nurse communication. Methods Semi-structured interviews were conducted with 20 physicians and nurses in five leading tertiary grade A hospitals in Beijing, China (two physicians and two nurses in each hospital). The interviews primarily included three aspects comprising the current situation and problems of clinical physician-nurse communication, the application and problems of Hospital Information Systems, and assessments on the improvement of physician-nurse communication through the usage of information technology. The inductive conventional content analysis approach was employed. Results (1) Physicians and nurses are generally quite satisfied with the current situation of communication. However, the information needs of nurses are prone to being overlooked, and the communication methods are primarily synchronous communication such as face-to-face and phone communication. (2) Hospital Information Systems are gradually being used for physician-nurse communication; in the meantime, physicians and nurses face challenges with regards to the improvement of physician-nurse communication through the usage of information technology. Challenges differ based on the different stages of using the system and the different levels of understanding of physicians and nurses towards information technology. Their dissatisfaction mainly deals with system errors and the level of convenience in using the system. (3) In-depth interviews found that in general, physicians and nurses have a strong interest and trust in improving physician-nurse communication through appropriate information technology, e.g., communication methods such as information reminders for physicians and nurses through mobile devices and instant voice-to-text conversion methods. Conclusions There are objective risks in physician-nurse communication in Chinese hospitals, and clinical information systems lack solutions to the relevant problems. Developing a dedicated, mobile, quick and convenient module for physician-nurse communication within existing hospital information system with automatic reminders for important information that segregates between synchronous and asynchronous communication according to the different types of information could help improve physician-nurse communication.

Abstract Drug resistance remains a significant challenge in cancer treatment. Recently, the interactions among various cell types within the tumor microenvironment (TME) have deepened our understanding of the mechanisms behind treatment resistance. Therefore, this review aims to synthesize current research focusing on infiltrating cells and drug resistance suggesting that targeting the TME could be a viable strategy to combat this issue. Numerous factors, including inflammation, metabolism, senescence, hypoxia, and angiogenesis, contribute to drug resistance could be a viable strategy to combat this issue. Overexpression of STAT3 is commonly associated with drug-resistant cancer cells or stromal cells. Current research often generalizes the impact of stromal cells on resistance, lacking specificity and statistical robustness. Thus, future research should take notice of this issue and aim to provide high-quality evidence. Despite the existing limitations, targeting the TME to overcome therapy resistance hold promising and valuable potential.

Abstract Background Healthcare-associated infections (HAIs) are important indicators of healthcare quality. The aseptic non touch technique (ANTT), a standardised aseptic technique, is a crucial preventative measure against HAIs. However, there is insufficient evidence currently available regarding ANTT awareness and proficiency among nurses. This study aimed to investigate the status of ANTT proficiency in a cohort of nurses and analyse the associated risk factors, with the ultimate goal of providing a reference for promoting the application of ANTT in clinical practice. Methods The study population was sampled from nurses working in a tertiary hospital in Zhejiang Province, China, in January 2024. A cross-sectional survey was conducted using a self-designed questionnaire to assess ANTT knowledge. Multivariate linear regression analysis was used to analyse the risk factors influencing ANTT knowledge in nurses. Results A total of 458 nurses were included in this study. The cohort had an overall score of 49.7% correct responses on the ANTT knowledge questionnaire, with a mean score of 12.4 ± 2.4 out of 25, and 30.1% of the nurses felt that they did not need training related to ANTT. Multivariate linear regression analysis indicated that professional title, educational level, and the need for ANTT training were independently associated with ANTT knowledge in nurses. Nurses with Master’s degrees and associated chief nurses were observed to have higher levels of ANTT knowledge compared to the rest. Conclusions ANTT knowledge is insufficient among nurses in China, and its importance is not widely recognised. Continuous efforts are required to strengthen this knowledge. Constructing sustained, multiform, and stratified training programmes may represent an effective method to strengthen ANTT knowledge among nurses and promote its clinical use.

Abstract Objective Thromboangiitis obliterans (TAO) remains clinical challenging due to its rarity and underwhelming management outcomes. This study aimed to describe a novel TAO rabbit model that demonstrates a closer resemblance to TAO. Methods Thirty-six New Zealand rabbits underwent the surgical implantation of calibrated gelatin sponge particles (CGSPs) into their right femoral artery. The CGSPs were soaked in different solutions to simulate different types of thrombi: normal (NT; normal saline); inflammatory TAO thrombus (TAO; dimethylsulfoxide [DMSO]), and DMSO with methotrexate (MTX). All groups underwent clinical assessment, digital subtraction angiography (DSA) and histopathological analysis at time points day 0 (immediate), week 1 (acute), week 2 (subacute), and week 4 (chronic). Results The TAO rabbit presented with signs of ischemia of the right digit at week 4. On DSA, the TAO rabbits exhibited formation of corkscrew collaterals starting week 1. On H&E staining, gradual CGSP degradation was observed along with increased red blood cell aggregation and inflammatory cells migration in week 1. On week 2, disorganization of the tunica media layer and vascular smooth muscle cell (VSMC) proliferation was observed. In the TAO rabbit, migrated VSMCs, inflammatory cells, and extracellular matrix with collagen-like substances gradually occluded the lumen. On week 4, the arterial lumen of the TAO rabbit was filled with relatively-organized VSMC and endothelial cell clusters with less inflammatory cells. Neorevascularization was found in the MTX-treated group. Conclusion The novel TAO rabbit model shows a closer resemblance to human TAO clinically, radiographically, and histopathologically. Histological analysis of the IT progression in the TAO model suggests that it is of VSMC origin.

Abstract Background The cranial-caudal-medial approach (CCMA) has been proposed for laparoscopic right hemicolectomy nowadays. This study aimed to investigate the safety and oncological efficacy of CCMA in the treatment of right-sided colon cancer compared to the medial–lateral approach (MLA). Methods Patients diagnosed with right-sided colon cancer were included from February 2015 to June 2018, retrospectively, dividing into the CCMA group and the MLA group. We compared the basic characteristics and the short-term and long-term outcomes in two groups. Results Two hundred and ninety-six patients were included in this study. The baseline characteristics were similar in two groups. Compared with MLA group, CCMA group exhibited shorter operation time (136.3 ± 25.3 min vs. 151.6 ± 21.5 min, P

Abstract Background SARS-CoV-2 infection in pregnant women during the third trimester resulted in overall adverse pregnancy outcomes compared to non-infected controls and a unique humoral and cellular response at delivery. In this study we aimed to assess the impact of SARS-CoV-2 infection on maternal/neonatal peripartum outcomes andimmunological profiles. Method In this study, we recruited 304 SARS-CoV-2 infected pregnant women and 910 SARS-CoV-2 non-infected pregnant women who were admitted for delivery. Peripartum and neonates’ outcomes response to SARS-CoV-2 infection were analyzed. Furthermore, we characterized the antibody and cytokines profile in SARS-CoV-2 infected maternal blood (MB) and cord blood (CB). We also assessed routine laboratory tests and liver function tests in MB before labor. Unpaired T test, Mann-Whitney test and Spearman test were used to analyze the data. Results SARS-CoV-2 infected pregnant women were significantly associated with increased risk of adverse pregnancy outcomes, including preterm labor (13.8% vs. 9.5%, p = 0.033) and meconium-stained amniotic fluid (8.9% vs. 5.5%, p = 0.039). The risk of low birth weight (

Abstract Background Metabolic syndrome (MetS) presents a notable public health challenge on a global scale, exerting a considerable impact on individuals’ health and quality of life. There is mounting evidence indicating a robust association between MetS and levels of sex hormones. Therefore, the study aims to explore the relationship between sex hormone binding-globulin (SHBG) and MetS, and to provide evidence that could inform the development of effective prevention strategies for MetS. Methods Data for this cross-sectional investigation were collected during the 2013–2016 cycle of the National Health and Nutrition Examination Survey (NHANES), from which 5,499 adults were sampled. The criteria established by the Adult Treatment Program III of the National Cholesterol Education Program were utilized to define MetS. SHBG levels were measured using a standardized technique. Multivariate-adjusted logistic regression, multivariate restricted cubic spline, and threshold effect analyses were utilized to investigate the association between SHBG levels and MetS. Moreover, the stratified analyses and interaction tests of covariables were presented in a forest plot. Finally, sensitivity analysis was utilized to ensure the robustness of the results. Results Overall, 1822 participants had MetS. After adjusting for possible confounders, SHBG levels were associated with MetS (Odds ratio [OR], 0.984; 95% confidence interval [CI], 0.981–0.986; P

Abstract Background Cytoplasmic male sterility (CMS) has greatly improved the utilization of heterosis in crops due to the absence of functional male gametophyte. The newly developed sporophytic D1 type CMS (CMS-D1) rice exhibits unique characteristics compared to the well-known sporophytic CMS-WA line, making it a valuable resource for rice breeding. Results In this research, a novel CMS-D1 line named Xingye A (XYA) was established, characterized by small, transparent, and shriveled anthers. Histological and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays conducted on anthers from XYA and its maintainer line XYB revealed that male sterility in XYA is a result of delayed degradation of tapetal cells and abnormal programmed cell death (PCD) of microspores. Transcriptome analysis of young panicles revealed that differentially expressed genes (DEGs) in XYA, compared to XYB, were significantly enriched in processes related to chromatin structure and nucleosomes during the microspore mother cell (MMC) stage. Conversely, processes associated with sporopollenin biosynthesis, pollen exine formation, chitinase activity, and pollen wall assembly were enriched during the meiosis stage. Metabolome analysis identified 176 specific differentially accumulated metabolites (DAMs) during the meiosis stage, enriched in pathways such as α-linoleic acid metabolism, flavone and flavonol biosynthesis, and linolenic acid metabolism. Integration of transcriptomic and metabolomic data underscored the jasmonic acid (JA) biosynthesis pathway was significant enriched in XYA during the meiosis stage compared to XYB. Furthermore, levels of JA, MeJA, OPC4, OPDA, and JA-Ile were all higher in XYA than in XYB at the meiosis stage. Conclusions These findings emphasize the involvement of the JA biosynthetic pathway in pollen development in the CMS-D1 line, providing a foundation for further exploration of the molecular mechanisms involved in CMS-D1 sterility.

Abstract Background Intraventricular hemorrhage (IVH) refers to bleeding within the brain’s ventricular system, and hydrocephalus is a life-threatening complication of IVH characterized by increased cerebrospinal fluid accumulation in the ventricles resulting in elevated intracranial pressure. IVH poses significant challenges for healthcare providers due to the complexity of the underlying pathophysiology and lack of standardized treatment guidelines. Herein, we performed a systematic review of the treatment strategies for hydrocephalus secondary to IVH. Methods This systematic review was prospectively registered with PROSPERO (CRD42023450786). The search was conducted in PubMed, Cochrane Library, and Web of Science on July 15, 2023. We included original studies containing valid information on therapy management and outcome of hydrocephalus secondary to primary, spontaneous, and subarachnoid or intracranial hemorrhage following IVH in adults that were published between 2000 and 2023. Glasgow Outcome Scale (GOS) or modified Ranking Scale (mRS) scores during follow-up were extracted as primary outcomes. The risk of bias was assessed using the Newcastle–Ottawa Scale for Cohort Studies or Cochrane Risk of Bias 2.0 Tool. Results Two hundred and seven patients from nine published papers, including two randomized controlled trials, were included in the analysis. The GOS was used in five studies, while the mRS was used in four. Seven interventions were applied, including craniotomy for removal of hematoma, endoscopic removal of hematoma with/without endoscopic third ventriculostomy (ETV), traditional external ventricular drainage (EVD), and various combinations of EVD, lumbar drainage (LD), and intraventricular fibrinolysis (IVF). Endoscopic removal of hematoma was performed in five of nine studies. Traditional EVD had no obvious benefit compared with new management strategies. Three different combinations of EVD, LD, and IVF demonstrated satisfactory outcomes, although more studies are required to confirm their reliability. Removal of hematoma through craniotomy generated reliable result. Generally, endoscopic removal of hematoma with ETV, removal of hematoma through craniotomy, EVD with IVF, and EVD with early continuous LD were useful. Conclusion EVD is still crucial for the management of IVH and hydrocephalus. Despite a more reliable result from the removal of hematoma through craniotomy, a trend toward endoscopic approach was observed due to a less invasive profile.

Abstract In the past decade, intestinal organoid technology has paved the way for reproducing tissue or organ morphogenesis during intestinal physiological processes in vitro and studying the pathogenesis of various intestinal diseases. Intestinal organoids are favored in drug screening due to their ability for high-throughput in vitro cultivation and their closer resemblance to patient genetic characteristics. Furthermore, as disease models, intestinal organoids find wide applications in screening diagnostic markers, identifying therapeutic targets, and exploring epigenetic mechanisms of diseases. Additionally, as a transplantable cellular system, organoids have played a significant role in the reconstruction of damaged epithelium in conditions such as ulcerative colitis and short bowel syndrome, as well as in intestinal material exchange and metabolic function restoration. The rise of interdisciplinary approaches, including organoid-on-chip technology, genome editing techniques, and microfluidics, has greatly accelerated the development of organoids. In this review, VOSviewer software is used to visualize hot co-cited journal and keywords trends of intestinal organoid firstly. Subsequently, we have summarized the current applications of intestinal organoid technology in disease modeling, drug screening, and regenerative medicine. This will deepen our understanding of intestinal organoids and further explore the physiological mechanisms of the intestine and drug development for intestinal diseases.

Abstract Objective Understanding the characteristics related to cardiorespiratory fitness after stroke can provide reference values for patients in clinical rehabilitation exercise. This meta- analysis aimed to investigate the effect of robot-assisted gait training in improving cardiorespiratory fitness in post-stroke patients, compared to conventional rehabilitation training. Methods PubMed, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, CBM, CNKI and Wanfang databases were searched until March 18th, 2024. Randomized controlled trials (RCTs) comparing the effectiveness of robot-assisted gait training versus control group were included. The main outcome variable was peak oxygen uptake. 6-minute walking test, peak heart rate, peak inspiratory expiratory ratio as our secondary indicators. RevMan 5.3 software was used for statistical analysis. Results A total of 17 articles were included, involving 689 subjects. The results showed a significant effect for robot-assisted gait training to improve VO2peak (MD = 1.85; 95% CI: -0.13 to 3.57; p = 0.04) and 6WMT (MD = 19.26; 95% CI: 10.43 to 28.08; p

Abstract Background Cellular immunotherapy, represented by the chimeric antigen receptor T cell (CAR-T), has exhibited high response rates, durable remission, and safety in vitro and in clinical trials. Unfortunately, anti-CD19 CAR-T (CART-19) treatment alone is prone to relapse and has a particularly poor prognosis in relapsed/refractory (r/r) B-ALL patients. To date, addressing or reducing relapse remains one of the research priorities to achieve broad clinical application. Methods We manufactured second generation CART-19 cells and validated their efficacy and safety in vitro and in vivo. Through co-culture of Nalm-6 cells with short-term cultured CART-19 cells, CD19-negative Nalm-6 cells were detected by flow cytometry, and further investigation of the relapsed cells and their resistance mechanisms was evaluated in vitro. Results In this study, we demonstrated that CART-19 cells had enhanced and specific antileukemic activities, and the survival of B-ALL mouse models after CART-19 treatment was significantly prolonged. We then shortened the culture time and applied the serum-free culture to expand CAR-T cells, followed by co-culturing CART-19 cells with Nalm-6 cells. Surprisingly, we observed the proliferation of CD19-negative Nalm-6 cells around 28 days. Identification of potential resistance mechanisms showed that the relapsed cells express truncated CD19 proteins with decreased levels and, more importantly, CAR expression was detected on the relapsed cell surface, which may ultimately keep them antigen-negative. Furthermore, it was validated that CART-22 and tandem CART-22/19 cells could effectively kill the relapsed cells, but neither could completely eradicate them. Conclusions We successfully generated CART-19 cells and obtained a CD19-negative refractory relapsed B-ALL cell line, providing new insights into the underlying mechanisms of resistance and a new in vitro model for the treatment of r/r B-ALL patients with low antigen density.

Abstract Background Periprosthetic joint infection (PJI) is a severe complication that can occur after total joint arthroplasty (TJA). The timely and accurate diagnosis of PJI is the key to treatment. This study investigated the diagnostic value of platelet to lymphocyte ratio (PLR), platelet count to mean platelet volume ratio (PVR), neutrophil to lymphocyte ratio (NLR) and monocyte to lymphocyte ratio (MLR) in PJI after total knee arthroplasty (TKA) and total hip arthroplasty (THA). Methods We performed a retrospective analysis of the patients who underwent revision hip or knee arthroplasty at our Institute between June 2015 and June 2020. Of the 187 patients reviewed, 168 were included in the study. According to the diagnostic criteria of the Musculoskeletal Infection Society (MSIS), 58 patients were in the PJI group, and 110 patients were in the aseptic loosening (AL) group. We recorded and compared the preoperative peripheral blood white blood cell (WBC) count, platelet count (PLT), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), PLR, PVR, NLR, and MLR in both groups. The diagnostic performance of the WBC, PLT, PLR, PVR, NLR, and MLR individually and in combination with the ESR and CRP for PJI diagnosis was evaluated by receiver operating characteristic (ROC) curves, and the sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Results Compared to those in the AL group, the mean WBC, PLT, ESR, CRP, PLR, PVR, NLR, and MLR in the peripheral blood of the PJI group were significantly greater (P

Abstract Paraquat (PQ) is a widely used herbicide and a common cause of poisoning that leads to pulmonary fibrosis with a high mortality rate. However, the underlying mechanisms of PQ-induced pulmonary fibrosis and whether pulmonary epithelial cell senescence is involved in the process remain elusive. In this study, PQ-induced pulmonary epithelial cell senescence and Hippo-YAP/TAZ activation were observed in both C57BL/6 mice and human epithelial cells. PQ-induced senescent pulmonary epithelial cells promoted lung fibroblast transformation through secreting senescence-associated secretory phenotype (SASP) factors. Yap/Taz knockdown in mice lungs significantly decreased the expression of downstream profibrotic protein Ctgf and senescent markers p16 and p21, and alleviated PQ-induced pulmonary fibrosis. Interfering YAP/TAZ in senescent human pulmonary epithelial cells resulted in decreased expression of the anti-apoptosis protein survivin and elevated level of apoptosis. In conclusion, our findings reveal a novel mechanism by which the involvement of Hippo-YAP/TAZ activation in pulmonary epithelial cell senescence mediates the pathogenesis of PQ-induced pulmonary fibrosis, thereby offering novel insights and potential targets for the clinical management of PQ poisoning as well as providing the mechanistic insight of the involvement of Yap/Taz activation in cell senescence in pulmonary fibrosis and its related pulmonary disorders. The YIN YANG balance between cell senescence and apoptosis is important to maintain the homeostasis of the lung, the disruption of which will lead to disease.

Abstract Background Gout is caused by monosodium urate (MSU) crystals deposition to trigger immune response. A recent study suggested that inhibition of Class I Histone deacetylases (HDACs) can significantly reduce MSU crystals-induced inflammation. However, which one of HDACs members in response to MSU crystals was still unknown. Here, we investigated the roles of HDAC3 in MSU crystals-induced gouty inflammation. Methods Macrophage specific HDAC3 knockout (KO) mice were used to investigate inflammatory profiles of gout in mouse models in vivo, including ankle arthritis, foot pad arthritis and subcutaneous air pouch model. In the in vitro experiments, bone marrow-derived macrophages (BMDMs) from mice were treated with MSU crystals to assess cytokines, potential target gene and protein. Results Deficiency of HDAC3 in macrophage not only reduced MSU-induced foot pad and ankle joint swelling but also decreased neutrophils trafficking and IL-1β release in air pouch models. In addition, the levels of inflammatory genes related to TLR2/4/NF-κB/IL-6/STAT3 signaling pathway were significantly decreased in BMDMs from HDAC3 KO mice after MSU treatment. Moreover, RGFP966, selective inhibitor of HDAC3, inhibited IL-6 and TNF-α production in BMDMs treated with MSU crystals. Besides, HDAC3 deficiency shifted gene expression from pro-inflammatory macrophage (M1) to anti-inflammatory macrophage (M2) in BMDMs after MSU challenge. Conclusions Deficiency of HDAC3 in macrophage alleviates MSU crystals-induced gouty inflammation through inhibition of TLR2/4 driven IL-6/STAT3 signaling pathway, suggesting that HDAC3 could contribute to a potential therapeutic target of gout.

Abstract Background Carcass traits are crucial indicators of meat production efficiency. However, the molecular regulatory mechanisms associated with these traits remain unclear. Results In this study, we conducted comprehensive transcriptomic and genomic analyses on 399 Tiannong partridge chickens to identify key genes and variants associated with carcass traits and to elucidate the underlying regulatory mechanisms. Based on association analyses with the elastic net (EN) model, we identified 12 candidate genes (AMY1A, AP3B2, CEBPG, EEF2, EIF4EBP1, FGFR1, FOXD3, GOLM1, LOC107052698, PABPC1, SERPINB6 and TBC1D16) for 4 carcass-related traits, namely live weight, dressed weight, eviscerated weight, and breast muscle weight. SERPINB6 was identified as the only overlapping gene by 3 analyses, EN model analysis, weighted gene co-expression network analysis and differential expression analysis. Cell-level experiments confirmed that SERPINB6 promotes the proliferation of chicken DF1 cells and primary myoblasts. Further expression genome-wide association study and association analysis indicated that rs317934171 is the critical site that enhances SERPINB6 expression. Furthermore, a dual-luciferase reporter assay proved that gga-miR-1615 targets the 3′UTR of SERPINB6. Conclusions Collectively, our findings reveal that SERPINB6 serves as a novel gene for chicken carcass traits by promoting fibroblast and myoblast proliferation. Additionally, the downstream variant rs317934171 regulates SERPINB6 expression. These results identify a new target gene and molecular marker for the molecular mechanisms of chicken carcass traits.

Abstract Objective This study introduced the modified Q-type purse-string suture duodenal stump embedding method, a convenient way to strengthen the duodenum, and compared it to the conventional one to assess its efficacy and safety. Methods This retrospective analysis examined 612 patients who received laparoscopic gastrectomy for gastric Cancer at a single center. The patients were divided into Not Reinforced Group (n = 205) and Reinforced Group (n = 407) according to the surgical approach to the duodenal stump. The reinforced group was further divided into a modified Q-type purse-string suture embedding method group (QM, n = 232) and a conventional suture duodenal stump embedding method group (CM, n = 175) according to the methods of duodenal stump enhancement. Clinicopathological characteristics, operative variables, and short-term complications were documented and analyzed. Results The incidence of duodenal stump leakage(DSL) in the Not Reinforced Group was higher compared to the Reinforced Group, although the difference was not statistically significant [2.4% (5/205) vs 0.7% (3/407), p = 0.339]. Additionally, the Not Reinforced Group exhibited a higher rate of Reoperation due to DSL compared to the Reinforced Group [2 (1.0%) vs. 0, p = 0.046], with one patient in the Not Reinforced Group experiencing mortality due to DSL [1 (0.5%) vs 0, p = 0.158]. Subgroup analysis within the Reinforced Group revealed that the modified Q-type purse-string suture embedding group (QM) subgroup demonstrated statistically significant advantages over the conventional suture embedding group (CM) subgroup. QM exhibited shorter purse-string closure times (4.11 ± 1.840 vs. 6.05 ± 1.577, p = 0.001), higher purse-string closure success rates (93.1% vs. 77.7%, p = 0.001), and greater satisfaction with purse-string closure [224 (96.6%) vs 157 (89.7%), p = 0.005]. No occurrences of duodenal stump leakage were observed in the QM subgroup, while the CM subgroup experienced two cases [2 (1.1%)], though the difference was not statistically significant. Both groups did not exhibit statistically significant differences in secondary surgery or mortality related to duodenal stump leakage. Conclusion Duodenal Stump Leakage (DSL) is a severe but low-incidence complication. There is no statistically significant relationship between the reinforcement of the duodenal stump and the incidence of DSL. However, laparoscopic reinforcement of the duodenal stump can reduce the severity of fistulas and the probability of Reoperation. The laparoscopic Q-type purse-string suture duodenal stump embedding method is a simple and effective technique that can, to some extent, shorten the operation time and enhance satisfaction with purse-string closure. There is a trend towards reducing the incidence of DSL, thereby improving patient prognosis to a certain extent.

Abstract The interaction between programmed cell death ligand 1 (PD-L1), which is expressed on the surface of tumor cells, and programmed cell death 1 (PD-1), which is expressed on T cells, impedes the effective activation of tumor antigen-specific T cells, resulting in the evasion of tumor cells from immune-mediated killing. Blocking the PD-1/PD-L1 signaling pathway has been shown to be effective in preventing tumor immune evasion. PD-1/PD-L1 blocking antibodies have garnered significant attention in recent years within the field of tumor treatments, given the aforementioned mechanism. Furthermore, clinical research has substantiated the efficacy and safety of this immunotherapy across various tumors, offering renewed optimism for patients. However, challenges persist in anti-PD-1/PD-L1 therapies, marked by limited indications and the emergence of drug resistance. Consequently, identifying additional regulatory pathways and molecules associated with PD-1/PD-L1 and implementing judicious combined treatments are imperative for addressing the intricacies of tumor immune mechanisms. This review briefly outlines the structure of the PD-1/PD-L1 molecule, emphasizing the posttranslational modification regulatory mechanisms and related targets. Additionally, a comprehensive overview on the clinical research landscape concerning PD-1/PD-L1 post-translational modifications combined with PD-1/PD-L1 blocking antibodies to enhance outcomes for a broader spectrum of patients is presented based on foundational research.

Abstract Background We aimed to investigate the anatomical features of optical coherence tomography (OCT) and vitreous cytokine levels as predictors of outcomes of combined phacovitrectomy with intravitreal dexamethasone (DEX) implants for idiopathic epiretinal membrane (iERM) treatment. Methods A prospective, single-masked, randomized, controlled clinical trial included 48 eyes. They were randomly assigned in a 1:1 ratio to undergo the DEX group (combined phacovitrectomy with ERM peeling and Ozurdex implantation) and control group (phacovitrectomy only). Best-corrected visual acuity (BCVA) and central macular thickness (CMT) were assessed at 1 d, 1 week, 1 month, and 3 months. The structural features of OCT before surgery were analysed for stratified analysis. Baseline soluble CD14 (sCD14) and sCD163 levels in the vitreous fluid were measured using ELISA. Results BCVA and CMT were not significantly different in the DEX and control groups. Eyes with hyperreflective foci (HRF) at baseline achieved better BCVA (P time*group=0.746; P group=0.043, Wald χ²=7.869) and lower CMT (Ptime*group = 0.079; Pgroup = 0.001, Wald χ²=6.774) responses to DEX during follow-up. In all patients, the mean vitreous level of sCD163 in eyes with HRF was significantly higher than that in eyes without HRF (P = 0.036, Z=-2.093) at baseline. In the DEX group, higher sCD163 predicted greater reduction in CMT from baseline to 1 month (r = 0.470, P = 0.049). Conclusions We found that intraoperative DEX implantation did not have beneficial effects on BCVA and CMT over a 3-month period in all patients with iERM, implying that the use of DEX for all iERM is not recommended. In contrast, for those with HRF on OCT responded better to DEX implants at the 3-month follow-up and thier vitreous fluid expressed higher levels of sCD163 at baseline. These data support the hypothesis that DEX implants may be particularly effective in treating cases where ERM is secondary to inflammation. Trial registration The trail has been registered at Chinese Clinical Trail Registry( https://www.chictr.org.cn ) on 2021/03/12 (ChiCTR2100044228). And all patients in the article were enrolled after registration.

Abstract Black rot, caused by Xanthomonas campestris pv. campestris (Xcc) significantly affects the production of cabbage and other cruciferous vegetables. Plant antioxidant system plays an important role in pathogen invasion and is one of the main mechanisms underlying resistance to biological stress. Therefore, it is important to study the resistance mechanisms of the cabbage antioxidant system during the early stages of Xcc. In this study, 108 CFU/mL (OD600 = 0.1) Xcc race1 was inoculated on “zhonggan 11” cabbage using the spraying method. The effects of Xcc infection on the antioxidant system before and after Xcc inoculation (0, 1, 3, and 5 d) were studied by physiological indexes determination, transcriptome and metabolome analyses. We concluded that early Xcc infection can destroy the balance of the active oxygen metabolism system, increase the generation of free radicals, and decrease the scavenging ability, leading to membrane lipid peroxidation, resulting in the destruction of the biofilm system and metabolic disorders. In response to Xcc infection, cabbage clears a series of reactive oxygen species (ROS) produced during Xcc infection via various antioxidant pathways. The activities of antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) increased after Xcc infection, and the ROS scavenging rate increased. The biosynthesis of non-obligate antioxidants, such as ascorbic acid (AsA) and glutathione (GSH), is also enhanced after Xcc infection. Moreover, the alkaloid and vitamin contents increased significantly after Xcc infection. We concluded that cabbage could resist Xcc invasion by maintaining the stability of the cell membrane system and improving the biosynthesis of antioxidant substances and enzymes after infection by Xcc. Our results provide theoretical basis and data support for subsequent research on the cruciferous vegetables resistance mechanism and breeding to Xcc.

Abstract Background Pneumonic-type lung adenocarcinoma (P-ADC) is a rare and challenging subtype of primary lung cancer that can be difficult to distinguish from pneumonia based on radiological images. Furthermore, no drugs are currently available that specifically target KRAS G12V. Case presentation Here we report a case of P-ADC with typical and informative imaging features throughout the course of the disease, including patchy shadows, high-density lesions with aerated bronchus, diffuse ground-glass opacities, and nodular shadows from computed tomography (CT) scan. The KRAS G12V mutation was detected using Next-generation sequencing (NGS). An individualized Afatinib-based therapeutic schedule was prescribed and achieved sustained response after multiple lines of treatment had failed. Conclusion Our case highlights the typical and dynamic changes in imaging features of P-ADC and provides an indicative treatment strategy for KRAS G12V-mutated lung adenocarcinoma.

Abstract Background To investigate serum irisin levels in girls at different developmental status and explore the significance of irisin for the diagnosis of central precocious puberty (CPP) in girls. Methods In this cross-sectional study 111 girls were enrolled, including 43 cases of CPP, 44 cases of peripheral precocious puberty (PPP) and 24 cases of girls with normal sexual development as controls. The data on age, weight and height, measured blood levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, and irisin were collected. Pelvic Doppler ultrasound was performed to evaluate uterine length, transverse diameter, anteroposterior diameter. The girls were divided into non-CPP group and CPP group according to gonadotropin-releasing hormone (GnRH) stimulation test. Results Serum irisin levels were significantly higher in CPP group than in PPP group and normal control group. Serum irisin level was positively correlated with basal LH level, basal FSH level, peak LH level, peak LH /FSH ratio, uterine volume, bone age, and bone age index. The area under the curve, cut-off value, sensitivity and specificity of serum irisin were 0.958, 219.255 pg/ml, 100% and 80.6%. The combined diagnosis of CPP in girls by serum irisin and serum basal LH combined with uterine volume had an AUC, sensitivity, and specificity of 0.994, 97.6%, and 100%, superior to that of the single index. Conclusions Serum irisin level in girls with CPP is significantly increased. An irisin combined index could help the diagnosis of CPP in girls.

Abstract In recent years, advancements in single-cell and spatial transcriptomics, which are highly regarded developments in the current era, particularly the emerging integration of single-cell and spatiotemporal transcriptomics, have enabled a detailed molecular comprehension of the complex regulation of cell fate. The insights obtained from these methodologies are anticipated to significantly contribute to the development of personalized medicine. Currently, single-cell technology is less frequently utilized for prostate cancer compared with other types of tumors. Starting from the perspective of RNA sequencing technology, this review outlined the significance of single-cell RNA sequencing (scRNA-seq) in prostate cancer research, encompassing preclinical medicine and clinical applications. We summarize the differences between mouse and human prostate cancer as revealed by scRNA-seq studies, as well as a combination of multi-omics methods involving scRNA-seq to highlight the key molecular targets for the diagnosis, treatment, and drug resistance characteristics of prostate cancer. These studies are expected to provide novel insights for the development of immunotherapy and other innovative treatment strategies for castration-resistant prostate cancer. Furthermore, we explore the potential clinical applications stemming from other single-cell technologies in this review, paving the way for future research in precision medicine.

Abstract Background Body weight and size are important economic traits in chickens. While many growth-related quantitative trait loci (QTLs) and candidate genes have been identified, further research is needed to confirm and characterize these findings. In this study, we investigate genetic and genomic markers associated with chicken body weight and size. This study provides new insights into potential markers for genomic selection and breeding strategies to improve meat production in chickens. Methods We performed whole-genome resequencing of and Wenshang Barred (WB) chickens (n = 596) and three additional breeds with varying body sizes (Recessive White (RW), WB, and Luxi Mini (LM) chickens; (n = 50)). We then used selective sweeps of mutations coupled with genome-wide association study (GWAS) to identify genomic markers associated with body weight and size. Results We identified over 9.4 million high-quality single nucleotide polymorphisms (SNPs) among three chicken breeds/lines. Among these breeds, 287 protein-coding genes exhibited positive selection in the RW and WB populations, while 241 protein-coding genes showed positive selection in the LM and WB populations. Genomic heritability estimates were calculated for 26 body weight and size traits, including body weight, chest breadth, chest depth, thoracic horn, body oblique length, keel length, pelvic width, shank length, and shank circumference in the WB breed. The estimates ranged from 0.04 to 0.67. Our analysis also identified a total of 2,522 genome-wide significant SNPs, with 2,474 SNPs clustered around two genomic regions. The first region, located on chromosome 4 (7.41-7.64 Mb), was linked to body weight after ten weeks and body size traits. LCORL, LDB2, and PPARGC1A were identified as candidate genes in this region. The other region, located on chromosome 1 (170.46-171.53 Mb), was associated with body weight from four to eighteen weeks and body size traits. This region contained CAB39L and WDFY2 as candidate genes. Notably, LCORL, LDB2, and PPARGC1A showed highly selective signatures among the three breeds of chicken with varying body sizes. Conclusion Overall this study provides a comprehensive map of genomic variants associated with body weight and size in chickens. We propose two genomic regions, one on chromosome 1 and the other on chromosome 4, that could helpful for developing genome selection breeding strategies to enhance meat yield in chickens.

Abstract Background As the second largest leafy vegetable, cabbage (Brassica oleracea L. var. capitata) is grown globally, and the characteristics of the different varieties, forms, and colors of cabbage may differ. In this study, five analysis methods—variance analysis, correlation analysis, cluster analysis, principal component analysis, and comprehensive ranking—were used to evaluate the quality indices (soluble protein, soluble sugar, and nitrate), antioxidant content (vitamin C, polyphenols, and flavonoids), and mineral (K, Ca, Mg, Cu, Fe, Mn, and Zn) content of 159 varieties of four forms (green spherical, green oblate, purple spherical, and green cow heart) of cabbage. Results The results showed that there are significant differences among different forms and varieties of cabbage. Compared to the other three forms, the purple spherical cabbage had the highest flavonoid, K, Mg, Cu, Mn, and Zn content. A scatter plot of the principal component analysis showed that the purple spherical and green cow heart cabbage varieties were distributed to the same quadrant, indicating that their quality indices and mineral contents were highly consistent, while those of the green spherical and oblate varieties were irregularly distributed. Overall, the green spherical cabbage ranked first, followed by the green cow heart, green oblate, and purple spherical varieties. Conclusions Our results provide a theoretical basis for the cultivation and high-quality breeding of cabbage.

Abstract Background With the emergence of numerous scientific outputs, growing attention is paid to research misconduct. This study aimed to investigate knowledge, attitudes and practices about research misconduct among medical residents in southwest China. Methods A cross-sectional study was conducted in southwest China from November 2022 through March 2023. The links to the questionnaire were sent to the directors of the teaching management department in 17 tertiary hospitals. Answers were collected and analyzed. Logistic regression analysis was performed to explore the factors associated with research misconduct among residents. Results 6200 residents were enrolled in the study, and 88.5% of participants attended a course on research integrity, but 53.7% of participants admitted to having committed at least one form of research misconduct. Having a postgraduate or above, publishing papers as the first author or corresponding author, attending a course on research integrity, lower self-reported knowledge on research integrity and lower perceived consequences for research misconduct were positively correlated to research misconduct. Serving as a primary investigator for a research project was negatively associated with research misconduct. Most residents (66.3%) agreed that the reason for research misconduct is that researchers lack research ability. Conclusions The high self-reported rate of research misconduct among residents in southwest China underscores a universal necessity for enhancing research integrity courses in residency programs. The ineffectiveness of current training in China suggests a possible global need for reevaluating and improving educational approaches to foster research integrity. Addressing these challenges is imperative not only for the credibility of medical research and patient care in China but also for maintaining the highest ethical standards in medical education worldwide. Policymakers, educators, and healthcare leaders on a global scale should collaborate to establish comprehensive strategies that ensure the responsible conduct of research, ultimately safeguarding the integrity of medical advancements and promoting trust in scientific endeavors across borders.

Abstract Brain damage is a common tissue damage caused by trauma or diseases, which can be life-threatening. Stem cell implantation is an emerging strategy treating brain damage. The stem cell is commonly embedded in a matrix material for implantation, which protects stem cell and induces cell differentiation. Cell differentiation induction by this material is decisive in the effectiveness of this treatment strategy. In this work, we present an injectable fibroin/MXene conductive hydrogel as stem cell carrier, which further enables in-vivo electrical stimulation upon stem cells implanted into damaged brain tissue. Cell differentiation characterization of stem cell showed high effectiveness of electrical stimulation in this system, which is comparable to pure conductive membrane. Axon growth density of the newly differentiated neurons increased by 290% and axon length by 320%. In addition, unfavored astrocyte differentiation is minimized. The therapeutic effect of this system is proved through traumatic brain injury model on rats. Combined with in vivo electrical stimulation, cavities formation is reduced after traumatic brain injury, and rat motor function recovery is significantly promoted. Graphical Abstract

Abstract Introduction Surgeries conducted at night can impact patients’ prognosis, and the mechanism may be related to circadian rhythm, which influence normal physiological functions and pathophysiological changes. Melatonin is primarily a circadian hormone with hypnotic and chronobiotic effects, thereby affecting disease outcomes through influencing the expression of inflammatory factors and biochemical metabolism. This study aims to observe the effects of circadian rhythms on emergence agitation and early postoperative delirium of older individuals undergoing thoracoscopic lung cancer surgery and explore the possible regulatory role of melatonin. Methods This prospective, observational, cohort study will involve 240 patients. Patients will be routinely divided into three groups based on the time of the surgery: T1 (8:00–14:00), T2 (14:00–20:00) and T3 group (20:00–08:00). The primary outcome will be the incidence of emergence agitation assessed via the Richmond Agitation and Sedation Scale (RASS) in the post-anesthesia care unit (PACU). Secondary outcomes will include the incidence of early postoperative delirium assessed via the Confusion Assessment Method (CAM) on postoperative day 1, pain status assessed via the numerical rating scale (NRS) in the PACU, sleep quality on postoperative day 1 and changes in perioperative plasma melatonin, clock genes and inflammatory factor levels. Postoperative surgical complications, intensive care unit admission and hospital length of stay will also be evaluated. Discussion This paper describes a protocol for investigating the effects of circadian rhythms on emergence agitation and early postoperative delirium of older individuals undergoing thoracoscopic lung cancer surgery, as well as exploring the potential regulatory role of melatonin. By elucidating the mechanism by which circadian rhythms impact postoperative recovery, we aim to develop a new approach for achieving rapid recovery during perioperative period. Trial registration The study was registered at the Chinese Clinical Trials Registry (ChiCTR2000040252) on November 26, 2020, and refreshed on September 4, 2022.

Abstract Background FLI1 is an oncogenic transcription factor that promotes diverse malignancies through mechanisms that are not fully understood. Herein, FLI1 is shown to regulate the expression of Ubiquitin Associated and SH3 Domain Containing A/B (UBASH3A/B) genes. UBASH3B and UBASH3A are found to act as an oncogene and tumor suppressor, respectively, and their combined effect determines erythroleukemia progression downstream of FLI1. Methods Promoter analysis combined with luciferase assays and chromatin immunoprecipitation (ChIP) analysis were applied on the UBASH3A/B promoters. RNAseq analysis combined with bioinformatic was used to determine the effect of knocking-down UBASH3A and UBASH3B in leukemic cells. Downstream targets of UBASH3A/B were inhibited in leukemic cells either via lentivirus-shRNAs or small molecule inhibitors. Western blotting and RT-qPCR were used to determine transcription levels, MTT assays to assess proliferation rate, and flow cytometry to examine apoptotic index. Results Knockdown of FLI1 in erythroleukemic cells identified the UBASH3A/B genes as potential downstream targets. Herein, we show that FLI1 directly binds to the UBASH3B promoter, leading to its activation and leukemic cell proliferation. In contrast, FLI1 indirectly inhibits UBASH3A transcription via GATA2, thereby antagonizing leukemic growth. These results suggest oncogenic and tumor suppressor roles for UBASH3B and UBASH3A in erythroleukemia, respectively. Mechanistically, we show that UBASH3B indirectly inhibits AP1 (FOS and JUN) expression, and that its loss leads to inhibition of apoptosis and acceleration of proliferation. UBASH3B also positively regulates the SYK gene expression and its inhibition suppresses leukemia progression. High expression of UBASH3B in diverse tumors was associated with worse prognosis. In contrast, UBASH3A knockdown in erythroleukemic cells increased proliferation; and this was associated with a dramatic induction of the HSP70 gene, HSPA1B. Accordingly, knockdown of HSPA1B in erythroleukemia cells significantly accelerated leukemic cell proliferation. Accordingly, overexpression of UBASH3A in different cancers was predominantly associated with good prognosis. These results suggest for the first time that UBASH3A plays a tumor suppressor role in part through activation of HSPA1B. Conclusions FLI1 promotes erythroleukemia progression in part by modulating expression of the oncogenic UBASH3B and tumor suppressor UBASH3A.

Abstract Background Metabolic syndrome (MetS) is a health issue consisting of multiple metabolic abnormalities. The impact of exposure to volatile organic compounds (VOCs) on MetS and its components remains uncertain. This study aimed to assess the associations of individual urinary metabolites of VOC (mVOCs) and mVOC mixtures with MetS and its components among the general adult population in the United States. Methods A total of 5345 participants with eligible data were filtered from the 2011–2020 cycles of the National Health and Nutrition Examination Survey. Multivariate logistic regression models were applied to assess the associations of individual mVOCs with MetS and its components. The least absolute shrinkage and selection operator (LASSO) regression models were constructed to identify more relevant mVOCs. The weight quantile sum regression model was applied to further explore the links between mVOC co-exposure and MetS and its components. Results The results indicated positive associations between multiple mVOCs and MetS, including CEMA, DHBMA, and HMPMA. CEMA was found to be positively correlated with all components of MetS. HMPMA was associated with elevated triglyceride (TG), reduced high-density lipoprotein, and fasting blood glucose (FBG) impairment; 3HPMA was associated with an elevated risk of high TG and FBG impairment; and DHBMA had positive associations with elevated TG and high blood pressure. The co-exposure of LASSO-selected mVOCs was associated with an increased risk of elevated TG, high blood pressure, and FBG impairment. Conclusion Positive associations of certain individual urinary mVOCs and mVOC mixtures with MetS and its components were observed by utilizing multiple statistical models and large-scale national data. These findings may serve as the theoretical basis for future experimental and mechanistic studies and have important implications for public health.

Abstract Background The impact of the coexistence of type 2 diabetes mellitus (T2DM) in patients with non-ischemic dilated cardiomyopathy (DCM) on clinical profiles, myocardial fibrosis, and outcomes remain incompletely understood. Method A total of 1152 patients diagnosed with non-ischemic DCM were prospectively enrolled from June 2012 to October 2021 and categorized into T2DM and non-T2DM groups. Clinical characteristics, cardiac function, and myocardial fibrosis evaluated by CMR were compared between the two groups. The primary endpoint included both all-cause mortality and heart transplantation. Cause of mortality was classified into heart failure death, sudden cardiac death, and non-cardiac death. Cox regression analysis and Kaplan-Meier analysis were performed to identify the association between T2DM and clinical outcomes. Propensity score matching (PSM) cohort including 438 patients was analyzed to reduce the bias from confounding covariates. Results Among the 1152 included DCM patients, 155 (13%) patients had T2DM. Patients with T2DM were older (55 ± 12 vs. 47 ± 14 years, P

Abstract Background Malaria-associated acute lung injury (MA-ALI) is a well-recognized clinical complication of severe, complicated malaria that is partly driven by sequestrations of infected red blood cells (iRBCs) on lung postcapillary induced impaired blood flow. In earlier studies the mechanosensitive Piezo1 channel emerged as a regulator of mechanical stimuli, but the function and underlying mechanism of Piezo1 impacting MA-ALI severity via sensing the impaired pulmonary blood flow are still not fully elucidated. Thus, the present study aimed to explore the role of Piezo1 in the severity of murine MA-ALI. Methods Here, we utilized a widely accepted murine model of MA-ALI using C57BL/6 mice with Plasmodium berghei ANKA infection and then added a Piezo1 inhibitor (GsMTx4) to the model. The iRBC-stimulated Raw264.7 macrophages in vitro were also targeted with GsMTx4 to further explore the potential mechanism. Results Our data showed an elevation in the expression of Piezo1 and number of Piezo1+-CD68+ macrophages in lung tissues of the experimental MA-ALI mice. Compared to the infected control mice, the blockage of Piezo1 with GsMTx4 dramatically improved the survival rate but decreased body weight loss, peripheral blood parasitemia/lung parasite burden, experimental cerebral malaria incidence, total protein concentrations in bronchoalveolar lavage fluid, lung wet/dry weight ratio, vascular leakage, pathological damage, apoptosis and number of CD68+ and CD86+ macrophages in lung tissues. This was accompanied by a dramatic increase in the number of CD206+ macrophages (M2-like subtype), upregulation of anti-inflammatory cytokines (e.g. IL-4 and IL-10) and downregulation of pro-inflammatory cytokines (e.g. TNF-α and IL-1β). In addition, GsMTx4 treatment remarkably decreased pulmonary intracellular iron accumulation, protein level of 4-HNE (an activator of ferroptosis) and the number of CD68+-Piezo1+ and CD68+-4-HNE+ macrophages but significantly increased protein levels of GPX4 (an inhibitor of ferroptosis) in experimental MA-ALI mice. Similarly, in vitro study showed that the administration of GsMTx4 led to a remarkable elevation in the mRNA levels of CD206, IL-4, IL-10 and GPX-4 but to a substantial decline in CD86, TNF-α, IL-1β and 4-HNE in the iRBC-stimulated Raw264.7 cells. Conclusions Our findings indicated that blockage of Piezo1 with GsMTx4 alleviated the severity of experimental MA-ALI in mice partly by triggering pulmonary macrophage M2 polarization and subsequent anti-inflammatory responses but inhibited apoptosis and ferroptosis in lung tissue. Our data suggested that targeting Piezo1 in macrophages could be a promising therapeutic strategy for treating MA-ALI. Graphical Abstract

Abstract Objective To study the changes of retinal function in type 2 diabetes mellitus(DM) patients without apparently diabetic retinopathy via multifocal electroretinogram. Methods: Thirty-six type 2 DM patients (72 eyes) without visible diabetic retinopathy were selected as the experimental group, and thirty-five healthy subjects (70 eyes) were selected as the control group. All subjects were underwent multifocal electroretinogram (mf- ERG). Results Compared with the control group, the implicit time delay of the P1 wave in the first ring, third ring, fourth ring, and fifth ring of the experimental group was significant (t = -3.154, p = 0.004, t = -8.21, p = 0.000, t = -3.067, p = 0.004, t = -4.443, p = 0.000, respectively). The implicit time of the N1 wave in the fourth- and fifth-ring were also significantly delayed compared with the control group (t = -3.549, p = 0.001, t = 2.961, p = 0.005, respectively). Compared with the control group, the implicit time of the P1 wave and N1 wave in the temporal region of the experimental group were delayed (t = -2.148, p = 0.037, t = -2.834, p = 0.007, respectively). There were no significant difference between the experimental group and the control group of the temporal area in the amplitude density of P1 wave, N1 wave. There was no difference in the implicit time and amplitude density of the N1 and P1 waves in the nasal region between the experimental group and the control group. The multifocal electroretinogram complex parameters showed better specificity and sensitivity in the diagnosis of diabetic retinopathy. Conclusion The multifocal electroretinogram can detect abnormal changes in the retina of type 2 DM patients without visible diabetic retinopathy. The multifocal electroretinogram complex parameter is a potential indicator for the early diagnosis of diabetic retinopathy.

Abstract Post-translational modifications (PTMs) of the non-histone protein high-mobility group protein B1 (HMGB1) are involved in modulating inflammation and immune responses. Recent studies have implicated that the RNA-binding protein (RBP) Musashi-2 (MSI2) regulates multiple critical biological metabolic and immunoregulatory functions. However, the precise role of MSI2 in regulating PTMs and tumor immunity in colorectal cancer (CRC) remains unclear. Here, we present data indicating that MSI2 potentiates CRC immunopathology in colitis-associated colon cancer (CAC) mouse models, cell lines and clinical specimens, specifically via HMGB1-mediated dendritic cell (DC) maturation and migration, further contributes to the infiltration of CD4+ and CD8+ T cells and inflammatory responses. Under stress conditions, MSI2 can exacerbate the production, nucleocytoplasmic transport and extracellular release of damage-associated molecular patterns (DAMPs)-HMGB1 in CRC cells. Mechanistically, MSI2 mainly enhances the disulfide HMGB1 production and protein translation via direct binding to nucleotides 1403–1409 in the HMGB1 3′ UTR, and interacts with the cytoplasmic acetyltransferase P300 to upregulate its expression, further promoting the acetylation of K29 residue in HMGB1, thus leading to K29-HMGB1 nucleocytoplasmic translocation and extracellular release. Furthermore, blocking HMGB1 activity with glycyrrhizic acid (Gly) attenuates MSI2-mediated immunopathology and immune infiltration in CRC in vitro and in vivo. Collectively, this study suggests that MSI2 may improve the prognosis of CRC patients by reprogramming the tumor immune microenvironment (TIME) through HMGB1-mediated PTMs, which might be a novel therapeutic option for CRC immunotherapy.

Abstract Background Partial nephrectomy (PN) is usually recommended for T1 stage clear cell renal cell carcinoma (ccRCC) regardless of the nuclear grades. However, the question remains unresolved as to whether PN is non-inferior to RN in patients with T1-ccRCC at higher risk of recurrence. In fact, we found that patients with high nuclear grades treated with PN had poorer prognosis compared with those treated with radical nephrectomy (RN). Therefore, this study was designed to evaluate the associations of PN and RN in the four nuclear grade subsets with oncologic outcomes. Methods A retrospective study was conducted in three Chinese urological centers that included 1,714 patients who underwent PN or RN for sporadic, unilateral, pT1, N0, and M0 ccRCC without positive surgical margins and neoadjuvant therapy between 2010 and 2019. Associations of nephrectomy type with local ipsilateral recurrence, distant metastases, and all-cause mortality (ACM) were evaluated using the Kaplan–Meier method and multivariable Cox proportional hazards regression models after overlap weighting (OW). Results A total of 1675 patients entered the OW cohort. After OW, in comparison to PN, RN associated with a reduced risk of local ipsilateral recurrence in the G2 subset (HR = 0.148, 95% CI 0.046–0.474; p

Abstract Background Triglyceride glucose index (TyG index) was related with both type 2 diabetes (T2DM) and hypertension (HTN). Prospective studies linking the TyG index to the incidence of T2DM and HTN comorbidity remain unclear. This study aimed to to explore the longitudinal association between TyG and new-onset T2DM with HTN. Methods 4,434 subjects (1249 males and 3185 females) without initial T2DM and HTN were followed up for 7 years. This study was conducted from November 2011 to August 2018 in the Gucheng, Laoshan and Jinding communities of Beijing. The incidence of T2DM with HTN during the 7-year follow-up was identified as the endpoint. The TyG index was divided into four quartiles: the

Abstract Background Noninvasive ventilation (NIV) is commonly used in patients with acute respiratory distress syndrome (ARDS). However, the incidence and distribution of treatment failure are unclear. Methods A comprehensive online search was conducted to select potentially eligible studies with reports of the rate of NIV failure in patients with ARDS. A manual search was also performed to identify additional studies. Data were extracted to calculate the pooled incidences of NIV failure and mortality. Based on oxygenation, the severity of the disease was classified as mild, moderate, or severe ARDS. Based on etiologies, ARDS was defined as being of pulmonary origin or extrapulmonary origin. Results We enrolled 90 studies in this meta-analysis, involving 98 study arms. The pooled incidence of NIV failure was 48% (n = 5847, 95% confidence interval [CI]: 43–52%). The pooled incidence of ICU mortality was 29% (n = 2363, 95%CI: 22–36%), and that of hospital mortality was 33% (n = 2927, 95%CI: 27–40%). In patients with mild, moderate, and severe ARDS, the pooled incidence of NIV failure was 30% (n = 819, 95%CI: 21–39%), 51% (n = 1332, 95%CI: 43–60%), and 71% (n = 525, 95%CI: 62–79%), respectively. In patients with pulmonary ARDS, it was 45% (n = 2687, 95%CI: 39–51%). However, it was 30% (n = 802, 95%CI: 21–38%) in those with extrapulmonary ARDS. In patients with immunosuppression, the incidence of NIV failure was 62% (n = 806, 95%CI: 50–74%). However, it was 46% (n = 5041, 95%CI: 41–50%) in those without immunosuppression. Conclusions Nearly half of patients with ARDS experience NIV failure. The incidence of NIV failure increases with increasing ARDS severity. Pulmonary ARDS seems to have a higher rate of NIV failure than extrapulmonary ARDS. ARDS patients with immunosuppression have the highest rate of NIV failure.

Abstract Background The diagnostic assay leveraging multiple reverse transcription loop-mediated isothermal amplification (RT-LAMP) could meet the requirements for rapid nucleic acid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods The devised assay merged the lateral flow assay with the RT-LAMP technology and designed specific primers for the simultaneous detection of the target and human-derived internal reference genes within a single reaction. An inquiry into the assay's limit of detection (LOD), sensitivity, and specificity was carried out. The effectiveness of this assay was validated using 498 clinical specimens. Results This LOD of the assay was determined to be 500 copies/mL, and there was no observed cross-reaction with other respiratory pathogens. The detection results derived from clinical specimens showed substantial concordance with those from real-time reverse transcription-polymerase chain reaction (RT-qPCR) (Cohen's kappa, 0.876; 95% CI: 0.833-0.919; p

Abstract Background Atrial fibrillation (AF) is highly prevalent in the population, yet the factors contributing to AF events in susceptible individuals remain partially understood. The potential relationship between meteorological factors and AF, particularly with abnormal electrocardiograph (ECG) repolarization, has not been adequately studied. This case-crossover study aims to investigate the association between meteorological factors and daily hospital visits for AF with abnormal ECG repolarization in Shanghai, China. Methods The study cohort comprised 10,325 patients with ECG-confirmed AF who sought treatment at Shanghai Sixth People's Hospital between 2015 and 2018. Meteorological and air pollutant concentration data were matched with the patient records. Using a case-crossover design, we analyzed the association between meteorological factors and the daily count of hospital visitors for AF with abnormal ECG repolarization at our AF center. Lag analysis models were applied to examine the temporal relationship between meteorological factors and AF events. Results The analysis revealed statistically significant associations between AF occurrence and specific meteorological factors. AF events were significantly associated with average atmospheric pressure (lag 0 day, OR 0.9901, 95% CI 0.9825–0.9977, P