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Abstract Protein-energy wasting (PEW) is a major contributor to the high mortality among maintenance hemodialysis (MHD) patients. Cardiovascular disease (CVD) is the leading cause of death in dialysis patients, and PEW can significantly increase cardiovascular mortality in MHD patients. Previous studies have confirmed that PA may be a good objective indicator for determining the nutritional status and prognosis of MHD patients. Our study aimed to determine the predictive value of phase angle (PA) as detected by bioelectrical impedance analysis (BIA) on PEW and cardiovascular (CV) risk among MHD patients. Our retrospective observational study involved 161 adult patients with HD. The Cardiovascular risk score is a risk model based on the Japan Dialysis Outcome and Practice Patterns Study (J-DOPPS). We established LASSO logistic regression analysis model to identify key parameters related to body composition that can predict PEW in MHD patients. The area under the curve (AUC) values for PA, appendicular skeletal muscle mass index (ASMI), body cell mass (BCM), and mid-arm circumference (MAC) in predicting PEW in male MHD patients were relatively large, with 0.708, 0.674, 0.663, and 0.735, respectively. The predicted PEW values of these parameters were slightly lower in female patients than in men. We incorporated PA, ASMI, BCM, and MAC into a model that predicted the incidence of PEW in maintenance hemodialysis patients using LASSO technology. We discovered that the model predicted a greater AUC of PEW occurrence than any single factor, 0.877 for men and 0.76 for women. The results of the univariate logistic regression analysis showed that the low PA tertile array group had a greater incidence of PEW than the high PA group (P

Introduction: Coronavirus 2019 (COVID-19) has had a devastating impact on mental health and access to addiction treatment in the United States, including in California, which resulted in the highest rates of emergency department visits (ED) for opioid poisoning in 2020. As California slowly returns to pre-pandemic normalcy, it remains uncertain whether the rates of opioid-related events have slowed down over time. We hypothesized that the number of opioid-related ED visits were exacerbated after the period of the COVID-19 pandemic and continue at a high rate in the present. Methods: In this analysis we searched the University of California (UC) Health Data Warehouse—a database of electronic health records from six academic medical centers—for opioid related ED visits, identifiying using the following International Classification of Diseases, 10th Ed, Clinical Modification codes: F11 codes, and T40.0*, T40.1*, T40.2*, T40.3*, T40.4*, T40.6*. Opioid overdose-associated visits were classified by types of opioids involved: heroin (T40.1*); prescription opioids (T40.2* or T40.3*); and synthetic opioids (T40.4*). We performed interrupted time analysis to estimate the immediate (level) change and change-in-time trend (trend change), from before (January 2018–October 2019) and during the pandemic (April 2020–December 2022). Monthly visit rates were evaluated with negative binomial regression adjusted for first-order autoregression and using all-cause ED counts as the offset. We present effect sizes as rate ratios (RR) and 95% confidence intervals (CI), tested at α = .05. Results: We observed a decrease in overall ED visits from 28,426 to 25,121 visits in December 2019 and June 2021, respectively across all six UC Health Centers. Before COVID-19, we found that ED visit rates steadily increased for all outcomes (P

Abstract Traditional linear correlation analysis may not fully capture the true relationship between these variables. Therefore, multi-scale running correlation analysis, such as time-dependent intrinsic correlation (TDIC) and continuous wavelet transform based on Hilbert–Huang transform (HHT), provides valuable insights into local correlations and the evolving relationship between nutrients and environmental factors over time. In this study, we investigated seven environmental factors and four water quality nutrient indicators in deep lakes on the Yungui Plateau in southwestern China. The results revealed that there may be strong correlations between environmental factors and nutrient levels during certain periods, while opposite trends may emerge at other times. These variations in correlation could be attributed to uncertain physical processes, spatial heterogeneity, or the impact of different climatic factors on local hydrological processes. Wavelet analysis indicated that changes in environmental factors lag behind those in nutrient levels, particularly on a cycle of about 12 months. This suggests that changes in environmental factors align with natural patterns after the water body has been polluted. These conclusions underscore the complexity and dynamic nature of the relationship between environmental factors and nutrient levels in water bodies, highlighting the importance of employing advanced analysis techniques to capture this complexity.

Abstract Background This study evaluated the real-world impact of acupuncture on analgesics and healthcare resource utilization among breast cancer survivors. Methods From a United States (US) commercial claims database (25% random sample of IQVIA PharMetrics® Plus for Academics), we selected 18–63 years old malignant breast cancer survivors experiencing pain and ≥ 1 year removed from cancer diagnosis. Using the difference-in-difference technique, annualized changes in analgesics [prevalence, rates of short-term (

Abstract Background Traumatic brain injury (TBI) causes axon tearing and synapse degradation, resulting in multiple neurological dysfunctions and exacerbation of early neurodegeneration; the repair of axonal and synaptic structures is critical for restoring neuronal function. C-C Motif Chemokine Ligand 5 (CCL5) shows many neuroprotective activities. Method A close-head weight-drop system was used to induce mild brain trauma in C57BL/6 (wild-type, WT) and CCL5 knockout (CCL5-KO) mice. The mNSS score, rotarod, beam walking, and sticker removal tests were used to assay neurological function after mTBI in different groups of mice. The restoration of motor and sensory functions was impaired in CCL5-KO mice after one month of injury, with swelling of axons and synapses from Golgi staining and reduced synaptic proteins-synaptophysin and PSD95. Administration of recombinant CCL5 (Pre-treatment: 300 pg/g once before injury; or post-treatment: 30 pg/g every 2 days, since 3 days after injury for 1 month) through intranasal delivery into mouse brain improved the motor and sensory neurological dysfunctions in CCL5-KO TBI mice. Results Proteomic analysis using LC-MS/MS identified that the “Nervous system development and function”-related proteins, including axonogenesis, synaptogenesis, and myelination signaling pathways, were reduced in injured cortex of CCL5-KO mice; both pre-treatment and post-treatment with CCL5 augmented those pathways. Immunostaining and western blot analysis confirmed axonogenesis and synaptogenesis related Semaphorin, Ephrin, p70S6/mTOR signaling, and myelination-related Neuregulin/ErbB and FGF/FAK signaling pathways were up-regulated in the cortical tissue by CCL5 after brain injury. We also noticed cortex redevelopment after long-term administration of CCL5 after brain injury with increased Reelin positive Cajal-Rerzius Cells and CXCR4 expression. CCL5 enhanced the growth of cone filopodia in a primary neuron culture system; blocking CCL5’s receptor CCR5 by Maraviroc reduced the intensity of filopodia in growth cone and also CCL5 mediated mTOR and Rho signalling activation. Inhibiting mTOR and Rho signaling abolished CCL5 induced growth cone formation. Conclusions CCL5 plays a critical role in starting the intrinsic neuronal regeneration system following TBI, which includes growth cone formation, axonogenesis and synaptogensis, remyelination, and the subsequent proper wiring of cortical circuits. Our study underscores the potential of CCL5 as a robust therapeutic stratagem in treating axonal injury and degeneration during the chronic phase after mild brain injury. Graphical Abstract

Abstract Insulin resistance (IR) has a strong association with acute ischemic stroke (AIS) occurrence and poor prognosis of afflicted patients. However, the relation between early neurological deterioration (END) risk and IR in elderly and middle-aged patients remains to be thoroughly studied. Here, we investigated the relationship between four indicators of IR and the risk of END in middle-aged patients patients with AIS. The study retrospectively analyzed 1696 elderly and middle-aged patients having AIS between January 2019 and June 2023. Within 7 days of admission, the patients were then stratified relying upon alternations in the National Institutes of Health Stroke Scale. Subsequently, we employed logistic regression analyses for assessing each index correlation with END on the basis of the tertiles of TyG index (TyGI), triglyceride to high-density lipoprotein ratio (TG/HDL), TyG-BMI, alongside IR metabolic score (METS-IR). These four indicators were significantly heightened in the END group (n = 680) in comparison to the non-END group (n = 1016). When grouping using tertiles, the four aforementioned indicators emerged as independent risk factors for END occurrence, whether or not adjusted for confounding factors. The results revealed a progressive elevation in END occurrence risk with the rise in the tertile of each indicator. Finally, we utilized receiver operating characteristic (ROC) curves for assessing the indicators' predictive power. TyG-BMI, TyGI, TG/HDL, and METS-IRs’ area under the curve (AUC) were, respectively, 0.736 (95% CI: 0.712–0.761; P

Cerebral ischemic stroke is a major cerebrovascular disease and the leading cause of adult disability. We and others previously demonstrated that transplantation of human Wharton’s jelly mesenchymal stromal cells (WJ-MSCs) attenuated neuronal damage and promoted functional improvement in stroke animals. This study aimed to investigate the protective effects of human WJ-MSC exosome (Exo) transplant in cellular and rat models of cerebral stroke. Administration of Exo significantly antagonized glutamate-mediated neuronal loss and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-X nick end labeling (TUNEL) in rat primary cortical neuronal cultures. Adult male rats underwent a 60-min middle cerebral artery occlusion (MCAo); Exo or vehicle was injected through the tail vein 5–10 min after the MCAo. Two days later, the rats underwent a series of behavioral tests. Stroke rats receiving Exo developed a significant improvement in locomotor function and forelimb strength while reductions in body asymmetry and Bederson’s neurological score. After the behavioral test, brain tissues were harvested for histological and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analyses. Animals receiving Exo had less infarction volume, measured by 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Transplantation of Exo increased the expression of protective neurotrophic factors (BMP7, GDNF) and anti-apoptotic factors (Bcl2, Bcl-xL) in the ischemic brain. These findings suggest that early post-treatment with WJ-MSC Exo, given non-invasively through the vein, improved functional recovery and reduced brain damage in the stroke brain.

The increasing demand for disease modeling, preclinical drug testing, and long waiting lists for alternative organ substitutes has posed significant challenges to current limitations in organoid technology. Consequently, organoid technology has emerged as a cutting-edge tool capable of accurately recapitulating the complexity of actual organs in physiology and functionality. To bridge the gaps between basic research and pharmaceutical as well as clinical applications, efforts have been made to develop organoids from tissue-derived stem cells or pluripotent stem cells. These developments include optimizing starting cells, refining culture systems, and introducing genetic modifications. With the rapid development of organoid technology, organoid composition has evolved from single-cell to multi-cell types, enhancing their level of biomimicry. Tissue structure has become more refined, and core challenges like vascularization are being addressed actively. These improvements are expected to pave the way for the construction of organoid atlases, automated large-scale cultivation, and universally compatible organoid biobanks. However, major obstacles remain to be overcome before urgently proof-of-concept organoids can be readily converted to practical applications. These obstacles include achieving structural and functional summarily to native tissue, remodeling the microenvironment, and scaling up production. This review aims to summarize the status of organoid development and applications, highlight recent progress, acknowledge existing limitations and challenges, and provide insights into future advancements. It is expected that this will contribute to the establishment of a reliable, scalable, and practical platform for organoid production and translation, further promoting their use in the pharmaceutical industry and regenerative medicine.

Studies on the prognosis of hepatitis B virus (HBV) reactivation following modern therapies for newly diagnosed MM (NDMM) are lacking. In this retrospective study, we aimed to assess the incidence, risk factors and prognosis of HBV reactivation in NDMM. A total of 33 of 355 patients with NDMM and HBV reactivation were included in this study. Multivariable analysis showed that hepatitis B surface antigen-positivity, hepatitis B core antibody-positivity, bortezomib-containing regimens, autologous stem cell transplantation, and gain of 1q21 were identified as independent risk factors of HBV reactivation in NDMM patients. The NDMM patients with HBV reactivation had poorer 3-year overall survival (OS) and progression-free survival (PFS) than did those without HBV reactivation, as confirmed by multivariate analysis. In conclusion, HBV reactivation in patients with NDMM constitutes a significant complication, correlating with reduced OS and PFS, and emerges as a potential adverse prognostic factor in the contemporary era of treatment.

Abstract With an increasing prevalence of thyroid nodules globally, this study investigates the potential correlation between the use of Bluetooth headsets and the incidence of thyroid nodules, considering the cumulative effects of non-ionizing radiation (NIR) emitted by these devices. In this study, we analyzed 600 valid questionnaires from the WenJuanXing platform using Propensity Score Matching (PSM) and the XGBOOST model, supplemented by SHAP analysis, to assess the risk of thyroid nodules. PSM was utilized to balance baseline characteristic differences, thereby reducing bias. The XGBOOST model was then employed to predict risk factors, with model efficacy measured by the area under the Receiver Operating Characteristic (ROC) curve (AUC). SHAP analysis helped quantify and explain the impact of each feature on the prediction outcomes, identifying key risk factors. Initially, 600 valid questionnaires from the WenJuanXing platform underwent PSM processing, resulting in a matched dataset of 96 cases for modeling analysis. The AUC value of the XGBOOST model reached 0.95, demonstrating high accuracy in differentiating thyroid nodule risks. SHAP analysis revealed age and daily Bluetooth headset usage duration as the two most significant factors affecting thyroid nodule risk. Specifically, longer daily usage durations of Bluetooth headsets were strongly linked to an increased risk of developing thyroid nodules, as indicated by the SHAP analysis outcomes. Our study highlighted a significant impact relationship between prolonged Bluetooth headset use and increased thyroid nodule risk, emphasizing the importance of considering health impacts in the use of modern technology, especially for devices like Bluetooth headsets that are frequently used daily. Through precise model predictions and variable importance analysis, our research provides a scientific basis for the formulation of public health policies and personal health habit choices, suggesting that attention should be paid to the duration of Bluetooth headset use in daily life to reduce the potential risk of thyroid nodules. Future research should further investigate the biological mechanisms of this relationship and consider additional potential influencing factors to offer more comprehensive health guidance and preventive measures.

Abstract Non-small cell lung cancer (NSCLC)-originating cancer-associated fibroblasts (CAFs) expressing CD248 regulate interaction with immune cells to accelerate cancer progression. Epithelial–mesenchymal transition (EMT) is a key feature of metastatic cells. In our pervious study, we found that CD248+CAFs activated M2-polarized macrophages, enhancing the progression of NSCLC. However, it is yet unclear how CD248+CAFs inducing M2-polarized macrophages induce EMT program in NSCLC cells. Herein, we examined CD248 expression from CAFs derived from NSCLC patient tumour tissues. Furthermore, we determined the influence of CD248 knock down CAFs on macrophages polarization. Next, we explored the influences of CD248-harboring CAFs-mediated M2 macrophage polarization to promote NSCLC cells EMT in vitro. We constructed fibroblasts specific CD248 gene knock out mice to examine the significance of CD248-harboring CAFs-induced M2-polarized macrophages to promote NSCLC cells EMT in vivo. Based on our analysis, CD248 is ubiquitously expressed within NSCLC-originating CAFs. CD248+CAFs mediated macrophages polarized to M2 type macrophages. CD248+CAFs induced M2 macrophage polarization to enhance NSCLC cells EMT both in vivo and in vitro. Our findings indicate that CD248-harboring CAFs promote NSCLC cells EMT by regulating M2-polarized macrophages.

Abstract The purpose of this study was to investigate the relationship between circulating cytokines and liver function and prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with radiotherapy combined with tislelizumab and anlotinib. The liver function indexes and pre-treatment levels of cytokines in 47 patients were measured by chemical method and flow cytometry. The median follow-up was 23.1 months. The objective response and the disease control rates were 46.8% and 68.1%, while overall survival (OS) and progression-free survival (PFS) were 12.6 and 11.4 months, respectively. Adverse events (2.1%) were grade 3–4. In addition to stage, intrahepatic metastasis and Child–Pugh score, pre-treatment interleukin-6 (IL-6) was the main cytokine affecting OS and PFS (p

Abstract The Patient-Reported Outcomes Measurement Information System 29-item Profile version 2.1 (PROMIS-29 V2.1) is a widely utilized self-reported instrument for assessing health outcomes from the patients’ perspectives. This study aimed to evaluate the psychometric properties of the PROMIS-29 V2.1 Chinese version among patients with hematological malignancy. Conducted as a cross-sectional, this research was approved by the Medical Ethical Committee of the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (registration number QTJC2022002-EC-1). We employed convenience sampling to enroll eligible patients with hematological malignancy from four tertiary hospitals in Tianjin, Shandong, Jiangsu, and Anhui province in China between June and August 2023. Participants were asked to complete a socio-demographic information questionnaire, the PROMIS-29 V2.1, and the Functional Assessment of Cancer Therapy-General (FACT-G). We assessed the reliability, ceiling and floor effects, structural, convergent discriminant and criterion validity of the PROMIS-29 V2.1. A total of 354 patients with a mean age of 46.93 years was included in the final analysis. The reliability of the PROMIS-29 V2.1 was affirmed, with Cronbach’s α for the domains ranging from 0.787 to 0.968. Except sleep disturbance, the other six domains had ceiling effects, which were seen on physical function (26.0%), anxiety (37.0%), depression (40.4%), fatigue (18.4%), social roles (18.9%) and pain interference (43.2%), respectively. Criterion validity was supported by significant correlations between the PROMIS-29 V2.1 and FACT-G scores, as determined by the Spearman correlation test (P

Abstract Calendula officinalis L.is a versatile medicinal plant with numerous applications in various fields. However, its chloroplast genome structure, features, phylogeny, and patterns of evolution and mutation remain largely unexplored. This study examines the chloroplast genome, phylogeny, codon usage bias, and divergence time of C. officinalis, enhancing our understanding of its evolution and adaptation. The chloroplast genome of C. officinalis is a 150,465 bp circular molecule with a G + C content of 37.75% and comprises 131 genes. Phylogenetic analysis revealed a close relationship between C. officinalis, C. arvensis, and Osteospermum ecklonis. A key finding is the similarity in codon usage bias among these species, which, coupled with the divergence time analysis, supports their close phylogenetic proximity. This similarity in codon preference and divergence times underscores a parallel evolutionary adaptation journey for these species, highlighting the intricate interplay between genetic evolution and environmental adaptation in the Asteraceae family. Moreover unique evolutionary features in C. officinalis, possibly associated with certain genes were identified, laying a foundation for future research into the genetic diversity and medicinal value of C. officinalis.

Abstract Refinement of intermetallic compounds (IMCs) through enhancing heterogeneous nucleation during casting process is an important approach to improve the properties of aluminium alloys, which greatly increases the economy value of recycled Al-alloys. However, heterogeneous nucleation of IMCs is inherently more difficult than that of a pure metal or a solid solution. It requires not only creation of a crystal structure but also the positioning of 2 or more different types of atoms in the lattice with specific composition close to that of the nucleated IMCs. Previous understanding on heterogeneous nucleation is based on structural templating, usually considering the small lattice misfit at the interface between the nucleating solid and substrate. In this work, we proposed a hypothesis and demonstrated that composition templating plays a critical role in heterogeneous nucleation of IMCs. The experimental results revealed that segregation of Fe atoms on the AlB2 surface, i.e., the Fe modified AlB2 particle, provides the required composition templating and hence enhances heterogeneous nucleation of α-Al15(Fe, Mn)3Si2, resulting in a significant refinement of the α-Al15(Fe, Mn)3Si2 particles in an Al-5 Mg-2Si-1.0Mn-1.2Fe alloy.

Summary: Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. Methods: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan–Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. Findings: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48–1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41–0.66, p

Abstract Human brucellosis has reemerged in China, with a distinct change in its geographical distribution. The incidence of human brucellosis has significantly risen in inland regions of China. To gain insights into epidemic characteristics and identify factors influencing the geographic spread of human brucellosis, our study utilized the Extreme Gradient Boosting (XGBoost) algorithm and interpretable machine learning techniques. The results showed a consistent upward trend in the incidence of human brucellosis, with a significant increase of 8.20% from 2004 to 2021 (95% CI: 1.70, 15.10). The northern region continued to face a serious human situation, with a gradual upward trend. Meanwhile, the western and southern regions have experienced a gradual spread of human brucellosis, encompassing all regions of China over the past decade. Further analysis using Shapley Additive Explanations (SHAP) demonstrated that higher Gross Domestic Product (GDP) per capita and increased funding for education have the potential to reduce the spread. Conversely, the expansion of human brucellosis showed a positive correlation with bed availability per 1000 individuals, humidity, railway mileage, and GDP. These findings strongly suggest that socioeconomic factors play a more significant role in the spread of human brucellosis than other factors.

Abstract The shear yield stress is an important parameter for the industrial application of magnetorheological (MR) fluids. A test equipment was designed and built to perform investigations on the behaviours of compression and shear after squeeze of MR fluids. Mathematical expression of magnetic flux density was further established. Furthermore, the magnetic field distribution of the test device based on two-coil mode and single-coil mode was simulated and compared using finite element analysis(ANSYS/Multiphysics). An experimental test system was fabricated and modified based on the final conditions and simulation results. The compression and shear after squeeze performances of MR fluids were tested. The results showed that a smaller initial gap distance or a larger compressive strain corresponds to a larger compressive stress under the same external magnetic field strength. The shear yield stress after the squeeze of MR fluids increases quickly with the increasing compression stress and the increasing magnetic flux density. This test equipment was thought to be suitable for studying the compression and shear after squeeze performances of MR fluids.

Background Stroke is a disease with high morbidity, disability, and mortality. Immune factors play a crucial role in the occurrence of ischemic stroke (IS), but their exact mechanism is not clear. This study aims to identify possible immunological mechanisms by recognizing immune-related biomarkers and evaluating the infiltration pattern of immune cells. Methods We downloaded datasets of IS patients from GEO, applied R language to discover differentially expressed genes, and elucidated their biological functions using GO, KEGG analysis, and GSEA analysis. The hub genes were then obtained using two machine learning algorithms (least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE)) and the immune cell infiltration pattern was revealed by CIBERSORT. Gene-drug target networks and mRNA-miRNA-lncRNA regulatory networks were constructed using Cytoscape. Finally, we used RT-qPCR to validate the hub genes and applied logistic regression methods to build diagnostic models validated with ROC curves. Results We screened 188 differentially expressed genes whose functional analysis was enriched to multiple immune-related pathways. Six hub genes (ANTXR2, BAZ2B, C5AR1, PDK4, PPIH, and STK3) were identified using LASSO and SVM-RFE. ANTXR2, BAZ2B, C5AR1, PDK4, and STK3 were positively correlated with neutrophils and gamma delta T cells, and negatively correlated with T follicular helper cells and CD8, while PPIH showed the exact opposite trend. Immune infiltration indicated increased activity of monocytes, macrophages M0, neutrophils, and mast cells, and decreased infiltration of T follicular helper cells and CD8 in the IS group. The ceRNA network consisted of 306 miRNA-mRNA interacting pairs and 285 miRNA-lncRNA interacting pairs. RT-qPCR results indicated that the expression levels of BAZ2B, C5AR1, PDK4, and STK3 were significantly increased in patients with IS. Finally, we developed a diagnostic model based on these four genes. The AUC value of the model was verified to be 0.999 in the training set and 0.940 in the validation set. Conclusion Our research explored the immune-related gene expression modules and provided a specific basis for further study of immunomodulatory therapy of IS.

Abstract In order to reveal the effect of activated carbon (AC) properties on the adsorption of chlorophyll a (Chl a) and chlorophyll b (Chl b) in Andrographis paniculata extract, four commercial activated carbons were first tested and characterized. The results showed that activated carbon 1 (AC1) had the best surface area, pore structure and adsorption capacity. Therefore, adsorption isotherms, adsorption kinetics and adsorption mechanism were further carried out on AC1. The application of Langmuir model (R 2 > 0.978) and Freundlich model (R 2 > 0.977) indicated that the adsorption process of Chl a and Chl b on AC1 may be a complex adsorption process of single-layer and multilayer adsorption. The adsorption kinetics indicated that the pseudo-second-order kinetic model (R 2 > 0.999) was dominant and was mainly chemisorption. The intra-particle diffusion model (R 2 > 0.937) shows that the intra-particle diffusion is the rate-limiting step. The decrease of adsorption of AC1 to Chl a and Chl b due to the oxidation of acrylic acid proves the importance of π–π interaction.

Abstract Background Attentional deficits are among the most common pain-induced cognitive disorders. Pain disrupts attention and may excessively occupy attentional resources in pathological states, leading to daily function impairment and increased disability. However, the neural circuit mechanisms by which pain disrupts attention are incompletely understood. Methods We used a three-choice serial reaction time task (3CSRTT) to construct a sustained-attention task model in male C57BL/6J mice. Formalin or complete Freund's adjuvant was injected into a paw to establish an inflammatory pain model. We measured changes in 3CSRTT performance in the two inflammatory pain models, and investigated the neural circuit mechanisms of pain-induced attentional deficits. Results Acute inflammatory pain impaired 3CSRTT performance, while chronic inflammatory pain had no effect. Either inhibition of the ascending pain pathway by blockade of the conduction of nociceptive signals in the sciatic nerve using the local anesthetic lidocaine or chemogenetic inhibition of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) neurons in the lateral parabrachial nucleus (LPBN) attenuated the acute inflammatory pain-induced impairment of 3CSRTT performance, while chemogenetic activation of CaMKIIα neurons in the LPBN disrupted the 3CSRTT. Furthermore, the activity of CaMKIIα neurons in the LPBN was significantly lower on Day 2 after complete Freund's adjuvant injection than on the day of injection, which correlated with the recovery of 3CSRTT performance during chronic inflammatory pain. Conclusions Activation of excitatory neurons in the LPBN is a mechanism by which acute inflammatory pain disrupts sustained attention. This finding has implications for the treatment of pain and its cognitive comorbidities.

Abstract Objective The latest research proposed a novel copper-dependent programmed cell death named cuproptosis. We aimed to elucidate the influence of cuproptosis in clear cell renal cell carcinoma (ccRCC) from a multi-omic perspective. Methods This study systematically assessed mRNA expression, methylation, and genetic alterations of cuproptosis genes in TCGA ccRCC samples. Through unsupervised clustering analysis, the samples were classified as different cuproptosis subtypes, which were verified through NTP method in the E-MTAB-1980 dataset. Next, the cuproptosis score (Cuscore) was computed based on cuproptosis-related genes via PCA. We also evaluated clinical and immunogenomic features, drug sensitivity, immunotherapeutic response, and post-transcriptional regulation. Results Cuproptosis genes presented multi-layer alterations in ccRCC, and were linked with patients’ survival and immune microenvironment. We defined three cuproptosis subtypes [C1 (moderate cuproptosis), C2 (low cuproptosis), and C3 (high cuproptosis)], and the robustness and reproducibility of this classification was further proven. Overall survival was best in C3, moderate in C1, and worst in C2. C1 had the highest sensitivity to pazopanib, and sorafenib, while C2 was most sensitive to sunitinib. Furthermore, C1 patients benefited more from anti-PD-1 immunotherapy. Patients with high Cuscore presented the notable survival advantage. Cuscore was highly linked with immunogenomic features, and post-transcriptional events that contributed to ccRCC development. Finally, several potential compounds and druggable targets (NMU, RARRES1) were selected for low Cuscore group. Conclusion Overall, our study revealed the non-negligible role of cuproptosis in ccRCC development. Evaluation of the cuproptosis subtypes improves our cognition of immunogenomic features and better guides personalized prognostication and precision therapy.

Worldwide, tea is a popular beverage; within the realm of Chinese tea, Sichuan tea holds particular significance for its role in the origin and composition of Chinese tea cultivars. Sichuan tea is noted for its rich content of free amino acids (FAAs) and tea polyphenols (TPs), which has made it an important subject for studying genetic diversity and the genes regulating these compounds. In this study, 139 varieties of tea were collected from areas in Sichuan Province, China, with similar geographical and climatic conditions. The FAA content was approximately 3% and the TP content was approximately 17%. Using RAD sequencing, 5,656,224 variant loci were identified, primarily comprising SNPs (94.17%) and indels (5.83%). Evolutionary analysis revealed that genetic divergence was not closely linked to the collection location. Population structure analysis confirmed a division into two main populations having a similar composition to the phylogenetic clusters. Screening for FAA-related SNPs identified significant loci associated with 33 genes that potentially regulate FAA content. Similarly, TP-related analysis pinpointed 8 SNPs significantly linked to 20 candidate genes. Notably, genetic associations hinted at the genes involved in the stress response and the accumulation of phenolic compounds, enhancing the understanding of determinants of tea quality. This research underscores the potential for molecular breeding based on genetic insights, suggesting pathways to improve the FAA and TP contents in tea. These findings not only provide a solid foundation for exploring gene-chemical interactions but also offer practical strategies for improving the nutritional and sensory attributes of tea cultivars through informed breeding practices.

ObjectiveThis study investigated the positive rate and related influencing factors of anxiety screening in pregnant women during the first fetal magnetic resonance examination.MethodsA total of 303 pregnant women who met the criteria for magnetic resonance pregnancy examination in a Grade III maternity hospital from December 2021 to December 2022 were included by the convenience sampling method. A cross-sectional survey was conducted before the examination using the General Situation Questionnaire and Self-rating Anxiety Scale (SAS).ResultsThe positive rate of anxiety was 31.02% (94/303), and the average score of anxiety was 45.71±9.84. Univariate analysis results showed that age, educational level, occupation, place of residence, per capita monthly income, and number of pregnancies were related to the anxiety status of pregnant women in the fetal magnetic resonance examination (PConclusionsThe positive rate of anxiety screening of pregnant women before the first prenatal magnetic resonance examination is high. A low education level and living in the countryside will increase the probability of anxiety in pregnant women during magnetic resonance examination. Based on the above research results, it is suggested that medical institutions pay attention to the mental health of pregnant women, improve mental health care services, and reduce the adverse psychological problems caused by prenatal examination.

Radiotherapy is a commonly used method in the treatment of bladder cancers (BC). Radiation-induced immunogenic cell death (ICD) is related to the immune response against cancers and their prognoses. Even though dendritic cells (DC) act as powerful antigen-presenting cells in the body, their precise role in this ICD process remains unclear. Accordingly, an in vitro study was undertaken to ascertain whether high-dose radiation-induced ICD of BC cells could regulate the immune response of DC. The results indicated that high-dose radiation treatments of BC cells significantly increased their levels of apoptosis, blocked their cell cycle in the G2/M phase, increased their expression of ICD-related proteins, and upregulated their secretion of CCL5 and CCL21 which control the directed migration of DC. It was also noted that expression of CD80, CD86, CCR5, and CCR7 on DC was upregulated in the medium containing the irradiated cells. In conclusion, the present findings illustrate that high-dose radiation can induce the occurrence of ICD within BC cells, concomitantly resulting in the activation of DC. Such findings could be of great significance in increasing the understanding how radiotherapy of BC may work to bring about reductions in cell activity and how these processes in turn lead to immunoregulation of the function of DC.

Majority of macrozooplankton have a wider dietary niche breadth and utilize small invertebrates, microzooplankton and mesozooplankton, so effect on primary production might be through trophic cascading effect. To better understand the ecosystem structure of benthic oyster-macroalgae reefs, we analyzed zooplankton community structure before (July 2016) and after (from September 2016 to October 2017) the construction of benthic reefs in the 2 km2 sea ranch area in Xiangyun Cove, Tangshan, China. We identified 57 zooplankton species, including the 12 cnidarian (e.g., Clytia hemisphaerica Linnaeus and Eirene ceylonensis Browne), 1 ctenopharyngodon (Pleurobrachia globosa Moser), 24 crustacean (e.g., Calanus sinicus Brodsky, Paracalanus parvus Claus, Labibocera euchaeta Glesbrecht, Labibocera bipinnata Tanaka, Calanopia thompsoni Scott, and Centropages dorsispinatus Thompson), 1 chaetognath (Sagitta crassa Tokioka), 1 urochordate species (Oikopleura dioica Fol), and 18 species of planktonic polychaete and gastropod larvae. The zooplankton density and biomass values before reef construction were 266.14 ind/m3 and 2.72 mg/m3, respectively, and those after reef construction were 138.06 ind/m3 and 32.91 mg/m3, respectively. The biomass trend was as follow: October 2017 (89.08 mg/m3) > August 2017 (70.97) > September 2016 (3.17) > July 2016 (2.72) > June 2017 (0.86) > May 2017 (0.44). The common dominant organisms were crustaceans and chaetognaths. According to the RDA ranking results, water temperature was positively correlated with the Shannon-Wiener diversity index and Margalef's richness indexes. With the increasement of Margalef's richness index, the value of dissolved oxygen content showed a significant negative correlation with zooplankton abundance. The results of this study are applicable to sustainable development and management strategies of coastal reef ecosystems and provide a basis for further surveys of secondary productivity in the sea ranch area.

Investigating cytokine levels in ICU patients reveals their potential in predicting the occurrence of Persistent Inflammatory Response-Immunosuppression-Catabolic Syndrome (PICS). Our study encompassed clinical data from ICU patients admitted between December 2020 and January 2022. The cohort was divided based on the incidence of PICS, and a comparative analysis was conducted on their clinical data. Using logistic regression, we identified independent factors influencing PICS. Among 132 patients meeting our inclusion criteria, 39 (31.70%) developed PICS. Significant differences were observed between the PICS and non-PICS groups in terms of average age, APACHE II scores, hospital stay duration, mortality, and infection rates. Notably, laboratory parameters indicated lower pre-albumin and IL-4 levels, alongside higher IL-6, IL-10, IL-17, and IFN-y levels in the PICS group. Multivariate analysis pinpointed pre-albumin, IL-4, IL-6, and IL-10 as independent risk factors for PICS in ICU settings. Our findings underscore the importance of IL-4, IL-6, and IL-10 as key cytokines in the early detection and management of PICS, offering significant insights for clinical practice.

BackgroundNumerous metabolomic studies have confirmed the pivotal role of metabolic abnormalities in the development of idiopathic pulmonary fibrosis (IPF). Nevertheless, there is a lack of evidence on the causal relationship between circulating metabolites and the risk of IPF.MethodsThe potential causality between 486 blood metabolites and IPF was determined through a bidirectional two-sample Mendelian randomization (TSMR) analysis. A genome-wide association study (GWAS) involving 7,824 participants was performed to analyze metabolite data, and a GWAS meta-analysis involving 6,257 IPF cases and 947,616 control European subjects was conducted to analyze IPF data. The TSMR analysis was performed primarily with the inverse variance weighted model, supplemented by weighted mode, MR-Egger regression, and weighted median estimators. A battery of sensitivity analyses was performed, including horizontal pleiotropy assessment, heterogeneity test, Steiger test, and leave-one-out analysis. Furthermore, replication analysis and meta-analysis were conducted with another GWAS dataset of IPF containing 4,125 IPF cases and 20,464 control subjects. Mediation analyses were used to identify the mediating role of confounders in the effect of metabolites on IPF.ResultsThere were four metabolites associated with the elevated risk of IPF, namely glucose (odds ratio [OR] = 2.49, 95% confidence interval [95%CI] = 1.13-5.49, P = 0.024), urea (OR = 6.24, 95% CI = 1.77-22.02, P = 0.004), guanosine (OR = 1.57, 95%CI = 1.07-2.30, P = 0.021), and ADpSGEGDFXAEGGGVR (OR = 1.70, 95%CI = 1.00-2.88, P = 0.0496). Of note, the effect of guanosine on IPF was found to be mediated by gastroesophageal reflux disease. Reverse Mendelian randomization analysis displayed that IPF might slightly elevate guanosine levels in the blood.ConclusionConclusively, hyperglycemia may confer a promoting effect on IPF, highlighting that attention should be paid to the relationship between diabetes and IPF, not solely to the diagnosis of diabetes. Additionally, urea, guanosine, and ADpSGEGDFXAEGGGVR also facilitate the development of IPF. This study may provide a reference for analyzing the potential mechanism of IPF and carry implications for the prevention and treatment of IPF.

[This corrects the article DOI: 10.1371/journal.pone.0255479.].

Abstract. Background:. Amygdala plays an important role in the neurobiological basis of panic disorder (PD), and the amygdala contains different subregions, which may play different roles in PD. The aim of the present study was to examine whether there are common or distinct patterns of functional connectivity of the amygdala subregions in PD using resting-state functional magnetic resonance imaging and to explore the relationship between the abnormal spontaneous functional connectivity patterns of the regions of interest (ROIs) and the clinical symptoms of PD patients. Methods:. Fifty-three drug-naïve, non-comorbid PD patients and 70 healthy controls (HCs) were recruited. Seed-based resting-state functional connectivity (rsFC) analyses were conducted using the bilateral amygdalae and its subregions as the ROI seed. Two samples t test was performed for the seed-based Fisher's z-transformed correlation maps. The relationship between the abnormal spontaneous functional connectivity patterns of the ROIs and the clinical symptoms of PD patients was investigated by Pearson correlation analysis. Results:. PD patients showed increased rsFC of the bilateral amygdalae and almost all the amygdala subregions with the precuneus/posterior cingulate gyrus compared with the HC group (left amygdala [lAMY]: t = 4.84, P

Abstract Insulin-producing pancreatic β cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to type 2 diabetes (T2D). Moreover, metabolic disorder is another hallmark of T2D. Mammalian sterile 20-like kinase 1 (MST1) contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreatic β cell dysfunction. AMP-activated protein kinase (AMPK) is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases. Thus, pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy. Here, we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39, which exhibits anti-apoptosis efficacy and improves the survival of pancreatic β cells under diabetogenic conditions, as well as primary pancreatic islets in an ex vivo disease model. Mechanistically, IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro, combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic mice. Taken together, IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.

The global outbreak of the 2022 monkeypox virus infection of humans and the 2023 documentation of a more virulent monkeypox in the Democratic Republic of the Congo raised public health concerns about the threat of human-to-human transmission of zoonotic diseases. Currently available vaccines may not be sufficient to contain outbreaks of a more transmissible and pathogenic orthopoxvirus. Development of a safe, effective, and scalable vaccine against orthopoxviruses to stockpile for future emergencies is imminent. In this study, we have developed an mRNA vaccine candidate, ALAB-LNP, expressing four vaccinia viral antigens A27, L1, A33, and B5 in tandem in one molecule, and evaluated the vaccine immunogenicity in rodent models. Immunization of animals with the candidate mRNA vaccine induced a potent cellular immune response and long-lasting antigen-specific binding antibody and neutralizing antibody responses against vaccinia virus. Strikingly, the sera from the vaccine-immunized mice cross-reacted with all four homologous antigens of multiple orthopoxviruses and neutralized monkeypox virus in vitro, holding promise for this mRNA vaccine candidate to be used for protection of humans from the infection of monkeypox and other orthopoxvirus.

Background Maize is sensitive to salt stress, especially during the germination and seedling stages. Methods We conducted germination experiments on 60 maize materials under salt stress, and screened out the most salt-tolerant and salt-sensitive varieties based on germination indicators. Afterwards, transcriptome analysis was performed to screen for key regulators in the plumule and flag leaf at the germination and seedling stages, respectively. Following that, transgenic tobacco was developed to expose the roles and mechanisms of the candidate genes, enabling a deeper investigation of their functions. Results Out of the 60 inbred lines of maize, “975-12” exhibits the highest level of salt tolerance, while “GEMS64” displays the lowest. The application of salt stress resulted in a significant increase in the levels of antioxidant enzymes in both “975-12” and “GEMS64”. ABA signal transduction and jasmonic acid pathways were the pathways that mainly affected by salt stress. In addition, a significant finding has been made indicating that when exposed to high levels of salt stress, the expression of ZmHSP90 in ‘975-12’ increased while in ‘GEMS64’ decreased. Furthermore, in tobacco plants overexpressing ZmHSP90, there was an increase in antioxidant enzyme activity associated with salt tolerance. ZmHSP90 enhanced the expression levels of NtSOS1, NtHKT1, and NtNHX1 as compared to those in the salt treatment, causing the maintenance of Na+ and K+ homeostasis, suggesting that high expression of ZmHSP90 was conducive to regulate Na+ transporters to maintain K+/Na+ balanced in tobacco.

The aim of our study was to evaluate the relationship between body mass index (BMI) and all-cause mortality among elderly Chinese. The subjects of our study were a cohort of 13 319 elderly Chinese enrolled between 2008 and 2018. Participants were classified in three groups: underweight (

Abstract Background Cancer-associated fibroblasts (CAFs), an important component of the tumor microenvironment (TME), play crucial roles in tumor stemness. It has been shown in various cancer studies that stanniocalcin-1 (STC1) is secreted by CAFs, however, its function in HCC is still not clear. Methods The serum concentration and intracellular expression level of STC1 were quantified by ELISA and western blotting, respectively. The role of CAF-derived STC1 in HCC stemness was investigated by sphere formation, sorafenib resistance, colony formation, and transwell migration and invasion assays in vitro and in an orthotopic liver xenograft model in vivo. An HCC tissue microarray containing 72 samples was used to evaluate the expression of STC1 and Notch1 in HCC tissues. Coimmunoprecipitation (CoIP) and dual-luciferase reporter assays were performed to further explore the underlying mechanisms. ELISAs were used to measure the serum concentration of STC1 in HCC patients. Results We demonstrated that CAFs were the main source of STC1 in HCC and that CAF-derived STC1 promoted HCC stemness through activation of the Notch signaling pathway. In HCC patients, the expression of STC1 was positively correlated with Notch1 expression and poor prognosis. The co-IP assay showed that STC1 directly bound to Notch1 receptors to activate the Notch signaling pathway, thereby promoting the stemness of HCC cells. Our data further demonstrated that STC1 was a direct transcriptional target of CSL in HCC cells. Furthermore, ELISA revealed that the serum STC1 concentration was higher in patients with advanced liver cancer than in patients with early liver cancer. Conclusions CAF-derived STC1 promoted HCC stemness via the Notch1 signaling pathway. STC1 might serve as a potential biomarker for the prognostic assessment of HCC, and the stromal-tumor amplifying STC1-Notch1 feedforward signal could constitute an effective therapeutic target for HCC patients.

Abstract Our research group has recently found that radiation-induced airborne stress signals can be used for communication among Caenorhabditis elegans (C. elegans). This paper addresses the question of whether heat stress can also induce the emission of airborne stress signals to alert neighboring C. elegans and elicit their subsequent stress response. Here, we report that heat-stressed C. elegans produces volatile stress signals that trigger an increase in radiation resistance in neighboring unheated C. elegans. When several loss-of-function mutations affecting thermosensory neuron (AFD), heat shock factor-1, HSP-4, and small heat-shock proteins were used to test heat-stressed C. elegans, we found that the production of volatile stress signals was blocked, demonstrating that the heat shock response and ER pathway are involved in controlling the production of volatile stress signals. Our data further indicated that mutations affecting the DNA damage response (DDR) also inhibited the increase in radiation resistance in neighboring unheated C. elegans that might have received volatile stress signals, indicating that the DDR might contribute to radioadaptive responses induction by volatile stress signals. In addition, the regulatory pattern of signal production and action was preliminarily clarified. Together, the results of this study demonstrated that heat-stressed nematodes communicate with unheated nematodes via volatile stress signals.

Abstract Background Accurate pathological diagnosis of invasion depth and histologic grade is key for clinical management in patients with bladder cancer (BCa), but it is labour-intensive, experience-dependent and subject to interobserver variability. Here, we aimed to develop a pathological artificial intelligence diagnostic model (PAIDM) for BCa diagnosis. Methods A total of 854 whole slide images (WSIs) from 692 patients were included and divided into training and validation sets. The PAIDM was developed using the training set based on the deep learning algorithm ScanNet, and the performance was verified at the patch level in validation set 1 and at the WSI level in validation set 2. An independent validation cohort (validation set 3) was employed to compare the PAIDM and pathologists. Model performance was evaluated using the area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value and negative predictive value. Results The AUCs of the PAIDM were 0.878 (95% CI 0.875–0.881) at the patch level in validation set 1 and 0.870 (95% CI 0.805–0.923) at the WSI level in validation set 2. In comparing the PAIDM and pathologists, the PAIDM achieved an AUC of 0.847 (95% CI 0.779–0.905), which was non-inferior to the average diagnostic level of pathologists. There was high consistency between the model-predicted and manually annotated areas, improving the PAIDM’s interpretability. Conclusions We reported an artificial intelligence-based diagnostic model for BCa that performed well in identifying invasion depth and histologic grade. Importantly, the PAIDM performed admirably in patch-level recognition, with a promising application for transurethral resection specimens.

Abstract Emerging evidence suggests that epigenetic alterations are responsible for the oncogenesis and progression of cancer. However, the role of epigenetic reprogramming in pancreatic cancer is still not clear. In this study, we used the limma R package to identify differentially expressed protein-coding genes (PCGs) between pancreatic cancer tissues and normal control tissues. The cell-type identification by the estimating relative subsets of RNA transcripts (CIBERSORT) package was used to quantify relative cell fractions in tumors. Prognostic molecular clusters were constructed using ConsensusClusterPlus analysis. Furthermore, the least absolute shrinkage and selection operator and stepAIC methods were used to construct a risk model. We identified 2351 differentially expressed PCGs between pancreatic cancer and normal control tissues in The cancer genome atlas dataset. Combined with histone modification data, we identified 363 epigenetic PCGs (epi-PCGs) and 19,010 non-epi-PCGs. Based on the epi-PCGs, we constructed three molecular clusters characterized by different expression levels of chemokines and immune checkpoint genes and distinct abundances of various immune cells. Furthermore, we generated a 9-gene model based on dysfunctional epi-PCGs. Additionally, we found that patients with high risk scores showed poorer prognoses than patients with low risk scores (p

Background: In China and other countries, cynomolgus monkeys are commonly used experimental animal models in biomedical research. Reference hematologic and biochemical parameters must be established to evaluate healthy cynomolgus monkeys and investigate drug safety in non-clinical research. In the present study, data from 4,834 healthy cynomolgus monkeys were used to establish a reference for various age groups. Methods: A total of 4834 healthy cynomolgus monkeys (649 males and 4185 females) were selected and divided into six groups according to age and sex. Twenty hematological parameters and 17 serum biochemical parameters were detected, and the effects of age and sex were analyzed. Results: A reference database of hematological and biochemical parameters was established according to age (six groups) and sex (male and female). Significant differences were observed in White blood cell, Red blood cell, Hemoglobin, Hematocrit, Total protein, Albumin, Total bilirubin, Direct bilirubin, Alkaline phosphatase, Glucose, Blood urea nitrogen, Creatinine, Calcium, Total cholesterol, Triglyceride, and Lactate dehydrogenase values according to age in the juvenile and young groups (P

Abstract Background Arteriovenous fistula (AVF) maturation is a process involving remodeling of venous arm of the AVFs. It is a challenge to balance adaptive AVF remodeling and neointima formation. In this study we temporally controlled Notch activation to promote AVF maturation while avoiding neointima formation. Methods Temporal Notch activation was controlled by regulating the expression of Notch transcription factor, RBP-Jκ, or dnMAML1 (dominant negative MAML2) in vascular smooth muscle cells (VSMCs). AVF mouse model was created and VSMC phenotype dynamic changes during AVF remodeling were determined. Results Activated Notch was found in the nuclei of neointimal VSMCs in AVFs from uremic mice. We found that the VSMCs near the anastomosis became dedifferentiated and activated after AVF creation. These dedifferentiated VSMCs regained smooth muscle contractile markers later during AVF remodeling. However, global or VSMC-specific KO of RBP-Jκ at early stage (before or 1 week after AVF surgery) blocked VSMC differentiation and neointima formation in AVFs. These un-matured AVFs showed less intact endothelium and increased infiltration of inflammatory cells. Consequently, the VSMC fate in the neointima was completely shut down, leading to an un-arterialized AVF. In contrast, KO of RBP-Jκ at late stage (3 weeks after AVF surgery), it could not block neointima formation and vascular stenosis. Inhibition of Notch activation at week 1 or 2, could maintain VSMC contractile markers expression and facilitate AVF maturation. Conclusions This work uncovers the molecular and cellular events in each segment of AVF remodeling and found that neither sustained increasing nor blocking of Notch signaling improves AVF maturation. It highlights a novel strategy to improve AVF patency: temporally controlled Notch activation can achieve a balance between adaptive AVF remodeling and neointima formation to improve AVF maturation. Translational perspective Adaptive vascular remodeling is required for AVF maturation. The balance of wall thickening of the vein and neointima formation in AVF determines the fate of AVF function. Sustained activation of Notch signaling in VSMCs promotes neointima formation, while deficiency of Notch signaling at early stage during AVF remodeling prevents VSMC accumulation and differentiation from forming a functional AVFs. These responses also delay EC regeneration and impair EC barrier function with increased inflammation leading to failed vascular remodeling of AVFs. Thus, a strategy to temporal regulate Notch activation will improve AVF maturation.

Abstract Background Aberrant DNA methylation plays a crucial role in the progression of myeloid neoplasms. Previously, our literature reported that slit guidance ligand 2 (SLIT2) promoter methylation was associated with disease progression and indicated a poor prognosis in patients with myelodysplastic syndrome. Herein, we further investigated the clinical implications and role of SLIT2 promoter methylation in patients with chronic myeloid leukemia (CML). Methods The level of SLIT2 promoter methylation was determined in 104 CML patients, and its clinical significance was analyzed. Moreover, demethylation studies were performed in K562 cells to determine the epigenetic mechanism by which SLIT2 promoter methylation is regulated in CML. Results The level of SLIT2 promoter methylation was similar between CML patients and controls. However, deeper analysis revealed that the SLIT2 promoter methylation level in the accelerated phase (AP) and blast crisis (BC) was markedly higher than that in the chronic phase (CP) and controls. Additionally, a marked difference was identified between the SLIT2 promoter hypermethylated and non-hypermethylated groups among CML patients grouped by clinical stage. The frequency of SLIT2 hypermethylation was markedly increased with the progression of clinical stage, that is, it was the lowest in CP samples (12/80, 15%), higher in AP samples (4/8, 50%) and the highest in BC samples (11/16, 69%). Importantly, the level/density of SLIT2 promoter methylation was significantly higher in the advanced stage than in the early stage among the 6 tested paired CML patients. Epigenetically, the expression of the SLIT2-embedded non-coding genes SLIT2-IT1 and miR-218 expression was decreased in patients with CML. SLIT2 promoter hypermethylated cases had a markedly lower SLIT2-IT1 expression level than SLIT2 promoter non-hypermethylated cases. Moreover, SLIT2-IT1 and miR-218 expression was remarkably upregulated in a dose-dependent manner after demethylation treatment of K562 cells. Conclusions Hypermethylation of the SLIT2 promoter is correlated with disease progression in CML. Furthermore, SLIT2 promoter methylation may function by regulating the expression of the SLIT2-embedded non-coding genes SLIT2-IT1 and miR-218 during CML progression.

We investigated the proportion and characteristics of severe Corynebacterium striatum pneumonia in South Korea during 2014–2019. As part of an ongoing observational study of severe pneumonia among adult patients, we identified 27 severe C. striatum pneumonia cases. Most (70.4%) cases were hospital-acquired, and 51.9% of patients were immunocompromised. C. striatum cases among patients with severe hospital-acquired pneumonia (HAP) increased from 1.0% (2/200) during 2014–2015 to 5.4% (10/185) during 2018–2019, but methicillin-resistant Staphylococcus aureus (MRSA) infections among severe HAP cases decreased from 12.0% to 2.7% during the same timeframe. During 2018–2019, C. striatum was responsible for 13.3% of severe HAP cases from which bacterial pathogens were identified. The 90-day mortality rates were similarly high in the C. striatum and MRSA groups. C. striatum was a major cause of severe HAP and had high mortality rates. This pathogen is emerging as a possible cause for severe pneumonia, especially among immunocompromised patients.

Objective To analyze the causes of staff burnout and various errors during group blood donation in blood centers, and to explore the significance of overall planning to improve above problems. Methods Various errors occurred during group blood donation from January 2016 to December 2020 in a blood center were selected as the research object. Job burnout related survey data including emotional exhaustion (MBI-EE), work attitude (MBI-DP), sense of achievement (MBI-PA) etc. were collected. The influence of six variables, including blood collection quantity, staff, order control, plan compliance, overload blood collection and over-stock blood collection, on the occurrence of errors was analyzed, and an ordered logistic regression model was established. After optimizing overall planning measures, the occurrence of errors and the improvement of burnout were compared. Results In addition to the volume of blood collected (P>0.05), the other five variables had significant influence on the occurrence of errors (P0.05). Conclusion Scientific inventory management and effective blood collection assessment measures are helpful to improve work quality, and the ordered Logistic regression model has a good fitting degree for error rectification. Analyzing the occurrence of errors during blood collection and supply from the influencing factors is conducive to formulate corrective and preventive measures and promote the continuous improvement of work quality.

Objective To investigate the incidence and possible risk factors of FMH among pregnant women in Changsha. Methods A total of pregnant women (6~42 weeks of gestation) who underwent prenatal examinations in our hospital from June 2019 to December 2020 were enrolled as subjects. In this study, the modified Kleihauer-Betke (K-B) test was used for preliminary screening and flow cytometry was applied to confirme initially positive samples to evaluate the incidence of FMH and estimate fetal blood loss. The logistic regression analysis was used to study the risk factors of FMH. Results The incidence of FMH in pregnant women was 10.45% (183/1 752), the average volume of fetal blood loss was (2.50±3.87)mL, and 0.11% (2/1 752) of the fetal losed blood > 30 mL. Univariate analysis showed that age, twin pregnancy, pregnancy complicated with uterine fibroids, in vitro fertilization, fetal growth restriction, preeclampsia, and number of pregnancies may be risk factors for FMH. Multivariate analysis showed that twin pregnancy (OR 2.274, 95%CI: 1.135-4.458, P