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Obesity and comorbid sleep disordered breathing (SDB) lead to high cardiovascular morbidity and mortality via multiple mechanisms including hypertension. Obesity also leads to high levels of leptin, which is produced in adipocytes. Increased leptin levels have also been implicated in increased sympathetic activity and the pathogenesis of hypertension in obesity. However, mechanisms for the effects of leptin on blood pressure are unclear. The carotid bodies (CB) express leptin receptor (Lepr b ), and diet-induced obesity (DIO) increases Lepr b expression levels, but the mechanisms and consequences of leptin action in CB are poorly understood. We hypothesize that leptin signaling in CB in obesity leads to hypertension, which can be treated by Lepr b knockdown specifically in CB. DIO male and female mice and lean male C57BL/6J mice were implanted with telemetry in the left femoral artery for continuous blood pressure monitoring. The adenoviral vectors carrying antisense RNA, Ad-LepR shRNA or Ad-scrambled control shRNA, were administered locally to the CB region. Blood pressure measurements were performed at baseline and 9-11 days after CB infection with the adenoviral vector. DIO male mice showed increased blood pressure compared with lean males and DIO females. Ad-LepR shRNA induced a twofold decrease in Lepr b mRNA level in CB and abolished obesity-induced hypertension. Lepr b knockdown was particularly effective during the light phase, when animals were predominantly asleep, decreasing mean arterial pressure by 8.5 mmHg. Control shRNA had no effect on DIO-induced hypertension. We conclude that inhibition of Lepr b in the carotid bodies abolished obesity-induced hypertension. NEW & NOTEWORTHY Obesity and comorbid sleep apnea are key predisposing factors to hypertension. Obesity increases circulating leptin levels and hyperleptinemia may contribute to hypertension but mechanisms are not clear. Here, we have shown that knockdown of the leptin receptor LepR b in the carotid body decreased blood pressure and treated hypertension in diet-induced obese mice. Thus, we identified a novel mechanism of obesity hypertension and a novel drug target, LepR b in the carotid body.

Background and Aims: Inflammatory response is crucial for bile acid (BA)-induced cholestatic liver injury, but molecular mechanisms remain to be elucidated. Solute Carrier Family 35 Member C1 (SLC35C1) can transport Guanosine diphosphate-fucose into the Golgi to facilitate protein glycosylation. Its mutation leads to the deficiency of leukocyte adhesion and enhances inflammation in humans. However, little is known about its role in liver diseases., Approach and Results: Hepatic SLC35C1 mRNA transcripts and protein expression were significantly increased in patients with obstructive cholestasis and mouse models of cholestasis. Immunofluorescence revealed that the upregulated SLC35C1 expression mainly occurred in hepatocytes. Liver-specific ablation of Slc35c1 ( Slc35c1 cKO ) significantly aggravated liver injury in mouse models of cholestasis induced by bile duct ligation and 1% cholic acid-feeding, evidenced by increased liver necrosis, inflammation, fibrosis, and bile ductular proliferation. The Slc35c1 cKO increased hepatic chemokine Ccl2 and Cxcl2 expression and T cell, neutrophil, and F4/80 macrophage infiltration but did not affect the levels of serum and liver BA in mouse models of cholestasis. Liquid chromatography with tandem mass spectrometry analysis revealed that hepatic Slc35c1 deficiency substantially reduced the fucosylation of cell-cell adhesion protein CEACAM1 at N153. Mechanistically, cholestatic levels of conjugated BAs stimulated SLC35C1 expression by activating the STAT3 signaling to facilitate CEACAM1 fucosylation at N153, and deficiency in the fucosylation of CEACAM1 at N135 enhanced the BA-stimulated CCL2 and CXCL2 mRNA expression in primary mouse hepatocytes and Primary Liver Carcinoma/Poliomyelitis Research Foundation/5- ASBT cells., Conclusions: Elevated hepatic SLC35C1 expression attenuates cholestatic liver injury by enhancing CEACAM1 fucosylation to suppress CCL2 and CXCL2 expression and liver inflammation., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To analyze and predict the dynamic influence trends and degrees caused by various factors that may affect the expansion of the hospital pharmacist team in China., Methods: Time series data including the number of hospital visits in all hospitals in China, the total number of pharmacists, per capita health expenditure, and per capita GDP from 2002 to 2022 were collected at the national level. A vector autoregressive (VAR) model was constructed, and methods such as the Granger causality test, impulse response analysis, and variance decomposition were employed to explore the influence process and direction of various influencing factors on the number of pharmacists in China., Results: The Augmented Dickey-Fuller (ADF) test indicates the first-order difference series of the time series is stationary (P<0.05). The model stability test shows the modulus of all specific root reciprocals falls within the unit circle, indicating model stability and credible results. The cointegration test reveals a cointegration relationship among the number of hospital visits, per capita health expenditure, per capita GDP, and the number of pharmacists (P<0.05). The Granger causality test indicates a unidirectional Granger causality relationship between the number of hospital visits, per capita health expenditure, and the number of pharmacists. The impulse response function indicates that the number of pharmacists shows an upward trend after being impacted by one unit of the number of hospital visits and per capita GDP, while the positive impact of per capita health expenditure on the number of pharmacists turns into a negative impact in the third stage. Variance decomposition shows that the contribution rate of the number of hospital visits to the number of pharmacists is 12%, the contribution rate of per capita health expenditure to the number of pharmacists is 57%, and the contribution rate of per capita GDP to the number of pharmacists is 80%., Conclusion: The number of hospital visits, per capita health expenditures, and per capita GDP all positively contribute to the development of the pharmacist workforce. Per capita health expenditures lead to an increase in the number of pharmacists in the short term. Among the selected indicators, the primary drivers of pharmacist workforce development are per capita health expenditures and per capita GDP. Hospital visits have a relatively minor contribution to the growth in the number of pharmacists., Competing Interests: The authors declare that they have no competing interests in this work., (© 2025 Guo et al.)

Magnesium batteries offer a safer alternative for next-generation battery technology due to their insusceptibility to dendrite deposition. Selective membranes tailored for magnesium-ion conduction will unlock further technological advancement. Herein, we demonstrate fluorine-free magnesiated sulfonated poly(ether ether ketone) (Mg-SPEEK) selective membranes capable of facilitating magnesium-ion conduction while effectively rejecting soluble organic species. These membranes demonstrate a reversible Mg plating and stripping Coulombic efficiency (CE) of 85.4% and an ionic conductivity of 3.3 × 10 -4 S cm -1 at room temperature, surpassing those for a Mg-Nafion selective membrane. Theoretical density functional theory (DFT) calculations reveal that SPEEK possesses more localized charge centers along its backbone compared with Nafion, potentially facilitating enhanced ion conduction. Full cells assembled with Mg-SPEEK coupled with the organic cathode pyrene-4,5,9,10-tetraone (PTO) and Mg metal demonstrated significantly improved capacity retention as compared to those assembled with conventional nonselective separators.

Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid-mTOR-FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.

B cells play a critical role in the adaptive recognition of foreign antigens through diverse receptor generation. While targeted immune sequencing methods are commonly used to profile B cell receptors (BCRs), they have limitations in cost and tissue availability. Analyzing B cell receptor profiling from non-targeted transcriptomics data is a promising alternative, but a systematic pipeline integrating tools for accurate immune repertoire extraction is lacking. Here, we present bcRflow, a Nextflow pipeline designed to characterize BCR repertoires from non-targeted transcriptomics data, with functional modules for alignment, processing, and visualization. bcRflow is a comprehensive, reproducible, and scalable pipeline that can run on high-performance computing clusters, cloud-based computing resources like Amazon Web Services (AWS), the Open OnDemand framework, or even local desktops. bcRflow utilizes institutional configurations provided by nf-core to ensure maximum portability and accessibility. To demonstrate the functionality of the bcRflow pipeline, we analyzed a public dataset of bulk transcriptomic samples from COVID-19 patients and healthy controls. We have shown that bcRflow streamlines the analysis of BCR repertoires from non-targeted transcriptomics data, providing valuable insights into the B cell immune response for biological and clinical research. bcRflow is available at https://github.com/Bioinformatics-Core-at-Childrens/bcRflow., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth., (© 2024. The Author(s).)

The progression of atherosclerosis (AS), the pathological foundation of coronary artery disease (CAD), is featured by massive lipid deposition in the vessel wall. LncRNAs are implicated in lipid disorder and AS, whereas the specific role of lncRNA DANCR in atherogenesis remains unknown. Here, we demonstrated that DANCR promotes macrophage lipid accumulation by regulating the expression of membrane cholesterol transport proteins. qPCR showed that compared to control groups, CAD patients and atherosclerotic mice had higher DANCR levels. Treating human THP-1 macrophages and mouse RAW264.7 macrophages with ox-LDL significantly upregulated the expression levels of DANCR. Oil Red O staining showed that the silence of DANCR robustly reduced, while overexpression of DANCR significantly increased the numbers and size of lipid droplets in ox-LDL-treated THP-1 macrophages. In contrast, the opposite phenomena were observed in DANCR overexpressing cells. The expression of ABCA1, ABCG1, SR-BI, and NBD-cholesterol efflux was increased obviously by DANCR inhibition and decreased by DANCR overexpression, respectively. Furthermore, transfection with DANCR siRNA induced a robust decrease in the levels of CD36, SR-A, and Dil-ox-LDL uptake, while DANCR overexpression amplified the expression of CD36, SR-A and the uptake of Dil-ox-LDL in lipid-laden macrophages. Lastly, we found that the effects of DANCR on macrophage lipid accumulation and the expression of membrane cholesterol transport proteins were not likely related to miR-33a. The present study unraveled the adverse role of DANCR in foam cell formation and its relationship with cholesterol transport proteins. However, the competing endogenous RNA network underlying these phenomena warrants further exploration.

Objective: To investigate the prevalence and associated factors of suicidal ideation and suicide attempts among adolescent and young adults in China from December 14, 2022 to February 28, 2023, when COVID-19 restrictions were lifted., Methods: Students in middle and high schools and colleges and universities in the province of Sichuan, China were asked to complete on-line cross-sectional surveys. Information was collected about sociodemographics, experiences related to the COVID-19 pandemic, suicidal ideation and suicide attempts. Participants also filled out the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 and the Social Support Rate Scale surveys. Factors associated with suicidal ideation or suicide attempts were explored using logistic regression., Results: Of the 82,873 respondents (aged 12 to 24 years), 21,292 (25.7%) reported having thought of suicide at least once in their lifetime, 10,382 (12.5%) reported having thought about suicide within the previous 12 months, and 1,123 (1.4%) reported having attempted it within the previous 12 months. Risk of lifetime suicidal ideation was higher among middle school students than among older students. Risk of suicidal ideation and risk of suicide attempts correlated directly with severity of symptoms of depression and anxiety, and inversely with level of social support. Greater risk of suicidal ideation and suicidal attempts was associated with: being female, living in an urban environment, attending a boarding school, currently being in love, having parents who divorced or remarried, having parents who exhibit non-authoritative parenting behavior, having higher family income, having been COVID-19 infected, having been quarantined for a long time, and being dissatisfied with one's education., Conclusions: Suicidal ideation and suicide attempts remain prevalent among young people in China. The potential associated factors identified in our study may be useful for targeting appropriate psychosocial interventions and developing mental health policies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiao, Huang, Yang, Mu, Wang, Deng, Cai, Deng, Tang, Chen, Shi, Jiang, Xu, Yin, Huang, Zhang and Ran.)

The Mann-Whitney-Wilcoxon rank sum test (MWWRST) is a widely used method for comparing two treatment groups in randomized control trials, particularly when dealing with highly skewed data. However, when applied to observational study data, the MWWRST often yields invalid results for causal inference. To address this limitation, Wu et al. ( Causal inference for Mann-Whitney-Wilcoxon rank sum and other nonparametric statistics , Stat. Med. 33 (2014), pp. 1261-1271) introduced an approach that incorporates inverse probability weighting (IPW) into this rank-based statistic to mitigate confounding effects. Subsequently, Mao ( On causal estimation using U-statistics , Biometrika 105 (2018), pp. 215-220), Zhang et al. ( Estimating Mann Whitney-type causal effects , J. Causal Inference 7 (2019), ARTICLE ID 20180010), and Ai et al. ( A Mann-Whitney test of distributional effects in a multivalued treatment , J. Stat. Plan. Inference 209 (2020), pp. 85-100) extended this IPW estimator to develop doubly robust estimators. Nevertheless, each of these approaches has notable limitations. Mao's method imposes stringent assumptions that may not align with real-world study data. Zhang et al. 's ( Estimating Mann Whitney-type causal effects , J. Causal Inference 7 (2019), ARTICLE ID 20180010) estimators rely on bootstrap inference, which suffers from computational inefficiency and lacks known asymptotic properties. Meanwhile, Ai et al. ( A Mann-Whitney test of distributional effects in a multivalued treatment , J. Stat. Plan. Inference 209 (2020), pp. 85-100) primarily focus on testing the null hypothesis of equal distributions between two groups, which is a more stringent assumption that may not be well-suited to the primary practical application of MWWRST. In this paper, we aim to address these limitations by leveraging functional response models (FRM) to develop doubly robust estimators. We demonstrate the performance of our proposed approach using both simulated and real study data., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 Informa UK Limited, trading as Taylor & Francis Group.)

Background: The pathophysiology and the potential risks of placental transfusion (PT) differ substantially in preterm infants, necessitating specific studies in this population. This study aimed to evaluate the safety and efficacy of PT in preterm infants from the perspective of long-term neurodevelopmental outcomes., Methods: We conducted a systematic literature search using placental transfusion, preterm infant, and its synonyms as search terms. Cochrane Central Register of Controlled Trials, Medline, and Embase were searched until March 07, 2023. Two reviewers independently identified, extracted relevant randomized controlled trials, and appraised the risk of bias. The extracted studies were included in the meta-analysis of long-term neurodevelopmental clinical outcomes using fixed-effects models., Results: A total of 5612 articles were identified, and seven randomized controlled trials involving 2551 infants were included in our meta-analysis. Compared with immediate cord clamping (ICC), PT may not impact adverse neurodevelopment events. No clear evidence was found of a difference in the risk of neurodevelopmental impairment (risk ratio [RR]: 0.89, 95% confidence interval [CI]: 0.76 to 1.03, P = 0.13, I 2  = 0). PT was not associated with the incidence of cerebral palsy (RR: 1.23, 95% CI: 0.59 to 2.57, P = 0.79, I 2  = 0). Analyses showed no differences between the two interventions in cognitive, language, and motor domains of neurodevelopment., Conclusions: From the perspective of long-term neurodevelopment, PT at preterm birth may be as safe as ICC. Future studies should focus on standardized, high-quality clinical trials and individual participant data to optimize cord management strategies for preterm infants after birth., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

West Nile virus (WNV) is an important neurotropic virus that accounts for the emergence of human arboviral encephalitis and meningitis. The interaction of WNV with signaling pathways plays a key role in controlling WNV infection. We have investigated the roles of the AKT and ERK pathways in supporting WNV propagation and modulating the inflammatory response following WNV infection. WNV established a productive infection in neuronal cell lines originated from human and mouse. Expression of IL-11 and TNF-α was markedly up-regulated in the infected human neuronal cells, indicating elicitation of inflammation response upon WNV infection. WNV incubation rapidly activated signaling cascades of AKT (AKT-S6-4E-BP1) and ERK (MEK-ERK-p90RSK) pathways. Treatment with AKT inhibitor MK-2206 or MEK inhibitor U0126 abrogated WNV-induced AKT or ERK activation. Strong activation of AKT and ERK signaling pathways could be detectable at 24 h after WNV infection, while such activation was abolished at 48 h post infection. U0126 treatment or knockdown of ERK expression significantly increased WNV RNA levels and viral titers and efficiently decreased IL-11 production induced by WNV, suggesting the involvement of ERK pathway in WNV propagation and IL-11 induction. MK-2206 treatment enhanced WNV RNA replication accompanied with a moderate decrease in IL-11 production. These results demonstrate that engagement of AKT and ERK signaling pathways facilitates viral infection and may be implicated in WNV pathogenesis., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors.)

Compression of small molecules can induce solid-state reactions that are difficult or impossible under conventional, solution-phase conditions. Of particular interest is the topochemical-like reaction of arenes to produce polymeric nanomaterials. However, high reaction onset pressures and poor selectivity remain significant challenges. Herein, the incorporation of electron-withdrawing and -donating groups into π-stacked arenes is proposed as a strategy to reduce reaction barriers to cycloaddition and onset pressures. Nevertheless, competing side-chain reactions between functional groups represent alternative viable pathways. For the case of a diaminobenzene:tetracyanobenzene cocrystal, amidine formation between amine and cyano groups occurs prior to cycloaddition with an onset pressure near 9 GPa, as determined using vibrational spectroscopy, X-ray diffraction, and first-principles calculations. This work demonstrates that reduced-barrier cycloaddition reactions are theoretically possible via strategic functionalization; however, the incorporation of pendant groups may enable alternative reaction pathways. Controlled reactions between pendant groups represent an additional strategy for producing unique polymeric nanomaterials.

Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood. In this study, we sought to determine whether epigenetic reprogramming of the cell-cell adhesion molecule E-cadherin, encoded by the CDH1 gene, disrupts epithelial integrity. By reducing these epigenetic marks, we can restore epithelial integrity and rescue alveolar airspace destruction. We used differentiated normal and COPD-derived primary human airway epithelial cells, genetically manipulated mouse tracheal epithelial cells, and mouse and human precision-cut lung slices to assess the effects of epigenetic reprogramming. We show that the loss of CDH1 in COPD is due to increased DNA methylation site at the CDH1 enhancer D through the downregulation of the ten-eleven translocase methylcytosine dioxygenase (TET) enzyme TET1 . Increased DNA methylation at the enhancer D region decreases the enrichment of RNA polymerase II binding. Remarkably, treatment of human precision-cut slices derived from patients with COPD with the DNA demethylation agent 5-aza-2'-deoxycytidine decreased cell damage and reduced air space enlargement in the diseased tissue. Here, we present a novel mechanism that targets epigenetic modifications to reverse the tissue remodeling in human COPD lungs and serves as a proof of concept for developing a disease-modifying target.

Measures of substance concentration in urine, serum or other biological matrices often have an assay limit of detection. When concentration levels fall below the limit, exact measures cannot be obtained, and thus are left censored. The problem becomes more challenging when the censored data come from heterogeneous populations consisting of exposed and non-exposed subjects. If the censored data come from non-exposed subjects, their measures are always zero and hence censored, forming a latent class governed by a distinct censoring mechanism compared with the exposed subjects. The exposed group's censored measurements are always greater than zero, but less than the detection limit. It is very often that the exposed and non-exposed subjects may have different disease traits or different relationships with outcomes of interest, so we need to disentangle the two different populations for valid inference. In this article, we aim to fill the methodological gaps in the literature by developing a novel joint modeling approach to not only address the censoring issue in predictors, but also untangle different relationships of exposed and non-exposed subjects with the outcome. Simulation studies are performed to assess the numerical performance of our proposed approach when the sample size is small to moderate. The joint modeling approach is also applied to examine associations between plasma metabolites and blood pressure in Bogalusa Heart Study, and identify new metabolites that are highly associated with blood pressure., (© 2023 John Wiley & Sons Ltd.)

The carotid bodies (CBs) have been implicated in glucose abnormalities in obesity via elevation of activity of the sympathetic nervous system. Obesity-induced hypertension is mediated by insulin receptor (INSR) signaling and by leptin, which binds to the leptin receptor (LEPR b ) in CB and activates transient receptor potential channel subfamily M member 7 (TRPM7). We hypothesize that in mice with diet-induced obesity, hyperglycemia, glucose intolerance, and insulin resistance will be attenuated by the CB denervation (carotid sinus nerve dissection, CSND) and by knockdown of Lepr b , Trpm7, and Insr gene expression in CB. In series of experiments in 75 male diet-induced obese (DIO) mice, we performed either CSND (vs. sham) surgeries or shRNA-induced suppression of Lepr b , Trpm7 , or Insr gene expression in CB, followed by blood pressure telemetry, intraperitoneal glucose tolerance and insulin tolerance tests, and measurements of fasting plasma insulin, leptin, corticosterone, glucagon and free fatty acids (FFAs) levels, hepatic expression of gluconeogenesis enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G-6-Pase) mRNA and liver glycogen levels. CSND decreased blood pressure, fasting blood glucose levels and improved glucose tolerance without any effect on insulin resistance. CSND did not affect any hormone levels and gluconeogenesis enzymes, but increased liver glycogen level. Genetic knockdown of CB Lepr b , Trpm7, and Insr had no effect on glucose metabolism. We conclude that CB contributes to hyperglycemia of obesity, probably by modulation of the glycogen-glucose equilibrium. Diabetogenic effects of obesity on CB in mice do not occur via activation of CB Lepr b , Trpm7, and Insr . NEW & NOTEWORTHY This paper provides first evidence that carotid body denervation abolishes hypertension and improves fasting blood glucose levels and glucose tolerance in mice with diet-induced obesity. Furthermore, we have shown that this phenomenon is associated with increased liver glycogen content, whereas insulin sensitivity and enzymes of gluconeogenesis were not affected.

Objective: To analyse the relationship between the adverse drug reactions (ADRs) of essential drugs and visits, based on the recorded annual increase in ADRs associated with essential medicines in China, to provide a reliable theoretical basis for further analysis and optimization of the safety of essential drugs., Methods: The data of adverse reactions of essential drugs in China from 2011 to 2020, time series analysis was conducted, and vector autoregressive (VAR) model was established. The relationship between the number of ADRs and visits was explored empirically through Granger causality test, impulse response function and variance decomposition., Results: There was a long-term cointegration relationship and one-way causality between the number of visits and ADRs caused by essential medicines. In the initial stage, the ADR response to the number of visits increased sharply, but with an increase in the number of lag periods, the impact remained basically stable, even showing a slight decreasing trend., Conclusion: The number of visits impacts ADRs caused by essential medicines, but this impact remains basically stable after reaching a certain level., Competing Interests: The authors declare that they have no competing interests., (© 2023 Tang et al.)

The progression of cholestasis is characterized by excessive accumulation of bile acids (BAs) in the liver, which leads to oxidative stress (OS), inflammation and liver injury. There are currently limited treatments for cholestasis. Therefore, appropriate drugs for cholestasis treatment need to be developed. Dimethyl fumarate (DMF) has been widely used in the treatment of various diseases and exerts antioxidant and anti-inflammatory effects, but its effect on cholestatic liver disease remains unclarified. We fed mice 3,5-diethoxycarbonyl-1,4-dihydrocollidine or cholic acid to induce cholestatic liver injury and treated these mice with DMF to evaluate its protective ability. Alanine aminotransferase, aspartate aminotransferase, and total liver BAs were assessed as indicators of liver function. The levels of OS, liver inflammation, transporters and metabolic enzymes were also measured. DMF markedly altered the relative ALT and AST levels and enhanced the liver antioxidant capacity. DMF regulated the MST/NRF2 signaling pathway to protect against OS and reduced liver inflammation through the NLRP3/GSDMD signaling pathway. DMF also regulated the levels of BA transporters by promoting FXR protein expression. These findings provide new strategies for the treatment of cholestatic liver disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: To prepare for rollout of a COVID-19 vaccine in fall 2020, there was an urgent need to understand barriers to ensuring equitable access and addressing vaccine skepticism and resistance. This study aimed to understand the association between trusted sources of COVID-19 information and likelihood of vaccination during that time, focusing on lessons learned to prepare for future public health crises., Methods: From December 2020-March 2021, we surveyed a probability-based, cross-sectional sample of 955 patients across seven federally qualified health centers (FQHCs) serving predominantly low-income, Black and White populations in southeastern Louisiana. Vaccination likelihood was measured on a 7-point scale; "very likely to vaccinate" was defined as score=7. Trust in healthcare provider was measured with a single survey item. High trust in personal contacts, government, and media, respectively, were defined as the highest tertiles of summative scores of trust items. Weighted multivariable logistic regression estimated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for being very likely to vaccinate., Results: Participants were 56% Black, 64% women, mean age 44.6 years; 33% were very likely to vaccinate. High trust in healthcare provider (aOR=4.14, 95% CI 2.26-7.57) and government sources (aOR=3.23, 95% CI 1.98-5.28) were associated with being very likely to vaccinate., Conclusions: During initial COVID-19 vaccination rollout, trust in healthcare providers and government sources of COVID-19 information was associated with likelihood to vaccinate in FQHC patients. To inform public health planning for future crises, we highlight lessons learned for translating community-relevant insights into direct action to reach those most impacted., Competing Interests: Declaration of Competing Interest Nothing to disclose, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The inhibition of matrix metalloproteinases (MMPs) has shown potential in the treatment of various neurodegenerative diseases, and perioperative neurocognitive disorders (PND) is accompanied by the increased expression of MMP-2 and MMP-9 in the hippocampus. However, the effect of inhibiting MMP-2 and MMP-9 on PND is not clear. In this study we aimed to evaluate the effects of inhibiting MMP-2 and MMP-9 on cognitive function in the aged mice after surgery, in order to find a possible target for the prevention and treatment of PND METHODS: In this study, 14-month-old C57BL/6 mice were used to establish a PND model by tibial fracture surgery and sevoflurane anesthesia. Three days later, part of the mice were subjected to cognitive assessment and the other was sacrificed for biochemical analysis. We used the Novel object recognition test and Fear conditioning test to evaluate the postoperative cognitive function of mice. The expression of mmp-2 and MMP-9 was detected by western blotting. We also examined the expression of claudin-5 and occludin using Western blotting, and the activation of microglia and astrocytes using immunofluorescence., Results: The results showed that surgery increased the expression of MMP-2 and MMP-9 in the hippocampus of mice, accompanied by cognitive impairment, decreased expression of claudin-5 and occludin, and increased activation of microglia and astrocytes. However, inhibition of MMP-2 and MMP-9 expression by SB-3CT reversed these changes., Conclusions: Our study shows that inhibition of MMP-2 and MMP-9 alleviates anesthesia/surgery-induced cognitive decline by increasing BBB integrity and inhibiting glial cell activation., Competing Interests: Declaration of Competing Interest the authors declare no conflicts of interest in the submission of this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes can protect lung tissues against sepsis, but its related mechanism remains elusive. BMSCs were primed with or without lipopolysaccharide (LPS) before extracting exosomes. The isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. LPS-stimulated macrophages were cocultured with exosomes for 24 h, followed by enzyme-linked immunosorbent assay, flow cytometry, and molecular experiments. Bioinformatics and luciferase assay were employed to investigate the interaction between miR-150-3p and inhibin subunit beta A (INHBA). MiR-150-3p expression was increased in exosomes in a proinflammatory environment. Exosomes suppressed proinflammatory polarization by downregulating IL-6 , IL-1β , iNOS , and CD86, as well as promoted anti-inflammatory polarization by upregulating IL-10 , ARG-1 , and CD206 in LPS-stimulated macrophages. Such effects were more pronounced by LPS-primed exosomes, which was reversed in the absence of miR-150-3p . MiR-150-3p targeted INHBA. INHBA silencing decreased CD86 expression and increased CD206 expression in macrophages, but these effects were reversed by exosomal miR-150-3p inhibition. Proinflammatory BMSC-derived exosomal miR-150-3p suppressed proinflammatory polarization and promoted anti-inflammatory polarization of alveolar macrophages to attenuate LPS-induced sepsis by targeting INHBA.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a common disease among newborns, which is a leading cause of neonatal death and permanent neurological sequelae. Therapeutic hypothermia (TH) is the only method for the treatment of HIE that has been recognized effective clinically at home and abroad, but the efficacy is limited. Recent research suggests that the cord blood-derived mononuclear cells (CB-MNCs), which the refer to blood cells containing one nucleus in the cord blood, exert anti-oxidative, anti-inflammatory, anti-apoptotic effects and play a neuroprotective role in HIE. This review focuses on safety and efficacy, the route of administration, dose, timing and combination treatment of CB-MNCs in HIE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Introduction: Use of sugammadex is associated with fewer postoperative pulmonary complications (PPCs). This study investigated the relationship between sugammadex and PPCs in specific patients with respiratory dysfunction., Materials and Methods: We reviewed the electronic medical and anesthesia records of patients with respiratory dysfunction who underwent laparoscopic gastric or intestinal surgery at a single center between May 1, 2018 and December 31, 2019. The patients were divided into the sugammadex group and the nonsugammadex group, based on whether they received sugammadex or neostigmine. Binary logistic regression analyses were used to characterize the differences in incidence of PPC., Results: A total of 112 patients were included, of which 46 patients (41.1%) received sugammadex. In the logistic regression analysis, the incidences of PPC were fewer in the sugammadex group. Postoperative fever (odds ratio [OR] 0.330; 95% confidence interval [CI] 0.137-0.793, P = 0.0213), postoperative intensive care unit admission (OR 0.204; 95% CI 0.065-0.644, P = 0.007), cough (OR 0.143; 95% CI 0.061- 0.333, P < 0.001), pleural effusion (all) (OR: 0.280; 95% CI 0.104- 0.759, P = 0.012), pleural effusion (massive) (OR: 0.142; 95% CI 0.031- 0.653, P = 0.012), and difficulty in breathing (OR: 0.111; 95% CI 0.014-0.849, P = 0.039) showed significant differences between the two groups., Conclusions: Sugammadex is associated with a reduction in PPC in patients with respiratory dysfunction., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

An ultrahigh-performance liquid chromatography coupled with ion mobility quadrupole time-of-flight mass spectrometry method was developed for the separation and identification of phenols, organic acids, flavonoids and curcumin in different species of ginger. The parameters affecting the separation and response of liquid chromatography, including the stationary phase and mobile phase, were systematically investigated and optimized. To further identify the differential metabolites in the six types of samples, a chemometric approach was introduced. Principal component analysis, cluster analysis and partial least squares discriminant analysis were used to identify the major components in the samples and to compare the compositional differences between the various samples. In addition, antioxidant experiments were designed to investigate the differences in antioxidant activity among the six ginger samples. The method showed good linearity (R 2 ≥0.9903), satisfactory precision (RSD% ≤ 4.59 %), low LOD (0.35-25.86 ng/mL) and acceptable recovery (78-109 %) and reproducibility (RSD% ≤ 4.20 %). Therefore, the method has great potential for application in the compositional analysis and quality control of ginger., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, “Chemometrics and antioxidant activity assisted nontargeted metabolomics for the identification of ginger species”., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: To establish and independently validate nomograms for predicting singleton preterm birth (PTB) risk based on a large sample size comprising data from two independent datasets., Methods: This cohort study used data from 50 states and the District of Columbia in the National Vital Statistics System (NVSS) database between January 2016 and December 2020. Multivariate logistic regression analysis was used to confirm the independent risk factors for PTB. Statistically significant variables were incorporated into the logistic regression models to establish PTB prediction nomograms. The models were developed using the United States (US)-derived data and were independently validated using data from US Territories., Results: A total of 16,294,529 mother-newborn pairs from the US were included in the training set, and 54,708 mother-newborn pairs from the US Territories were included in the validation set. In all, 4 nomograms were built: 1 to predict PTB probability, and another 3 to predict moderately and late PTB probability, very PTB probability, and extremely PTB probability, respectively. Hypertensive eclampsia and infertility treatment were found to be the top 2 contributors to PTB., Conclusions: We developed and validated nomograms to predict the individualized probability of PTB, which could be useful to physicians for improved early identification of PTB and in making individualized clinical decisions., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-611/coif). The authors have no conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

Proportional odds models are commonly used to model ordinal responses, but the proportional odds assumption may not hold in practice, leading to biased inference. Tests such as score, Wald and likelihood ratio (LR) have been proposed to evaluate the proportional odds assumption based on models without the assumption. Brant has proposed an independent binary model-based Wald-type test, and Wolfe and Gould have extended the idea to propose an LR-type test. This paper provides a brief review of the Brant and Wolfe-Gould tests for evaluating the proportional odds assumption and evaluates their performance through simulation studies and a real data example. Sample programs are provided in SAS, SPSS and Stata to facilitate the implementation of these tests using standard statistical software packages. This study highlights the importance of evaluating the proportional odds assumption when using proportional odds models for ordinal responses. The sample programs provided in this paper make it easy for researchers to apply these tests in their own analyses using standard statistical software packages., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The Swanson Nolan, and Pelham scale version IV (SNAP-IV) is the most critical tool for ADHD screening and diagnosis, which has two scoring methods. ADHD requires symptom assessment in multiple scenarios, and parent and teacher reports are indispensable for diagnosing ADHD. But the differences of assessment results from fathers, mothers and teachers, and the consistency of results from different scoring methods are unknown. Therefore, we carried out this study to understand the differences in the scores of fathers, mothers and teachers using SNAP-IV for children with ADHD and to explore the differences in scoring results under different scoring methods., Methods: The SNAP-IV scale and Demographics Questionnaire and Familiarity Index were used to survey fathers, mothers and head teachers. Measurement data are expressed as the mean ± standard deviation (x ± s). The enumeration data were described by frequency and percentage. ANOVA was used to compare group differences in mothers', fathers', and teachers' mean SNAP-IV scores. The Bonferroni method was used for post hoc multiple comparison tests. Cochran's Q test was used to compare the differences in the abnormal rate of SNAP-IV score results of mothers, fathers and teachers. Dunn's test was used for post hoc multiple comparison tests., Results: There were differences in scores among the three groups, and the differences showed inconsistent trends across the different subscales. Differences between groups were calculated again with familiarity as a control variable. The results showed the familiarity of parents and teachers with the patients did not affect the differences in their scores. The evaluation results were different under two assessment methods., Conclusion: Results concluded that fathers did not appear to be an appropriate candidate for evaluation. When using the SNAP-V for assessment, it should be comprehensively considered from both the scorer and symptom dimensions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Li, Simpson, Xu, Tang and Li.)

Tick-borne encephalitis virus (TBEV) belonging to arboviruses is a major member of zoonotic pathogens. TBEV infection causes severe human encephalitis without specific antiviral drugs. Due to its use of antiviral drug against a wide range of viruses, we investigated antiviral effect of ribavirin against TBEV in susceptible human cell lines A549 and SH-SY5Y. Ribavirin displayed minor cytotoxicity on multiple cell lines. Ribavirin obviously impaired TBEV replication and protected the infected cells from cytopathic effect. Importantly, ribavirin markedly inhibited TBEV propagation, as evidenced by impairment of TBEV production and viral RNA replication. Treatment with ribavirin (co-treatment and post-treatment) led to a dose-dependent reduction in TBEV titers as well as the viral RNA levels. Antiviral protein myxovirus resistance A mRNA expression was significantly up-regulated and signal transducer and activator of transcription 3 was activated in TBEV-infected A549 cells upon the ribavirin treatment. Induction of inflammatory cytokine tumor necrosis factor alpha by TBEV was decreased in A549 cells with the treatment of ribavirin, whereas interleukin 1 beta release appeared to be unaffected. These results suggest that ribavirin might represent a promising safe and effective antiviral drug against TBEV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tang, Tang, Peng, Ren, Zhao and Zhao.)

Extracellular vesicles (EVs) have been suggested to transmit the health-promoting effects of exercise throughout the body. Yet, the mechanisms by which beneficial information is transmitted from extracellular vesicles to recipient cells are poorly understood, precluding a holistic understanding of how exercise promotes cellular and tissue health. In this study, using articular cartilage as a model, we introduced a network medicine paradigm to simulate how exercise facilitates communication between circulating EVs and chondrocytes, the cells resident in articular cartilage. Using the archived small RNA-seq data of EV before and after aerobic exercise, microRNA regulatory network analysis based on network propagation inferred that circulating EVs activated by aerobic exercise perturb chondrocyte-matrix interactions and downstream cellular aging processes. Building on the mechanistic framework identified through computational analyses, follow up experimental studies interrogated the direct influence of exercise on EV-mediated chondrocyte-matrix interactions. We found that pathogenic matrix signaling in chondrocytes was abrogated in the presence of exercise-primed EVs, restoring a more youthful phenotype, as determined by chondrocyte morphological profiling and evaluation of chondrogenicity. Epigenetic reprograming of the gene encoding the longevity protein, α-Klotho, mediated these effects. These studies provide mechanistic evidence that exercise transduces rejuvenation signals to circulating EVs, endowing EVs with the capacity to ameliorate cellular health even in the presence of an unfavorable microenvironmental signals., Competing Interests: Competing interest statement The authors declare no competing interests.

Magnetic quantum dot (QD) barcode holds great potential for automatic suspension array and rapid point-of-care detection since it enables simultaneous target encoding, enrichment and separation. However, a serious obstacle to enhancing the encoding capacity of magnetic QD microbeads (MBs) is the fluorescence quenching of magnetic nanoparticles (MNPs) to quantum dots (QDs) in the visible wavelength range due to the broad and strong optical absorption spectrum of MNPs. Here, we report Fe 3 O 4 /TiO 2 core/shell MNPs and CdSe/ZnS QDs for the construction of dual-function magnetic QD barcodes. Fe 3 O 4 /TiO 2 MNPs can significantly inhibit fluorescence quenching because the weak absorption of visible light by the TiO 2 . The two-dimension barcode library of 30 magnetic QD barcodes was constructed based on Fe 3 O 4 /TiO 2 MNPs and CdSe/ZnS QDs. Moreover, the magnetic QD barcodes showed high sensitivity for the multiplex detection of four tumor markers, cancer antigen 125 (CA125), cancer antigen 199 (CA199), alpha-fetoprotein (AFP), and neuron specific enolase (NSE) with detection limits of 0.89 KU/L, 0.72 KU/L, 0.05 ng/mL, and 0.15 ng/mL, respectively. This bifunctional magnetic QD barcodes are promising for automatic high-sensitivity multiplex bioassay., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Extracellular matrix stiffening is a quintessential feature of cartilage aging, a leading cause of knee osteoarthritis. Yet, the downstream molecular and cellular consequences of age-related biophysical alterations are poorly understood. Here, we show that epigenetic regulation of α-Klotho represents a novel mechanosensitive mechanism by which the aged extracellular matrix influences chondrocyte physiology. Using mass spectrometry proteomics followed by a series of genetic and pharmacological manipulations, we discovered that increased matrix stiffness drove Klotho promoter methylation, downregulated Klotho gene expression, and accelerated chondrocyte senescence in vitro. In contrast, exposing aged chondrocytes to a soft matrix restored a more youthful phenotype in vitro and enhanced cartilage integrity in vivo. Our findings demonstrate that age-related alterations in extracellular matrix biophysical properties initiate pathogenic mechanotransductive signaling that promotes Klotho promoter methylation and compromises cellular health. These findings are likely to have broad implications even beyond cartilage for the field of aging research., (© 2023. The Author(s).)

Perinatal white matter injury (PWMI) can lead to permanent neurological damage in preterm infants and bring a huge economic burden to their families and society. Liver X receptors (LXRs) are transcription factors that have been confirmed to mediate the myelination process under physiological conditions and are involved in regulating neurogenesis in adult animal models of acute and chronic cerebral ischemia. However, the role of LXRs in PWMI induced by both ischemic and hypoxic stimulation in the immature brain has not been reported. Herein, we investigated the role of LXRs in a neonatal rat model of white matter loss after hypoxia-ischemia (HI) injury through intraperitoneal injection of the LXR agonist T0901317 (T09) 1 day before and 15 min postinjury. The in vivo data showed that T09 treatment significantly facilitated myelination and ameliorated neurological behavior after PWMI. Moreover, T09 enhanced the proliferation of oligodendrocyte lineage cells and reduced microgliosis and astrogliosis in the microenvironment for oligodendrocytes (OLs), maintaining a healthy microenvironment for myelinating OLs. In vitro data suggested that the expression of the myelin-related genes Plp and Cnpase was increased in OLN-93 cells after T09 intervention compared with OLN-93 cells injured by oxygen and glucose deprivation (OGD). In primary mixed astrocytes/microglia cells, T09 also reduced the expression of Il6, Cox2, Tnfa and Il10 that was induced by OGD. Mechanistically, the mRNA expression level and the protein level of ATP binding cassette subfamily A member 1 (Abca1) decreased after HI injury, and the protective effect of T09 might be related to the activation of the LXRβ-ABCA1 signaling pathway. Our study revealed the protective role of LXRs in myelination and white matter homeostasis, providing a potential therapeutic option for PWMI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

A molecular dysprosium(III) complex [Dy(DClQ) 3 (H 2 O) 2 ] (1) was used as a building unit for the construction of lanthanide SMMs, leading to the isolation of two dinuclear Dy(III) complexes, namely [Dy 2 (DClQ) 6 (MeOH) 2 ] (2) and [Dy 2 (DClQ) 6 (bpmo) 2 ]·6MeCN (3) ( DClQ = 5,7-dichloro-8-hydroxyquinoline, bpmo = 4,4'-dipyridine-oxide). Structural analyses revealed the same N 3 O 5 coordination environment of the Dy(III) centers with a distorted biaugmented trigonal prism ( C 2V symmetry) and triangular dodecahedron ( D 2d symmetry) for 2 and 3, respectively. Magnetic studies revealed the presence of ferromagnetic and weak antiferromagnetic exchange interactions between the Dy 3+ centers in 2 and 3, respectively. Interestingly, slow relaxation of magnetization at zero fields was evidenced with an U eff of 51.4 K and 159.0 K for complexes 2 and 3, respectively. The detailed analysis of relaxation dynamics discloses that the Orbach process is dominant for 2 whereas Raman and QTM play an important role in 3. Theoretical calculations were carried out to provide insight into the magnetic exchange interactions and relaxation dynamics for the complexes. Due to a single-ion magnet (SIM) of 1, the foregoing results demonstrate a SIM modular synthetic route for the preparation of dinuclear lanthanide SMMs.

Self-supervised learning approaches have seen success transferring between similar medical imaging datasets, however there has been no large scale attempt to compare the transferability of self-supervised models against each other on medical images. In this study, we compare the generalisability of seven self-supervised models, two of which were trained in-domain, against supervised baselines across eight different medical datasets. We find that ImageNet pretrained self-supervised models are more generalisable than their supervised counterparts, scoring up to 10% better on medical classification tasks. The two in-domain pretrained models outperformed other models by over 20% on in-domain tasks, however they suffered significant loss of accuracy on all other tasks. Our investigation of the feature representations suggests that this trend may be due to the models learning to focus too heavily on specific areas.

Dual-modal magnetic resonance/fluorescent imaging (MRI/FI) attracts moreandmoreattentions in diagnosis of tumors. A corresponding dual-modal imaging agent with sufficient tumor sensitivity and specificity should be matched to improve imaging quality. Tripeptide (RGD) and pentapeptide (YIGSR) were selected as the tumor-targeting groups and attached to gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and rhodamine B (RhB), and then make two novel polypeptide-based derivatives (RGD-Gd-DTPA-RhB and YIGSR-Gd-DTPA-RhB), respectively. These derivatives were further characterized and their properties, such as cell uptake, cell cytotoxicity, MRI and FI assay, were measured. YIGSR-Gd-DTPA-RhB and RGD-Gd-DTPA-RhB had high relaxivity, good tumor-targeting property, low cell cytotoxicity and good red FI in B16F10 melanoma cells. Moreover, YIGSR-Gd-DTPA-RhB and RGD-Gd-DTPA-RhB possessed high uptake to B16F10 melanoma, and then achieve highly enhanced FI and MRI of tumors in mice for a prolonged time. Therefore, YIGSR-Gd-DTPA-RhB and RGD-Gd-DTPA-RhB can be applied as the potential agents for tumor targeted MRI/FI in vivo., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Sleep-disordered breathing (SDB) affects over 50% of obese individuals. Exaggerated hypoxic chemoreflex is a cardinal trait of SDB in obesity. We have shown that leptin acts in the carotid bodies (CB) to augment chemoreflex and that leptin activates the transient receptor potential melastatin 7 (TRPM7) channel. However, the effect of leptin-TRPM7 signalling in CB on breathing and SDB has not been characterized in diet-induced obesity (DIO). We hypothesized that leptin acts via TRPM7 in the CB to increase chemoreflex leading to SDB in obesity. DIO mice were implanted with EEG/EMG electrodes and transfected with Lepr b short hairpin RNA (shRNA) or Trpm7 shRNA vs. control shRNA in the CB area bilaterally. Mice underwent a full-polysomnography and metabolic studies at baseline and after transfection. Ventilatory responses to hypoxia and hypercapnia were assessed during wakefulness. Lepr b and Trpm7 were upregulated and their promoters were demethylated in the CB of DIO mice. Lepr b knockdown in the CB did not significantly affect ventilation. Trpm7 knockdown in the CB stimulated breathing during sleep in normoxia. These effects were not driven by changes in CB chemosensitivity or metabolism. Under sustained hypoxia, Trpm7 shRNA in the CB augmented ventilation during sleep, but decreased oxyhaemoglobin saturation. We conclude that the suppression of TRPM7 in the CB improved sleep-related hypoventilation and that the respiratory effects of CB TRPM7 channels in obesity are independent of leptin. TRPM7 signalling in the CB could be a therapeutic target for the treatment of obesity-related SDB. KEY POINTS: The leptin-TRPM7 axis in the carotid bodies may play an important role in the pathogenesis of sleep-disordered breathing. TRPM7 channels regulate breathing during sleep by acting peripherally in the carotid bodies. Suppression of TRPM7 signalling in the carotid bodies improves the obesity-induced hypoventilation in mice. Pharmacological blockade of TRPM7 channels in the carotid bodies could be a therapy for sleep-disordered breathing in obesity., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Human microbiome research has become a hot-spot in health and medical research in the past decade due to the rapid development of modern high-throughput. Typical data in a microbiome study consisting of the operational taxonomic unit counts may have over-dispersion and/or structural zero issues. In such cases, negative binomial models can be applied to address the over-dispersion issue, while zero-inflated negative binomial models can be applied to address both issues. In practice, it is essential to know if there is zero-inflation in the data before applying negative binomial or zero-inflated negative binomial models because zero-inflated negative binomial models may be unnecessarily complex and difficult to interpret, or may even suffer from convergence issues if there is no zero-inflation in the data. On the other hand, negative binomial models may yield invalid inferences if the data does exhibit excessive zeros. In this paper, we develop a new test for detecting zero-inflation resulting from a latent class of subjects with structural zeros in a negative binomial regression model by directly comparing the amount of observed zeros with what would be expected under the negative binomial regression model. A closed form of the test statistic as well as its asymptotic properties are derived based on estimating equations. Intensive simulation studies are conducted to investigate the performance of the new test and compare it with the classical Wald, likelihood ratio, and score tests. The tests are also applied to human gut microbiome data to test latent class in microbial genera.

Background: Effectiveness of integrated care management for common, comorbid physical and mental disorders has been insufficiently examined in low- and middle-income countries (LMICs). We tested hypotheses that older adults treated in rural Chinese primary care clinics with integrated care management of comorbid depression and hypertension (HTN) would show greater improvements in depression symptom severity and HTN control than those who received usual care., Methods and Findings: The study, registered with ClinicalTrials.gov as Identifier NCT01938963, was a cluster randomized controlled trial with 12-month follow-up conducted from January 1, 2014 through September 30, 2018, with analyses conducted in 2020 to 2021. Participants were residents of 218 rural villages located in 10 randomly selected townships of Zhejiang Province, China. Each village hosts 1 primary care clinic that serves all residents. Ten townships, each containing approximately 20 villages, were randomly selected to deliver either the Chinese Older Adult Collaborations in Health (COACH) intervention or enhanced care-as-usual (eCAU) to eligible village clinic patients. The COACH intervention consisted of algorithm-driven treatment of depression and HTN by village primary care doctors supported by village lay workers with telephone consultation from centrally located psychiatrists. Participants included clinic patients aged ≥60 years with a diagnosis of HTN and clinically significant depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥10). Of 2,899 eligible village residents, 2,365 (82%) agreed to participate. They had a mean age of 74.5 years, 67% were women, 55% had no schooling, 59% were married, and 20% lived alone. Observers, older adult participants, and their primary care providers (PCPs) were blinded to study hypotheses but not to group assignment. Primary outcomes were change in depression symptom severity as measured by the Hamilton Depression Rating Scale (HDRS) total score and the proportion with controlled HTN, defined as systolic blood pressure (BP) <130 mm Hg or diastolic BP <80 for participants with diabetes mellitus, coronary heart disease, or renal disease, and systolic BP <140 or diastolic BP <90 for all others. Analyses were conducted using generalized linear mixed effect models with intention to treat. Sixty-seven of 1,133 participants assigned to eCAU and 85 of 1,232 COACH participants were lost to follow-up over 12 months. Thirty-six participants died of natural causes, 22 in the COACH arm and 14 receiving eCAU. Forty COACH participants discontinued antidepressant medication due to side effects. Compared with participants who received eCAU, COACH participants showed greater reduction in depressive symptoms (Cohen's d [±SD] = -1.43 [-1.71, -1.15]; p < 0.001) and greater likelihood of achieving HTN control (odds ratio [OR] [95% CI] = 18.24 [8.40, 39.63]; p < 0.001). Limitations of the study include the inability to mask research assessors and participants to which condition a village was assigned, and lack of information about participants' adherence to recommendations for lifestyle and medication management of HTN and depression. Generalizability of the model to other regions of China or other LMICs may be limited., Conclusions: The COACH model of integrated care management resulted in greater improvement in both depression symptom severity and HTN control among older adult residents of rural Chinese villages who had both conditions than did eCAU., Trial Registration: ClinicalTrials.gov Identifier NCT01938963 https://clinicaltrials.gov/ct2/show/NCT01938963., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Natural plant-derived baicalein which is extracted from Chinese herb Scutellaria baicalensis Georgi belongs to the flavonoid compounds and possesses multiple pharmacological activities. In this study, we designed and synthesized new series of derivatives of baicalein (BE) through catalytic coupling reactions, and screened for their antiviral activity against arboviruses including Chikungunya virus (CHIKV), West Nile virus (WNV) or Zika virus (ZIKV). Our results revealed for the first time that BE and its derivatives had potent anti-CHIKV, anti-WNV and anti-ZIKV effects. And modification of 8 or 4' position could lead to obtain potent antiviral compounds against CHIKV, WNV and ZIKV with lower cytotoxicity. Among the baicalein derivatives, C3 and F3 showed the most potent antiviral activities against CHIKV, WNV and ZIKV, which were 5-10 times more potent than baicalein. Our findings will provide research basis for the development of baicalein derivatives as effective antiviral agents., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In order to study the comprehensive effects of different types of dehydrating agents on the dewatering and solidification of dredged sediments, this study took the dredged sediments of Taihu Lake as the research object and selected microorganisms, polymeric iron aluminum salts, organic polymers, organic-inorganic composites, and aluminum salt microorganisms. These five types of composite dehydrating agents were used to conduct a three-month solidification test on the dredged sediment by means of geotechnical pipe bag solidification. The results of the study showed that the dehydration efficiency of organic polymers and organic-inorganic composite chemicals was better. After one month, the water content of sediment dropped to 61.78% and 63.26%, respectively, which then dropped to 40.56% and 32.16% after three months. Compared with that of the unsolidified sludge, the total nitrogen of the bottom sludge after solidification by the organic-inorganic composite agent was reduced by 74.82%, reaching 591 mg·kg -1 , primarily due to the reduction in ammonia nitrogen. The solid sludge contained mainly aluminum-bound phosphorus, calcium-bound phosphorus, and iron-bound phosphorus. Among them, four groups (organic-inorganic composite) had the largest reduction in active phosphorus, with the lowest being 64.3 mg·kg -1 . In addition, organic polymer agents had the best curing effect on heavy metals, the comprehensive ecological risk index of heavy metals was reduced by 51.3%, and the leaching toxicity concentration was far below the standard threshold. This study showed that organic polymers and organic-inorganic composite medicaments have a better effect on the dehydration and solidification of bottom sludge and thus have good application prospects.

Atherosclerosis, the pathological basis of most cardiovascular disease, is characterized by plaque formation in the intima. Secondary lesions include intraplaque hemorrhage, plaque rupture, and local thrombosis. Vascular endothelial function impairment and smooth muscle cell migration lead to vascular dysfunction, which is conducive to the formation of macrophage-derived foam cells and aggravates inflammatory response and lipid accumulation that cause atherosclerosis. Histone deacetylase (HDAC) is an epigenetic modifying enzyme closely related to chromatin structure and gene transcriptional regulation. Emerging studies have demonstrated that the Class I member HDAC3 of the HDAC super family has cell-specific functions in atherosclerosis, including 1) maintenance of endothelial integrity and functions, 2) regulation of vascular smooth muscle cell proliferation and migration, 3) modulation of macrophage phenotype, and 4) influence on foam cell formation. Although several studies have shown that HDAC3 may be a promising therapeutic target, only a few HDAC3-selective inhibitors have been thoroughly researched and reported. Here, we specifically summarize the impact of HDAC3 and its inhibitors on vascular function, inflammation, lipid accumulation, and plaque stability in the development of atherosclerosis with the hopes of opening up new opportunities for the treatment of cardiovascular diseases., Competing Interests: Competing interests The authors declare that there are no disputes of interest., (Copyright: © 2022 Jiang et al.)

Early diagnosis of tumor markers is of great importance for the successful treatment of cancer. As a high-throughput and high-sensitivity detection technology, liquid suspension biochips based on quantum dot (QD) encoded microspheres have been widely used in the immunodetection of tumor markers. In this work, maleic anhydride grafted PLA (PLA-MA) microspheres based on quantum dot encoding were used as carriers for liquid phase suspension biochips for the immunoassay of tumor markers. PLA-MA fluorescent beads are prepared by embedding CdSe/ZnS quantum dots in PLA-MA using Shirasu porous glass (SPG) membrane emulsification technology, which has high fluorescence intensity, good stability, and good dispersion. Fluorescent immunoassays on dipsticks found that PLA-MA microspheres have high biological activity and good stability, which is conducive to immunoassays. Based on this, using the characteristics of CdSe/ZnS quantum dots and flow cytometry, monochromatic and two-color coding methods were developed, and 9 distinguishable coding beads were prepared. The results showed that PLA-MA fluorescent microspheres exhibited good biocompatibility, stable coding signals, low background noise, and low detection limits when performing quaternary immunoassays on tumor markers CA125, CA199, CA724, and CEA by CdSe/ZnS QD-encoded PLA-MA microsphere binding flow cytometry.

Background: Ultrasound-guided internal jugular vein (IJV) catheterization has become a standard procedure as it yields a higher success rate and fewer mechanical complications compared with an anatomical landmark technique. There are several common methods for ultrasound guidance IJV catheterization, such as short-axis out-of-plane, long-axis in-plane and oblique axis in-plane, but these technologies are still developing. It is important to further study the application of different ultrasound-guided IJV puncture techniques and find an effective and safe ultrasound-guided puncture technique., Methods: A China randomized, open-label, parallel, single center, positive-controlled, non-inferiority clinical trial will evaluate 190 adult patients undergoing elective surgery and need right jugular vein catheterization. Study participants randomized in a 1:1 ratio into control and experimental groups. The control group will take the oblique axis in-plane method for IJV catheterization. The experimental group will take the Modified combined short and long axis method. The primary endpoint of the trial is the rate of one-time successful guidewire insertion without posterior wall puncture (PWP). Secondary endpoints are the number of needle insertion attempts, the total success rate, the procedure time, and mechanical complications., Conclusion: This randomized controlled trial will evaluate the effectiveness and safety of Modified combined short and long axis method and oblique axis in-plane method for right IJV catheterization in adult patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tang, Wang, Nian, Tang, Tang, Xiao and Liu.)

The wild pig louse Haematopinus apri is one of the commonest ectoparasites of wild pigs. In the present study, the entire mitochondrial (mt) genome of wild pig louse H. apri from China was sequenced and compared with previously characterized wild pig louse H. apri from Japan. We identified all of the 37 mt genes in the wild pig louse H. apri from China which are on nine circular minichromosomes. Each mt minichromosome is 2.9 kb-4.2 kb size and contains 2-8 genes and one non-coding region (1543 bp-2534 bp). The number of minichromosomes, gene content and gene order in the both mt genomes of wild pig louse H. apri from China and Japan are the same. The identity of the both mt genomes (except for non-coding regions) was 98.3% between wild pig louse H. apri from China and Japan. The entire mt genome sequence (except for non-coding regions) of wild pig louse H. apri from China is longer (3 bp) than that from Japan. For the 13 protein-coding genes, this comparison showed sequence differences in each gene at both the nucleotide (0.8%-2.4%) and amino acid (0.4%-3.5%) levels. The most conserved of these genes was the nad 6, whereas the nad 2 was least conserved at the nucleotide levels. This is the first comprehensive comparison of the mt genomes of a louse species from different geographic locations. This useful data provides additional genetic markers to study the phylogeny, systematics and population genetics of wild pig louse H. apri ., Competing Interests: The authors declare that they have no competing interests., (© 2022 The Authors.)

Background: The malignant probability of MRI BiRADS 4 breast lesions ranges from 2% to 95%, leading to unnecessary biopsies. The purpose of this study was to construct an optimal XGboost prediction model through a combination of DKI independently or jointly with other MR imaging features and clinical characterization, which was expected to reduce false positive rate of MRI BiRADS 4 masses and improve the diagnosis efficiency of breast cancer., Methods: 120 patients with 158 breast lesions were enrolled. DKI, Diffusion-weighted Imaging (DWI), Proton Magnetic Resonance Spectroscopy ( 1 H-MRS) and Dynamic Contrast-Enhanced MRI (DCE-MRI) were performed on a 3.0-T scanner. Wilcoxon signed-rank test and χ2 test were used to compare patient's clinical characteristics, mean kurtosis (MK), mean diffusivity (MD), apparent diffusion coefficient (ADC), total choline (tCho) peak, extravascular extracellular volume fraction (V e ), flux rate constant (K ep ) and volume transfer constant (K trans ). ROC curve analysis was used to analyze the diagnostic performances of the imaging parameters. Spearman correlation analysis was performed to evaluate the associations of imaging parameters with prognostic factors and breast cancer molecular subtypes. The Least Absolute Shrinkage and Selectionator operator (lasso) and the area under the curve (AUC) of imaging parameters were used to select discriminative features for differentiating the breast benign lesions from malignant ones. Finally, an XGboost prediction model was constructed based on the discriminative features and its diagnostic efficiency was verified in BiRADS 4 masses., Results: MK derived from DKI performed better for differentiating between malignant and benign lesions than ADC, MD, tCho, K ep and K trans ( p < 0.05 ). Also, MK was shown to be more strongly correlated with histological grade, Ki-67 expression and lymph node status. MD, MK, age, shape and menstrual status were selected to be the optimized feature subsets to construct an XGboost model, which exhibited superior diagnostic ability for breast cancer characterization and an improved evaluation of suspicious breast tumors in MRI BiRADS 4., Conclusions: DKI is promising for breast cancer diagnosis and prognostic factor assessment. An optimized XGboost model that included DKI, age, shape and menstrual status is effective in improving the diagnostic accuracy of BiRADS 4 masses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tang, Zhou, Quan, Chen, Zhang, Lin and Wu.)

Background: Internet addiction (IA) is associated with adverse consequences, especially for younger people. Evidence indicates that IA is associated with depression, but no studies have yet investigated potential common vulnerability between them., Methods: IA (measured by the Young's 20-item Internet Addiction Test Scale) and depressive symptoms (measured by the Patient Health Questionnaire-9 Scale) among 12 043 undergraduates were surveyed at baseline and at a respective 12 month follow-up for each participant. Application of a cross-lagged panel model approach (CLPM) revealed an association between IA and depression after adjusting for demographic variables., Results: Rates of baseline IA and depression were 5.47% (95% CI: 5.07%, 5.88%) and 3.85% (95% CI: 3.51%, 4.20%), respectively; increasing to 9.47% (95% CI: 8.94%, 9.99%) and 5.58% (95% CI: 5.17%,5.99%), respectively, at follow-up. Rates of new-incidences of IA and depression over 12 months were 7.43% (95% CI: 6.95%, 7.91%) and 4.47% (95% CI: 4.09%, 4.84%), respectively. Models in the present analysis revealed that baseline depression had a significant net-predictive effect on follow-up IA, and baseline IA had a significant net-predictive effect on follow-up depression., Limitations: The follow-up survey response rate was moderate (54.69%) in this analysis of university students. Moreover, the IAT-20 scale did not allow differentiate between specific forms of Internet activity., Conclusions: Common vulnerability and bidirectional cross-causal effects may both contribute to the association between IA and depression, with common vulnerability likely playing a more significant role than cross-causal effects., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: The main aim of the present study was to establish whether mesenchymal stem cell microvesicles (MSC MVs) exert anti-fibrotic effects and investigate the mechanisms underlying these effects in a mouse model of acute respiratory distress syndrome (ARDS)-associated early pulmonary fibrosis., Methods: An ARDS-associated pulmonary fibrosis model was established in mice by an intratracheal injection of lipopolysaccharide (LPS). At 1, 3, and 7 days after LPS-mediated injury, the lungs of mice treated with MSC MVs and untreated controls were carefully excised and fibrosis was assessed based on the extent of collagen deposition. In addition, the development of epithelial-mesenchymal transition (EMT) was evaluated based on loss of E-cadherin and zona occludens-1 (ZO-1) along with the acquisition of α-smooth muscle actin (α-SMA) and N-cadherin. Nuclear translocation and β-catenin expression analyses were also used to evaluate activation of the Wnt/β-catenin signaling pathway., Results: Blue-stained collagen fibers were evident as early as 7 days after LPS injection. Treatment with MSC MVs suppressed pathological progression to a significant extent. MSC MVs markedly reversed the upregulation of N-cadherin and α-SMA and attenuated the downregulation of E-cadherin and ZO-1. The expression and nuclear translocation of β-catenin were clearly decreased on day 7 after MSC MV treatment., Conclusion: Analyses indicated that MSC MVs could ameliorate ARDS-associated early pulmonary fibrosis via the suppression of EMT and might be related to Wnt/β-catenin transition signaling., Competing Interests: The authors have no conflicts of interest to declare., (© 2022 Zhang et al.)

Objectives: The present study aimed to determine whether bone marrow mesenchymal stem cell-derived microvesicles (MSC MVs) were effective in restoring lung tissue structure, and to assess the potential role of miRNAs in the pathogenesis and progression of acute respiratory distress syndrome (ARDS)., Materials and Methods: ARDS was induced by lipopolysaccharide in male C57BL/6 mice. The degree of lung injury was assessed by histological analysis, lung's wet weight/body weight, and protein levels in the bronchoalveolar lavage fluid (BALF). Sequencing was performed on the BGISEQ-500 platform. Differentially expressed miRNAs (DEMs) were screened with the DEGseq software. The target genes of DEMs were predicted by iRNAhybrid, miRanda, and TargetScan., Results: Compared with LPS-injured mice, MSC MVs reduced lung water and total protein levels in the BALF, demonstrating a protective effect. 52 miRNAs were differentially expressed following treatment with MSC MVs in ARDS mice. Among them, miR-532-5p, miR-223-3p, and miR-744-5p were significantly regulated. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed the target genes were mainly located in the cell, organelle, and membrane. Furthermore, KEGG pathways such as ErbB, PI3K-Akt, Ras, MAPK, Toll, and Wnt signaling pathways were the most significant pathways enriched by the target genes., Conclusion: MSC MVs treatment was involved in alleviating lung injury and promoting lung tissue repair by dysregulated miRNAs.

According to statistics 2020, female breast cancer (BRCA) became the most commonly diagnosed malignancy worldwide. Prognosis of BRCA patients is still poor, especially in population with advanced or metastatic. Particular functions of each members of the solute carrier 35A (SLC35A) gene family in human BRCA are still unknown regardless of awareness that they play critical roles in tumorigenesis and progression. Using integrated bioinformatics analyses to identify therapeutic targets for specific cancers based on transcriptomics, proteomics, and high-throughput sequencing, we obtained new information and a better understanding of potential underlying molecular mechanisms. Leveraging BRCA dataset that belongs to The Cancer Genome Atlas (TCGA), which were employed to clarify SLC35A gene expression levels. Then we used a bioinformatics approach to investigate biological processes connected to SLC35A family genes in BRCA development. Beside that, the Kaplan-Meier estimator was leveraged to explore predictive values of SLC35A family genes in BCRA patients. Among individuals of this family gene, expression levels of SLC35A2 were substantially related to poor prognostic values, result from a hazard ratio of 1.3 (with 95 percent confidence interval (95% CI: 1.18-1.44), the p for trend (ptrend) is 3.1 × 10 -7 ). Furthermore, a functional enrichment analysis showed that SLC35A2 was correlated with hypoxia-inducible factor 1A (HIF1A), heat shock protein (HSP), E2 transcription factor (E2F), DNA damage, and cell cycle-related signaling. Infiltration levels observed in specific types of immune cell, especially the cluster of differentiation found on macrophages and neutrophils, were positively linked with SLC35A2 expression in multiple BRCA subclasses (luminal A, luminal B, basal, and human epidermal growth factor receptor 2). Collectively, SLC35A2 expression was associated with a lower recurrence-free survival rate, suggesting that it could be used as a biomarker in treating BRCA.

Importance: American Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions., Objective: To investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model., Design, Setting, and Participants: This prospective study, including a discovery cohort (the Strong Heart Study [SHS]) and 4 additional cohorts (the Women's Health Initiative [WHI], the Framingham Heart Study [FHS], the Atherosclerosis Risk in Communities Study ([ARIC]-Black, and ARIC-White), evaluated 12 American Indian communities in 4 US states; African American women, Hispanic women, and White women throughout the US; White men and White women from Massachusetts; and Black men and women and White men and women from 4 US communities. A total of 2321 men and women (mean [SD] follow-up, 19.1 [9.2] years) were included in the SHS, 1874 women (mean [SD] follow-up, 15.8 [5.9] years) in the WHI, 2128 men and women (mean [SD] follow-up, 7.7 [1.8] years) in the FHS, 2114 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-Black, and 931 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-White. Data were collected from May 1989 to December 2018 and analyzed from February 2019 to May 2021., Exposure: Blood DNA methylation., Main Outcome and Measure: Using a high-dimensional time-to-event elastic-net model for the association of 407 224 CpG sites with incident CHD in the SHS (749 events), this study selected the differentially methylated CpG positions (DMPs) selected in the SHS and evaluated them in the WHI (531 events), FHS (143 events), ARIC-Black (350 events), and ARIC-White (121 events) cohorts., Results: The median (IQR) age of participants in SHS was 55 (49-62) years, and 1359 participants (58.6%) were women. Elastic-net models selected 505 DMPs associated with incident CHD in the SHS beyond established risk factors, center, blood cell counts, and genetic principal components. Among those DMPs, 33 were commonly selected in 3 or 4 of the other cohorts and the pooled hazard ratios from the standard Cox models were significant at P < .05 for 10 of the DMPs. For example, the hazard ratio (95% CI) for CHD comparing the 90th and 10th percentiles of differentially methylated CpGs was 0.86 (0.78-0.95) for cg16604233 (tagged to COL11A2) and 1.23 (1.08-1.39) for cg09926486 (tagged to FRMD5). Some of the DMPs were consistent in the direction of the association; others showed associations in opposite directions across cohorts. Untargeted independent elastic-net models of CHD showed distinct DMPs, genes, and network of genes in the 5 cohorts., Conclusions and Relevance: In this multi-cohort study, blood-based DNAm findings supported an association between a complex blood epigenomic signature and CHD that was largely different across populations.