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Yan Xiao,1 Xin-Yue Yao,1 Yong-Hui Wang,1 Lan-Wen Han,1 Lian-Xia Li,1 Ming Li,2 Shan Gao3 1Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Endocrinology, Beijing Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Shan Gao, Department of Endocrinology, Beijing Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Xuanwu District, Beijing, 100053, People’s Republic of China, Tel +8613910599635, Email gaoshanmw@163.comPurpose: Type 2 diabetes mellitus (T2DM) is a common risk factor for cardiovascular disease which increases the risk of heart failure. This study aimed to determine whether clinical characteristics and subclinical cardiovascular disease (CVD) features are correlated with echocardiographic morpho-functional parameters of T2DM patients.Patients and Methods: Two hundred and fifty-five T2DM patients without a history of coronary heart disease were enrolled in this cross-sectional study. The demographic characteristics, glucose and lipid levels were assessed for each patient. Carotid ultrasonography and peripheral artery examination were performed to measure carotid intima-media thickness (cIMT), carotid plaque, ankle-brachial index (ABI), brachial artery pulse wave velocity (baPWV), and carotid-femoral pulse wave velocity (cfPWV). Furthermore, echocardiography was conducted to evaluate cardiac morphology and systolic and diastolic function. The relationship between clinical characteristics, subclinical cardiovascular diseases, and cardiac morpho-functional parameters was explored with the Pearson and stepwise multivariable linear regression analyses.Results: A total of 255 subjects aged 18– 80 years were enrolled in the study. Multiple regression analysis revealed that left ventricular mass index (LVMI) was correlated with age (β=0.463, p = 0.000) and systolic blood pressure (SBP) (β=0.179, p = 0.003). Relative wall thickness (RWT) was related to cfPWV (β=0.006, p = 0.007) and homeostasis model assessment of insulin resistance (HOMA-IR) (β=0.000, p = 0.036). In contrast, left ventricular ejection fraction (LVEF) was inversely related to cIMT (β=− 0.925, p = 0.019). The ratio of the peak flow velocity of early diastole to atrial contraction (peak E/A) was correlated with age (β=− 0.014, p = 0.000), diastolic blood pressure (DBP) (β=− 0.006, p = 0.001) and cfPWV (β=− 0.025, p = 0.044).Conclusion: In preclinical stage A/B heart failure adults with T2DM, age, BP, HOMA-IR, cfPWV and cIMT are correlated with cardiac morpho-functional parameters.Keywords: type 2 diabetes mellitus, preclinical stage A/B heart failure, subclinical cardiovascular diseases, echocardiography

Yu-Jie Wang,1,&ast; Chun-Hua Jin,2,&ast; Jiang-Feng Ke,1 Jun-Wei Wang,1 Yi-Lin Ma,1 Jun-Xi Lu,1 Mei-Fang Li,3 Lian-Xi Li1 1Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, People’s Republic of China; 2Department of Endocrinology and Metabolism, Shanghai Songjiang District Central Hospital, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Preparatory Stage), Shanghai, People’s Republic of China; 3Department of Emergency, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mei-Fang Li, Department of Emergency, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, People’s Republic of China, Tel +86 18930170426, Email 15821955054@126.com Lian-Xi Li, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, 600 Yishan Road, Shanghai, 200233, People’s Republic of China, Tel +86 21 64369181x58337, Email lilx@sjtu.edu.cnPurpose: The association between serum osteocalcin (OCN) levels and metabolic dysfunction-associated fatty liver disease (MAFLD) is still controversial. Moreover, few studies have explored their relationship in type 2 diabetes mellitus (T2DM) patients so far. The present study aimed to investigate the association of serum OCN levels with MAFLD in Chinese T2DM patients.Methods: This cross-sectional, real-world study included 1889 Chinese T2DM inpatients. MAFLD was diagnosed by abdominal ultrasonography. Participants were divided into four groups according to serum OCN quartiles, among which the clinical characteristics were compared. The association of serum OCN levels with the presence of MAFLD was also analyzed in subjects.Results: After controlling for sex, age, and diabetes duration, the prevalence of MAFLD significantly decreased across the serum OCN quartiles (55.3%, 52.0%, 48.6%, and 42.1% for the first, second, third, and fourth quartiles, respectively, P < 0.001 for trend). A fully adjusted multiple logistic regression analysis showed that serum OCN levels were independently and negatively associated with the presence of MAFLD in T2DM patients (odds ratio, 0.832; 95% confidence interval, 0.719– 0.962; P = 0.013). Furthermore, there were significant decreases in HOMA-IR (P = 0.001 for trend) and C-reactive protein (P < 0.001 for trend) levels across the serum OCN quartiles after controlling for sex, age, and diabetes duration.Conclusion: Serum OCN levels were independently and negatively associated with the presence of MAFLD in Chinese T2DM patients, partially due to the improvement of insulin resistance and inflammation mediated by OCN. Serum OCN may be used as a biomarker to assess the risk of MAFLD in T2DM patients.Keywords: diabetes mellitus, type 2, metabolic dysfunction-associated fatty liver disease, osteocalcin, insulin resistance, inflammation

Qian Zhao,&ast; Xue-Yu Sun,&ast; Shu-Qi Ma, Meng-Wei Miao, Gai-Ling Li, Jing-Lu Wang, Rui-Xia Guo, Liu-Xia Li Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rui-Xia GuoDepartment of Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1 of Jianshe Dong Street, Erqi District, Zhengzhou, 450000, People’s Republic of ChinaTel +86 13525569376Email guoruixia70@163.comObjective: This study aims to evaluate the clinical value of laparoscopic temporary internal iliac artery blockage (TIIAB) compared with uterine artery embolization (UAE) in type III cesarean scar pregnancy (CSP).Methods: A total of 76 patients with type III CSP admitted to the Department of Gynecology the First Affiliated Hospital of Zhengzhou University between September 2017 and June 2019 were selected for this retrospective study. Thirty-six of them in the study group received TIIAB, and the rest in control group received UAE. Laparoscopic pregnancy tissue was removed from all patients, and the uterine defects were repaired. The absence of remnants was then confirmed using ultrasonography. Follow-ups were performed in the two groups for six months, and the factors of intraoperative blood loss, operation and menelipsis time, 24-h human chorionic gonadotropin decline rate, postoperative complications, hospitalization days, hospitalization costs, peri-operative hormone levels, and ovarian function indicators were compared between the two groups and within each group.Results: There were statistically significant differences in the hospitalization cost, menelipsis time, and postoperative complication incidence between the two groups (p < 0.05). There were statistically significant differences between ovarian function at one month and three months after surgery (p < 0.05) as well as among the follicle-stimulating hormone, luteinizing hormone, and estradiol levels at one, three, and six months after surgery in the control group (p < 0.05).Conclusion: Compared with uterine artery embolization, laparoscopic TIIAB has the advantages of a low hospitalization cost, lower postoperative complication rate, and shorter menelipsis time. Moreover, it avoids ovarian function damage. It is a safe method worthy of clinical popularization.Keywords: type III cesarean scar pregnancy, laparoscopic internal iliac artery, occlusion, uterine artery embolization, ovarian function

Yang Hu,1 Peng Guo,1 Teng-Hong Lian,1 Li-Jun Zuo,1 Shu-Yang Yu,1 Li Liu,2 Zhao Jin,1 Qiu-Jin Yu,1 Rui-Dan Wang,1 Li-Xia Li,2 Ying-Shan Piao,3 Wei Zhang3– 7 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China; 2Department of Internal Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China; 3Center for Cognitive Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China; 4China National Clinical Research Center for Neurological Diseases, Beijing, 100070, People’s Republic of China; 5Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, People’s Republic of China; 6Center of Parkinson’s Disease, Beijing Institute for Brain Disorders, Beijing, 100053, People’s Republic of China; 7Beijing Key Laboratory on Parkinson’s Disease, Beijing, 100053, People’s Republic of ChinaCorrespondence: Wei ZhangCenter for Cognitive Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of ChinaTel +8613911996107Fax +86-10-59978429Email ttyyzw@163.comBackground: To investigate the clinical characteristics, iron metabolism and neuroinflammation in Parkinson’s disease (PD) patients with excessive daytime sleepiness (EDS).Methods: We studied 379 patients with PD and 30 age-matched controls. All subjects were evaluated by Epworth sleepiness scale (ESS) and a series of rating scales and were divided into PD-EDS and PD-NEDS groups according to ESS score. The concentrations of iron and iron-related proteins and inflammatory cytokines in both cerebrospinal fluid (CSF) and serum were examined.Results: 1. The occurrence rate of EDS in total PD patients was 16.09%. 2. PD-EDS group had significantly severer disease stages, more severe motor and non-motor features of the disease. 3. In CSF, the concentrations of iron and IL-1β in the PD-EDS group were significantly higher and ferritin concentration was prominently lower when compared with the PD-NEDS group and the control group; ESS score was significantly associated with high concentrations of iron and IL-1β and low concentration of ferritin in the PD group. Iron concentration was positively correlated with IL-1β concentration in the PD-EDS group. 4. In serum, no changes were observed in iron and iron-related proteins and inflammatory cytokines among the three groups.Conclusion: EDS was a common symptom in PD patients. PD patients with EDS had more severe motor and some non-motor symptoms. Overloaded iron-relevant inflammation in the brain might be an underlying mechanism of PD-EDS.Keywords: Parkinson disease, excessive daytime sleepiness, clinical features, iron metabolism, inflammation

Zhuo Li,1– 3,* La-Xiu Li,3,4,* Yan-Jun Diao,3 Juan Wang,3 Yun Ye,1,3 Xiao-Ke Hao2,3,5 1Department of Laboratory Medicine, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi 710077, People’s Republic of China; 2The National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi’an, Shaanxi 710069, People’s Republic of China; 3Department of Laboratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi 710032, People’s Republic of China; 4Department of Laboratory Medicine, Xi’an Fourth Hospital, Xi’an, Shaanxi 710004, People’s Republic of China; 5School of Medicine, Northwest University, Xi’an, Shaanxi 710069, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Ke HaoSchool of Medicine, Northwest University, Xi’an, Shaanxi 710069, People’s Republic of ChinaEmail haoxkg@126.comBackground: Novel and non-invasive biomarkers with higher sensitivity and specificity for the diagnosis of prostate cancer (PCa) is urgently needed. In this study, we used next-generation sequencing (NGS) to characterize the genome-wide exosomal miRNA expression profiling in urine specimens and explored the diagnostic potential of urinary exosomal miRNAs for PCa.Methods: Urinary exosomal microRNA expression profiling was performed by next-generation sequencing (NGS) and then validated by quantitative real-time PCR.Results: Significant downregulation of urinary exosomal miR-375 was observed in PCa patients compared with healthy controls, while the expression levels of urinary exosomal miR-451a, miR-486-3p and miR-486-5p were found to be significantly up-regulated in the PCa patients. Furthermore, the expression level of urinary exosomal miR-375 showed a significant correlation with the clinical T-stage and bone metastasis of patients with PCa (P< 0.05). Receiver operator characteristic curve demonstrated that the urinary exosomal miR-375, miR-451a, miR-486-3p and miR-486-5p levels can be used to differentiate PCa patients from healthy controls, with area under the curves (AUCs) of 0.788, 0.757, 0.704 and 0.796, respectively. The urinary exosomal miR-375 was found to be superior in discriminating between localized and metastatic PCa with an AUC of 0.806. Moreover, PCa patients can be distinguished from patients with benign prostatic hyperplasia by using a panel combining urinary exosomal miR-375 and miR-451a with an AUC of 0.726.Conclusion: These findings demonstrate that the urinary exosomal miRNAs can serve as novel and non-invasive biomarkers for diagnosing and predicting the progression of PCa.Keywords: prostate cancer, next-generation sequencing, urinary, exosomal miRNAs

Purpose: The purpose of this study was to assess the value of isocentric C-arm three-dimensional (Iso-C 3D) fluoroscopy for the insertion of an anterior odontoid screw. The results of the Iso-C 3D group were compared with that of an historic control group using conventional fluoroscopy.Methods: Twenty-nine patients diagnosed with type II or rostral-type III odontoid fractures were treated with a single anterior screw fixation in this study. The Iso-C 3D group included 13 patients and the other 16 patients were in the historic control group. All operations were performed by a single surgeon using standard procedure and manner. The clinical and radiographic results were recorded and compared between the two groups.Results: The fluoroscopy time in the Iso-C 3D group was 42.9 s as compared to 68.1 s in the control group (P < 0.01). The mean operative time was 91.5 min in the Iso-C 3D group when compared with 81.6 min in the control group (P = 0.20). The rate of bony fusion was 96.6% (28/29), the failure rate of reduction or fixation was 13.8% (7.7% in Iso-C 3D group; 18.8% in control group). The Smiley-Webster scale showed that 90% of patients achieved good or better outcomesConclusions: In conclusion, this technique can be safely extended to the treatment of technically difficult to treat spinal injuries and at the same time reduce total radiation exposure time both for the patient and the surgeon. [ABSTRACT FROM AUTHOR]

Sacral fractures with both transverse and bilateral vertical fracture components are by definition multiplanar fractures, and often present with spinopelvic instability and cauda equina deficits. The treatment is challenging. Between 2006 and 2009, we treated nine such patients at our trauma centre. There were six men and three women, with a mean age of 32.2 years. Preoperative neurologic deficits were noted in seven patients; four patients had complete cauda equina paralysis, and three patients had incomplete cauda equina syndrome. All patients were treated using lumbopelvic instrumented fixation without other devices for their multiplanar sacral fractures. Six patients who had neurological deficits and sacral canal compression underwent decompression laminectomy. The mean postoperative follow-up time was 21.7 months (range, 14-32 months). All fractures went on to union without loss of reduction or hardware failure. The mean Gibbons score improved from 3.5 preoperatively to 2.3 postoperatively among the patients who underwent decompression laminectomy. Eight out of nine patients had fair or better results based on radiographic criteria and the Majeed pelvic fracture outcome score. Our experience suggests lumbopelvic fixation can be used for the treatment of multiplanar sacral fractures with spinopelvic instability with a low rate of complications. Neurologic improvement can be expected, but whether surgical decompression results in substantially better neurologic recovery than conservative treatment remains uncertain. [ABSTRACT FROM AUTHOR]

Objectives: To explore the associations of parental smoking and alcohol consumption during the periconceptional period and their interactions with risk of congenital heart disease (CHD) in offspring., Methods: The parents of children with simple CHD aged 0 to 1 year ( n =683) were recruited as the case group, while the parents of healthy children aged 0 to 1 year ( n =740) served as the control group. A case-control study was conducted, and a questionnaire was used to collect information on perinatal exposures. After controlling for relevant confounding factors using multivariate logistic regression analysis and propensity score matching, the associations of parental smoking and alcohol consumption during the periconceptional period and their interactions with CHD were examined, as well as the cumulative effects of smoking and drinking on CHD risk., Results: Maternal active smoking ( OR =2.91, 95% CI : 1.60-5.30), passive smoking ( OR =1.94, 95% CI : 1.56-2.42), and alcohol consumption ( OR =2.59, 95% CI : 1.89-3.54), as well as paternal smoking ( OR =1.52; 95% CI : 1.22-1.90) and drinking ( OR =1.48, 95% CI : 1.19-1.84), were associated with an increased risk of CHD in offspring. There was no interaction between parental smoking and drinking behaviors during the periconceptional period concerning the risk of CHD in offspring ( P >0.05). The more parents' smoking and drinking behaviors during the perinatal pregnancy, the higher the risk of CHD in their offspring ( OR =1.50, 95% CI : 1.36-1.65)., Conclusions: Parental smoking and alcohol consumption during the periconceptional period are associated with the occurrence of CHD in offspring, and there is a cumulative effect on CHD risk, suggesting that reducing tobacco and alcohol exposure during the periconceptional period may lower the incidence of CHD.

Background: Amid growing emphasis from pharmaceutical companies, advocacy groups, and regulatory bodies for sharing of individual participant data, recent audits reveal limited sharing, particularly for high-revenue medicines. Therefore, this study aimed to assess the individual participant data-sharing eligibility of clinical trials supporting the Food and Drug Administration approval of the top 30 highest-revenue medicines for 2021., Methods: A cross-sectional analysis was conducted on 316 clinical trials supporting approval of the top 30 revenue-generating medicines of 2021. The study assessed whether these trials were eligible for individual participant data sharing, defined as being publicly listed on a data-sharing platform or confirmed by the trial sponsors as in scope for independent researcher individual participant data investigations. Information was gathered from various sources including ClinicalTrials.gov, the European Union Clinical Trials Register, and PubMed. Key factors such as the trial phase, completion dates, and the nature of the data-sharing process were also examined., Results: Of the 316 trials, 201 (64%) were confirmed eligible for sharing, meaning they were either publicly listed on a data-sharing platform or confirmed by the trial sponsors as in scope for independent researcher individual participant data investigations. A total of 102 (32%) were confirmed ineligible, and for 13 (4%), the sponsor indicated that a full research proposal would be required to determine eligibility. The analysis also revealed a higher rate of individual participant data sharing among companies that utilized independent platforms, such as Vivli, for managing their individual participant data-sharing process. Trials not marked as completed had significantly lower eligibility for individual participant data sharing., Conclusion: This study highlights that a substantial portion of trials for top revenue-generating medicines are eligible for individual participant data sharing. However, challenges persist, particularly for trials that are marked as ongoing and for trials where the sharing processes are managed internally by pharmaceutical companies. Data-sharing rates could be improved by adopting open-access individual participant data-sharing models or using independent platforms. Standardizing policies to facilitate immediate individual participant data availability for approved medicines is necessary., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.R and M.J.S. are recipients of investigator-initiated funding for research outside the scope of the current study from AstraZeneca, Boehringer Ingelheim, Pfizer, and Takeda. A.R. is a recipient of speaker fees from Boehringer Ingelheim and Genentech outside the scope of the current study. The author team have no other support, financial relationship, or other relationship activities that could appear to have influenced the submitted work.

Ethnopharmacological Relevance: Chuanminshen violaceum M. L. Sheh & R. H. Shan (CV) is used as a medicine with roots, which have the effects of benefiting the lungs, harmonizing the stomach, resolving phlegm and detoxifying. Polysaccharide is one of its main active components and has various pharmacological activities, but the structural characterization and pharmacological activities of polysaccharide from the stems and leaves parts of CV are still unclear., Aim of the Study: The aim of this study was to investigate the optimal extraction conditions for ultrasound-assisted extraction of polysaccharide from CV stems and leaves, and to carry out preliminary structural analyses, anti-inflammatory and antioxidant effects of the obtained polysaccharide and to elucidate the underlying mechanisms., Materials and Methods: The ultrasonic-assisted extraction of CV stems and leaves polysaccharides was carried out, and the response surface methodology (RSM) was used to optimize the extraction process to obtain CV polysaccharides (CVP) under the optimal conditions. Subsequently, we isolated and purified CVP to obtain the homogeneous polysaccharide CVP-AP-I, and evaluated the composition, molecular weight, and structural features of CVP-AP-I using a variety of technical methods. Finally, we tested the pharmacological activity of CVP-AP-Ⅰ in an LPS-induced model of oxidative stress and inflammation in intestinal porcine epithelial cells (IPEC-J2) and explored its possible mechanism of action., Results: The crude polysaccharide was obtained under optimal extraction conditions and subsequently isolated and purified to obtain CVP-AP-Ⅰ (35.34 kDa), and the structural characterization indicated that CVP-AP-Ⅰ was mainly composed of galactose, galactose, rhamnose and glucose, which was a typical pectic polysaccharide. In addition, CVP-AP-Ⅰ attenuates LPS-induced inflammation and oxidative stress by inhibiting the expression of pro-inflammatory factor genes and proteins and up-regulating the expression of antioxidant enzyme-related genes and proteins in IPEC-J2, by a mechanism related to the activation of the Nrf2/Keap1 signaling pathway., Conclusion: The results of this study suggest that the polysaccharide isolated from CV stems and leaves was a pectic polysaccharide with similar pharmacological activities as CV roots, exhibiting strong anti-inflammatory and antioxidant activities, suggesting that CV stems and leaves could possess the same traditional efficacy as CV roots, which is expected to be used in the treatment of intestinal diseases., Competing Interests: Declaration of competing interest 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 Elsevier B.V. All rights reserved.)

Rationale: The epidemiology and clinical impact of COVID-19-associated candidemia (CAC) remained uncertain, leaving gaps in understanding its prevalence, risk factors and outcomes., Methods: A systematic review and meta-analysis were conducted by searching PubMed, Embase and Scopus for reports of CAC prevalence, risk factors and clinical outcomes up to June 18, 2024. The generalised linear mixed model was employed to determine the prevalence and 95% confidence intervals (CIs). The risk factors and clinical outcomes were compared between patients with and without CAC using the inverse variance method., Results: From 81 studies encompassing 29 countries and involving 351,268 patients, the global prevalence of CAC was 4.33% (95% Cl, 3.16%-5.90%) in intensive care unit (ICU) patients. In ICUs, the pooled prevalence of CAC in high-income countries was significantly higher than that of lower-middle-income countries (5.99% [95% Cl, 4.24%-8.40%] vs. 2.23% [95% Cl, 1.06%-4.61%], p = 0.02). Resistant Candida species, including C. auris, C. glabrata (Nakaseomyces glabratus) and C. krusei (Pichia kudriavzveii), constituted 2% of ICU cases. The mortality rate for CAC was 68.40% (95% Cl, 61.86%-74.28%) among ICU patients. Several risk factors were associated with CAC, including antibiotic use, central venous catheter placement, dialysis, mechanical ventilation, tocilizumab, extracorporeal membrane oxygenation and total parenteral nutrition. Notably, the pooled odds ratio of tocilizumab was 2.59 (95% CI, 1.44-4.65)., Conclusions: The prevalence of CAC is substantial in the ICU setting, particularly in high-income countries. Several risk factors associated with CAC were identified, including several that are modifiable, offering the opportunity to mitigate the risk of CAC., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Receptor chromatography is an efficient analytical technique that combines the high separation ability of chromatography with the high specificity of receptors for drug recognition. In addition, this technique offers the advantages of active recognition, online separation, and convenient multidimensional target tracking. This strategy allows target active ingredients in complex systems, such as traditional Chinese medicines, to be efficiently screened and accurately identified. Furthermore, the interactions between ligands and immobilized proteins can be studied. To avoid a loss in function, receptor chromatography requires efficient, mild, and simple immobilization methods that do not damage the structure of the immobilized receptors. Improvements in the activity, stability, and ligand-recognition specificity of immobilized functional proteins can be achieved by selecting appropriate immobilization conditions. Notably, the protein immobilization method is not only closely related to the recognition ability of receptor chromatography but also determines the accuracy of the technique. Common methods for immobilizing functional proteins include physical adsorption, chemical reactions, biological affinity reactions, and click chemistry. Despite being easy to operate under mild reaction conditions, these methods have shortcomings, including poor reaction specificity and the necessity of using high-purity functional proteins to prepare chromatography columns. Maintaining the high activity of immobilized receptors and ensuring excellent identification and separation abilities are key challenges in the further development of receptor chromatography. In this work, these issues were addressed by introducing a specific bioorthogonal reaction involving haloalkane dehalogenase (Halo) and 6-chlorohexanoic acid for the immobilization of the α 1A -adrenergic receptor ( α 1A -AR). Specifically, Halo- α 1A -AR was immobilized on the surface of 6-chlorohexanoic acid-modified aminopropyl silica gel in one step. The stationary phase with immobilized Halo- α 1A -AR was characterized using scanning electron microscopy. Moreover, the activity of the Halo- α 1A -AR chromatographic column was evaluated using specific ligands (terazosin hydrochloride, phentolamine mesylate, tamsulosin hydrochloride, and urapidil) and nonspecific ligands (yohimbe and metoprolol) for α 1A -AR. Halo- α 1A -AR was successfully immobilized on the silica gel surface with good stability over 30 days, and the Halo- α 1A -AR chromatographic column exhibited good ligand-recognition activity. The nonlinear chromatography results indicated that prazosin hydrochloride, terazosin hydrochloride, and urapidil interacted with immobilized Halo- α 1A -AR through one type of binding site, with association constants of 3.85×10 5 , 5.00×10 5 , and 5.90×10 5 L/mol, respectively. In contrast, phentolamine mesylate and tamsulosin hydrochloride interacted with immobilized Halo- α 1A -AR through two types of binding site. The association constants with the high- and low-affinity binding sites were 3.12×10 6 and 6.01×10 5 L/mol, respectively, for phentolamine mesylate and 9.98×10 5 and 0.21×10 5 L/mol, respectively, for tamsulosin hydrochloride. Compared with the traditional carbonyldiimidazole method, the immobilization method developed in this work did not require receptor purification and thus minimized the loss of receptor activity. The affinity constants obtained with immobilized Halo- α 1A -AR were consistent with the values determined for receptor-ligand binding in solution, indicating that the Halo- α 1A -AR chromatography column is suitable for studying drug-protein interactions. This approach also provides a foundation for the efficient screening and accurate determination of target active ingredients in complex systems.

Mycobacterium tuberculosis (Mtb)-infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils to the lung is linked to increased bacterial burden and aggravated pathology in TB. The basis for the permissiveness of neutrophils for Mtb and the ability to be pathogenic in TB has been elusive. Here, we identified metabolic and functional features of neutrophils that contribute to their permissiveness in Mtb infection. Using single-cell metabolic and transcriptional analyses, we found that neutrophils in the Mtb-infected lung displayed elevated mitochondrial metabolism, which was largely attributed to the induction of activated neutrophils with enhanced metabolic activities. The activated neutrophil subpopulation was also identified in the lung granulomas from Mtb-infected non-human primates. Functionally, activated neutrophils harbored more viable bacteria and displayed enhanced lipid uptake and accumulation. Surprisingly, we found that interferon-γ promoted the activation of lung neutrophils during Mtb infection. Lastly, perturbation of lipid uptake pathways selectively compromised Mtb survival in activated neutrophils. These findings suggest that neutrophil heterogeneity and metabolic diversity are key to their permissiveness for Mtb and that metabolic pathways in neutrophils represent potential host-directed therapeutics in TB., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We explore the construction of gluing together an arbitrary number of spacetimes along a common interface. This provides a general tool to construct new gravitational backgrounds with multiple boundaries. We derive junction conditions across the interface, in both Einstein gravity and dilaton gravity, using two methods (1) by developing a geometrical technique of introducing an auxiliary reverse extension manifold and (2) by the variational principle. Our junction condition works for both spacelike and timelike interfaces. We illustrate applications of the junction conditions in Jackiw-Teitelboim gravity and analyze their constraints on the allowed dilaton profile. We further comment on the geometry of a web of spacetime in the presence of multiple interfaces and its resemblance to Feynman diagrams.

Gene regulatory network (GRNs) models provide mechanistic understanding of the gene regulations and interactions that control various aspects of cellular behaviors. While researchers have constructed GRNs to model specific sets of gene regulations or interactions, little work has been made to integrate or merge these models into larger, more comprehensive ones that could encompass more genes, and improve the accuracy of predicting biological processes. Here, we present a workflow for merging logical GRN models, which requires sequential steps including model standardization, reproducing, merging and evaluations, and demonstrate its application in acute myeloid leukemia (AML) study. We demonstrate the feasibility and benefits of model merging by integrating two pairs of published models. Our integrated models were able to retain similar accuracy of the original publications, while increasing the coverage and explainability of the biological system. This approach highlights the integration of logical models in advancing system biology and enhancing the understanding of complex diseases.

Objectives: To investigate how maternal MTR gene polymorphisms and their interactions with periconceptional folic acid supplementation are associated with the incidence of ventricular septal defects (VSD) in offspring., Methods: A case-control study was conducted, recruiting 426 mothers of infants with VSD under one year old and 740 mothers of age-matched healthy infants. A questionnaire survey collected data on maternal exposures, and blood samples were analyzed for genetic polymorphisms. Multivariable logistic regression analysis and inverse probability of treatment weighting were used to analyze the associations between genetic loci and VSD. Crossover analysis and logistic regression were utilized to examine the additive and multiplicative interactions between the loci and folic acid intake., Results: The CT and TT genotypes of the maternal MTR gene at rs6668344 increased the susceptibility of offspring to VSD ( P <0.05). The GC and CC genotypes at rs3768139, AG and GG at rs1050993, AT and TT at rs4659743, GG at rs3768142, and GT and TT at rs3820571 were associated with a decreased risk of VSD ( P <0.05). The variations at rs6668344 demonstrated an antagonistic multiplicative interaction with folic acid supplementation in relation to VSD ( P <0.05)., Conclusions: Maternal MTR gene polymorphisms significantly correlate with the incidence of VSD in offspring. Mothers with variations at rs6668344 can decrease the susceptibility to VSD in their offspring by supplementing with folic acid during the periconceptional period, suggesting the importance of periconceptional folic acid supplementation in genetically at-risk populations to prevent VSD in offspring.

Phytochemical study on the stems and leaves of Artocarpus tonkinensis led to the isolation of a new 2-arylbenzofuran, artocartone ( 1 ), as well as seven known 2-arylbenzofurans ( 2-8 ). The chemical structure of 1 was established by means of comprehensive spectroscopic analyses and the known compounds were determined by comparing their MS and NMR data with those reported data in literature. The antiproliferative activities of all isolates 1-8 against five human cancer cell lines: HL-60, SMMC-7721, A-375, MCF-7 and SW480 in vitro were evaluated. As a result, compounds 1- 8 displayed notable antiproliferative activities against various human cancer cell lines with IC 50 values in the range of 0.28 ± 0.05-26.89 ± 0.18 μM.

In the vanguard of neuromorphic engineering, we develop a paradigm of biocompatible polymer memcapacitors using a seamless solution process, unleashing comprehensive synaptic capabilities depending on both the stimulation form and history. Like the human brain to learn and adapt, the memcapacitors exhibit analogue-type and evolvable capacitance shifts that mirror the complex flexibility of synaptic strengthening and weakening. With increasing frequency and intensity of the stimulation, the memcapacitors demonstrate an evolution from short-term plasticity (STP) to long-term plasticity (LTP), and even to metaplasticity (MP) at a higher level. A physical picture, featuring the stimulus-controlled spatiotemporal ion redistribution in the polymer, elaborates the origin of the memcapacitive prowess and resultant versatile synaptic plasticity. The distinctive MP behavior endows the memcapacitors with a dynamic learning rate (LR), which is utilized in an artificial neural network. The superiority of implementing a dynamic LR compared with conventional practices of using constant LR shines light on the potential of the memcapacitors to exploit organic neuromorphic computing hardware.

Storage is an important process involved in the postharvest treatment of grain-oilseed and is necessary for maintaining high quality and ensuring the long-term supply of these commodities in the food industry. Proper storage practices help prevent spoilage, maintain nutritional value, and preserve marketable quality. It is of great interest for storage to investigate flow, heat and mass transfer processes, and quality change for optimizing the operation parameters and ensuring the quality of grain-oilseed. This review discusses the mathematical models developed and applied to describe the physical field, biological field, and quality change during the storage of grain-oilseed. The advantages, drawbacks, and industrial relevance of the existing mathematical models were also critically evaluated, and an organic system was constructed by correlating them. Finally, the future research trends of the mathematical models toward the development of multifield coupling models based on biological fields to control quality were presented to provide a reference for further directions on the application of numerical simulations in this area. Meanwhile, artificial intelligence (AI) can greatly enhance our understanding of the coupling relationships within grain-oilseed storage. AI's strengths in both qualitative and quantitative analysis, as well as its effectiveness, make it an invaluable tool for this purpose., (© 2024 Institute of Food Technologists®.)

Reduced feed intake in early lactation prompts increased fat mobilization to meet dairy cow energy needs for milk production. The increased lipolysis in cows presents significant health risks with unclear mechanisms. The objectives of our study were to compare the longitudinal profiles of metabolites and lipids of serum from high- and low-lipolysis cows. Forty multiparous Holstein dairy cows were enrolled in the retrospective study. Serum samples were collected on d 7 before expected calving, as well as on d 5, 7, 14, and 21 postpartum. Dairy cows were grouped according to mean serum nonesterified fatty acids on d 5 and 7 after parturition as low (<0.600 mmol/L; n = 8; LFM) and high (>0.750 mmol/L; n = 8; HFM), indicating fat mobilization during early lactation. Lactational performance and serum metabolic parameters related to glucose and lipid metabolism, liver functions, oxidative status, and inflammatory responses were determined. Serum samples were subjected to liquid chromatography-MS-based metabolomics and lipidomics. Despite differences in postpartum BW change, there were no observed variations in milk yield and composition between the 2 groups. Serum β-hydroxybutyric acid, glucose, leptin, aspartate aminotransferase, IL-6, and tumor necrosis factor alpha were greater in cows with HFM than in cows with LFM. Serum adiponectin, revised quantitative insulin sensitivity check index, and albumin were lower in cows with HFM than in cows with LFM. Intensified fat mobilization in the HFM cows came along with reduced estimated insulin sensitivity, impaired liver functions, and increased oxidative stress and inflammatory responses. Differences in metabolic patterns were observed across the transition period when comparing serum blood matrixes (e.g., in different amino acids, acylcarnitines, and sphingolipids). The serum metabolome of the HFM cows was characterized by higher concentrations of glycine, acylcarnitines, carnosine, Cer(d20:0/18:0), Cer(d18:1/16:0), and Cer(t18:0/24:0) compared with LFM cows. The differential serum metabolites and lipids at different sampling times during the peripartum period were enriched in the sphingolipid metabolism. Differences in serum metabolic status parameters suggest that cows adopt varied metabolic adaptation strategies to cope with energy deficits postpartum. Our investigation found a comprehensive remodeling of the serum metabolic profiles in transition dairy cattle, highlighting the significance of alterations in sphingolipid species, as they play a crucial role in insulin resistance and metabolic disorders., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

This systematic review and meta-analysis evaluated the risk factors for bronchopulmonary dysplasia associated pulmonary hypertension (BPD-PH) in extremely premature infants (gestational age < 32 weeks) and its impact on outcomes. A computerized search of eight databases was performed, from the time of library construction to February 2024. The quality of the included studies was assessed with the Newcastle‒Ottawa scale. Statistical analyses were performed using RevMan 5.4.1 and Stata 16.0 software. Meta-analysis of 2137 extremely premature infants revealed that oligohydramnios (OR = 2.21, 95% CI 1.06-4.61), low gestational age (SMD = -0.36, 95% CI -0.47 to -0.24), low birth weight (SMD = -0.54, 95% CI -0.74 to -0.35), small for gestational age (OR = 1.61, 95% CI 1.06-2.44), neonatal respiratory distress syndrome (OR = 2.05, 95% CI 1.45-2.91), grade III bronchopulmonary dysplasia (OR = 4.67, 95% CI 1.34-16.30), and sepsis (OR = 2.25, 95% CI 1.69-4.66) were risk factors for BPD-PH, whereas antenatal steroids (OR = 0.66, 95% CI 0.49-0.88) were protective factors. BPD-PH led to the extension of oxygen therapy (SMD = 0.67, 95% CI 0.42-0.92) and hospital stay (SMD = 0.77, 95% CI 0.14-1.40), and elevated the risk of discharged on oxygen (OR = 2.77, 95% CI 1.35-5.70) and death (OR = 4.38, 95% CI 2.21-8.69). BPD-PH is a multifactorial disease. In this study, a total of seven risk factors, and one protective factor for BPD-PH were identified in extremely premature infants. By managing and mitigating these factors, it is possible to decrease the occurrence of BPD-PH. Furthermore, BPD-PH may increase the risk of a poor prognosis in extremely premature infants., (© 2024 Wiley Periodicals LLC.)

Background: The introduction of direct-acting antivirals (DAA) has revolutionized hepatitis C virus (HCV) treatment but has not translated into an appreciable decline in HCV prevalence, which is estimated to be 2.4 million in the United States. Efforts are thought to be limited by the lack of experience among nonspecialist providers in managing HCV. However, there have been no comprehensive surveys assessing HCV knowledge among medical trainees to determine if trends have shifted since the discovery of DAAs., Methods: We performed a retrospective observational study of internal medicine (IM) residents in the United States ( n = 1763) who completed the Physician Education and Assessment Center HCV learning module between 2021 and 2022. Participant pre- and post-test performance was compared with further stratified analysis by training year, geography, training program type, and local HCV prevalence using ANOVA and Chi-squared tests of proportions, respectively., Results: IM residents universally lacked baseline HCV knowledge (average score ± standard deviation, 43% ± 19%); less than 50% of participants answered correctly in the majority of tested domains. There were no consistent trends in performance regardless of resident characteristic used to stratify the participants. Knowledge gaps improved after completing an online educational training module ( P < .001)., Conclusions: HCV knowledge remains limited among IM residents despite expansion of treatment options. Addressing these gaps during clinical training may substantially increase the availability of HCV treatment in the community, and online modules may be one means by which to integrate these efforts into medical training., Competing Interests: The author (Dr Megan E. Buresh) is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for AJMO and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Johns Hopkins University receives payments from subscriptions to the PEAC curriculum. M.E.B., S.D.S., and D.R. receive annual stipends for maintaining and updating modules. These are managed in accordance with JHU technology licensing and conflict of interest policies. None of the authors have any other conflicts of interest to declare., (© 2024 Published by Elsevier Inc.)

Objective: To evaluate the effect of insulin resistance (IR) on in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcomes in patients with polycystic ovary syndrome (PCOS)., Study Design: PubMed, Google Scholar,Web of Science, Embase, Scopus and the Cochrane Library were searched to identify relevant studies. A total of 6,137 PCOS women undergoing IVF/ICSI with or without IR were included in the systematic review and meta-analysis., Results: The systematic review and meta-analysis included twelve observational studies that were free from inherent bias. When comparing PCOS women undergoing IVF/ICSI, the IR and non-IR groups did not show significant differences in oocytes retrieved (WMD = -0.63, 95 % CI: -2.37 to 1.12, P = 0. 483), fertilization rate (WMD = 1.01, 95 % CI: -0.66 to 2.67, P = 0.236; OR = 0.97, 95 % CI: 0.79 to 1.19, P = 0.783), and live birth rate (OR = 1.02, 95 % CI: 0.78 to 1.33, P = 0.892). However, the group with IR had a lower number of MII oocytes (WMD = -1.07, 95 % CI: -1.54 to -0.59, P < 0.001), total embryos (WMD = -1.37, 95 % CI: -1. 78 to -0.95, P < 0.001), and clinical pregnancy rate (OR = 0.77, 95 % CI: 0.59 to 0.99, P = 0.042), as well as a higher miscarriage rate (OR = 1.11, 95 % CI: 1.02 to 1.22, P = 0.017) compared to the non-IR group., Conclusion: In women with PCOS, IR had a negative impact on IVF/ICSI outcomes. To obtain more favourable empirical support, larger studies are necessary., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alteration of DNA methylation leads to diverse diseases, and the dynamic changes of DNA methylation (DNAm) on sets of CpG dinucleotides in mammalian genomes are termed "DNAm age" and "epigenetic clocks" that can predict chronological age. However, whether and how dysregulation of DNA methylation promotes cyst progression and epigenetic age acceleration in autosomal dominant polycystic kidney disease (ADPKD) remains elusive. Here, we show that DNA methyltransferase 1 (DNMT1) is upregulated in cystic kidney epithelial cells and tissues and that knockout of Dnmt1 and targeting DNMT1 with hydralazine, a safe demethylating agent, delays cyst growth in Pkd1 mutant kidneys and extends life span of Pkd1 conditional knockout mice. With methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq), DNMT1 chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing analysis, we identified two novel DNMT1 targets, PTPRM and PTPN22 (members of the protein tyrosine phosphatase family). PTPRM and PTPN22 function as mediators of DNMT1 and the phosphorylation and activation of PKD-associated signaling pathways, including ERK, mTOR and STAT3. With whole-genome bisulfide sequencing in kidneys of patients with ADPKD versus normal individuals, we found that the methylation of epigenetic clock-associated genes was dysregulated, supporting that epigenetic age is accelerated in the kidneys of patients with ADPKD. Furthermore, five epigenetic clock-associated genes, including Hsd17b14, Itpkb, Mbnl1, Rassf5 and Plk2, were identified. Thus, the diverse biological roles of these five genes suggest that their methylation status may not only predict epigenetic age acceleration but also contribute to disease progression in ADPKD., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Metabolic abnormalities and immune inflammation are deeply involved in pulmonary vascular remodelling and the development of pulmonary hypertension (PH). However, the regulatory mechanisms of glycolysis in macrophages are still elusive. Cumulative evidence indicates that β-catenin plays a crucial role in metabolic reprogramming. This study aimed to investigate the effect of β-catenin on macrophage glycolysis in PH., Methods: LPS-induced BMDMs were generated via in vitro experiments. A monocrotaline (MCT)-induced PH rat model was established, and the β-catenin inhibitor XAV939 was administered in vivo. The role of β-catenin in glycolysis was analysed. The degree of pulmonary vascular remodelling was measured., Results: β-catenin was significantly increased in both in vitro and in vivo models. In LPS-induced BMDMs, β-catenin increased the levels of hexokinase 2 (HK2), phosphofructokinase (PFK), M2-pyruvate kinase (PKM2), lactate dehydrogenase (LDH), and lactate (LA) and the expression of inflammatory cytokines and promoted PASMC proliferation and migration in vitro. XAV939 decreased the level of glycolysis and downregulated the expression of inflammatory cytokines in vivo. MCT promoted pulmonary arterial structural remodelling and right ventricular hypertrophy, and XAV939 alleviated these changes., Conclusions: Our findings suggest that β-catenin is involved in the development of PH by promoting glycolysis and the inflammatory response in macrophages. Inhibition of β-catenin could improve the progression of PH., (© 2024. The Author(s).)

Solar-driven interfacial evaporation (SIE) is very promising to solve the issue of fresh water shortage, however, poor salt resistance severely hinders long-term stable SIE and fresh water collection. Here, we report design of superhydrophilic solar evaporators for long-term stable desalination, fresh water collection and salt collection by vertical salt deposition. The evaporators are prepared by sequentially deposition of silicone nanofilaments, polypyrrole and Au nanoparticles on a polyester fabric composed of microfibers. The evaporators feature excellent photothermal effect and ultrafast water transport, due to their unique micro-/nanostructure and superhydrophilicity. As a result, during SIE the salt gradually deposits vertically rather than occupies larger area on the evaporators. Consequently, long-term stable SIE with high evaporation rates of 2.4-2.1 kg m -2  h -1 for 3.5-20 wt % brine in continuous 10 h is achieved under 1 sun illumination. Meanwhile, the loosely deposited salt can be easily collected, realizing zero brine discharge. Moreover, scalable preparation of the evaporator is achieved, which exhibits efficient collection of high quality fresh water (10.08 kg m -2 in 8 h) via SIE desalination under weak natural sunlight (0.46~0.66 sun). This strategy sheds a new light on the design of high-performance solar evaporators and their real-world fresh water collection., (© 2024 Wiley-VCH GmbH.)

Background: To investigate the association of serum bilirubin within normal range, especially unconjugated bilirubin (UCB), with diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM)., Methods: In this cross-sectional, real-world study, 7617 T2DM patients were stratified into quartiles based on serum UCB levels. DR was determined by digital fundus photography and further classified into non-proliferative diabetic retinopathy (NPDR) and PDR. The associations of serum bilirubin levels and UCB quartiles with DR were investigated by logistic regression analysis., Results: After controlling for age, sex, and diabetes duration, the DR prevalence was significantly decreased across the serum UCB quartiles (40.4 %, 33.4 %, 29.7 %, 26.6 % for each quartile, respectively, p < 0.001 for trend). The subjects with DR had lower serum total bilirubin (TB) and UCB, rather than conjugated bilirubin (CB), compared with those without DR (p = 0.003 for TB, p < 0.001 for UCB, and p = 0.528 for CB, respectively), while all three types of serum bilirubin in the subjects with PDR were obviously lower than those with NPDR (p = 0.006 for TB, and p < 0.001 for UCB and CB, respectively). After adjustment for confounding factors, logistic regression demonstrated negative associations of serum TB and UCB levels, rather than CB, with the presence of DR (OR: 0.844, 95%CI: 0.774-0.920, p < 0.001 for TB; OR: 0.828, 95%CI: 0.763-0.899, p < 0.001 for UCB; and OR: 0.984, 95%CI: 0.900-1.074, p = 0.713 for CB, respectively). Additionally, a fully-adjusted analysis revealed a negative correlation between UCB quartiles and DR (p < 0.001)., Conclusion: High-normal serum TB and UCB were closely associated with the decreased odds of DR, while all types of serum bilirubin were negatively correlated with the severity of DR in T2DM patients. Serum bilirubin may be used as a potential indicator to assess the risk and severity of DR in T2DM., Competing Interests: 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., (© 2024 Published by Elsevier Ltd.)