Search

In the burgeoning realm of cryptocurrency, social media platforms like Twitter have become pivotal in influencing market trends and investor sentiments. In our study, we leverage GPT-4 and a fine-tuned transformer-based BERT model for a multimodal sentiment analysis, focusing on the impact of emoji sentiment on cryptocurrency markets. By translating emojis into quantifiable sentiment data, we correlate these insights with key market indicators such as BTC Price and the VCRIX index. Our architecture’s analysis of emoji sentiment demonstrated a distinct advantage over FinBERT’s pure text sentiment analysis in such predicting power. This approach may be fed into the development of trading strategies aimed at utilizing social media elements to identify and forecast market trends. Crucially, our findings suggest that strategies based on emoji sentiment can facilitate the avoidance of significant market downturns and contribute to the stabilization of returns. This research underscores the practical benefits of integrating advanced AI-driven analyzes into financial strategies, offering a nuanced perspective on the interaction between digital communication and market dynamics in an academic context.

Abstract Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population influenced by immunosenescence, are more susceptible to sepsis and have a worse prognosis. However, the immunopathogenic mechanisms underlying sepsis in elderly patients remain unclear. Here, we performed single-cell RNA sequencing of peripheral blood samples from young and old subjects and patients with sepsis. By exploring the transcriptional profiles of immune cells, we analyzed immune cell compositions, phenotype shifts, expression heterogeneities, and intercellular communication. In elderly patients with sepsis, innate immune cells (e.g., monocytes and DCs) exhibit decreased antigen presentation, presenting an overactive inflammatory and senescent phenotype. However, the immunophenotype of T cells shifted to characterize effector, memory, and exhaustion. Moreover, we identified strong interferon-γ responses of T cells in both aging and sepsis groups and a deranged inflammaging status in elderly sepsis patients. Tregs in elderly patients with sepsis showed increased abundance and enhanced immunosuppressive effects. In addition, metabolism-associated pathways were upregulated in T cells in elderly patients with sepsis, and the lysine metabolism pathway was enriched in Tregs. Cell–cell interaction analysis showed that the expression profile of ligand-receptor pairs was probably associated with aggravated immune dysfunction in elderly patients with sepsis. A novel HLA-KIR interaction was observed between Tregs and CD8 + T cells. These findings illustrate the immunological hallmarks of sepsis in elderly patients, and highlight that immunosuppressive and metabolic regulatory pathways may undergo important alterations in elderly patients with sepsis.

Abstract Background Aberrant Derlin-1 (DERL1) expression is associated with an overactivation of p-AKT, whose involvement in breast cancer (BRCA) development has been widely speculated. However, the precise mechanism that links DERL1 expression and AKT activation is less well-studied. Methods Bioinformatic analyses hold a promising approach by which to detect genes’ expression levels and their association with disease prognoses in patients. In the present work, a dual-luciferase assay was employed to investigate the relationship between DERL1 expression and the candidate miRNA by both in vitro and in vivo methods. Further in-depth studies involving immunoprecipitation-mass spectrum (IP-MS), co-immunoprecipitation (Co-IP), as well as Zdock prediction were performed. Results Overexpression of DERL1 was detected in all phenotypes of BRCA, and its knockdown showed an inhibitory effect on BRCA cells both in vitro and in vivo. The Cancer Genome Atlas (TCGA) database reported that DERL1 overexpression was correlated with poor overall survival in BRCA cases, and so the quantification of DERL1 expression could be a potential marker for the clinical diagnosis of BRCA. On the other hand, miR-181c-5p was downregulated in BRCA, suggesting that its overexpression could be a potent therapeutic route to improve the overall survival of BRCA cases. Prior bioinformatic analyses indicated a somewhat positive correlation between DERL1 and TRAF6 as well as between TRAF6 and AKT, but not between miR-181c-5p and DERL1. In retrospect, DERL1 overexpression promoted p-AKT activation through K63 ubiquitination. DERL1 was believed to directly interact with the E3 ligase TRAF6. As Tyr77Ala or Tyr77Ala/Gln81Ala/Arg85Ala/Val158Ala attempts to prevent the interaction between DERL1 and TRAF domain of TRAF6, resulted in a significant reduction in K63-ubiquitinated p-AKT production. However, mutations in Gln81Ala, Arg85Ala, or Val158Ala could possibly interrupt with these processes. Conclusions Our data confirm that mediation of the miR-181c-5p/DERL1 pathway by TRAF6-linked AKT K63 ubiquitination holds one of the clues to set our focus on toward meeting the therapeutic goals of BRCA.

Regeneration of adsorption saturated activated carbon by traditional electrochemical technology has the advantages of high regeneration efficiency and no mass loss of activated carbon, but it has defects such as low mineralization efficiency, generation of toxic by-products, and high energy consumption. Electrochemical advanced oxidation(E-AOP) regeneration technology can effectively overcome the problems of traditional electrochemical regeneration. In this paper, the regeneration efficiency and mechanism of activated carbon by traditional electrochemical are briefly described, and the effects of operating parameters (current, electrolyte type and concentration, regeneration location,anode material, etc.) on the desorption-adsorption balance and the mineralization efficiency of pollutants are analyzed. The mechanism and application of three types of E-AOP regeneration technologies(electro-Fenton regeneration, electro-peroxone regeneration, and electro-persulfate regeneration) in the process of activated carbon regeneration are summarized. The electric-Fenton regeneration technology has better regeneration effect, and the problem of metal ion pollution in the system can be effectively overcome by new regeneration. The electro-peroxone regeneration technology does not require the addition of any chemicals and catalysts, which is conducive to the control of reaction conditions and automation of the regeneration process. The electro-persulfate regeneration technology is convenient in operation with low energy consumption and wide applicability. Finally, the problems and development prospects of E-AOP regeneration technology are proposed. This review provides theoretical basis for the development of new efficient and environmentally friendly activated carbon regeneration technologies.

Abstract Deep Brain Stimulation can improve tremor, bradykinesia, rigidity, and axial symptoms in patients with Parkinson’s disease. Potentially, improving each symptom may require stimulation of different white matter tracts. Here, we study a large cohort of patients (N = 237 from five centers) to identify tracts associated with improvements in each of the four symptom domains. Tremor improvements were associated with stimulation of tracts connected to primary motor cortex and cerebellum. In contrast, axial symptoms are associated with stimulation of tracts connected to the supplementary motor cortex and brainstem. Bradykinesia and rigidity improvements are associated with the stimulation of tracts connected to the supplementary motor and premotor cortices, respectively. We introduce an algorithm that uses these symptom-response tracts to suggest optimal stimulation parameters for DBS based on individual patient’s symptom profiles. Application of the algorithm illustrates that our symptom-tract library may bear potential in personalizing stimulation treatment based on the symptoms that are most burdensome in an individual patient.

Abstract Background Ruptured atherosclerotic plaques often precipitate severe ischemic events, such as stroke and myocardial infarction. Unraveling the intricate molecular mechanisms governing vascular smooth muscle cell (VSMC) behavior in plaque stabilization remains a formidable challenge. Methods In this study, we leveraged single-cell and transcriptomic datasets from atherosclerotic plaques retrieved from the gene expression omnibus (GEO) database. Employing a combination of single-cell population differential analysis, weighted gene co-expression network analysis (WGCNA), and transcriptome differential analysis techniques, we identified specific genes steering the transformation of VSMCs in atherosclerotic plaques. Diagnostic models were developed and validated through gene intersection, utilizing the least absolute shrinkage and selection operator (LASSO) and random forest (RF) methods. Nomograms for plaque assessment were constructed. Tissue localization and expression validation were performed on specimens from animal models, utilizing immunofluorescence co-localization, western blot, and reverse-transcription quantitative-polymerase chain reaction (RT-qPCR). Various online databases were harnessed to predict transcription factors (TFs) and their interacting compounds, with determination of the cell-specific localization of TF expression using single-cell data. Results Following rigorous quality control procedures, we obtained a total of 40,953 cells, with 6,261 representing VSMCs. The VSMC population was subsequently clustered into 5 distinct subpopulations. Analyzing inter-subpopulation cellular communication, we focused on the SMC2 and SMC5 subpopulations. Single-cell subpopulation and WGCNA analyses revealed significant module enrichments, notably in collagen-containing extracellular matrix and cell-substrate junctions. Insulin-like growth factor binding protein 4 (IGFBP4), apolipoprotein E (APOE), and cathepsin C (CTSC) were identified as potential diagnostic markers for early and advanced plaques. Notably, gene expression pattern analysis suggested that IGFBP4 might serve as a protective gene, a hypothesis validated through tissue localization and expression analysis. Finally, we predicted TFs capable of binding to IGFBP4, with Krüppel-like family 15 (KLF15) emerging as a prominent candidate showing relative specificity within smooth muscle cells. Predictions about compounds associated with affecting KLF15 expression were also made. Conclusion Our study established a plaque diagnostic and assessment model and analyzed the molecular interaction mechanisms of smooth muscle cells within plaques. Further analysis revealed that the transcription factor KLF15 may regulate the biological behaviors of smooth muscle cells through the KLF15/IGFBP4 axis, thereby influencing the stability of advanced plaques via modulation of the PI3K-AKT signaling pathway. This could potentially serve as a target for plaque stability assessment and therapy, thus driving advancements in the management and treatment of atherosclerotic plaques.

Aims: To investigate the effects of senescent osteocytes on bone homeostasis in the progress of age-related osteoporosis and explore the underlying mechanism. Methods: In a series of in vitro experiments, we used tert-Butyl hydroperoxide (TBHP) to induce senescence of MLO-Y4 cells successfully, and collected conditioned medium (CM) and senescent MLO-Y4 cell-derived exosomes, which were then applied to MC3T3-E1 cells, separately, to evaluate their effects on osteogenic differentiation. Furthermore, we identified differentially expressed microRNAs (miRNAs) between exosomes from senescent and normal MLO-Y4 cells by high-throughput RNA sequencing. Based on the key miRNAs that were discovered, the underlying mechanism by which senescent osteocytes regulate osteogenic differentiation was explored. Lastly, in the in vivo experiments, the effects of senescent MLO-Y4 cell-derived exosomes on age-related bone loss were evaluated in male SAMP6 mice, which excluded the effects of oestrogen, and the underlying mechanism was confirmed. Results: The CM and exosomes collected from senescent MLO-Y4 cells inhibited osteogenic differentiation of MC3T3-E1 cells. RNA sequencing detected significantly lower expression of miR-494-3p in senescent MLO-Y4 cell-derived exosomes compared with normal exosomes. The upregulation of exosomal miR-494-3p by miRNA mimics attenuated the effects of senescent MLO-Y4 cell-derived exosomes on osteogenic differentiation. Luciferase reporter assay demonstrated that miR-494-3p targeted phosphatase and tensin homolog (PTEN), which is a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overexpression of PTEN or inhibition of the PI3K/AKT pathway blocked the functions of exosomal miR-494-3p. In SAMP6 mice, senescent MLO-Y4 cell-derived exosomes accelerated bone loss, which was rescued by upregulation of exosomal miR-494-3p. Conclusion: Reduced expression of miR-494-3p in senescent osteocyte-derived exosomes inhibits osteogenic differentiation and accelerates age-related bone loss via PTEN/PI3K/AKT pathway. Cite this article: Bone Joint Res 2024;13(2):52–65.

Abstract Targeting C5aR1 modulates the function of infiltrated immune cells including tumor-associated macrophages (TAMs). The gut microbiome plays a pivotal role in colorectal cancer (CRC) tumorigenesis and development through TAM education. However, whether and how the gut flora is involved in C5aR1 inhibition-mediated TAMs remains unclear. Therefore, in this study, genetic deletion of C5ar1 or pharmacological inhibition of C5aR1 with anti-C5aR1 Ab or PMX-53 in the presence or absence of deletion Abs were utilized to verify if and how C5aR1 inhibition regulated TAMs polarization via affecting gut microbiota composition. We found that the therapeutic effects of C5aR1 inhibition on CRC benefited from programming of TAMs toward M1 polarization via driving AKT2-mediated 6-phosphofructokinase muscle type (PFKM) stabilization in a TLR5-dependent manner. Of note, in the further study, we found that C5aR1 inhibition elevated the concentration of serum IL-22 and the mRNA levels of its downstream target genes encoded antimicrobial peptides (AMPs), leading to gut microbiota modulation and flagellin releasement, which contributed to M1 polarization. Our data revealed that high levels of C5aR1 in TAMs predicted poor prognosis. In summary, our study suggested that C5aR1 inhibition reduced CRC growth via resetting M1 by AKT2 activation-mediated PFKM stabilization in a TLR5-dependent manner, which relied on IL-22-regulated gut flora.

Abstract. Background:. A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI. Methods:. In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints. Results:. From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA (n = 384) or rt-PA (n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a -15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: -3.4%; 95% confidence interval [CI]: -11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: -0.5%; 95% CI: -5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups. Conclusion:. rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI. Trial registration:. www.ClinicalTrials.gov (No. NCT02835534).

Summary: Background: Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment. Methods: Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader). Findings: We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation in vitro and in vivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application. Interpretation: This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer. Funding: This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.

Summary: Background: Previous trials of renal denervation (RDN) have been designed to investigate reduction of blood pressure (BP) as the primary efficacy endpoint using non-selective RDN without intraoperatively verified RDN success. It is an unmet clinical need to map renal nerves, selectively denervate renal sympathetic nerves, provide readouts for the interventionalists and avoid futile RDN. We aimed to examine the safety and efficacy of renal nerve mapping/selective renal denervation (msRDN) in patients with uncontrolled hypertension (HTN) and determine whether antihypertensive drug burden is reduced while office systolic BP (OSBP) is controlled to target level (＜140 mmHg). Methods: We conducted a randomized, prospective, multicenter, single-blinded, sham-controlled trial. The study combined two efficacy endpoints at 6 months as primary outcomes: The control rate of patients with OSBP ＜140 mmHg (non-inferior outcome) and change in the composite index of antihypertensive drugs (Drug Index) in the treatment versus Sham group (superior outcome). This design avoids confounding from excess drug-taking in the Sham group. Antihypertensive drug burden was assessed by a composite index constructed as: Class N (number of classes of antihypertensive drugs) × (sum of doses). 15 hospitals in China participated in the study and 220 patients were enrolled in a 1:1 ratio (msRDN vs Sham). The key inclusion criteria included: age (18–65 years old), history of essential HTN (at least 6 months), heart rate (≥70 bpm), OSBP (≥150 mmHg and ≤180 mmHg), ambulatory BP monitoring (ABPM, 24-h SBP ≥130 mmHg or daytime SBP ≥135 mmHg or nighttime SBP ≥120 mmHg), renal artery stenosis (＜50%) and renal function (eGFR ＞45 mL/min/1.73 m2). The catheter with both stimulation and ablation functions was inserted in the distal renal main artery. The RDN site (hot spot) was selected if SBP increased (≥5 mmHg) by intra-renal artery (RA) electrical stimulation; an adequate RDN was confirmed by repeated electronic stimulation if no increase in BP otherwise, a 2nd ablation was performed at the same site. At sites where there was decreased SBP (≥5 mmHg, cold spot) or no BP response (neutral spot) to stimulation, no ablation was performed. The mapping, ablation and confirmation procedure was repeated until the entire renal main artery had been tested then either treated or avoided. After msRDN, patients had to follow a predefined, vigorous drug titration regimen in order to achieve target OSBP (＜140 mmHg). Drug adherence was monitored by liquid chromatography-tandem mass spectrometry analysis using urine. This study is registered with ClinicalTrials.gov (NCT02761811) and 5-year follow-up is ongoing. Findings: Between July 8, 2016 and February 23, 2022, 611 patients were consented, 220 patients were enrolled in the study who received standardized antihypertensive drug treatments (at least two drugs) for at least 28 days, presented OSBP ≥150 mmHg and ≤180 mmHg and met all inclusion and exclusion criteria. In left RA and right RA, mapped sites were 8.2 (3.0) and 8.0 (2.7), hot/ablated sites were 3.7 (1.4) and 4.0 (1.6), cold spots were 2.4 (2.6) and 2.0 (2.2), neutral spots were 2.0 (2.1) and 2.0 (2.1), respectively. Hot, cold and neutral spots was 48.0%, 27.5% and 24.4% of total mapped sites, respectively. At 6 M, the Control Rate of OSBP was comparable between msRDN and Sham group (95.4% vs 92.8%, p = 0.429), achieved non-inferiority margin −10% (2.69%; 95% CI −4.11%, 9.83%, p ＜ 0.001 for non-inferiority); the change in Drug Index was significantly lower in msRDN group compared to Sham group (4.37 (6.65) vs 7.61 (10.31), p = 0.010) and superior to Sham group (−3.25; 95% CI −5.56, −0.94, p = 0.003), indicating msRDN patients need significantly fewer drugs to control OSBP ＜140 mmHg. 24-hour ambulatory SBP decreased from 146.8 (13.9) mmHg by 10.8 (14.1) mmHg, and from 149.8 (12.8) mmHg by 10.0 (14.0) mmHg in msRDN and Sham groups, respectively (p 0.05 between groups). Safety profiles were comparable between msRDN and Sham groups, demonstrating the safety and efficacy of renal mapping/selective RDN to treat uncontrolled HTN. Interpretation: The msRDN therapy achieved the goals of reducing the drug burden of HTN patients and controlling OSBP

Summary: Background: Endovascular therapy (EVT) was demonstrated effective in acute large vessel occlusion (LVO) with large infarction. Revealing subgroups of patients who would or would not benefit from EVT will further inform patient selection for EVT. Methods: This post-hoc analysis of the ANGEL-ASPECT trial, a randomised controlled trial of 456 adult patients with acute anterior-circulation LVO and large infarction, defined by ASPECTS 3–5 or infarct core volume 70–100 mL, enrolled from 46 centres across China, between October 2, 2020 and May 18, 2022. Patients were randomly assigned (1:1) to receiving EVT and medical management or medical management alone. One patient withdrew consent, 455 patients were included in this post-hoc analysis and categorised into 4 subgroups by lower or higher NIHSS (< or ≥16) and smaller or larger infarct core (< or ≥70 mL). Those with lower NIHSS & smaller core, and higher NIHSS & larger core were considered clinical-radiological matched subgroups; otherwise clinical-radiological mismatched subgroups. Primary outcome was 90-day modified Rankin Scale (mRS). ANGEL-ASPECT is registered with ClinicalTrials.gov, NCT04551664. Findings: Overall, 139 (30.5%) patients had lower NIHSS & smaller core, 106 (23.3%) higher NIHSS & larger core, 130 (28.6%) higher NIHSS & smaller core, and 80 (17.6%) lower NIHSS & larger core. There was significant ordinal shift in the 90-day mRS toward a better outcome with EVT in clinical-radiological matched subgroups: lower NIHSS & smaller core (generalised OR, 1.76; 95% CI, 1.18–2.62; p = 0.01) and higher NIHSS & larger core (1.64; 1.06–2.54; 0.01); but not in the two clinical-radiological mismatched subgroups. Interpretation: Our findings suggested that in patients with anterior-circulation LVO and large infarction, EVT was associated with improved 90-day functional outcomes in those with matched clinical and radiological severities, but not in those with mismatched clinical and radiological severities. Simultaneous consideration of stroke severity and infarct core volume may inform patient selection for EVT. Funding: Unrestricted grants from industry [Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology].

Abstract Purpose In this study, we aimed to investigate the effects of postoperative malrotation alignment on the outcomes of Gartland type III/IV paediatric supracondylar humeral fracture (SCHF) treated by close reduction and percutaneous K-wire fixation. Methods Between January 2014 and December 2021, 295 Gartland type III/IV paediatric SCHFs treated by close reduction and percutaneous K-wire fixation were selected for this retrospective study. The demographic, clinical and radiographic parameters of all cases were collected. The lateral rotation percentage (LRP) was measured on X-rays to evaluate postoperative malrotation alignment of the fracture. All cases were categorized into 4 groups according to LRP: LRP ≤ 10% (210, 71.2%), 10% 30% (18, 6.1%). The carrying angle, ranges of multidirectional motions, Mayo Elbow Performance Score (MEPS) and Flynn’s Standard Score (FSS) of the injured elbow were assessed 6 months postoperation and compared among different groups. ROC analysis based on LRP and the excellent/good rate of FSS was performed to determine the acceptable maximum degree of postoperative malrotation alignment. Results There was no difference in the demographic characteristics (age, sex, injured side and fracture type), postoperative Baumann angle, carrying angle or range of forearm rotation among the 4 groups (P > 0.05). The operation time and time from operation to K-wire removal were longer in the 20% 30% groups than in the LRP 30% groups than in the LRP

Abstract Background Severe acute respiratory syndrome coronavirus 2 will coexist with humans for a long time, and it is therefore important to develop effective treatments for coronavirus disease 2019 (COVID-19). Recent studies have demonstrated that antiviral therapy is a key factor in preventing patients from progressing to severe disease, even death. Effective and affordable antiviral medications are essential for disease treatment and are urgently needed. Azvudine, a nucleoside analogue, is a potential low-cost candidate with few drug interactions. However, validation of high-quality clinical studies is still limited. Methods This is a multicentre, randomized, double-blind, placebo-controlled phase III clinical trial involving 1096 adult patients with mild-to-moderate symptoms of COVID-19 who are at high risk for progression to severe COVID-19. Patients will be randomized to (1) receive azvudine tablets 5 mg daily for a maximum of 7 days or (2) receive placebo five tablets daily. All participants will be permitted to use a standard treatment strategy except antiviral therapy beyond the investigational medications. The primary outcome will be the ratio of COVID-19-related critical illness and all-cause mortality among the two groups within 28 days. Discussion The purpose of this clinical trial is to determine whether azvudine can prevent patients at risk of severe disease from progressing to critical illness and death, and the results will identify whether azvudine is an effective and affordable antiviral treatment option for COVID-19. Trial registration ClinicalTrials.gov NCT05689034. Registered on 18 January 2023.

Abstract Background Alamandine is a newly characterized peptide of renin angiotensin system. Our study aims to investigate the osteo-preservative effects of alamandine, explore underlying mechanism and bring a potential preventive strategy for postmenopausal osteoporosis in the future. Methods An ovariectomy (OVX)-induced rat osteoporosis model was established for in vivo experiments. Micro-computed tomography and three-point bending test were used to evaluate bone strength. Histological femur slices were processed for immunohistochemistry (IHC). Bone turnover markers and nitric oxide (NO) concentrations in serum were determined with enzyme-linked immunosorbent assay (ELISA). The mouse embryo osteoblast precursor (MC3T3-E1) cells were used for in vitro experiments. The cell viability was analysed with a Cell Counting Kit‑8. We performed Alizarin Red S staining and alkaline phosphatase (ALP) activity assay to observe the differentiation status of osteoblasts. Western blotting was adopted to detect the expression of osteogenesis related proteins and AMP-activated protein kinase/endothelial nitric oxide synthase (AMPK/eNOS) in osteoblasts. DAF-FM diacetate was used for semi-quantitation of intracellular NO. Results In OVX rats, alamandine alleviated osteoporosis and maintained bone strength. The IHC showed alamandine increased osteocalcin and collagen type I α1 (COL1A1) expression. The ELISA revealed alamandine decreased bone turnover markers and restored NO level in serum. In MC3T3-E1 cells, alamandine promoted osteogenic differentiation. Western blotting demonstrated that alamandine upregulated the expression of osteopontin, Runt-related transcription factor 2 and COL1A1. The intracellular NO was also raised by alamandine. Additionally, the activation of AMPK/eNOS axis mediated the effects of alamandine on MC3T3-E1 cells and bone tissue. PD123319 and dorsomorphin could repress the regulating effect of alamandine on bone metabolism. Conclusion Alamandine attenuates ovariectomy-induced osteoporosis by promoting osteogenic differentiation via AMPK/eNOS axis.

The development of diabetes mellitus is highly associated with the poor lifestyle habits. The Traditional Chinese Medicine life nurturing plays a crucial role in prevention and control of diabetes mellitus. In perspectives of emotion, dietary, exercise and routine management, this paper summarized the application of Traditional Chinese Medicine life nurturing in health management of patients with type 2 diabetes mellitus, and provide reference for further research on health management of patients with type 2 diabetes mellitus. (糖尿病的发生发展与生活方式有着密不可分的关系, 中医养生在防治糖尿病方面发挥了重要作用。本研究就中医养生理论在2型糖尿病患者情志护理、饮食护理、运动护理以及常规护理方面的应用现状进行综述, 旨在为今后中医养生理论在2型糖尿病患者健康管理中的进一步深入研究提供参考。)

Abstract The internal combustion engine is a widely used power equipment in various fields, and its energy utilization is measured using brake specific fuel consumption (BSFC). BSFC map plays a crucial role in the analysis, optimization, and assessment of internal combustion engines. However, due to cost constraints, some values on the BSFC map are estimated using techniques like K-nearest neighbor, inverse distance weighted interpolation, and multi-layer perceptron, which are recognized for their limited accuracy, particularly when dealing with distributed sampled data. To address this, an improved random forest method is proposed for the estimation of BSFC. Polynomial features are employed to increase higher dimensions of features for random forest by nonlinear transformation, and critical parameters are optimized by particle swarm optimization algorithms. The performance of different methods was compared on two datasets to estimate 20%, 30%, and 40% of BSFC data, and the results reveal that the method proposed in this paper outperforms other common methods and is suitable for estimating the BSFC map.

Objective·To study whether mutations at the I72 site of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) can induce resistance in acute lymphoblastic leukemia (ALL) cells to thiopurine chemotherapy drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), and explain their mechanisms of action.Methods·The PRPS1 gene mutations (I72F, R177S and V316L) found in clinical practice and PRPS1 gene mutations (V208A and V289A) present in two ALL cell lines (KOPN72bi and RS4;11) were constructed into the vector pGV303 fused with green fluorescent protein (GFP), respectively. The PRPS1 A190T mutation that has been proven to be resistant to thiopurine chemotherapy drugs was used as the positive control, and the empty vector pGV303 (Vector), PRPS1 wild-type (WT) and PRPS1 I72V were used as the negative controls. The various mutants of PRPS1 were transiently transfected into HEK-293T cells (referred to as 293T cells), and the expression of these exogenous PRPS1 was detected by Western blotting. The half maximal inhibitory concentration (IC50) of 6-MP or 6-TG on the above 293T cell lines transiently transfected with PRPS1 mutants was detected and calculated by drug sensitivity experiments. Subsequently, in addition to PRPS1 I72F and I72V, multiple mutations I72M, I72L, I72N, I72S and I72T were constructed into the vector pGV303, respectively, by changing the isoleucine (I) at position 72 into other amino acids. The various mutants were transiently transfected into 293T cells, respectively, and the protein expression of each mutant and IC50 values of 6-MP or 6-TG were detected by Western blotting and drug sensitivity experiments. PRPS1 WT, I72F, I72V, A190T and pGV303 vectors were transfected into REH cell lines by lentivirus infection, and GFP-positive cells were sorted by flow cytometry to obtain cells with stable expression of PRPS1 mutants. The protein expression of each mutant in REH cells and IC50 values of 6-MP or 6-TG were detected by Western blotting and drug sensitivity experiments to verify the results of drug sensitivity experiments obtained by 293T cells. Annexin V/DAPI double staining was used to evaluate the apoptosis of each REH cell line, and Western blotting was used to detect the levels of DNA damage-related proteins [phosphorylation at S139 of histone H2AX (phosphorylated H2AX-S139, γ-H2AX), phosphorylated check point kinase 2 (pCHK2)], and apoptosis-related protein cleaved poly (ADP-ribose) polymerase (cleaved PARP) in each REH cell line. The diagrams of amino acid residues and spatial conformations of I72 locus, I72V and I72F were predicted and drawn through three-dimensional imaging and PyMOL software by using the crystal structure data of PRPS1-numbered 2HCR (PDB code 2HCR) in the PDB (Protein Data Bank) database.Results·Western blotting results showed that the transiently transfected exogenous PRPS1-mutated proteins were successfully expressed in 293T cells. The drug sensitivity experiment results showed that the IC50 values of 6-MP or 6-TG in 293T cells expressing PRPS1 I72F, R177S, V316L, V208A and the positive control A190T were much higher than those in cells expressing V289A and the negative control Vector, PRPS1 WT and I72V (all P =0.000). After mutating the isoleucine (I) at position 72 with other amino acids, Western blotting results showed successful expression of exogenous PRPS1-mutated proteins at position I72 after transient transfection in 293T cells. Drug sensitivity experiments revealed the IC50 values of 6-MP or 6-TG in 293T cells expressing PRPS1 I72M, I72F, I72L, I72N, I72S, I72T and positive control A190T were much higher than those in cells expressing negative control Vector, PRPS1 WT and I72V (all P=0.000). Western blotting results showed that the protein expression levels of PRPS1 WT, A190T, I72F and I72V in the REH stable cell lines constructed by lentivirus were high and similar. The drug sensitivity experiment results showed that the IC50 values of 6-MP or 6-TG in REH cells expressing PRPS1 I72F and positive control A190T were much higher than those in cells expressing negative control Vector, PRPS1 WT and I72V (all P=0.000), which was consistent with the drug sensitivity results obtained by transient transfection in 293T cells. The results of Annexin V/DAPI double staining method and the detection of DNA damage and apoptosis-related proteins by Western blotting showed that after 6-MP treatment, the DNA damage and apoptosis rates of REH cell lines expressing PRPS1 A190T and I72F were significantly lower than those of cells expressing negative control Vector, PRPS1 WT and I72V (all P=0.000). The protein structure analysis results showed that PRPS1 I72F could change the conformation of PRPS1.Conclusion·The PRPS1 I72F, R177S, V316L, V208A, I72M, I72L, I72N, I72S and I72T mutations can confer drug resistance to the thiopurine chemotherapy drugs in cells, while the PRPS1 V289A and I72V mutations do not affect cell sensitivity to the thiopurine chemotherapy drugs. The drug sensitivity experiment results in 293T cells are consistent with those in REH cells, demonstrating that 293T cells can serve as a rapid research model for detecting the resistance of PRPS1 mutations to thiopurine chemotherapy drugs. The effects of the PRPS1 I72 mutations on the resistance of the thiopurine chemotherapy drugs may be related to changes in the structure of PRPS1.

Abstract Hyperhomocysteinemia with hypertension can synergistically increase the risk of stroke. The China stroke primary prevention trial showed that combining 0.8 mg folic acid (FA) with angiotensin‐converting enzyme inhibitor (ACEI) can effectively lower plasma total homocysteine (tHcy) and blood pressure (BP); and reduce first stroke risk by additional 21% compared to ACEI alone. However, intolerance to ACEI is common in Asians and amlodipine can be alternative. This is a multicenter, randomized, double‐blind, parallel‐controlled clinical trial (RCT) which evaluated whether amlodipine combined with FA is more efficacious than amlodipine alone in lowering tHcy and BP among Chinese hypertensive with hyperhomocysteinemia and intolerance to ACEI. 351 Eligible patients were randomly assigned by 1:1:1 ratio to receive amlodipine‐FA tablet daily (amlodipine 5 mg/FA 0.4 mg, A group); amlodipine 5 mg/FA 0.8 mg tablet daily (B group); amlodipine 5 mg daily (C group, control group). Follow‐up was conducted at 2, 4, 6, and 8 weeks. The primary outcome was efficacy of lowering both tHcy and BP at the end of 8‐week treatment. Compared with C group, A group had a significantly higher rate of lowering both tHcy and BP (23.3% vs. 6.0%; Odds Ratio [OR], 8.68; 95% CI, 3.04‐24.78, P

This paper summarized the replacement of implantable venous access port and nursing management for a patient with port exposure on the upper arm. Based on the analysis of port exposure and infection condition, targeted nursing interventions were carried out to lessen tissue injury and reduce the risk of complications. (本文总结1例上臂植入式静脉输液港港体外露行港体移位的护理经验。恶性肿瘤患者一旦发生静脉输液港港体外露应及时处理, 根据外露程度选择处置方法, 明确是否存在感染, 并采取针对性护理措施, 减轻损伤, 尽可能保留输液港, 避免并发症。)

Abstract Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p

Abstract Objectives We aimed to use machine learning (ML) algorithms to risk stratify the prognosis of critical pulmonary embolism (PE). Material and methods In total, 1229 patients were obtained from MIMIC-IV database. Main outcomes were set as all-cause mortality within 30 days. Logistic regression (LR) and simplified eXtreme gradient boosting (XGBoost) were applied for model constructions. We chose the final models based on their matching degree with data. To simplify the model and increase its usefulness, finally simplified models were built based on the most important 8 variables. Discrimination and calibration were exploited to evaluate the prediction ability. We stratified the risk groups based on risk estimate deciles. Results The simplified XGB model performed better in model discrimination, which AUC were 0.82 (95% CI: 0.78–0.87) in the validation cohort, compared with the AUC of simplified LR model (0.75 [95% CI: 0.69—0.80]). And XGB performed better than sPESI in the validation cohort. A new risk-classification based on XGB could accurately predict low-risk of mortality, and had high consistency with acknowledged risk scores. Conclusions ML models can accurately predict the 30-day mortality of critical PE patients, which could further be used to reduce the burden of ICU stay, decrease the mortality and improve the quality of life for critical PE patients.

In recent years, arginine has received extensive attention from researchers and scholars in the field of food and nutrition because of its important role in patients' postoperative recovery and cardiovascular health. This article describes the metabolic pathways, physiological functions, absorption and intake of arginine, summarizes the application of arginine in clinical research and food for special medical purpose, and the future direction of development and research of the food for special medical purpose is also prospected.

Obesity has been reported to promote disordered folliculogenesis, but the exact molecular mechanisms are still not fully understood. In this study, we find that miR-133a is involved in obesity-induced follicular development disorder. After feeding with a high-fat diet (HFD) and fructose water for nine weeks, the mouse body weight is significantly increased, accompanied by an inflammatory state and increased expression of miR-133a in the adipose tissues and ovaries as well as accelerated follicle depletion. Although miR-133a is increased in the fat and ovaries of HFD mice, the increased miR-133a in the HFD ovaries is not derived from exosome transferred from obese adipose tissues but is synthesized by ovarian follicular cells in response to HFD-induced inflammation. In vivo experiments show that intrabursal injection of miR-133a agomir induces a decrease in primordial follicles and an increase in antral follicles and atretic follicles, which is similar to HFD-induced abnormal folliculogenesis. Overexpression of miR-133a modestly promotes granulosa cell apoptosis by balancing the expression of anti-apoptotic proteins such as C1QL1 and XIAP and pro-apoptotic proteins such as PTEN. Overall, this study reveals the function of miR-133a in obesity-induced ovarian folliculogenesis dysfunction and sheds light on the etiology of female reproductive disorders.

Abstract Background Atherosclerosis (AS) is a leading cause of morbidity and mortality in older patients and features progressive formation of plaques in vascular tissues. With the progression of atherosclerosis, plaque rupture may occur and cause stroke, myocardial infarction, etc. Different forms of cell death promote the formation of a necrotic core of the plaque, leading to rupture. Necroptosis is a type of programmed cell death that contributes to the development of cardiovascular disease. However, the role of necroptosis in AS has not yet been investigated. Methods The Gene Expression Omnibus (GEO) database was used to obtain gene expression profiles. Differentially expressed genes (DEGs) and necroptosis gene sets were used to identify necroptosis-related differentially expressed genes (NRDEGs). The NRDEGs were used to construct a diagnostic model and were further screened using least absolute shrinkage selection operator (LASSO) regression and random forest (RF) analysis. The discriminatory capacity of the NRDEGs was evaluated using receiver operating characteristic (ROC) curves. Immune infiltration levels were estimated based on CIBERSORTx analysis. The GSE21545 dataset, containing survival information, was used to determine prognosis-associated genes. Univariate and multivariate Cox regression analyses combined with survival analysis determined gene prognostic values. RNA and protein levels were detected by RT-qPCR and western blotting in arteriosclerosis obliterans(ASO) and normal vascular tissues. Vascular smooth muscle cells (VSMCs) were treated with oxidized low-density lipoprotein (ox-LDL) to develop cell models of advanced AS. The effects of protein knockdown on necroptosis were assessed by western blotting and flow cytometry. EdU and Cell Counting Kit-8 assays were used to examine cell proliferation. Results TNF Receptor Associated Factor 5 (TRAF5) was identified as a diagnostic marker for AS based on the AUC value in both the GSE20129 and GSE43292 datasets. According to differential expression analysis, LASSO regression analysis, RF analysis, univariate analysis, multivariate analysis, and gene-level survival analysis, TRAF5 was markedly associated with necroptosis in AS. Silencing TRAF5 promotes necroptosis and attenuates the proliferation of ox-LDL-induced cell models of advanced AS. Conclusions This study identified a diagnostic marker of necroptosis-related atherosclerosis, TRAF5, which can also be used to diagnose and assess atherosclerotic plaque stability. This novel finding has important implications in the diagnosis and assessment of plaque stability in atherosclerosis.

Stroke is a disease with a high disability rate， and often leads to limb dysfunction， especially upper limb motor dysfunction， which significantly affects the patients’ abilities and quality of life. With patients' increasing demand for functional recovery， various therapeutic techniques of rehabilitation medicine have been rapidly developed. As an important active central intervention technology， motor imagery training can be initiated by the patient's brain and activate the sensorimotor network to accelerate the repair of limb functions. The development of preventive medicine has promoted the continuous evolution of the concept of rehabilitation. The strategies of full cycle functional protection and disability prevention have been improved and developed in the clinical and scientific research practice of upper limb rehabilitation after stroke. The motor imagery training can activate the upper limb motor neural network in the early stage of stroke to prevent functional loss； In the recovery period， it can accelerate the neural function remodeling and reduce the upper limb disability； In the later stage after stroke， it can improve the performance of upper limb function in daily life， thus helping patients return to family life and society. This article reviews the research progress in recent years in China and abroad in the application of motor imagery training for the full cycle function protection and disability prevention of stroke.

Abstract Rheumatoid arthritis (RA) is a risk factor for atherosclerotic cardiovascular diseases (CVD). Given the critical roles of the immune system and inflammatory signals in the pathogenesis of CVD, we hypothesized that interrogation of CVD-related proteins using integrative genomics might provide new insights into the pathophysiology of RA. We utilized two-sample Mendelian randomization (MR) for causal inference between circulating protein levels and RA by incorporating genetic variants, followed by colocalization to characterize the causal associations. Genetic variants from three sources were obtained: those associated with 71 CVD-related proteins measured in nearly 7000 Framingham Heart Study participants, a published genome-wide association study (GWAS) of RA (19 234 cases, 61 565 controls), and GWAS of rheumatoid factor (RF) levels from the UK Biobank (n = 30 565). We identified the soluble receptor for advanced glycation end products (sRAGE), a critical inflammatory pathway protein, as putatively causal and protective for both RA (odds ratio per 1-standard deviation increment in inverse-rank normalized sRAGE level = 0.364; 95% confidence interval 0.342–0.385; P = 6.40 × 10–241) and RF levels (β [change in RF level per sRAGE increment] = − 1.318; SE = 0.434; P = 0.002). Using an integrative genomic approach, we highlight the AGER/RAGE axis as a putatively causal and promising therapeutic target for RA.

Abstract Background Systemic corticosteroid therapy failure is quite common in patients with newly diagnosed acute graft-versus-host disease (aGVHD). Growing evidence has suggested that mesenchymal stem cell (MSC) therapy could be a promising treatment option for aGVHD due to its distinctive immunomodulating functions. However, there is a lack of randomized well-controlled clinical trials. Methods This is a clinical trial protocol for a multicenter, randomized, double-blind, placebo-controlled phase II study. The aim of the trial is to evaluate the efficacy and safety of the administration of the human umbilical cord-derived MSC product hUC-MSC PLEB001 in patients with grade II–IV, steroid-refractory aGVHD. A total of 96 patients will be randomized 1:1 to receive MSC or placebo treatment twice per week for 4 weeks, in addition to second-line therapy according to institutional standards. Patients who achieve partial response (PR) at day 28 will be eligible to receive further infusions twice per week for an additional 4 weeks. Discussion This study will evaluate the efficacy and safety of MSC therapy in patients who have failed first-line steroid treatment for grade II–IV aGVHD. Trial registration Chinese Clinical Trial Registry (ChiCTR), ChiCTR2000035740. Registered on 16 August 2020.

BackgroundMulticenter clinical trials play an indispensable role for assessing the efficacy of a new intervention or treatment, particularly in Phase II or III studies. Previous studies have shown that these studies often suffer from inadequate reporting of key details related to their design, implementation, and analysis, both in the protocol and final reports. This limitation reduces the practical and scientific value of the findings. Furthermore, the lack of guidance on how to report multicenter features can contribute to poor reporting. Therefore, this study aims to develop guidelines to improve the reporting of multicenter trials, including two Extensions of the CONSORT 2010 and the SPIRIT 2013.Methods/designThe standard methodology for developing health research reporting guidelines involves the following steps: (i) Identifying the need for development and launching the research project; (ii) Preparing the registration and reviewing the literatures; (iii) Proposing the initial Checklists and conducting the Delphi exercise; (iv) Arranging the consensus meeting and formulating the Checklists; (v) Conducting the pilot test and drafting explanatory documents (E&E); (vi) Seeking comments from advisory group and finalizing the guidelines; and (vii) Developing the publication and dissemination strategies.ConclusionBy using the CONSORT and SPIRIT checklists as starting points, the development of extensions specific to multicenter trials can help researchers design and report high-quality clinical research. This, in turn, can facilitate the application of study findings in the current evidence-based healthcare system.

Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P

ObjectiveSpontaneous isolated abdominal aortic dissection (SIAAD) is a rare aortic emergency and not yet fully understood. This study aims to report the characteristics and treatments of 31 patients with SIAAD in the past 12 years.MethodsA total of 31 consecutive patients with SIAAD between 2010 and 2022 were included. The clinical manifestations, treatment strategies, and outcomes were reviewed. Following the SVS/STS reporting standard, we compared the clinical characteristics with different locations of primary entry, or different numbers of dissected zones. Furthermore, we compared the effects of surgical and conservative therapies on the outcome during the follow-up.ResultsAmong the 31 patients with SIAAD, 16 (51.6%) were in the acute phase on admission. The primary entry of SIAAD was mainly located in Zone 9 (67.7%). Most patient presented with dissection involving 1 or 2 aortic zones (61.3%). In addition, 35.5% and 64.5% of SIAADs involved the visceral and iliac arteries, respectively. Compared with asymptomatic SIAADs, the symptomatic ones had longer dissection lengths (P = 0.008) and tended to involve iliac artery more frequently (P = 0.098). There were differences in the number of dissected aortic zones (P = 0.005) among patients with primary entry located in Zone 5 (Supraceliac aorta), Zone 6–8 (Paravisceral aorta) and Zone 9 (Infrarenal aorta). The involvement of visceral artery (P = 0.039) and iliac artery (P = 0.006) was significantly different between the subgroups of SIAAD involving one, two, and three or more aortic zones. The cumulative incidence of adverse false lumen progression events was significantly lower (P = 0.000) and the rate of false lumen thrombogenesis or disappearance was higher in patients receiving surgery (P = 0.001). The cumulative all-cause mortality was 9.7% at 1-year, and 19.7% at 5-year, with no significant difference between surgical and conservative therapies.ConclusionsClinical features of SIAAD vary depending on the location of the primary entry and the number of dissected aortic zones. Although surgery was not associated with a lower all-cause mortality compared with conservative therapy, it was associated with a lower incidence of adverse false lumen progression and a higher rate of aortic remodeling.

BackgroundeSources consist of data that were initially documented in an electronic structure. Typically, an eSource encompasses the direct acquisition, compilation, and retention of electronic information (such as electronic health records [EHRs] or wearable devices), which serves to streamline clinical research. eSources have the potential to enhance the accuracy of data, promote patient safety, and minimize expenses associated with clinical trials. An opinion study published in September 2020 by TransCelerate outlined a road map for the future application of eSource technology and identified 5 key areas of challenges. The background of this study concerns the use of eSource technology in clinical research. ObjectiveThe aim of this study was to present challenges and possible solutions for the implementation of eSource technology in real-world studies by summarizing team experiences and lessons learned from an eSource record (ESR) project. MethodsAfter initially developing a simple prototype of the ESR software that can be demonstrated systematically, the researchers conducted in-depth interviews and interacted with different stakeholders to obtain guidance and suggestions. The researchers selected 5 different roles for interviewees: regulatory authorities, pharmaceutical company representatives, hospital information department employees, medical system providers, and clinicians. ResultsAfter screening all consultants, the researchers concluded that there were 25 representative consultants. The hospital information department needs to implement many demands from various stakeholders, which makes the existing EHR system unable to meet all the demands of eSources. The emergence of an ESR is intended to divert the burden of the hospital information department from the enormous functional requirements of the outdated EHR system. The entire research process emphasizes multidisciplinary and multibackground expert opinions and considers the complexity of the knowledge backgrounds of personnel involved in the chain of clinical source data collection, processing, quality control, and application in real-world scenarios. To increase the readability of the results, the researchers classified the main results in accordance with the paragraph titles in “Use of Electronic Health Record Data in Clinical Investigations,” a guide released by the US Food and Drug Administration. ConclusionsThis study introduces the requirement dependencies of different stakeholders and the challenges and recommendations for designing ESR software when implementing eSource technology in China. Experiences based on ESR projects will provide new insights into the disciplines that advance the eSource research field. Future studies should engage patients directly to understand their experiences, concerns, and preferences regarding the implementation of eSource technology. Moreover, involving additional stakeholders, including community health care providers and social workers, will provide valuable insights into the challenges and potential solutions across various health care settings.

Summary: Lymphoid tissue inducer (LTi) cells, a subset of innate lymphoid cells (ILCs), play an essential role in the formation of secondary lymphoid tissues. However, the regulation of the development and functions of this ILC subset is still elusive. In this study, we report that the transcription factor T cell factor 1 (TCF-1), just as GATA3, is indispensable for the development of non-LTi ILC subsets. While LTi cells are still present in TCF-1-deficient mice, the organogenesis of Peyer’s patches (PPs), but not of lymph nodes, is impaired in these mice. LTi cells from different tissues have distinct gene expression patterns, and TCF-1 regulates the expression of lymphotoxin specifically in PP LTi cells. Mechanistically, TCF-1 may directly and/or indirectly regulate Lta, including through promoting the expression of GATA3. Thus, the TCF-1-GATA3 axis, which plays an important role during T cell development, also critically regulates the development of non-LTi cells and tissue-specific functions of LTi cells.

CONTEXT: Closure rate of endovenous thermal ablation is limited by the trunk diameter of great saphenous vein. AIMS: This study aimed to investigate the safety and efficacy of transluminal injection of foam sclerotherapy (TLFS) after thermal ablation in improving the closure rate of primary varicose veins with large trunk. SUBJECTS AND METHODS: In this retrospective cohort study with 170 patients (189 legs), the outcomes of varicose veins patients treated with thermal ablation plus injection of sclerotherapy were compared with those treated with thermal ablation only. The primary outcome of this study was the rate of ablated segment closure after surgery and during patient follow-up. Propensity score matching model was used to eliminate the bias. RESULTS: After matching, 75 legs (65 patients) from the thermal ablation plus sclerotherapy group and 71 legs (66 patients) from the thermal ablation only group were further analyzed. The closure rate of the thermal ablation plus sclerotherapy group was 97.3%, which was significantly higher than that of the thermal ablation only group (87.3%, P = 0.048), and the closure rate of the thermal ablation plus sclerotherapy group remained higher during 1-year follow-up. No serious complications were observed in groups. CONCLUSIONS: TLFS can improve the efficacy of thermal ablation, increasing the closure rate of the ablation segment, and thus improving the symptoms.

OBJECTIVES: Aortic dissection with aberrant right subclavian artery (ARSA) is rare but fatal, with its optimal treatment remaining controversial. In this retrospective study, we presented the outcome of endovascular repair for these patients, aiming to evaluate the efficacy and safety of this technique. MATERIALS AND METHODS: From January 2016 to January 2022, seven patients diagnosed with aortic dissection with ARSA in the First Affiliated Hospital of Sun Yat-sen University were enrolled. All these seven patients received thoracic endovascular aortic repair (TEVAR) within 1 week after their admission to our center. The data of baseline characteristics, imaging parameters, perioperative information, and follow-up were collected till March 2023. RESULTS: The mean age was 48.57 ± 9.41 years. Kommerell diverticulum was found in 2 (28.6%) patients. Among these seven patients, 4 (57.1%) were treated by TEVAR + branched stent graft + chimney technique, 2 (28.6%) were treated by TEVAR + chimney technique, and 1 (14.3%) was treated by TEVAR + chimney and periscope techniques. The mean time of procedures was 196.67 ± 31.18 min. Clinical success was achieved in 6 (85.7%) patients, while 1 (14.3%) patient died of nonaortic related cause. Bird beak configuration was discovered in 4 (57.1%) patients with an average length of 17.87 ± 3.93 mm and angle of 21.9° ±3.70°. One early type I endoleak and one mild cerebral ischemia were discovered, and recovered spontaneously before discharge. The diameter of the aorta remained stable, and no complication was found during the follow-up of the six patients. CONCLUSION: Endovascular repair of aortic dissection with ARSA was feasible and safe, with a favorable early to mid-term outcome.

The uncertainty in determination of nickel in soy milk powder by ultra-wave digestion- inductively coupled plasma mass spectrometry was evaluated and optimized. According to JJF1059.1—2012 Evaluation and expression of uncertainty in measurement and CNAS—GL006: 2019 Guidance on quantifying uncertainty in chemical analysis, the mathematical model of uncertainty evaluation was built. The main sources of uncertainty were analyzed and their uncertainty components were evaluated. Then the relative standard uncertainty and the expanded uncertainty were computed. Finally, the influence of different sources was analyzed and the possible optimization methods for reducing the uncertainty were proposed. When the coverage probability was 95% (i.e., the coverage factor was k=2), the expanded uncertainty of nickel is 0.222 mg/kg, which indicates the determination result of nickel in soy milk powder was (3.825±0.222) mg/kg. The relative uncertainty was reduced from 0.029 0 to 0.023 8 by the optimization methods. Configuration of standard working solution and fitting of standard curve were the main sources of the uncertainty in determination of nickel in soy milk powder by ultra-wave digestion-inductively coupled plasma mass spectrometry, and the optimization could reduce the determination uncertainty significantly.

Objective To evaluate the safety and efficacy of cold snare polypectomy (CSP) and hot snare polypectomy (HSP) in the treatment of small colorectal polyps. Methods The clinical data of 3 750 patients who underwent endoscopic polypectomy for small colorectal polyps in our hospital from January 1, 2020 to August 31, 2021 were collected and analyzed retrospectively. There were 1 796 cases assigned into CSP group and 1 954 cases into HSP group. Their general data, number and utilization rate of titanium clips, complete resection rate, specimen recovery rate, incidence of delayed bleeding, perforation rate and incidence of abdominal discomfort were analyzed and compared between the 2 groups. Results There were no significant differences in the general data (age, gender, BMI, and number, size, location, morphology and pathological type of polyps) and in proportions of comorbidities (hypertension and diabetes) between the 2 groups (P>0.05). The utilization rate and average number of clips used were significantly lower in the CSP group than the HSP group (11.19% vs 19.55%, P < 0.001; 0.16±0.49 vs 0.27±0.63, P < 0.001). No statistical difference was found in the complete resection rate between the 2 groups (93.99% vs 95.04%, P=0.158). The CSP group had higher specimen recovery rate (99.55% vs 98.26%, P < 0.001), lower incidence of delayed bleeding (0.06% vs 0.46%, P=0.037) and incidence of abdominal discomfort (4.18% vs 9.31%, P < 0.001) when compared with the HSP group. In terms of perforation, no occurrence was observed in the CSP group and 1 case (0.05%) in the HSP group, though no statistical difference (P=0.521). Conclusion When compared with HSP, CSP has advantages of lower utilization rate and less number of titanium clips, higher specimen recovery rate, and lower incidence of complications in the treatment of small colorectal polyps. It is a safe and effective treatment, and worthy of clinical application.

Transparency Ecosystem for Research and Journals in Medicine (TERM) working group summarized the essential recommendations that should be considered to review and publish a high-quality guideline. These recommendations from editors and reviewers included 10 components of essential requirements: systematic review of existing relevant guidelines, guideline registration, guideline protocol, stakeholders, conflicts of interest, clinical questions, systematic reviews, recommendation consensus, guideline reporting and external review. TERM working group abbreviates them as PAGE (essential requirements for Publishing clinical prActice GuidelinEs), and recommends guideline authors, editors, and peer reviewers to use them for high-quality guidelines.

Abstract We here showed that ADCK1 (AarF domain-containing kinase 1), a mitochondrial protein, is upregulated in human osteosarcoma (OS) tissues and OS cells. In primary and established OS cells, ADCK1 shRNA or CRISPR/Cas9-induced ADCK1 knockout (KO) remarkably inhibited cell viability, proliferation and migration, and provoked apoptosis activation. Conversely, ectopic ADCK1 overexpression exerted pro-cancerous activity by promoting OS cell proliferation and migration. ADCK1 depletion disrupted mitochondrial functions in OS cells and induced mitochondrial membrane potential reduction, ATP depletion, reactive oxygen species production. Significantly, ADCK1 silencing augmented doxorubicin-induced apoptosis in primary OS cells. mTOR activation is important for ADCK1 expression in OS cells. The mTOR inhibitors, rapamycin and AZD2014, as well as mTOR shRNA, potently decreased ADCK1 expression in primary OS cells. In nude mice, the growth of subcutaneous pOS-1 xenografts was largely inhibited when bearing ADCK1 shRNA or ADCK1 KO construct. Moreover, ADCK1 KO largely inhibited pOS-1 xenograft in situ growth in proximal tibia of nude mice. ADCK1 depletion, apoptosis activation and ATP reduction were detected in pOS-1 xenografts bearing ADCK1 shRNA or ADCK1 KO construct. Together, the mitochondrial protein ADCK1 is required for OS cell growth and is a novel therapeutic target of OS.

Objective To investigate the effect of Traditional Chinese Medicine (TCM)characteristic nursing combined with Liuzijue Qigong on rehabilitation of cardiac function in patients with chronic heart failure (CHF). Methods A total of 80 CHF patients were randomly divided into the study group and control group, with 40 cases in each group. All patients received routine drug therapy during hospitalization. Patients in the control group were give routine care including work-rest schedule, dietary guidance, psychological care and daily care. Patients in the study group were given TCM characteristic nursing combined with Liuzijue Qigong in addition to routine care. The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was used to measure the patient quality of life, and outcomes of left ventricular ejection fractions (LVEF) and 6-minute walking test were measured and compared between two groups. Results Longer 6MWD and higher LEVF were reported in both groups at three months of intervention, and patients in the study group achieved better outcomes of 6MWD and higher LEVF compared with those in the control group(P＜0. 01). The score of MLHFQ decreased in both groups at three months of intervention, and score of MLHFQ in the study group was lower than that in the control group (P＜0. 01). Conclusion The TCM characteristic nursing combined with Liuzijue Qigong is potentially effective to improve the rehabilitation of cardiac function and long-term quality of life in CHF patients. (目的 探讨运用中医特色护理联合六字诀促进慢性心力衰竭患者心功能康复的效果。方法 选取2020年9月—2021年9月住院治疗的慢性心力衰竭患者80例为研究对象, 随机分为研究组和对照组, 各40例。两组患者均接受心力衰竭常规药物治疗。对照组采用常规护理, 指导患者休息与活动, 给予合理饮食指导、心理护理、生活护理等; 研究组在常规护理的基础上给予中医特色护理及气功六字诀指导。采用明尼苏达心力衰竭生活质量调查表(MLHFQ)评估患者生活质量, 记录左室射血分数(LVEF)和六分钟步行试验(6MWD)结果。结果 干预3个月时, 两组6MWD距离和LEVF均较入院时增加, 且研究组6MWD距离和LEVF较对照组改善明显, 差异有统计学意义(P＜0. 01)。干预3个月时, 两组MLHFQ评分均较入院时降低, 且研究组MLHFQ评分低于对照组, 差异有统计学意义(P＜0. 01)。结论 中医特色护理联合六字诀能改善慢性心力衰竭患者的心功能, 减轻临床症状, 提高患者的远期生活质量。)

Enterprises in China face two major challenges about their existence and energy supply at present. One is the difficulty in providing enough energy at an acceptable and reasonable price; the other is a severe environmental issue caused by over-consumption of energy. The government and relevant enterprises, therefore, mainly focus on carbon emission reduction, and the cost accounting of carbon emission, an essential prerequisite, and object of carbon emission reduction, should be further attention. The carbon emission cost is divided into internal cost and external cost, combined with the extended accounting model and cost calculation. This can comprehensively measure and reflect the two costs of the life cycle of the product, provide more relevant data and information support for the deepening and development of the circular economy, and provide an effective cost information basis and guide enterprise managers for scientific decision-making and governance.

Abstract Objective Post-thrombotic syndrome (PTS), an important complication of deep venous thrombosis (DVT), adversely affects patients’ quality of life. Endovascular intervention in PTS can relieve symptoms rapidly with high therapeutic value. This study mainly focuses on how to improve postoperative stent patency rates and aims to find prognostic factors impacting patency. Methods According to the specific inclusion and exclusion criteria, PTS patients who underwent endovascular intervention at the First Affiliated Hospital of Sun Yat-sen University from December 1, 2014, to December 31, 2019, were included in this single-center prospective study. Follow-up data were collected and analyzed regularly over 2 years. Results Overall, 31 PTS patients were enrolled in the study. The mean age of these patients was 55.39 ± 11.81, including 19 male patients. Stent implantation was successful in 22 PTS patients, with a technical success rate of 70.97%. The average Villalta scores of the stent-implanted group and the non-stent-implanted group were 5.95 ± 2.57 and 5.78 ± 2.95, respectively, with no significant difference observed. In the stent-implanted group, the perioperative patency rate was 81.81% (18/22), and the follow-up patency rates were 68.18% (15/22) within 3 months, 59.09% (13/22) within 6 months, 45.45% (10/22) within 1 year, and 36.36% (8/22) within 2 years. Based on the stent placement segments, the 22 PTS patients were divided into two subgroups: the iliofemoral vein balloon dilation + iliofemoral vein stent implantation (FV-S) subgroup and the iliofemoral vein balloon dilation + iliac vein stent implantation (FV-B) subgroup. In the FV-S subgroup, the perioperative patency rate was 100.00% (14/14), and the follow-up patency rates were 85.71% (12/14), 71.43% (10/14), 57.14% (8/14) and 50.00% (7/14), which were higher than those for overall stent patency of all patients. The postoperative patency rates in the FV-B subgroup were 50.00% (4/8), 37.50% (3/8), 37.50% (3/8), 25.00% (2/8), and 12.50% (1/8). The secondary postoperative patency rates in the FV-B subgroup were 100.00% (8/8), 87.50% (7/8), 75.00% (6/8), 62.50% (5/8) and 50.00% (4/8). Conclusions For PTS patients with iliofemoral vein occlusion but patent inflow, iliofemoral vein stent implantation is a more efficient therapeutic option than iliofemoral vein balloon dilation with iliac vein stent implantation for PTS patients.

Abstract Background This study was set to investigate the correlation between square dance and musculoskeletal system of early postmenopausal Chinese women. Methods Chinese postmenopausal women, who had been without menstruation for 1–10 years from the onset of menopause were recruited from community centers for this study. A standardized structured face-to-face interview was performed to collect demographic information, life styles, personal medical history, diet and menstrual status. Subjects who had been practicing regular square dance without participated in other sports activities for more than 2 years and over 4 h per week (usually more than 45 min per time and more than 5 times per week) were assigned to square dance group. Those postmenopausal women who had not participated in regular exercises (no more than 0.5 h per week) were recruited as the sedentary control group. Bone mineral density (BMD) of spine, total hip and femoral neck was measured by using dual-energy X-ray absorptiometry. Lower limb muscle strength was measured for the non-dominant leg, body flexibility was measured by a simple trunk bend-and-reach test, and body balance was evaluated using a single-stance test for the non-dominant leg. Independent two-tailed Student’s t-test was used for data analysis. Results 152 subjects from community centers were selected for this study and divided into square dance group (n = 74) and control group (n = 78). The square dance subjects had higher lumbar spine BMD (p = 0.01) and total hip BMD (p = 0.02) than control subjects, but there was no significant difference of femoral neck BMD (p = 0.48) between these two groups. Functional testing indicated that square dance subjects had higher lower limb muscle strength (p

Abstract Toll-like receptors (TLRs) play pivotal roles in inflammation and provide important links between the immune and skeletal systems. Although the activation of TLRs may affect osteoclast differentiation and bone metabolism, whether and how TLRs are required for normal bone remodeling remains to be fully explored. In the current study, we show for the first time that TLR9−/− mice exhibit a low bone mass and low-grade systemic chronic inflammation, which is characterized by the expansion of CD4+ T cells and increased levels of inflammatory cytokines, including TNFα, RANKL, and IL1β. The increased levels of these cytokines significantly promote osteoclastogenesis and induce bone loss. Importantly, TLR9 deletion alters the gut microbiota, and this dysbiosis is the basis of the systemic inflammation and bone loss observed in TLR9−/− mice. Furthermore, through single-cell RNA sequencing, we identified myeloid-biased hematopoiesis in the bone marrow of TLR9−/− mice and determined that the increase in myelopoiesis, likely caused by the adaptation of hematopoietic stem cells to systemic inflammation, also contributes to inflammation-induced osteoclastogenesis and subsequent bone loss in TLR9−/− mice. Thus, our study provides novel evidence that TLR9 signaling connects the gut microbiota, immune system, and bone and is critical in maintaining the homeostasis of inflammation, hematopoiesis, and bone metabolism under normal conditions.

Engineered ultrashort peptides, serving as an alternative to natural antimicrobial peptides, offer benefits of simple and modifiable structures, as well as ease of assembly. Achieving excellent antibacterial performance and favorable biocompatibility through structural optimization remains essential for further applications. In this study, we assembled lipoic acid (LA)–modified tripeptide RWR (LA–RWR) with β–cyclodextrin (β–CD) to form nano–inclusion complexes. The free cationic tripeptide region in the nano–inclusion complex provided high antibacterial activity, while β–CD enhanced its biocompatibility. Compared with peptides (LA–RWR, LA–RWR–phenethylamine) alone, inclusion complexes exhibited lower minimum inhibitory concentrations/minimum bactericidal concentrations (MICs/MBCs) against typical Gram–negative/Gram–positive bacteria and fungi, along with improved planktonic killing kinetics and antibiofilm efficiency. The antibacterial mechanism of the nano–inclusion complexes was confirmed through depolarization experiments, outer membrane permeability experiments, and confocal laser scanning microscopy observations. Furthermore, biological evaluations indicated that the hemolysis rate of the inclusion complexes decreased to half or even lower at high concentrations, and cell viability was superior to that of the non–included peptides. Preliminary in vivo studies suggested that the inclusion complexes, optimized for antibacterial activity and biosafety, could be used as promising antibacterial agents for potential applications.

Abstract Background Electronic sources (eSources) can improve data quality and reduce clinical trial costs. Our team has developed an innovative eSource record (ESR) system in China. This study aims to evaluate the efficiency, quality, and system performance of the ESR system in data collection and data transcription. Methods The study used time efficiency and data transcription accuracy indicators to compare the eSource and non-eSource data collection workflows in a real-world study (RWS). The two processes are traditional data collection and manual transcription (the non-eSource method) and the ESR-based source data collection and electronic transmission (the eSource method). Through the system usability scale (SUS) and other characteristic evaluation scales (system security, system compatibility, record quality), the participants’ experience of using ESR was evaluated. Results In terms of the source data collection (the total time required for writing electronic medical records (EMRs)), the ESR system can reduce the time required by 39% on average compared to the EMR system. In terms of data transcription (electronic case report form (eCRF) filling and verification), the ESR can reduce the time required by 80% compared to the non-eSource method (difference: 223 ± 21 s). The ESR accuracy in filling the eCRF field is 96.92%. The SUS score of ESR is 66.9 ± 16.7, which is at the D level and thus very close to the acceptable margin, indicating that optimization work is needed. Conclusions This preliminary evaluation shows that in the clinical medical environment, the ESR-based eSource method can improve the efficiency of source data collection and reduce the workload required to complete data transcription.

The micromechanical behavior of an Al/Al2Cu/Cu multilayer with characteristic crystal orientation during uniaxial tensile deformation was investigated by molecular dynamics. The simulation results showed that under tensile loading, the dislocation nucleates at the Cu/Al2Cu heterogeneous interface and moves toward the Cu layer along the {111} crystal plane. The deformation mechanism is intralayer confinement slip. As the dislocations proliferated, interactions between them occurred; resulting in the formation of insertion stacking faults and deformation twins in the Cu and Al layers. However, no dislocation lines were generated in the Al2Cu layer during tensile deformation. As the load increased, the stress concentration at the Al2Cu/Al interface led to the fracture of the complex. In addition, the microplastic deformation mechanism and mechanical properties of Al/Al2Cu/Cu composites at different temperatures and strain rates were significantly different. These results revealed the microdeformation mechanism of laminated composites containing brittle phases.