Age-related decline in melatonin contributes to enhanced osteoclastogenesis via disruption of redox homeostasis.

BACKGROUND: Increased oxidative stress contributes to enhanced osteoclastogenesis and age-related bone loss. Melatonin (MT) is an endogenous antioxidant and declines with aging. However, it was unclear whether the decline of MT was involved in the enhanced osteoclastogenesis during the aging process. METHODS: The plasma level of MT, oxidative stress status, bone mass, the number of bone marrow-derived monocytes (BMMs) and its osteoclastogenesis were analyzed in young (3-month old) and old (18-month old) mice (n = 6 per group). In vitro, BMMs isolated from aged mice were treated with or without MT, followed by detecting the change of osteoclastogenesis and intracellular reactive oxygen species (ROS) level. Furthermore, old mice were treated with MT for 2 months to investigate the therapeutic effect. RESULTS: The plasma level of MT was markedly lower in aged mice compared with young mice. Age-related decline in MT was accompanied by enhanced oxidative stress, osteoclastogenic potential and bone loss. MT intervention significantly suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, decreased intracellular ROS and enhanced antioxidant capacity of BMMs from aged mice. MT supplementation significantly attenuated oxidative stress, osteoclastogenesis, bone loss and deterioration of bone microstructure in aged mice. CONCLUSIONS: These results suggest that age-related decline of MT enhanced osteoclastogenesis via disruption of redox homeostasis. MT may serve as a key regulator in osteoclastogenesis and bone homeostasis, thereby highlighting its potential as a preventive agent for age-related bone loss.

CircRBM23 regulates the switch between osteogenesis and adipogenesis of mesenchymal stem cells via sponging miR-338-3p.

BACKGROUND: The disruption of the balance between osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) in bone marrow contributes to the adipocytes accumulation and bone loss, which leads to the development of osteoporosis (OP). The circular RNA (circRNA), circRBM23, was generated from the RNA binding motif protein 23 (RBM23) gene. It was reported that circRBM23 was down-regulated in OP patients, but it remains unknown whether its down-regulation is involved in the lineage switch of MSCs. OBJECTIVE: We aimed to explore the role and mechanism of circRBM23 in regulating the switch between osteogenic and adipogenic differentiation of MSCs. METHODS: The expression and function of circRBM23 in vitro were detected by qRT-PCR, alizarin red staining, and oil Red O staining. The interactions between circRBM23 and microRNA-338-3p (miR-338-3p) were analyzed by RNA pull-down assay, FISH, and dual-luciferase reporter assay. MSCs treated with lentivirus overexpression of circRBM23 was applied for both in vitro and in vivo experiments. RESULTS: CircRBM23 was expressed at lower levels in OP patients. Besides, circRBM23 was up-regulated during osteogenesis and down-regulated during adipogenesis of MSCs. CircRBM23 could promote the osteogenic differentiation but inhibit the adipogenic differentiation of MSCs. Mechanistically, circRBM23 acted as a sponge for microRNA-338-3p (miR-338-3p) to enhance the expression of RUNX family transcription factor 2 (RUNX2). CONCLUSIONS: Our research indicates that circRBM23 could promote the switch from adipogenic to osteogenic differentiation of MSCs via sponging miR-338-3p. It might improve the understanding of the lineage switch of MSCs and provide a potential target for diagnosing and treating OP.

Plantamajoside attenuates cardiac fibrosis via inhibiting AGEs activated-RAGE/autophagy/EndMT pathway.

Advanced glycation end products (AGEs) have been identified to transduce fibrogenic signals via inducing the activation of their receptor (RAGE)-mediated pathway. Recently, disrupting AGE-RAGE interaction has become a promising therapeutic strategy for chronic heart failure (CHF). Endothelial-to-mesenchymal transition (EndMT) is close to the cardiac fibrosis pathological process. Our previous studies have demonstrated that knockout RAGE suppressed the autophagy-mediated EndMT, and thus alleviated cardiac fibrosis. Plantamajoside (PMS) is the major bioactive compound of Plantago Asiatica, and its activity of anti-fibrosis has been documented in many reports. However, its effect on CHF and the underlying mechanism remains elusive. Thus, we tried to elucidate the protective role of PMS in CHF from the viewpoint of the AGEs/RAGE/autophagy/EndMT axis. Herein, PMS was found to attenuate cardiac fibrosis and dysfunction, suppress EndMT, reduce autophagy levels and serum levels of AGEs, yet did not affect the expression of RAGE in CHF mice. Mechanically, PMS possibly binds to the V-domain of RAGE, which is similar to the interaction between AGEs and RAGE. Importantly, this competitive binding disturbed AGEs-induced the RAGE-autophagy-EndMT pathway in vitro. Collectively, our results indicated that PMS might exert an anti-cardiac fibrosis effect by specifically binding RAGE to suppress the AGEs-activated RAGE/autophagy/EndMT pathway.

The role of foreign body response in peri-implantitis: What is the evidence?

Historically, there has been broad consensus that osseointegration represents a homeostasis between a titanium dental implant and the surrounding bone, and that the crestal bone loss characteristic of peri-implantitis is a plaque-induced inflammatory process. However, this notion has been challenged over the past decade by proponents of a theory that considers osseointegration an inflammatory process characterized by a foreign body reaction and peri-implant bone loss as an exacerbation of this inflammatory response. A key difference in these two schools of thought is the perception of the relative importance of dental plaque in the pathogenesis of crestal bone loss around implants, with obvious implications for treatment. This review investigates the evidence for a persistent foreign body reaction at osseointegrated dental implants and its possible role in crestal bone loss characteristic of peri-implantitis. Further, the role of implant-related material release within the surrounding tissue, particularly titanium particles and corrosion by-products, in the establishment and progression in peri-implantitis is explored. While it is acknowledged that these issues require further investigation, the available evidence suggests that osseointegration is a state of homeostasis between the titanium implant and surrounding tissues, with little evidence that a persistent foreign body reaction is responsible for peri-implant bone loss after osseointegration is established. Further, there is a lack of evidence for a unidirectional causative role of corrosion by-products and titanium particles as possible non-plaque related factors in the etiology of peri-implantitis.

[Types of clinical data and statistical methodology of human use experience in traditional Chinese medicine].

Application experience in humans, a summary of the clinical practice of traditional Chinese medicine(TCM), serves as an important data source for evaluating the safety, effectiveness, and clinical value of drugs in the development of new Chinese medicine. The collected data serving as the evaluation evidence through statistical analysis are critical to the research on the application experience in humans. This article summarized and analyzed the data characteristics and statistical methodology of application experience of Chinese medicine in humans, and concluded the data types, outcome evaluation, bias evaluation, confounding factors, and missing values. Furthermore, the article emphasized the importance of data analysis of application experience of Chinese medicine in humans for TCM evidence and put forward the current difficulties, such as low data quality and large internal bias, lack of individualized data processing methods, and lack of methods for "disease-syndrome combination" data. We believe that with the development of methodology, the application experience of Chinese medicine in humans can strongly support the development of new drugs in TCM.

Field-Tunable Interactions and Frustration in Underlayer-Mediated Artificial Spin Ice.

Artificial spin ice systems have opened experimental windows into a range of model magnetic systems through the control of interactions among nanomagnet moments. This control has previously been enabled by altering the nanomagnet size and the geometry of their placement. Here we demonstrate that the interactions in artificial spin ice can be further controlled by including a soft ferromagnetic underlayer below the moments. Such a substrate also breaks the symmetry in the array when magnetized, introducing a directional component to the correlations. Using spatially resolved magneto-optical Kerr effect microscopy to image the demagnetized ground states, we show that the correlation of the demagnetized states depends on the direction of the underlayer magnetization. Further, the relative interaction strength of nearest and next-nearest neighbors varies significantly with the array geometry. We exploit this feature to induce frustration in an inherently unfrustrated square lattice geometry, demonstrating new possibilities for effective geometries in two-dimensional nanomagnetic systems.

Molecular subtypes based on DNA methylation predict prognosis in lung squamous cell carcinoma.

BACKGROUND: Due to tumor heterogeneity, the diagnosis, treatment, and prognosis of patients with lung squamous cell carcinoma (LUSC) are difficult. DNA methylation is an important regulator of gene expression, which may help the diagnosis and therapy of patients with LUSC. METHODS: In this study, we collected the clinical information of LUSC patients in the Cancer Genome Atlas (TCGA) database and the relevant methylated sequences of the University of California Santa Cruz (UCSC) database to construct methylated subtypes and performed prognostic analysis. RESULTS: Nine hundred sixty-five potential independent prognosis methylation sites were finally identified and the genes were identified. Based on consensus clustering analysis, seven subtypes were identified by using 965 CpG sites and corresponding survival curves were plotted. The prognostic analysis model was constructed according to the methylation sites' information of the subtype with the best prognosis. Internal and external verifications were used to evaluate the prediction model. CONCLUSIONS: Models based on differences in DNA methylation levels may help to classify the molecular subtypes of LUSC patients, and provide more individualized treatment recommendations and prognostic assessments for different clinical subtypes. GNAS, FZD2, FZD10 are the core three genes that may be related to the prognosis of LUSC patients.

Arctigenin alleviates myocardial infarction injury through inhibition of the NFAT5-related inflammatory phenotype of cardiac macrophages/monocytes in mice.

In this study, we screened potential natural compounds for the treatment of myocardial infarction (MI) and explored the underlying mechanisms. We built three machine learning models to screen the potential compounds. qPCR, flow cytometry, immunohistochemistry, and immunofluorescence analyses were applied to analyze the pharmacological effects of the compounds on macrophages/monocytes in vivo and in vitro. Arctigenin (AG) was selected as a candidate, and echocardiography, Masson's trichrome staining, and TUNEL staining were utilized to detect the effect of AG on MI in vivo. Transcriptome analysis and subsequent bioinformatics analyses were performed to predict the target of the selected compound. Western blot and luciferase reporter assays were used to confirm the target and mechanism of AG. The reversibility of the effects of AG were verified through overexpression of NFAT5. The results showed that AG can improve cardiac injury after MI by reducing infarct size, improving heart function, and inhibiting cardiac death. In addition, AG suppresses inflammatory macrophages/monocytes and proinflammatory cytokines in vivo and in vitro. Transcriptomic and biological experiments revealed that AG modulates macrophage polarization via the NFAT5-induced signaling pathway. Therefore, our data suggest that AG can improve MI by inhibiting the inflammatory phenotype of macrophages/monocytes through targeting of NFAT5.

The pleiotropic association between IL-10 levels and CVD prognosis: Evidence from a meta-analysis.

We examined the precise association between IL-10 levels and cardiovascular disease (CVD) prognosis and explored the pleiotropic role of IL-10 in different cardiac pathologies. We performed a meta-analysis of cross-sectional and longitudinal studies investigating IL-10 levels. Meta-regression analyses were used to determine the cause of the discrepancies. To assess publication bias, funnel plots were constructed, and Egger's tests were performed. Data from the GSE58015 dataset were used to investigate the levels of IL-10 under certain conditions. Because of substantial heterogeneity in the data used to compare the IL-10 levels between patients with CVD and healthy people, we could not determine the differences between the healthy controls and patients with ischemic or nonischemic pathologies (p > 0.05). The analysis of the association between IL-10 levels and CVD prognosis indicated that higher IL-10 levels were significantly associated with a poor prognosis in patients with nonischemic pathologies (HR = 1.10, 95% CI = 1.00-1.20, p = 0.043) but differentially associated with the prognosis of patients with ischemic pathologies based on the sampling time point (before percutaneous coronary intervention (PCI): HR = 4.90, 95% CI = 1.24-19.30, p < 0.001; after PCI: HR = 0.57, 95% CI = 0.43-0.75, p = 0.023). The meta-regression analysis showed that the pooled HR of the IL-10 levels was positively correlated with the IL-10/IL-6 ratio (ß = 0.644, p = 0.024). The funnel plots and Egger's tests revealed no statistically significant bias in our meta-analysis (p > 0.1). Furthermore, our data mining analysis supported our findings. Our analysis showed that IL-10 levels may be pleiotropically associated with the CVD prognosis possibly based on the type of pathology, disease stage and levels of other proinflammatory factors, such as IL-6.

Performance of a simplified termination of resuscitation rule for adult traumatic cardiopulmonary arrest in the prehospital setting.

OBJECTIVE: The prehospital termination of resuscitation (TOR) guidelines for traumatic cardiopulmonary arrest (TCPA) was proposed in 2003. Its multiple descriptors of cases where efforts can be terminated make it complex to apply in the field. Here we proposed a simplified rule and evaluated its predictive performance. METHODS: We analysed Utstein registry data for 2009-2013 from a Taipei emergency medical service to test a simplified TOR rule that comprises two criteria: blunt trauma injury and the presence of asystole. Enrolees were adults (≥18 years) with TCPA. The predicted outcome was in-hospital death. We compared the areas under the curve (AUC) of the simple rule with each of four descriptors in the guidelines and with a combination of all four to assess their discriminatory ability. Test characteristics were calculated to assess predictive performance. RESULTS: A total of 893 TCPA cases were included. Blunt trauma occurred in 459 (51.4%) cases and asystole in 384 (43.0%). In-hospital mortality was 854 (95.6%) cases. The simplified TOR rule had greater discriminatory ability (AUC 0.683, 95% CI 0.618 to 0.747) compared with any single descriptor in the 2003 guidelines (range of AUC: 0.506-0.616) although the AUC was similar when all four were combined (AUC 0.695, 95% CI 0.615 to 0.775). The specificity of the simplified rule was 100% (95% CI 88.8% to 100%) and positive predictive value 100% (95% CI 96.8% to 100%). The false positive value, false negative value and decreased rate of unnecessary transport were 0% (95% CI 0% to 3.2%), 94.8% (95% CI 92.9% to 96.2%) and 16.4% (95% CI 14.1% to 19.1%), respectively. CONCLUSIONS: The simplified TOR rule appears to accurately predict non-survivors in adults with TCPA in the prehospital setting.

Liberal versus restricted fluid resuscitation strategies in trauma patients: a systematic review and meta-analysis of randomized controlled trials and observational studies*.

OBJECTIVE: Hemorrhage is responsible for most deaths that occur during the first few hours after trauma. Animal models of trauma have shown that restricting fluid administration can reduce the risk of death; however, studies in patients are difficult to conduct due to logistical and ethical problems. To maximize the value of the existing evidence, we performed a meta-analysis to compare liberal versus restricted fluid resuscitation strategies in trauma patients. DATA SOURCES: Medline and Embase were systemically searched from inception to February 2013. STUDY SELECTION: We selected randomized controlled trials and observational studies that compared different fluid administration strategies in trauma patients. There were no restrictions for language, population, or publication year. DATA EXTRACTION: Four randomized controlled trials and seven observational studies were identified from 1,106 references. One of the randomized controlled trials suffered from a high protocol violation rate and was excluded from the final analysis. DATA SYNTHESIS: The quantitative synthesis indicated that liberal fluid resuscitation strategies might be associated with higher mortality than restricted fluid strategies, both in randomized controlled trials (risk ratio, 1.25; 95% CI, 1.01-1.55; three trials; I(2), 0) and observational studies (odds ratio, 1.14; 95% CI, 1.01-1.28; seven studies; I(2), 21.4%). When only adjusted odds ratios were pooled for observational studies, odds for mortality with liberal fluid resuscitation strategies increased (odds ratio, 1.19; 95% CI, 1.02-1.38; six studies; I(2), 26.3%). CONCLUSIONS: Current evidence indicates that initial liberal fluid resuscitation strategies may be associated with higher mortality in injured patients. However, available studies are subject to a high risk of selection bias and clinical heterogeneity. This result should be interpreted with great caution.

A simplified herbal decoction attenuates myocardial infarction by regulating macrophage metabolic reprogramming and phenotypic differentiation via modulation of the HIF-1α/PDK1 axis.

BACKGROUND: Myocardial infarction (MI) poses a global public health challenge, often associated with elevated mortality rates and a grim prognosis. A crucial aspect of the inflammatory injury and healing process post-MI involves the dynamic differentiation of macrophages. A promising strategy to alleviate myocardial damage after MI is by modulating the inflammatory response and orchestrating the shift from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages, aiming to achieve a reduced M1/M2 ratio. Nuanxinkang (NXK), a simplified herbal decoction, has demonstrated noteworthy cardioprotective, inflammation-regulating, and myocardial energy metabolism-regulating properties. METHODS: In this study, we constructed an MI model by ligating coronary arteries to investigate the efficacy of NXK in improving ventricular remodeling and cardiac function. Mice were administered NXK (1.65 g/kg/d) or an equivalent volume of regular saline via gavage for 28 consecutive days, commencing the day after surgery. Then, we conducted echocardiography to assess the cardiac function, Masson staining to illustrate the extent of myocardial fibrosis, TUNEL staining to reveal myocardial apoptosis, and flow cytometry to analyze the polarization of M1 and M2 macrophages in the hearts. Besides, a lipopolysaccharide (LPS)-induced pro-inflammatory macrophage (M1) polarization model was implemented in RAW264.7 cells to elucidate the underlying mechanism of NXK in regulating macrophage polarization. RAW264.7 cells were pre-treated with or without NXK-containing serum. Oxidative stress was detected by MitoSox staining, followed by Seahorse energy metabolism assay to evaluate alterations in mitochondrial metabolic patterns and ATP production. Both In vivo and in vitro, HIF-1α and PDK1 were detected by fluorescent quantitative PCR and Western blotting. RESULTS: In vivo, MI mice exhibited a decline in cardiac function, adverse ventricular remodeling, and an increase in glycolysis, coupled with M1-dominant polarization mediated by the HIF-1α/PDK1 axis. Notably, robust responses were evident with high-dose NXK treatment (1.65 g/kg/day), leading to a significant enhancement in cardiac function, inhibition of cardiac remodeling, and partial suppression of macrophage glycolysis and the inflammatory phenotype in MI mice. This effect was achieved through the modulation of the HIF-1α/PDK1 axis. In vitro, elevated levels of mitochondrial ROS production and glycolysis were observed in LPS-induced macrophages. Conversely, treatment with NXK notably reduced the oxidative stress damage induced by LPS and enhanced oxidative phosphorylation (OXPHOS). Furthermore, NXK demonstrated the ability to modify the energy metabolism and inflammatory characteristics of macrophages by modulating the HIF-1α/PDK1 axis. The influence of NXK on this axis was partially counteracted by the HIF-1α agonist DMOG. And NXK downregulated PDK1 expression, curtailed glycolysis, and reversed LPS-induced M1 polarization in macrophages, similar to the PDK1 inhibitor DCA. CONCLUSION: In conclusion, NXK protects against MI-induced cardiac remodeling by inducing metabolic reprogramming and phenotypic differentiation of macrophages, achieved through the modulation of the HIF-1α/PDK1 axis. This provides a novel and promising strategy for the treatment of MI.

Xinyang tablet alleviated cardiac dysfunction in a cardiac pressure overload model by regulating the receptor-interacting serum/three-protein kinase 3/FUN14 domain containing 1-mediated mitochondrial unfolded protein response and mitophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Xinyang tablet (XYT) has been used for heart failure (HF) for over twenty years in clinical practice, but the underlying molecular mechanism remains poorly understood. AIMS OF THE STUDY: In the present study, we aimed to explore the protective effects of XYT in HF in vivo and in vitro. MATERIALS AND METHODS: Transverse aortic constriction was performed in vivo to establish a mouse model of cardiac pressure overload. Echocardiography, tissue staining, and real-time quantitative PCR (qPCR) were examined to evaluate the protective effects of XYT on cardiac function and structure. Adenosine 5'-triphosphate production, reactive oxygen species staining, and measurement of malondialdehyde and superoxide dismutase was used to detect mitochondrial damage. Mitochondrial ultrastructure was observed by transmission electron microscope. Immunofluorescence staining, qPCR, and Western blotting were performed to evaluate the effect of XYT on the mitochondrial unfolded protein response and mitophagy, and to identify its potential pharmacological mechanism. In vitro, HL-1 cells and neonatal mouse cardiomyocytes were stimulated with Angiotensin II to establish the cell model. Western blotting, qPCR, immunofluorescence staining, and flow cytometry were utilized to determine the effects of XYT on cardiomyocytes. HL-1 cells overexpressing receptor-interacting serum/three-protein kinase 3 (RIPK3) were generated by transfection of RIPK3-overexpressing lentiviral vectors. Cells were then co-treated with XYT to determine the molecular mechanisms. RESULTS: In the present study, XYT was found to exerta protective effect on cardiac function and structure in the pressure overload mice. And it was also found XYT reduced mitochondrial damage by enhancing mitochondrial unfolded protein response and restoring mitophagy. Further studies showed that XYT achieved its cardioprotective role through regulating the RIPK3/FUN14 domain containing 1 (FUNDC1) signaling. Moreover, the overexpression of RIPK3 successfully reversed the XYT-induced protective effects and significantly attenuated the positive effects on the mitochondrial unfolded protein response and mitophagy. CONCLUSIONS: Our findings indicated that XYT prevented pressure overload-induced HF through regulating the RIPK3/FUNDC1-mediated mitochondrial unfolded protein response and mitophagy. The information gained from this study provides a potential strategy for attenuating mitochondrial damage in the context of pressure overload-induced heart failure using XYT.

Accumulation of ß-aminoisobutyric acid mediates hyperalgesia in ovariectomized mice through Mas-related G protein-coupled receptor D signaling.

Hyperalgesia is typified by reduced pain thresholds and heightened responses to painful stimuli, with a notable prevalence in menopausal women, but the underlying mechanisms are far from understood. ß-Aminoisobutyric acid (BAIBA), a product of valine and thymine catabolism, has been reported to be a novel ligand of the Mas-related G protein coupled receptor D (MrgprD), which mediates pain and hyperalgesia. Here, we established a hyperalgesia model in 8-week-old female mice through ovariectomy (OVX). A significant increase in BAIBA plasma level was observed and was associated with decline of mechanical withdrawal threshold, thermal and cold withdrawal latency in mice after 6 weeks of OVX surgery. Increased expression of MrgprD in dorsal root ganglion (DRG) was shown in OVX mice compared to Sham mice. Interestingly, chronic loading with BAIBA not only exacerbated hyperalgesia in OVX mice, but also induced hyperalgesia in gonadally intact female mice. BAIBA supplementation also upregulated the MrgprD expression in DRG of both OVX and intact female mice, and enhanced the excitability of DRG neurons in vitro. Knockout of MrgprD markedly suppressed the effects of BAIBA on hyperalgesia and excitability of DRG neurons. Collectively, our data suggest the involvement of BAIBA in the development of hyperalgesia via MrgprD-dependent pathway, and illuminate the mechanisms underlying hyperalgesia in menopausal women.

Crosstalk between endothelial cells with a non-canonical EndoMT phenotype and cardiomyocytes/fibroblasts via IGFBP5 aggravates TAC-induced cardiac dysfunction.

Heart failure (HF) is a complex chronic condition characterized by structural and functional impairments. The differentiation of endothelial cells into myofibroblasts (EndoMT) in response to cardiac fibrosis is controversial, and the relative contribution of endothelial plasticity remains to be explored. Single-cell RNA sequencing was used to identify endothelial cells undergoing fibrotic differentiation within 2 weeks of transverse aortic constriction (TAC). This subset of endothelial cells transiently expressed fibrotic genes but had low expression of alpha-smooth muscle actin, indicating a non-canonical EndoMT, which we named a transient fibrotic-like phenotype (EndoFP). The role of EndoFP in pathological cardiac remodeling may be correlated with increased levels of osteopontin. Cardiomyocytes and fibroblasts co-cultured with EndoFP exhibited heightened pro-hypertrophic and pro-fibrotic effects. Mechanistically, we found that the upregulated expression of insulin-like growth factor-binding protein 5 may be a key mediator of EndoFP-induced cardiac dysfunction. Furthermore, our findings suggested that Rab5a is a novel regulatory gene involved in the EndoFP process. Our study suggests that the specific endothelial subset identified in TAC-induced pressure overload plays a critical role in the cellular interactions that lead to cardiac fibrosis and hypertrophy. Additionally, our findings provide insight into the mechanisms underlying EndoFP, making it a potential therapeutic target for early heart failure.

A simplified scoring model for predicting bacteremia in the unscheduled emergency department revisits: The SADFUL score.

BACKGROUND: Bacteremia is a severe complication of infectious disease. Patients with a high bacteremia risk in the emergency department (ED) but misidentified would lead to the unscheduled revisits. This study aimed to develop a simplified scoring model to predict bacteremia in patients with unscheduled ED revisits. METHODS: Adult patients with unscheduled ED revisits within 72 h with a final diagnosis of infectious disease were retrospectively included. The development cohort included patients visiting the ED from January 1, 2019 to December 31, 2021. Internal validation was performed in patients visiting the ED from January 1, 2022 to March 31, 2022. Variables including demographics, pre-comorbidities, triage levels, vital signs, chief complaints, and laboratory data in the index visit were analyzed. Bacteremia was the primary outcome determined by blood culture in either index visits or revisits. RESULTS: The SADFUL score for predicting bacteremia comprised the following predictors: "S"egmented neutrophil percentage (+3 points), "A"ge > 55 years (+1 point), "D"iabetes mellitus (+1 point), "F"ever (+2 points), "U"pper respiratory tract symptoms (-2 points), and "L"eukopenia (2 points). The area under receiver operating characteristic curve with 95% confidence interval in the development (1802 patients, 190 [11%] with bacteremia) and the validation cohort (134 patients, 17 [13%] with bacteremia) were 0.78 (0.74-0.81) and 0.79 (0.71-0.88), respectively. CONCLUSIONS: The SADFUL score is a simplified useful tool for predicting bacteremia in patients with unscheduled ED revisits. The scoring model could help ED physicians decrease misidentification of patients at a high risk for bacteremia and potential complications.

ZrTe2/CrTe2: an epitaxial van der Waals platform for spintronics.

The rapid discovery of two-dimensional (2D) van der Waals (vdW) quantum materials has led to heterostructures that integrate diverse quantum functionalities such as topological phases, magnetism, and superconductivity. In this context, the epitaxial synthesis of vdW heterostructures with well-controlled interfaces is an attractive route towards wafer-scale platforms for systematically exploring fundamental properties and fashioning proof-of-concept devices. Here, we use molecular beam epitaxy to synthesize a vdW heterostructure that interfaces two material systems of contemporary interest: a 2D ferromagnet (1T-CrTe2) and a topological semimetal (ZrTe2). We find that one unit-cell (u.c.) thick 1T-CrTe2 grown epitaxially on ZrTe2 is a 2D ferromagnet with a clear anomalous Hall effect. In thicker samples (12 u.c. thick CrTe2), the anomalous Hall effect has characteristics that may arise from real-space Berry curvature. Finally, in ultrathin CrTe2 (3 u.c. thickness), we demonstrate current-driven magnetization switching in a full vdW topological semimetal/2D ferromagnet heterostructure device.

Intravenous antibiotics at the index emergency department visit as an independent risk factor for hospital admission at the return visit within 72 hours.

INTRODUCTION: Although infection was the most common symptom in patients returning to the ED, whether intravenous antibiotic administration at the index visit could serve as an indicator of patients with infectious diseases at high risk for hospital admission after returning to the ED within a short period of time remains unclear. The study aimed to investigate the potential risk factors for hospital admission in patients returning to the ED within 72 hours with a final diagnosis of infectious diseases. MATERIAL AND METHODS: This retrospective cohort study analyzed return visits to the ED from January to December 2019. Adult patients aged >20 years who had a return visit to the ED within 72 hours with an infectious disease were included herein. In total, 715 eligible patients were classified into the intravenous antibiotics and non-intravenous antibiotics group (reference group). The outcome studied was hospital admission to general ward and intensive care unit (ICU) at the return visits. RESULTS: Patients receiving intravenous antibiotics at index visits had significantly higher risk-approximately two times-for hospital admission at the return visits than those did not (adjusted odds ratio = 2.47, 95% CI = 1.34-4.57, p = 0.004). For every 10 years increase in age, the likelihood for hospital admission increased by 38%. Other factors included abnormal respiratory rate and high C-reactive protein levels. CONCLUSIONS: Intravenous antibiotic administration at the index visit was an independent risk factor for hospital admission at return visits in patients with an infection disease. Physicians should consider carefully before discharging patients receiving intravenous antibiotics.

Single-cell transcriptomic analyses of cardiac immune cells reveal that Rel-driven CD72-positive macrophages induce cardiomyocyte injury.

AIMS: The goal of our study was to investigate the heterogeneity of cardiac macrophages (CMφs) in mice with transverse aortic constriction (TAC) via single-cell sequencing and identify a subset of macrophages associated with heart injury. METHODS AND RESULTS: We selected all CMφs from CD45+ cells using single-cell mRNA sequencing data. Through dimension reduction, clustering, and enrichment analyses, CD72hi CMφs were identified as a subset of pro-inflammatory macrophages. The pseudo-time trajectory and ChIP-Seq analyses identified Rel as the key transcription factor that induces CD72hi CMφ differentiation. Rel KD and Rel-/- bone marrow chimaera mice subjected to TAC showed features of mitigated cardiac injury, including decreased levels of cytokines and ROS, which prohibited cardiomyocyte death. The transfer of adoptive Rel-overexpressing monocytes and CD72hi CMφ injection directly aggravated heart injury in the TAC model. The CD72hi macrophages also exerted pro-inflammatory and cardiac injury effects associated with myocardial infarction. In humans, patients with heart failure exhibit increased CD72hi CMφ levels following dilated cardiomyopathy and ischaemic cardiomyopathy. CONCLUSION: Bone marrow-derived, Rel-mediated CD72hi macrophages play a pro-inflammatory role, induce cardiac injury and, thus, may serve as a therapeutic target for multiple cardiovascular diseases.

A molecular phenotypic screen reveals that lobetyolin alleviates cardiac dysfunction in 5/6 nephrectomized mice by inhibiting osteopontin.

BACKGROUND: Cardiovascular diseases are the major cause of mortality in patients with advanced chronic kidney diseases. The predominant abnormality observed among this population is cardiac dysfunction secondary to myocardial remodelings, such as hypertrophy and fibrosis, emphasizing the need to develop potent therapies that maintain cardiac function in patients with end-stage renal disease. AIMS: To identify potential compounds and their targets as treatments for cardiorenal syndrome type 4 (CRS) using molecular phenotyping and in vivo/in vitro experiments. METHODS: Gene expression was assessed using bioinformatics and verified in animal experiments using 5/6 nephrectomized mice (NPM). Based on this information, a molecular phenotyping strategy was pursued to screen potential compounds. Picrosirius red staining, wheat germ agglutinin staining, Echocardiography, immunofluorescence staining, and real-time quantitative PCR (qPCR) were utilized to evaluate the effects of compounds on CRS in vivo. Furthermore, qPCR, immunofluorescence staining and flow cytometry were applied to assess the effects of these compounds on macrophages/cardiac fibroblasts/cardiomyocytes. RNA-Seq analysis was performed to locate the targets of the selected compounds. Western blotting was performed to validate the targets and mechanisms. The reversibility of these effects was tested by overexpressing Osteopontin (OPN). RESULTS: OPN expression increased more remarkably in individuals with uremia-induced cardiac dysfunction than in other cardiomyopathies. Lobetyolin (LBT) was identified in the compound screen, and it improved cardiac dysfunction and suppressed remodeling in NPM mice. Additionally, OPN modulated the effect of LBT on cardiac dysfunction in vivo and in vitro. Further experiments revealed that LBT suppressed OPN expression via the phosphorylation of c-Jun N-terminal protein kinase (JNK) signaling pathway. CONCLUSIONS: LBT improved CRS by inhibiting OPN expression through the JNK pathway. This study is the first to describe a cardioprotective effect of LBT and provides new insights into CRS drug discovery.