Enediyne natural product biosynthesis unified by a diiodotetrayne intermediate.

Enediyne natural products are renowned for their potent cytotoxicities but the biosynthesis of their defining 1,5-diyne-3-ene core moiety remains largely enigmatic. Since the discovery of the enediyne polyketide synthase cassette in 2002, genome sequencing has revealed thousands of distinct enediyne biosynthetic gene clusters, each harboring the conserved enediyne polyketide synthase cassette. Here we report that (1) the products of this cassette are an iodoheptaene, a diiodotetrayne and two pentaynes; (2) the diiodotetrayne represents a common biosynthetic intermediate for all known enediynes; and (3) cryptic iodination can be exploited to increase enediyne titers. These findings establish a unified biosynthetic pathway for the enediynes, set the stage to further advance enediyne core biosynthesis and enable fundamental breakthroughs in chemistry, enzymology and translational applications of enediyne natural products.

Levels of trace metals and their impact on oocyte: A review.

Trace metals play a vital role in a variety of biological processes, but excessive amounts can be toxic and are receiving increasing attention. Trace metals in the environment are released from natural sources, such as rock weathering, volcanic eruptions, and other human activities, such as industrial emissions, mineral extraction, and vehicle exhaust. Lifestyle, dietary habits and environmental quality are the main sources of human exposure to trace metals, which play an important role in inducing human reproductive infertility. The purpose of this review is to summarize the distribution of various trace metals in oocyte and to identify the trace metals that may cause oocyte used in the design and execution of toxicological studies.

Anti-inflammatory discovery of sesquiterpenoids and a jasmonic acid derivative from Artemisia stolonifera.

Eleven previously undescribed sesquiterpenoids (8-18), one undescribed jasmonic acid derivative (35) and 28 known compounds were isolated from the leaves of Artemisia stolonifera. Undescribed compounds with their absolute configurations were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction and ECD calculation. Compound 8 was identified as a rare sesquiterpenoid featuring a rearranged 5/8 bicyclic ring system, whereas compound 17 was found to be an unprecedented monocyclic sesquiterpenoid with methyl rearrangement. Evaluation of biological activity showed that compounds 1-5 and 7 displayed cytotoxicity against six tumor cells. In the meantime, compounds 11, 12, 18 and 35 exhibited inhibitory effects against LPS-stimulated NO production in RAW 264.7 macrophage cells and reduced the transcription of IL-6 and IL-1ß in a dose-dependent manner at 25, 50 and 100 µM. Moreover, the anti-inflammatory-based network pharmacology and molecular docking analyses revealed potential target proteins of 11, 12, 18 and 35.

Analysis of the thickness characteristics of the left atrial posterior wall and its correlation with the low and no voltage areas of the left atrial posterior wall in patients with atrial fibrillation.

OBJECTIVE: To analyze the relationship between the thickness of the left atrial posterior wall and the low and no voltage zones in the left atrial posterior wall in patients with atrial fibrillation (AF). METHODS: 61 patients admitted to our cardiology department for AF and radiofrequency ablation of AF from January 1, 2020 to May 30, 2022 were enrolled according to inclusion and exclusion criteria. The atrial wall thickness was measured by CT scan. Baseline data, preoperative cardiac ultrasound data, preoperative biochemical parameters, low voltage zone (fibrotic zone) and no voltage zone (scar zone) in the left atrial posterior wall area, and various parameters of posterior left atrial wall thickness were collected. RESULTS: The differences of the thickness between the upper, middle and lower mean levels of the left atrial posterior wall were statistically significant (P = 0.004). The results showed that body mass index was weakly positively correlated with the mean level of total left atrial posterior wall thickness (r = 0.426, P = 0.001) and was statistically significant. The remaining indices were positively or negatively correlated with the mean level of total left atrial posterior wall thickness, but none were statistically significant (P > 0.05). CONCLUSIONS: Both left atrial posterior wall low-voltage zone and voltage-free zone were positively correlated with the mean total left atrial posterior wall thickness, and left atrial posterior wall low-voltage zone and voltage-free zone were significantly positively correlated. Body mass index was weakly positively correlated with total left atrial posterior wall thickness.

RNAi efficiency is enhanced through knockdown of double-stranded RNA-degrading enzymes in butterfly Papilio xuthus.

The efficiency of RNA interference (RNAi) has always limited the research on the phenotype innovation of Lepidoptera insects. Previous studies have found that double-stranded RNA-degrading enzyme (dsRNase) is an important factor in RNAi efficiency, but there have been no relevant reports in butterflies (Papilionoidea). Papilio xuthus is one of the important models in butterflies with an extensive experimental application value. To explore the effect of dsRNase in the RNAi efficiency on butterflies, six dsRNase genes (PxdsRNase 1-6) were identified in P. xuthus genome, and their dsRNA-degrading activities were subsequently detected by ex vivo assays. The result shows that the dsRNA-degrading ability of gut content (<1 h) was higher than hemolymph content (>12 h). We then investigated the expression patterns of these PxdsRNase genes during different tissues and developmental stages, and related RNAi experiments were carried out. Our results show that different PxdsRNase genes had different expression levels at different developmental stages and tissues. The expression of PxdsRNase2, PxdsRNase3, and PxdsRNase6 were upregulated significantly through dsGFP injection, and PxdsRNase genes can be silenced effectively by injecting their corresponding dsRNA. RNAi-of-RNAi studies with PxEbony, which acts as a reporter gene, observed that silencing PxdsRNase genes can increase RNAi efficiency significantly. These results confirm that silencing dsRNase genes can improve RNAi efficiency in P. xuthus significantly, providing a reference for the functional study of insects such as butterflies with low RNAi efficiency.

Causal Relationship Between Immune Cells/Cytokines and Dilated Cardiomyopathy.

To date, whether there is any causal relationship between dilated cardiomyopathy (DCM) and the changes in the levels/expression of immune cells/cytokines is still unclear. This study aimed to investigate the causal relationship between the levels of various types of immune cells/cytokines and DCM. Herein, two-sample Mendelian randomization (MR) (TSMR) using R software was conducted. Single nucleotide polymorphisms (SNPs) related to the levels of various types of immune cells/cytokines and DCM were screened based on the genome-wide association studies (GWAS) obtained from open-source databases. The TSMR was conducted using inverse variance weighted (IVW), method, MR-Egger regression, weighted median method, and simple estimator based on mode to explore the causal association between the levels of each immune cell/cytokine and DCM. Sensitivity analysis was conducted using MR-Egger regression and a leave-one-out sensitivity test. A total of 1816 SNPs related to host immune status and DCM were identified. The IVW results showed a relationship between DCM and the circulating levels of basophils/eosinophils, total eosinophils-basophils, lymphocytes, and C-reactive protein (CRP). Increased lymphocytes levels (odds ratio (OR) = 0.91, 95% confidence interval (CI): 0.84-0.97, P = 0.005) were seen as protective against DCM, whereas increased basophil (OR = 1.18, 95% CI: 1.04-1.33, P = 0.022), eosinophil (OR = 1.1, 95% CI: 1.03-1.17, P = 0.007), eosinophil-basophil (OR = 1.09, 95% CI: 1.02-1.17, P = 0.014), and CRP (OR = 1.1, 95% CI: 1.03-1.18, P = 0.013) levels were associated with an increased risk of DCM. These analyses revealed that there may be a relationship between immune cells/select cytokine status and the onset of DCM. Future studies are required to further validate these outcomes in animal models and clinical trials.

High-mobility group box 1 and its related receptors: potential therapeutic targets for contrast-induced acute kidney injury.

Percutaneous coronary intervention (PCI) is a crucial diagnostic and therapeutic approach for coronary heart disease. Contrast agents' exposure during PCI is associated with a risk of contrast-induced acute kidney injury (CI-AKI). CI-AKI is characterized by a sudden decline in renal function occurring as a result of exposure to intravascular contrast agents, which is associated with an increased risk of poor prognosis. The pathophysiological mechanisms underlying CI-AKI involve renal medullary hypoxia, direct cytotoxic effects, endoplasmic reticulum stress, inflammation, oxidative stress, and apoptosis. To date, there is no effective therapy for CI-AKI. High-mobility group box 1 (HMGB1), as a damage-associated molecular pattern molecule, is released extracellularly by damaged cells or activated immune cells and binds to related receptors, including toll-like receptors and receptor for advanced glycation end product. In renal injury, HMGB1 is expressed in renal tubular epithelial cells, macrophages, endothelial cells, and glomerular cells, involved in the pathogenesis of various kidney diseases by activating its receptors. Therefore, this review provides a theoretical basis for HMGB1 as a therapeutic intervention target for CI-AKI.

Development and validation of a risk model for intracardiac thrombosis in patients with dilated cardiomyopathy: a retrospective study.

Intracardiac thrombosis is a severe complication in patients with non-ischemic dilated cardiomyopathy. This study aims to develop and validate an individualized nomogram to evaluate the risk of intracardiac thrombosis in patients with non-ischemic dilated cardiomyopathy. This retrospective study included patients diagnosed with dilated cardiomyopathy at first admission. Clinical baseline characteristics were acquired from electronic medical record systems. Multiple methods were applied to screen the key variables and generate multiple different variable combinations. Multivariable logistic regression was used to build the models, and the optimal model was chosen by comparing the discrimination. Then we checked the performance of the model in different thrombus subgroups. Finally, the model was presented using a nomogram and evaluated from the perspectives of discrimination, calibration, and clinical usefulness. Internal validation was performed by extracting different proportions of data for Bootstrapping. Ultimately, 564 eligible patients were enrolled, 67 of whom developed an intracardiac thrombosis. Risk factors included d-dimer, white blood cell count, high-sensitivity C-reactive protein, pulse pressure, history of stroke, hematocrit, and NT-proBNP in the optimal model. The model had good discrimination and calibration, and the area under the curve (AUC) was 0.833 (0.782-0.884), and the model's performance in each subgroup was stable. Clinical decision curve analysis showed that the model had clinical application value when the high-risk threshold was between 2% and 78%. The AUC of interval validation (30% and 70% data resampling) was 0.844 (0.765-0.924) and 0.833 (0.775-0.891), respectively. This novel intracardiac thrombosis nomogram could be conveniently applied to facilitate the individual intracardiac thrombosis risk assessment in patients with non-ischemic dilated cardiomyopathy.

The Natural Products Discovery Center: Release of the First 8490 Sequenced Strains for Exploring Actinobacteria Biosynthetic Diversity.

Actinobacteria, the bacterial phylum most renowned for natural product discovery, has been established as a valuable source for drug discovery and biotechnology but is underrepresented within accessible genome and strain collections. Herein, we introduce the Natural Products Discovery Center (NPDC), featuring 122,449 strains assembled over eight decades, the genomes of the first 8490 NPDC strains (7142 Actinobacteria), and the online NPDC Portal making both strains and genomes publicly available. A comparative survey of RefSeq and NPDC Actinobacteria highlights the taxonomic and biosynthetic diversity within the NPDC collection, including three new genera, hundreds of new species, and ~7000 new gene cluster families. Selected examples demonstrate how the NPDC Portal's strain metadata, genomes, and biosynthetic gene clusters can be leveraged using genome mining approaches. Our findings underscore the ongoing significance of Actinobacteria in natural product discovery, and the NPDC serves as an unparalleled resource for both Actinobacteria strains and genomes.

Discovery of ent-labdane derivatives from Andrographis paniculata and their anti-inflammatory activity.

The plant Andrographis paniculata has a long history of cultivation in Southeast Asia, especially its extensive anti-inflammatory activity, and the famous natural antibiotic andrographolide comes from this plant. In China, A. paniculata, as the main crop, has become a major source of traditional Chinese medicine (TCM) for the clinical treatment of inflammation. To further explore the diverse diterpene lactones with better anti-inflammatory activity from A. paniculata, twenty-one ent-labdanes, including six undescribed compounds (andropanilides D-I), were isolated. Their structures with absolute configurations were thoroughly determined by comprehensive NMR spectroscopic data, HRESIMS analysis and quantum chemical calculations. All isolated compounds were evaluated for anti-inflammatory activities based on the Griess method. Meanwhile, after structure-activity relationships analysis, the anti-inflammatory activity of andropanilide D (1) (IC50 = 2.31 µM) was found to be better than that of the positive control drug (dexamethasone, IC50 = 6.52 µM) and andrographolide (IC50 = 5.89 µM). Further mechanisms of activity indicated that andropanilide D significantly reduced the secretion of TNF-α, IL-6 and IL-1ß and downregulated the protein expression of COX-2 and iNOS in LPS-induced RAW264.7 macrophages in a concentration-dependent manner based on Western blot and ELISA experiments. In conclusion, andropanilide D possesses potential medicinal value for the treatment of inflammation and further expands the material basis of the anti-inflammatory effect of A. paniculata.

Link prediction based on spectral analysis.

Link prediction in complex network is an important issue in network science. Recently, various structure-based similarity methods have been proposed. Most of algorithms are used to analyze the topology of the network, and to judge whether there is any connection between nodes by calculating the similarity of two nodes. However, it is necessary to get the extra attribute information of the node in advance, which is very difficult. Compared to the difficulty in obtaining the attribute information of the node itself, the topology of the network is easy to obtain, and the structure of the network is an inherent attribute of the network and is more reliable. The proposed method measures kinds of similarity between nodes based on non-trivial eigenvectors of Laplacian Matrix of the network, such as Euclidean distance, Manhattan distance and Angular distance. Then the classical machine learning algorithm can be used for classification prediction (two classification in this case), so as to achieve the purpose of link prediction. Based on this process, a spectral analysis-based link prediction algorithm is proposed, and named it LPbSA (Link Prediction based on Spectral Analysis). The experimental results on seven real-world networks demonstrated that LPbSA has better performance on Accuracy, Precision, Receiver Operating Curve(ROC), area under the ROC curve(AUC), Precision and Recall curve(PR curve) and balanced F Score(F-score curve) evaluation metrics than other ten classic methods.

Cofactorless oxygenases guide anthraquinone-fused enediyne biosynthesis.

The anthraquinone-fused enediynes (AFEs) combine an anthraquinone moiety and a ten-membered enediyne core capable of generating a cytotoxic diradical species. AFE cyclization is triggered by opening the F-ring epoxide, which is also the site of the most structural diversity. Previous studies of tiancimycin A, a heavily modified AFE, have revealed a cryptic aldehyde blocking installation of the epoxide, and no unassigned oxidases could be predicted within the tnm biosynthetic gene cluster. Here we identify two consecutively acting cofactorless oxygenases derived from methyltransferase and α/ß-hydrolase protein folds, TnmJ and TnmK2, respectively, that are responsible for F-ring tailoring in tiancimycin biosynthesis by comparative genomics. Further biochemical and structural characterizations reveal that the electron-rich AFE anthraquinone moiety assists in catalyzing deformylation, epoxidation and oxidative ring cleavage without exogenous cofactors. These enzymes therefore fill important knowledge gaps for the biosynthesis of this class of molecules and the underappreciated family of cofactorless oxygenases.

Meta-analysis of clinical adverse events after CABG vs. PCI in patients with chronic kidney disease and coronary artery disease.

AIM: To investigate the efficacy and postoperative clinical adverse events of coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) for chronic kidney disease (CKD) study participants combined with coronary artery disease (CAD). METHODS: All randomized controlled trials (RCTs) that focus on the therapeutic effect evaluation of CABG and PCI and their effect on postoperative clinical adverse events as well as main adverse cardiovascular and cerebrovascular events (MACCEs) in CKD study participants with CAD were screened from the following databases, including CNKI, CBM, Wan Fang, VIP, Embase, PubMed, as well as Cochrane library clinical controlled trials. The study was conducted under the PRISMA 2020 criteria. Data were extracted, and quality control was evaluated from the modified Jadad rating scale. Meta-analysis was then undertaken through STATA 16.0 software. RESULTS: A total of 5 RCTs were obtained, including 1198 patients. Study participants were subdivided into two groups, including the PCI group (n = 604) and the CABG group (n = 594). Meta-analysis of clinical adverse events results showed that the long-term survival results of CAD patients with CKD who underwent PCI were worsened compared to CABG, such as long-term MACCEs (RR = 1.59, 95%CI: 1.04-2.43) and the long-term repeated revascularization (RR = 2.48, 95%CI: 1.76-3.49). Also, cardiac death (RR = 1.68, 95%CI:1.04-2.71), as well as cerebrovascular accident (RR = 1.74, 95%CI:1.04-2.90) in CABG group was significantly lower than that in PCI group. CONCLUSION: This meta-analysis showed that CABG provided a better therapeutic effect than PCI in CKD patients with CAD when considering long-term prognosis. However, more prospective RCTs are needed to define the proper revascularization strategy for CAD patients with CKD.

Comparison of clinical outcomes of Ibutilide-guided cardioversion and direct current synchronized cardioversion after radiofrequency ablation of persistent atrial fibrillation.

Backgroup: Ibutilide has already been used for cardioversion of persistent atrial fibrillation (PsAF) after radiofrequency catheter ablation (RFCA). The purpose of this study was to determine the effect of Ibutilide-guided cardioversion on clinical outcomes after individualized ablation of PsAF. Methods: From October 2020 to September 2021, consecutive patients with PsAF accepted for RFCA were prospectively enrolled. After individualized ablation including pulmonary vein isolation plus left atrial roof line ablation and personalized linear ablation based on left atrial low-voltage zones, patients were divided into the spontaneous conversion (SCV) group, direct current synchronized cardioversion (DCC) group and Ibutilide group according to different cardioversion types during ablation. The rates of freedom from atrial tachyarrhythmia (ATT) among the three groups were evaluated after follow-up. Results: In this study, 110 patients were enrolled, including 12 patients with SCV, 50 patients receiving DCC and 48 patients receiving Ibutilide cardioversion after individualized ablation. Among the three groups, the SCV group had shorter AF duration {12 months [interquartile range (IQR) 12-16], P = 0.042} and smaller left atrial diameter (LAD) [35 mm (IQR: 33-42), P = 0.023]. A 12-month freedom from ATT rate was 83.3% in SCV group, 69.4% in DCC group, and 79.2% in Ibutilide group, respectively (Log-rank, P = 0.745). During the follow-up [17 months (IQR: 15-19)], the rate of freedom from ATT of SCV group (83.3%), and Ibutilide group (72.9%) were both higher than that of DCC group (53.1%, P = 0.042). Moreover, Kaplan-Meier analysis showed a significantly higher sinus rhythm (SR) maintenance in Ibutilide group than in DCC group (Log-rank, P = 0.041). After adjusting for risk factors of AF recurrence, the hazard ratio for AF recurrence of the DCC group with reference to the Ibutilide group was 4.10 [95% confidence interval (CI) (1.87-8.98), P < 0.001]. Furthermore, subgroup analysis showed that freedom from ATT rate in effective Ibutilide subgroup was significantly higher than noneffective Ibutilide subgroup (Log-rank, P < 0.001). Conclusion: For the treatment of the patients with PsAF, Ibutilide-guided cardioversion after individualized RFCA may be benefit for maintenance of SR compared to conventional DCC, especially for the patients who are effective for administration of Ibutilide.

Identification of the Key Genes of Immune Infiltration in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common cause of heart failure. In this study, we screened the immune infiltration-related genes associated with DCM to explore the potential molecular mechanisms and provide a basis for the early diagnosis and development of new immunotherapeutic targets. A dataset related to DCM was downloaded from the Gene Expression Omnibus (GEO) database. R software was applied to the genetic differential analysis of patients with DCM and healthy individuals, and the obtained differential expressed genes (DEGs) were screened for differentially expressed immune-related genes (DEIRGs) after comparison with the immune microsatellite database. Gene functional analysis established a protein interaction network (PPI). The immune infiltration in patients with DCM versus normal controls was assessed using the CIBERSORT algorithm, the hub genes were screened using the MOCDE app, and the hubs were validated in multiple datasets. A total of 246 DEGs were screened (adj. P < 0.05 and |logFC| > 0.3), and a total of 170 DEIRGs were compared. Gene Ontology analysis showed significant (adj. P < 0.05) Biological Process entries of 591, Cellular Component of 10, and Molecular Function of 39; Kyoto Encyclopedia of Genes and Genomes showed 20 significant entries, mainly focused on cytokines involved in immune-related response, etc. A protein interaction network comprising 28 hub DEGs was constructed in combination with the PPI network interactions. DEIRG was mainly distributed in the T-cell receptor pathway by immune infiltration detection analysis, and significant changes in central memory T-cells were found by analyzing T-cell-related subpathways, where INSR, HLA-B, IFITM1, and HBEGF were significantly differentially expressed. We selected 632 hospitalized patients for validation and found that INSR and HLA-B expression were associated with DCM development by Nomogram. The expression of HLA-B in peripheral blood T-cells was higher in DCM patients than in the normal group, as verified by qRT-PCR. However, the detailed mechanism needs to be further explored.

Exploring the diagnostic and prognostic value of the C-reactive protein/lymphocyte ratio for dilated cardiomyopathy based on a real-world study.

To determine the risk factors for dilated cardiomyopathy (DCM) and construct a risk model for predicting HF in patients with DCM, We enrolled a total of 2122 patients, excluding those who did not meet the requirements. A total of 913 patients were included in the analysis (611 males and 302 females) from October 2012 to May 2020, and data on demographic characteristics, blood biochemical markers, and cardiac ultrasound results were collected. Patients were strictly screened for DCM based on the diagnostic criteria. First, these patients were evaluated using propensity score matching (PSM). Next, unconditional logistic regression was used to assess HF risk. Furthermore, receiver operating characteristic (ROC) curve analysis was conducted to determine diagnostic efficiency, and a nomogram was developed to predict HF. Finally, the Kaplan‒Meier survival curve was plotted. Of the initial 2122 patients, the ejection fraction (EF) in males was worse. We included 913 patients after the final DCM diagnosis. The results showed that the levels of NT-proBNP, WBC, PLT, neutrophils, lymphocytes, eosinophils, and IL-6, C-reactive protein (CRP) and the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and CRP/lymphocyte ratio (CLR) were higher in males than in females (P < 0.001-0.009). The nomogram showed that factors such as sex, WBC, neutrophils, PLR, and CLR could predict the risk of worsening cardiac function in patients with DCM before and after PSM (P < 0.05). The ROC curve showed that CLR with an 85.6% area demonstrated higher diagnostic efficacy than the NLR (77.0%) and PLR (76.6%, P < 0.05). Survival analysis showed a higher mortality risk in females with higher CLR levels (P < 0.001-0.009). However, high CLR levels indicated a higher mortality risk (P < 0.001) compared to sex. Male EF is lower in DCM patients. CLR could predict the risk of declined cardiac function in patients with DCM. The mortality in females with higher CLR levels was highest; however, the exact mechanism should be investigated.

Searching for Intrinsic Causality between Colonic Dysbiosis and Non-Ischemic Cardiomyopathy: A Mendelian Randomization-Based Analysis.

Objective: Little is known about gut microbiota (GM) and cardiomyopathy. Their causal relationship was explored using two-sample Mendelian randomization (TSMR) performed by R software. Methods: The single nucleotide polymorphisms (SNPs) were further screened based on the genome-wide association studies (GWAS) of gut microbiota and cardiomyopathy obtained from an open database. TSMR was performed using an MR-Egger regression, simple estimator based on mode, weighted median method, inverse variance weighted (IVW), weighted estimator and CML-MA-BIC to explore the causal association. And the sensitivity analysis was carried out using an MR-Egger regression and the leave-one-out sensitivity test. Results: As for 211 GM taxa, IVW results confirmed that the class Actinobacteria (OR = 0.81, p = 0.021) and genus Coprobacter (OR = 0.85, p = 0.033) were protective factors for cardiomyopathy. The phylum Firmicutes (OR = 0.87, p < 0.01), family Acidaminococcaceae (OR = 0.89, p < 0.01), genus Desulfovibrio (OR = 0.92, p = 0.030) and genus Prevotella9 (OR = 0.93, p = 0.029) were protective factors for ischemic cardiomyopathy. The family Rhodospirillaceae (OR = 1.06, p = 0.036) and genus Turicibacter (OR = 1.09, p = 0.019) were risk factors for ischemic cardiomyopathy. The genus Olsenella (OR = 0.91, p = 0.032) was a protective factor for non-ischemic cardiomyopathy. The order Rhodospirillales (OR = 1.14, p = 0.024), family Rikenellaceae (OR = 1.21, p = 0.012) and genus Gordonibacter (OR = 1.12, p = 0.019) were risk factors for non-ischemic cardiomyopathy. The robustness of MR results was reflected in the heterogeneity (p > 0.05) and pleiotropy (p > 0.05) analyses. Conclusions: A potential causal relationship of cardiomyopathy with some GM taxa has been confirmed in the current study.

Early versus delayed antihypertensive treatment in patients with acute ischaemic stroke: multicentre, open label, randomised, controlled trial.

OBJECTIVES: To compared the effect of early antihypertensive treatment started within 24-48 h of stroke onset versus delaying treatment until day eight on reducing dependency or death. DESIGN: Multicentre, randomised, open label trial. SETTING: 106 hospitals in China between 13 June 2018 and 10 July 2022. PARTICIPANTS: 4810 patients (≥40 years) were enrolled with acute ischaemic stroke within 24-48 h of symptom onset and elevated systolic blood pressure between 140 mm Hg and <220 mm Hg. INTERVENTIONS: Patients were randomly assigned to receive antihypertensive treatment immediately after randomisation (aimed at reducing systolic blood pressure by 10%-20% within the first 24 h and a mean blood pressure <140/90 mm Hg within seven days) or to discontinue antihypertensive medications for seven days if they were taking them, and then receive treatment on day 8 (aimed at achieving mean blood pressure <140/90 mm Hg). MAIN OUTCOME MEASURES: The primary outcome was the combination of functional dependency or death (modified Rankin scale score ≥3) at 90 days. Intention to treat analyses were conducted. RESULTS: 2413 patients were assigned to the early treatment group and 2397 were assigned to the delayed treatment group. Mean systolic blood pressure was reduced by 9.7% (from 162.9 mm Hg to 146.4 mm Hg) in the early treatment group and by 4.9% (from 162.8 mm Hg to 154.3 mm Hg) in the delayed treatment group within 24 h after randomisation (P for group difference <0.001). Mean systolic blood pressure was 139.1 mm Hg in the early treatment group and 150.9 mm Hg in the delayed treatment group on day seven (P for group difference <0.001). Additionally, 54.6% of patients in the early treatment group and 22.4% in the delayed treatment group had blood pressure of less than 140/90 mm Hg (P<0.001 for group difference) on day seven. At day 90, 289 trial participants (12.0%) in the early treatment group, compared with 250 (10.5%) in the delayed treatment group, had died or experienced a dependency (odds ratio 1.18 (95% confidence interval 0.98 to 1.41), P=0.08). No significant differences in recurrent stroke or adverse events were reported between the two groups. CONCLUSIONS: Among patients with mild-to-moderate acute ischaemic stroke and systolic blood pressure between 140 mm Hg and <220 mm Hg who did not receive intravenous thrombolytic treatment, early antihypertensive treatment did not reduce the odds of dependency or death at 90 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03479554.

The use of D-dimer in the diagnosis and risk assessment of intracardiac thrombus among patients with dilated cardiomyopathy.

D-dimer is a biomarker of coagulation and fibrinolytic system activation in response to the body's hypercoagulable state. The study aims to investigate the usefulness of D-dimer in diagnosing and assessing the risk of intracardiac thrombus in patients with dilated cardiomyopathy (DCM). Consecutively enrolled in this study were patients with DCM who were admitted to our center for the first time. The diagnostic value was evaluated using the receiver operating characteristic (ROC) curve. Additionally, we used univariate and multivariate logistic regression to investigate the association between D-dimer and intracardiac thrombus. We also performed smooth curve fitting, threshold saturation effect analysis, and subgroup analysis. In total, 534 patients were enrolled in the study, and among them, 65 patients had intracardiac thrombus. Mural thrombus was the predominant type of thrombus, which was mainly located in the left ventricular apex. The optimal cut-off value of D-dimer for the diagnosis of intracardiac thrombus was 484 ng/mL, with a sensitivity and specificity of 0.769 and 0.646, respectively. In both unadjusted and adjusted logistic regression models, a positive association was found between D-dimer and intracardiac thrombus. Curve fitting and threshold effect analysis revealed two inflection points in the relationship between D-dimer and intracardiac thrombus (non-linear test: P = 0.032). When D-dimer was equal to 362 ng/mL, the odds ratio (OR) was 1, and the risk of thrombus gradually increased until it reached 4096 ng/mL, after which the trend no longer increased. Within this range, a twofold increase in D-dimer was associated with a 103.2% increased risk (OR = 2.032; 95% CI 1.293-3.193; P < 0.01). In the subgroup analysis, there was a significant interaction between D-dimer and BMI on intracardiac thrombus (P value for interaction was 0.013), and the risk was higher in patients with a BMI ≥ 25 kg/m2 (OR = 3.44; 95% CI 1.86-6.36; P < 0.01).