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Venous thromboembolism (VTE) is a life-threatening complication commonly occurring after acute ischemic stroke (AIS), with an increased risk of mortality. Traditional risk assessment tools lack precision in predicting VTE in AIS patients due to the omission of stroke-specific factors. We developed a machine learning model using clinical data from patients with acute ischemic stroke (AIS) admitted between December 2021 and December 2023. Predictive models were developed using machine learning algorithms, including Gradient Boosting Machine (GBM), Random Forest (RF), and Logistic Regression (LR). Feature selection involved stepwise logistic regression and LASSO, with SHapley Additive exPlanations (SHAP) used to enhance model interpretability. Model performance was evaluated using area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Among the 1,632 AIS patients analyzed, 4.17% developed VTE. The GBM model achieved the highest predictive accuracy with an AUC of 0.923, outperforming other models such as Random Forest and Logistic Regression. The model demonstrated strong sensitivity (90.83%) and specificity (93.83%) in identifying high-risk patients. SHAP analysis revealed that key predictors of VTE risk included elevated D-dimer levels, premorbid mRS, and large vessel occlusion, offering clinicians valuable insights for personalized treatment decisions. This study provides an accurate and interpretable method to predict VTE risk in patients with AIS using the GBM model, potentially improving early detection rates and reducing morbidity. Further validation is needed to assess its broader clinical applicability.

ObjectiveTo examine healthcare-seeking delays among immigrant patients with acute ischaemic stroke (AIS), identifying key factors contributing to these delays and proposing evidence-based interventions for policy formulation and research.DesignA retrospective observational study analysing healthcare-seeking behaviours and delay times among immigrant patients with AIS treated at the Department of Neurology, Longhua District People’s Hospital, Shenzhen, from December 2021 to October 2023. The study included 1356 patients with AIS, all part of the immigrant population as defined by Shenzhen Statistical Yearbook criteria. The study investigated sociodemographic, clinical data and stroke-specific scales (modified Rankin Scale, National Institutes of Health Stroke Scale, Glasgow Coma Scale) to identify factors influencing delays.SettingThe study was conducted in Shenzhen, a city characterised by a significant immigrant population, providing insights applicable to urban regions with similar demographics.ResultsOf the 1356 patients studied, 82.6% (n=1120) experienced healthcare-seeking delays, with a median delay of 12.67 hours (IQR: 3.5–28.8). Factors associated with prolonged delays included lack of stroke awareness (92.96% delay rate), low educational attainment, self-transportation to the hospital (adjusted OR (aOR): 2.36, 95% CI: 1.57 to 3.54) and wake-up strokes (aOR: 4.37, 95% CI: 2.28 to 8.36). Conversely, factors associated with shorter delays included cardioembolic strokes (aOR: 0.50, 95% CI: 0.28 to 0.90) and atrial fibrillation (aOR: 0.45, 95% CI: 0.23 to 0.89). Delay rates were significantly lower among patients referred by emergency medical services compared with those self-transporting. These findings highlight the influence of clinical, socioeconomic and demographic factors on delays in seeking care.ConclusionHealthcare-seeking delays in stroke care among immigrants, shaped by awareness, socioeconomic and clinical factors, necessitate urgent educational, policy and healthcare reforms. Enhancing early symptom recognition and promoting emergency service utilisation are essential for improving access to care and outcomes in this vulnerable group.

Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested as playing a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD); however, a mechanistic understanding of this association is lacking. Here, we identified a reduction of phosphorylation of Cx43 serines S325/S328/S330 in human and mouse DMD hearts. We hypothesized that hypophosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the lateral sides of cardiomyocytes (remodeling). Therefore, we generated knockin mdx mice in which the Cx43 serine-triplet was replaced with either phospho-mimicking glutamic acids (mdxS3E) or nonphosphorylatable alanines (mdxS3A). The mdxS3E, but not mdxS3A, mice were resistant to Cx43 remodeling, with a corresponding reduction of Cx43 hemichannel activity. MdxS3E cardiomyocytes displayed improved intracellular Ca2+ signaling and a reduction of NADPH oxidase 2 (NOX2)/ROS production. Furthermore, mdxS3E mice were protected against inducible arrhythmias, related lethality, and the development of cardiomyopathy. Inhibition of microtubule polymerization by colchicine reduced both NOX2/ROS and oxidized CaMKII, increased S325/S328/S330 phosphorylation, and prevented Cx43 remodeling in mdx hearts. Together, these results demonstrate a mechanism of dystrophic Cx43 remodeling and suggest that targeting Cx43 may be a therapeutic strategy for preventing heart dysfunction and arrhythmias in DMD patients.

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder that affects males. However, 8% of female carriers are symptomatic and underrepresented in research due to the lack of animal models. We generated a symptomatic mouse model of DMD carriers via injection of mdx (murine DMD) embryonic stem cells (ESCs) into wild-type (WT) blastocysts ( mdx /WT chimera). mdx /WT chimeras developed cardiomyopathic features and dystrophic skeletal muscle phenotypes including elevated mononuclear invasion, central nucleation, fibrosis and declined forelimb grip strength. The disease was accompanied by connexin-43 (Cx43) aberrantly enhanced in both cardiac and skeletal muscles and remodeled in the heart. Genetic reduction of Cx43-copy number in mdx /WT-Cx43(+/−) chimeras protected them from both cardiac and skeletal muscle fiber damage. In dystrophic skeletal muscle, Cx43 expression was not seen in the fibers but in adjacent F4/80+ mononuclear cells. Ethidium Bromide uptake in purified F4/80+/CD11b+ mdx macrophages revealed functional activity of Cx43, which was inhibited by administration of Gap19 peptide mimetic, a Cx43 hemichannel-specific inhibitor. Thus, we suggest that Cx43 reduction in symptomatic DMD carrier mice leads to prevention of Cx43 remodeling in the heart and prevention of aberrant Cx43 hemichannel activity in the skeletal muscle macrophages neighboring Cx43 non-expressing fibers.

Background Simple sequence repeats (SSRs) are tandem repeats of DNA that have been used to develop robust genetic markers. These molecular markers are powerful tools for basic and applied studies such as molecular breeding. In the model plants in Nicotiana genus e.g. N. benthamiana, a comprehensive assessment of SSR content has become possible now because several Nicotiana genomes have been sequenced. We conducted a genome-wide SSR characterization and marker development across seven Nicotiana genomes. Results Here, we initially characterized 2,483,032 SSRs (repeat units of 1–10 bp) from seven genomic sequences of Nicotiana and developed SSR markers using the GMATA® software package. Of investigated repeat units, mono-, di- and tri-nucleotide SSRs account for 98% of all SSRs in Nicotiana . More complex SSR motifs, although rare, are highly variable between Nicotiana genomes. A total of 1,224,048 non-redundant Nicotiana (NIX) markers were developed, of which 99.98% are novel. An efficient and uniform genotyping protocol for NIX markers was developed and validated. We created a web-based database of NIX marker information including amplicon sizes of alleles in each genome for downloading and online analysis. Conclusions The present work constitutes the first deep characterization of SSRs in seven genomes of Nicotiana, and the development of NIX markers for these SSRs. Our online marker database and an efficient genotyping protocol facilitate the application of these markers. The NIX markers greatly expand Nicotiana marker resources, thus providing a useful tool for future research and breeding. We demonstrate a novel protocol for SSR marker development and utilization at the whole genome scale that can be applied to any lineage of organisms. The Tobacco Markers & Primers Database (TMPD) is available at http://biodb.sdau.edu.cn/tmpd/index.html

The Inhibitor of DNA Binding (Id) proteins play a crucial role in regulating hematopoiesis and are known to interact with E proteins and the bHLH family of transcription factors. Current efforts seek to elucidate the individual roles of Id members in regulating hematopoietic development and specification. However, the nature of their functional redundancies remains elusive since ablation of multiple Id genes is embryonically lethal. We developed a model to test this compensation in the adult. We report that global Id3 ablation with Tie2Cre-mediated conditional ablation of Id1 in both hematopoietic and endothelial cells (Id cDKO) extends viability to 1 year but leads to multi-lineage hematopoietic defects including the emergence of anemia associated with defective erythroid development, a novel phenotype unreported in prior single Id knockout studies. We observe decreased cell counts in the bone marrow and splenomegaly to dimensions beyond what is seen in single Id knockout models. Transcriptional dysregulation of hematopoietic regulators observed in bone marrow cells is also magnified in the spleen. E47 protein levels were elevated in Id cDKO bone marrow cell isolates, but decreased in the erythroid lineage. Chromatin immunoprecipitation (ChIP) studies reveal increased occupancy of E47 and GATA1 at the promoter regions of β-globin and E2A. Bone marrow transplantation studies highlight the importance of intrinsic Id signals in maintaining hematopoietic homeostasis while revealing a strong extrinsic influence in the development of anemia. Together, these findings demonstrate that loss of Id compensation leads to dysregulation of the hematopoietic transcriptional network and multiple defects in erythropoietic development in adult mice.

Inhibitor of DNA binding (Id) proteins play important roles in regulating cardiac development via paracrine signaling. Id1/Id3 knockout mice die at mid-gestation with multiple cardiac defects. Single Id knockout studies have not reported cardiomyopathies. To bypass embryonic lethality we used Tie2CRE-mediated recombination to conditionally delete Id1 against global Id3 ablation (Id cDKOs), which develops adult-onset dilated cardiomyopathy. We confirm upregulation of thrombospondin-1 (TSP1) in Id cDKO hearts. Colocalization studies reveal increased TSP1 expression in the vicinity of endothelial cells and near regions of endocardial fibrosis/disruption. Downstream fibrotic molecules were upregulated. Endocardial capillary density was reduced with evidence of vascular distention. Treatment of Id cDKO cardiac explants with LSKL, a peptide antagonist of TSP1 activation of TGFβ, reversed the increased expression of fibrotic molecules. We conducted bone marrow transplant experiments in which we transferred bone marrow cells from Id cDKO mice into lethally irradiated WT mice. The majority of WT recipients of Id cDKO bone marrow cells phenocopied Id cDKO cardiac fibrosis 4 months post-transplantation. Injection of LSKL into adult Id cDKO mice led to downregulation of fibrotic molecules. The results prompt caution when bone marrow transfers from individuals potentially carrying mutations in the Id axis are applied in clinical settings.

Background and purposeAn analysis of the ASTER 2 trial revealed similar final recanalisation levels and clinical outcomes in acute large vessel occlusion (LVO) stroke between stent retrieval (SR) alone as a first-line mechanical thrombectomy (MT) technique (SR alone first-line) and concomitant use of contact aspiration (CA) plus SR as a first-line MT technique (SR+CA first-line). The purpose of the present study was to compare the safety and efficacy of SR+CA first-line with those of SR alone first-line for patients with LVO in China.MethodsWe conducted the present study by using the data from the ANGEL-ACT registry. We divided the selected patients into SR+CA first-line and SR alone first-line groups. We performed logistic regression and generalised linear models with adjustments to compare the angiographic and clinical outcomes, including successful/complete recanalisation after the first technique alone and all procedures, first-pass successful/complete recanalisation, number of passes, 90-day modified Rankin Scale, procedure duration, rescue treatment and intracranial haemorrhage within 24 hours.ResultsOf the 1233 enrolled patients, 1069 (86.7%) received SR alone first-line, and 164 (13.3%) received SR+CA first-line. SR+CA first-line was associated with more thrombectomy passes (3 (2–4) vs 2 (1–2); β=1.77, 95% CI=1.55 to 1.99, p<0.001), and longer procedure duration (86 (60–129) min vs 80 (50–122) min; β=10.76, 95% CI=1.08 to 20.43, p=0.029) than SR alone first-line group. Other outcomes were comparable (all p>0.05) between the two groups.ConclusionsPatients undergoing SR+CA first-line had more thrombectomy passes and longer procedure duration than patients undergoing SR alone first-line. Additionally, we suggested that SR+CA first-line was not superior to SR alone first-line in final recanalisation level, first-pass recanalisation level and 90-day clinical outcomes in the Chinese population.

Background and Purpose: Acute ischemic stroke (AIS) caused by large artery occlusion (LAO) poses considerable risks in terms of mortality and disability. Endovascular treatment (EVT) has emerged as a primary intervention for this condition. However, the occurrence of futile recanalization (FR) following EVT remains common, necessitating the identification of predictive markers for treatment outcomes. Although the lymphocyte to monocyte ratio (LMR) has been linked to various diseases, its association with FR after EVT in AIS patients has not been investigated. Methods: An analysis was conducted on patients with AIS who underwent EVT within 24 hours of symptom onset. The success of reperfusion was evaluated using the modified Thrombolysis in Cerebral Infarction (mTICI) scale, with patients achieving an mTICI score of [greater than or equal to]2b being included in the study. Various clinical, radiological, and laboratory variables, including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), were collected. Logistic regression analysis was used to determine factors associated with FR, and receiver operating characteristic (ROC) analysis was performed to assess the predictive value of LMR. Results: Among the cohort of 101 patients, it was observed that 52.4% experienced FR. Upon admission, lower levels of lymphocyte-to-monocyte ratio (LMR) were found to be associated with older age, higher baseline NIHSS scores, lower ASPECTS, and poorer mRS scores at 90 days. Both univariate and multivariate logistic regression analyses indicated that low LMR independently predicted FR, with an adjusted odds ratio of 0.64 (95% CI = 0.412-0.984, p = 0.042). ROC analysis further demonstrated that LMR had an area under the curve (AUC) of 0.789 for predicting FR. Conclusion: This study establishes the potential value of the lymphocyte-to-monocyte ratio (LMR) as a prognostic marker for predicting FR in patients with AIS undergoing EVT. Decreased LMR levels are associated with unfavorable clinical outcomes. Keywords: acute ischemic stroke, large artery occlusion, endovascular therapy, lymphocyte-to-monocyte ratio, futile recanalization, prognostic marker, inflammation, treatment outcomes

Duchenne muscular dystrophy (DMD) is an incurable neuromuscular degenerative disease, caused by a mutation in the dystrophin gene. Mdx mice recapitulate DMD features. Here we show that injection of wild-type (WT) embryonic stem cells (ESCs) into mdx blastocysts produces mice with improved pathology and function. A small fraction of WT ESCs incorporates into the mdx mouse nonuniformly to upregulate protein levels of dystrophin in the skeletal muscle. The chimeric muscle shows reduced regeneration and restores dystrobrevin, a dystrophin-related protein, in areas with high and with low dystrophin content. WT ESC injection increases the amount of fat in the chimeras to reach WT levels. ESC injection without dystrophin does not prevent the appearance of phenotypes in the skeletal muscle or in the fat. Thus, dystrophin supplied by the ESCs reverses disease in mdx mice globally in a dose-dependent manner.