The development and safety evaluation of chimeric antigen receptor T-cell (CAR-T) therapy have long been hindered by the physiological and immunological limitations of conventional two-dimensional cell cultures and animal models. In recent years, organoid and organ-on-a-chip technologies have emerged as highly promising in vitro platforms for advancing CAR-T research. Organoids are three-dimensional, self-organizing microtissues derived in vitro from adult tissue stem cells (ASCs), induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), or patient-derived tumor tissues. They faithfully recapitulate key structural, cellular, and functional features of native tissues or tumors, making them valuable for preclinical validation of CAR-T efficacy and specificity, though they typically lack systemic components such as circulating immune cells, vascular networks, and stromal elements. By integrating organoids with microfluidic systems, organ-on-a-chip platforms have been developed to better emulate the dynamic physiological microenvironment. These systems enable complex, multicellular co-cultures including immune, tumor, endothelial, and stromal cells, under controlled fluid flow and mechanical cues, thereby supporting more physiologically relevant assessment of CAR-T trafficking, infiltration, cytotoxicity, and persistence. This review summarizes recent advances in the design, fabrication, and application of organoid- and organ-on-a-chip-based models for the preclinical validation of CAR-T therapies.

Intracranial atherosclerotic stenosis (ICAS) and cerebral small vessel disease (CSVD) frequently co-exist and contribute to poor stroke outcomes. Whether distinct pathophysiological mechanisms mediate large-vessel versus small-vessel disease effects on stroke outcomes, and whether these are modifiable by thrombolysis, remains unknown. In this prospective cohort study, acute ischemic stroke patients with ICAS and/or CSVD were enrolled. ICAS was defined as ≥ 50

Antiviral agents are a cornerstone of therapeutic strategies against viral infections; however, the early-stage discovery and optimization of viral inhibitors remain time-consuming, resource-intensive, and mechanistically opaque. Here, we introduce a mechanism-guided strategy for rapid antiviral candidate identification and evaluation using confocal Raman microscopy (CRM) imaging across cellular and animal models. CRM enables label-free, quantitative, and spatially resolved assessment of drug efficacy at the single-cell level by correlating subcellular biochemical distributions, specifically of lipids, nucleic acids, and proteins, with virus-induced morphological alterations. To validate this approach, we evaluated α-linolenic acid (ALA) against influenza A virus (IAV) strain H1N1 PR8 in human non-small cell lung carcinoma A549 cells. CRM imaging revealed that ALA treatment restored lipid homeostasis, preserved nucleic acid integrity, and normalized protein expression profiles, changes those were spatially concordant with recovery of cellular architecture. These mechanistic insights directly informed the rational design of subsequent in vivo studies in murine models, markedly reducing reliance on empirical trial-and-error. Moreover, CRM was extended to ex vivo analysis of lung tissue, enabling high-resolution interrogation of alveolar architecture and surfactant layer composition in infected tissues. Collectively, our work establishes CRM as a rapid, mechanism-informed platform for prioritizing antiviral candidates, bridging molecular pharmacology and phenotypic response, and thereby accelerating the translation of promising leads into preclinical development.

Early neurological deterioration (END) occurs in a substantial proportion of minor stroke patients with large vessel occlusion or severe stenosis (LVO/SS) and is a strong predictor of poor outcome, yet its underlying mechanisms remain debated. The cerebral blood volume (CBV) index is defined as the ratio of the mean CBV in the hypoperfusion (Tmax>6s) region to the mean CBV in the normal brain tissue, incorporating hemodynamics beyond the ischemic zone into its calculation. In this multicenter retrospective study, we evaluated the predictive value and pathophysiological implications of CBV index for END in patients with anterior circulation LVO/SS and mild symptoms. Among 401 eligible patients, END occurred in 21.7%. Stepwise logistic regression analysis revealed that higher CBV index was independently associated with END (adjusted OR [95% CI]: 3.85 [1.14, 12.96], p = 0.030). Mediation analysis revealed that 27.9% of the effect of CBV index on END was explained by increased hypoperfusion volume (indirect effect: 0.06, 95% CI: [0.02, 0.11], p = 0.007). These findings indicate that although a higher CBV index reflects favorable baseline collaterals, it may also indicate insufficient hemodynamic reserve and vulnerability to hypoperfusion progression, potentially facilitating extension of ischemia and subsequent END.

Early and economical diagnosis of acute ischemic stroke (AIS) is pivotal for therapeutic efficacy, particularly for the settings where medical imaging resource is deficient. We have obtained evidence supporting our hypothesis that collective properties of the green autofluorescence (AF) of the fingernails and certain skin’s positions may be a novel diagnostic biomarker for AIS: both the green AF intensity and AF asymmetry of the AIS patients in their Index Fingernails and most examined skin’ s positions were significantly higher than that of the healthy subjects and the Non-AIS subjects. Receiver operating characteristic (ROC) analyses and machine learning-based analyses on the AF properties showed that area under curve (AUC) was 0.93 and 0.87, respectively, for differentiating the AIS patients from the healthy subjects and for differentiating the AIS patients from the Non-AIS subjects. The AIS patients had significantly higher AF intensity and AF asymmetry at several examined positions, compared to those of the patients of Parkinson’s disease, pulmonary infection and transient ischemic attack. The AUC was 0.79–0.88 for differentiating AIS patients from each of these diseases. Our study has also obtained evidence implicating that the AF originates from keratins. Collectively, our study has obtained preliminary evidence suggesting that the characteristic AIS’s ‘Pattern of AF’ is a novel diagnostic biomarker for the disease. The ‘Pattern of AF Technology’ holds potential to become a new non-invasive, label-free and economical diagnostic approach for AIS, which is particularly valuable when Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) imaging resource is deficient.

The detection of low-abundance microribonucleic acid (miRNA) frequently adopted nucleic acid sequence-based amplification detection, which was found to have poor selectivity for the nonspecific amplification of template-dependent ligation in enzyme-mediated cascade reactions. Here, a highly selective detection of miRNAs was developed that combined microsphere-enhanced fluorescence (MSEF) and solid-phase base-paired hybridization. The target miRNA could be accurately and quantitatively identified through the solid-phase hybridization assay on the surface of an optical microsphere, while the detected fluorescence signal could be physically amplified by MSEF. Hereinto, the optical microsphere acted as the fluorescence amplifier and whose surface supplied the space to carry out base-paired hybridization to recognize the target miRNA via the immobilized capture DNA sequence. The detected fluorescence signal of the single-base mismatched miRNA-21 sequence was just around 12% of that of the target miRNA-21 sequence in the measurement of model miRNA-21, while the limit of detection of miRNA-21 could be 1.0 fM. The developed detection of miRNA on an optical microsphere was demonstrated to be an excellent physically amplified method to selectively and sensitively detect the target miRNA and magnificently avoid the nonspecific amplification and false-positive results, which is expected to have wide applications in pathematology, pharmacology, clinic diagnosis, and on-site screening fields as well.

BACKGROUND:The glymphatic system and deep medullary veins (DMV) are closely linked to cognitive impairment in patients with cerebral small vessel disease (CSVD). This study aims to elucidate these complex associations through mediation analysis. METHODS:Patients who underwent multimodal magnetic resonance imaging (MRI) scans and the Montreal Cognitive Assessment (MoCA) were recruited. Glymphatic function was assessed using the diffusion tensor imaging along the perivascular space (DTI-ALPS) index. DMV was identified on susceptibility-weighted imaging (SWI), and a total DMV score was calculated based on segmental continuity and visibility. Regression models were employed to estimate the impact of the DMV score and DTI-ALPS index on cognitive impairment. Mediation analysis was conducted to examine the effect of the DTI-ALPS on DMV score and cognitive function. RESULTS:A total of 152 participants were included, of whom 65 had normal cognitive function and 87 had cognitive impairment. After adjusting for confounding factors, both the DMV score (OR=1.182, 95 % CI: 1.067-1.308, p = 0.005) and DTI-ALPS index (OR=0.496, 95 % CI: 0.306, 0.806, p = 0.005) were independently associated with cognitive impairment. Mediation analysis revealed that the DTI-ALPS index partially mediated the relationship between the DMV score and cognitive impairment, with an indirect effect of 0.040 (95 % CI: 0.011-0.084, p < 0.001). CONCLUSION:Both the DMV score and DTI-ALPS index are independent risk factors for cognitive impairment in patients with CSVD. The DTI-ALPS index significantly and partially mediates the relationship between the DMV score and cognitive impairment.

METHODS: Our study aimed to employ a machine learning models based on radiomics for automated dementia identification in cerebral small vessel disease (CSVD) patients with normal age-related hippocampal atrophy (HA). METHODS: CSVD patients were divided randomly into training and validation sets in a 6:4 ratio. Bilateral hippocampus segmented based on T2 and FLAIR were used for radiomics. Dementia radiomics models (T2 model, FLAIR model, T2-FLAIR model) were developed in the training sets and was further verified in the validation sets. The rad_score from the best models, along with clinical factors, was integrated to construct clinic-radiomics models for dementia through multifactor logistic regression analysis. RESULTS: 116 CSVD patients were recruited, 30 patients were demented and 86 patients were non-demented. In predicting dementia in the training and validation sets, the area under curves (AUC) were 0.811 and 0.779 for the T2 model, 0.807 and 0.755 for the FLAIR model, and 0.864 and 0.801 for the T2-FLAIR model. In the overall 116 patients, the AUCs were 0.801 for the T2 model, 0.783 for the FLAIR model, and 0.840 for the T2-FLAIR model. No statistical differences were found among the three models. Given the highest AUC value in the T2-FLAIR model, converting the rad-score of it into binary T2-FLAIR (No, Yes) revealed a correlation between a 'Yes' response and dementia (OR = 13.21, 95% CI 3.487−59.922, p < 0.001) after adjusting for risk factors. CONCLUSION: Radiomic analysis of the hippocampus in T2-FLAIR images can effectively identify dementia in CSVD patients with normal age-related HA.

BACKGROUND:Stroke is a significant global health issue, resulting in substantial mortality and morbidity. Environmental exposures are increasingly recognized as essential contributors to cerebrovascular risk profiles. Phthalates are ubiquitous synthetic plasticizers with well-established endocrine-disrupting properties and have been associated with various vascular and metabolic disturbances. However, their specific contribution to stroke pathogenesis, particularly concerning potential sex-specific vulnerability patterns, remains poorly understood. METHODS:A cross-sectional analysis was conducted on 8184 participants (4140 women and 4044 men) from the US National Health and Nutrition Examination Survey to evaluate the associations between urinary phthalate metabolite concentrations and stroke prevalence. The weighted quantile sum (WQS) regression methodology assessed the effects of cumulative exposure to the phthalate mixture. An integrative approach was used, incorporating network toxicology, protein-protein interaction mapping, and the Friends algorithm, to identify molecular targets related to stroke that may be affected by phthalate exposure. Molecular docking analyses were performed to characterise binding affinities between key phthalate metabolites and identified protein targets. We analyzed single-cell RNA sequencing data to determine cell-type-specific expression patterns of implicated molecular targets. RESULTS:Sex-stratified analyses revealed that phthalate exposure was positively associated with stroke risk in women but not in men. Specifically, higher urinary concentrations of mono(carboxynonyl) phthalate (MCNP) were significantly associated with self-reported stroke in women. WQS regression confirmed cumulative effects, with MCNP identified as the primary contributor. Network and docking analyses revealed strong interactions between MCNP and vascular proteins KDR, AKT1, and MAPK8, which were predominantly expressed in endothelial cells. These findings suggest that phthalate exposure may increase stroke risk in a sex-specific manner through disruption of an endothelial-specific KDR-AKT1-MAPK8 signaling pathway. CONCLUSION:This work highlights a novel mechanism of environmentally mediated cerebrovascular risk and provides potential targets for therapeutic intervention, particularly in women.

The pervasive presence of micro-nanoplastics (MNPs) in the human environment has raised concerns regarding their potential implications for neurological health. Once regarded as biologically inert, MNPs are now recognised as capable of penetrating the blood-brain barrier (BBB) or entering the central nervous system (CNS) through sensory neuronal pathways. Recent studies have demonstrated that MNPs can accumulate in key brain regions, such as the hippocampus and prefrontal cortex, which are critical for memory, emotion, and executive function. Animal experiments have revealed that chronic exposure to MNPs may result in cognitive deficits, behavioral disturbances, and pathological features resembling neurodegenerative diseases. The mechanisms underlying these adverse effects are likely multifaceted, involving oxidative stress, persistent neuroinflammation, synaptic dysfunction, and disturbances of the gut-brain axis. In addition to their direct neuronal effects, MNPs may also impair cerebrovascular health by promoting endothelial dysfunction, vascular calcification, and small vessel injury, further increasing the risk of cognitive decline and stroke. This review synthesizes current evidence from environmental exposure to neural accumulation, providing mechanistic insights into MNPs-induced neurotoxicity. The review also highlights critical knowledge gaps and emphasizes the urgent need for further research and public health interventions to address this emerging environmental threat.

BACKGROUND: Whether it is effective and safe to extend the time window of intravenous thrombolysis up to 24 hours after the last known well is unknown. We aimed to determine the efficacy and safety of tenecteplase in Chinese patients with acute ischemic stroke due to large/medium vessel occlusion within an extended time window. METHODS: Patients with ischemic stroke presenting 4.5 to 24 hours from the last known well, with a favorable penumbral profile and an associated large/medium vessel occlusion, were randomized 1:1 to either 0.25 mg/kg tenecteplase or the best medical treatment. A favorable penumbral profile was defined as a hypoperfusion lesion volume to infarct core volume ratio >1.2, with an absolute volume difference >10 mL, and an ischemic core volume <70 mL. The primary outcome was the achievement of major reperfusion without symptomatic intracranial hemorrhage within 24 to 48 hours post-randomization. Major reperfusion was defined as the restoration of blood flow of >50% of the involved ischemic territory. Secondary outcomes included recanalization, infarct growth, major neurological improvements, change in the National Institutes of Health Stroke Scale score, hemorrhagic transformation within 24 to 48 hours, systemic bleeding at discharge, and modified Rankin Scale (score 0–1, score 0–2, score 5–6, and modified Rankin Scale distribution) at 90 days. The comparison of the primary outcome between groups was conducted using modified Poisson regression with a log-link function and robust error variance, adjusted for time from the last known well to randomization, the site of vessel occlusion, and planned endovascular treatment. RESULTS: Among 224 enrolled patients, 111 were assigned to receive tenecteplase and 113 to receive the best medical treatment (including 23% [n=26] of participants who received intravenous tissue-type plasminogen activator). The mean (SD) age of the tenecteplase group and the best medical treatment group was 64.2 (10.4) and 63.6 (11.0) years old, with 72.1% (n=80) and 70.8% (n=80) male enrolled, respectively. A proportion of 54.9% (n=123) of patients were transferred to the catheter room for preplanned endovascular treatment. The primary outcome occurred in 33.3% (n=37) of the tenecteplase group versus 10.8% (n=12) in the best medical treatment group (adjusted relative risk, 3.0 [95% CI, 1.6–5.7]; P =0.001). Tenecteplase significantly increased the recanalization rate compared with the best medical treatment (35.8% [n=39] versus 14.3% [n=16], adjusted relative risk, 2.5 [95% CI, 1.4–4.4]; P =0.002). There were no significant differences in clinical efficacy outcomes or rates of hemorrhagic transformation between the groups. CONCLUSIONS: Administered at a dose of 0.25 mg/kg intravenously, tenecteplase increased reperfusion without symptomatic intracranial hemorrhage in patients with ischemic stroke selected by imaging in late-time window treatment but did not change clinical outcomes at 90 days. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04516993.

OBJECTIVE:Both insulin sensitivity and brain glymphatic function were linked to cognitive function in nondiabetic patients with cerebral small vessel disease (CSVD). This study aims to elucidate these complex associations through mediation analysis. METHODS:Patients who underwent multimodal magnetic resonance imaging (MRI) scans were recruited. Global cognitive assessment was performed by Mini-Mental State Examination (MMSE), four isolated cognitive domains were assessed simultaneously. Glymphatic function was assessed using the diffusion tensor imaging along the perivascular space (DTI-ALPS) index, insulin sensitivity was assessed by the homeostasis model assessment-estimated insulin resistance index (HOMA-IR), and HOMA-IR≥2.80 was defined as insulin resistance (IR). Mediation analysis was conducted to examine the effect of the DTI-ALPS on insulin sensitivity and cognitive function. RESULTS:110 CSVD patients were recruited, 40 patients were IR and 70 patients were non-IR. Both the HOMA-IR and DTI-ALPS index were significant predictors of cognitive function, with B = -0.592, 95%CI, -0.939 to -0.244, p = 0.001 and B = 9.378, 95% CI, 3.376 to 15.381, p = 0.003, respectively, after adjusting for age, sex, and other confounding factors. Mediation analysis revealed that the DTI-ALPS index served as a significant partial mediator in the relationship between HOMA-IR and cognitive function, with direct effect = -0.649 (95% CI, -1.015 to -0.282, p < 0.001), total effect = -0.743 (95% CI, -1.106 to -0.380, p < 0.001), and the indirect effect = -0.094 (95% CI, -0.236 to -0.006, p = 0.029), accounting for 12.66% of the total effect. CONCLUSION:Both the HOMA-IR and the DTI-ALPS index are independent risk factors for cognitive function. Furthermore, the DTI-ALPS index significantly and partially mediates the relationship between the HOMA-IR and cognitive function.

Obstructive sleep apnea (OSA) is a neglected global health issue and when left untreated could lead to cognitive impairment (CI), one of the most burdensome outcomes of OSA. Enlarged perivascular spaces (EPVS), an imaging feature as well as a subtype of cerebral small vessel disease and integral part of CSVD, are associated with cognitive function, but the relationship between EPVS and CI is not well understood and by extension the correlation between OSA and EPVS, how CI develops under the joint impact of OSA and EPVS remains unclear. It is the goal of This study to explore the associations among OSA, EPVS, and CI. This cross-sectional study included 175 older adults with imaging features of EPVS with or without other CSVD subtype features by cranial magnetic resonance imaging between January 2021 and June 2023 at the Shanghai Fifth People’s Hospital. We assessed OSA using polysomnography. Blood samples were collected to determine vascular risk factor indices. Cognitive scoring modalities included the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MOCA). To explore the relationship among OSA, EPVS, and CI, we used single-factor analysis, multifactorial analysis, and receiver operating characteristic (ROC) curves. A total of 136 participants were analyzed. In our statistical process, MMSE showed a more distinguished performance than MoCA. Participants with OSA had greater EPVS burdens in the midbrain (p < 0.001) and hippocampus (p < 0.001) and more serious CI (p = 0.001). OSA positively influenced EPVS in the midbrain (β = 0.052; 95

The identification and intervention of Alzheimer’s Disease (AD) in its early-stage allows for the timely implementation of lifestyle modifications and therapeutic strategies. Although dysregulation of protein expression has been reported in the brain from AD patients and AD animal models, the underlying mechanisms remain poorly understood. N4-acetylcytidine (ac4C), the only known form of RNA acetylation in eukaryotes, has recently been shown to regulate mRNA stability and translation efficiency. However, the dysregulation of ac4C associated with abnormal protein expression levels in the brain of early-stage mouse models of AD remains to be elucidated. This study investigated ac4C modifications, mRNA and protein expression in the hippocampus of 3 and 6-month-old 5×FAD mice, a mouse model of AD, and wild-type (WT) littermates. The multi-omics analysis was performed: acetylated RNA immunoprecipitation followed by next-generation sequencing (acRIP-seq) to identify ac4C mRNAs, deep RNA sequencing (RNA-seq) to quantify mRNA abundance, and label-free quantitative proteomics to assess protein expression levels. In addition, we used acRIP-qPCR, regular qPCR and western blots to verify the ac4C, mRNA and protein levels of some key genes that were identified by the high-throughput assays. Proteomic analysis revealed significant change of protein expression in the hippocampus of 3-months-old 5×FAD mice, compared with WT littermates. In contrast, RNA-seq analysis indicated that there were no substantial alterations in mRNA expression levels in the hippocampus of 3-months-old 5×FAD mice, compared to WT littermates. Strikingly, acRIP-seq revealed notable variations in ac4C modification on mRNAs, particularly those associated with synaptic structure and function, in the hippocampus of 3-months-old 5×FAD mice, compared with WT littermates. The ac4C modifications were found to be correlated with protein expression changes. Genes that are essential for synaptic function and cognition, including GRIN1, MAP2, and DNAJC6, exhibited reduced ac4C and protein levels in 3-months-old 5×FAD mice, without any corresponding changes in the mRNA levels, compared with WT littermates. Moreover, only a small part of dysregulated ac4C mRNAs identified in the 3-month-old 5×FAD mice were found in the 6-month-old 5×FAD mice. Altogether these results identified abnormal ac4C modification of mRNAs that may contribute to the dysregulation of protein synthesis in the hippocampus from an early-stage mouse model of AD.

The clinical significance and contribution of the lipid profile in atherosclerosis are well established. However, further investigation is needed in stroke patients, particularly regarding apolipoprotein B100 (ApoB100), a novel non-traditional lipid component in the lipid profile. To explore lipid parameters and their impact on stroke outcomes in patients with and without thrombolysis. We prospectively enrolled patients with acute ischemic stroke (AIS) at a single center, including those who did and did not receive thrombolysis. Participants were stratified into improvement (favorable outcome at 2 weeks) and non-improvement groups. Demographic, laboratory, imaging, and clinical scale data were compared between groups. Random forest analyses were used to evaluate the predictive value and importance of individual lipid measures: triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), ApoB100, and lipoprotein(a), which better describe the internal characteristics of the profile. Complete data were available for 262 AIS patients, 165 of whom received thrombolysis. Plasma ApoB100 levels were significantly lower in the thrombolysis group (p < 0.001) and decreased ApoB100 levels were independently associated with 2-week stroke improvement (p = 0.009, OR = 0.89, 95

Sirtuin-2 (SIRT2) is an NAD+-dependent deacetylase that has been implicated in neuronal stress responses. The present study investigates the hypothesis that SIRT2 directly regulates LC3B acetylation under ischemic-like conditions, and that dl-3-n-butylphthalide (NBP) modulates this axis. In SH-SY5Y cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), SIRT2 and the LC3B-II/I ratio increased, indicating autophagy activation. It was demonstrated that NBP was capable of restoring cell viability and normalizing SIRT2 and LC3B-II/I levels. Co-immunoprecipitation revealed the existence of an endogenous SIRT2-LC3B complex; SIRT2 overexpression resulted in a reduction of acetyl-LC3B, whereas the SIRT2 inhibitor AK-7 elevated LC3B-II/I. Molecular docking (AutoDock Vina) predicted stable NBP binding to the SIRT2 catalytic pocket, a prediction that was supported by 100-ns AMBER simulations (stable RMSD) and favorable binding free energy. The knockdown of SIRT2 resulted in the abrogation of the changes in LC3B-II/I that were driven by OGD/R- and NBP-, indicating a dependence on SIRT2. The findings of this study lend further support to the hypothesis that SIRT2 functions as an LC3B deacetylase under conditions of ischemic stress and suggest that NBP exerts its protective effect, at least in part, through the inhibition of SIRT2, thereby facilitating the normalization of autophagy.

Cerebral small vascular disease (CSVD) has a high incidence worldwide, but its pathological mechanisms remain poorly understood due to the lack of proper animal models. The current animal models of CSVD have several limitations such as high mortality rates and large-sized lesions, and thus it is urgent to develop new animal models of CSVD. Ultrasound can activate protoporphyrin to produce reactive oxygen species in a liquid environment. Here we delivered protoporphyrin into cerebral small vessels of rat brain through polystyrene microspheres with a diameter of 15 μm, and then performed transcranial ultrasound stimulation (TUS) on the model rats. We found that TUS did not affect the large vessels or cause large infarctions in the brain of model rats. The mortality rates were also comparable between the sham and model rats. Strikingly, TUS induced several CSVD-like phenotypes such as cerebral microinfarction, white matter injuries and impaired integrity of endothelial cells in the model rats. Additionally, these effects could be alleviated by antioxidant treatment with N-acetylcysteine (NAC). As control experiments, TUS did not lead to cerebral microinfarction in the rat brain when injected with the polystyrene microspheres not conjugated with protoporphyrin. In sum, we generated a rat model of CSVD that may be useful for the mechanistic study and drug development for CSVD.

BACKGROUND:Oxidized Low-Density Lipoprotein (ox-LDL) is crucial in the recrudescence and prognosis of acute ischemic stroke (AIS). We aimed to probe into the influence of cumulative ox-LDL exposure on the 90-day prognosis of AIS.METHODS:Patients with AIS were recruited in this research. AIS severity at admission was estimated with infarct volumes and National Institute of Health Stroke Scale (NIHSS) scores. AIS prognosis was assessed using Modified Rankin Scale (mRS) scores at 90 days and the change in NIHSS scores from admission to discharge. Cumulative ox-LDL exposure was defined as ox-LDL level (pg/mL) multiplied by age(y). Multivariate logistic regression analysis was employed to reveal the correlation between exposure factors and the prognosis of AIS. The prognostic prediction ability of cumulative ox-LDL exposure was compared with cumulative LDL exposure by the receiver operating characteristic curve (ROC).RESULTS:Higher cumulative ox-LDL exposure was related to worse prognosis, including neurological worsening at discharge (NIHSS increasing more than 2 points) (OR = 3.02, 95% CI, 1.30-6.98, P = 0.01) and poor functional prognosis at 90 days (mRS ≥ 3) (OR = 21.21, 95% CI, 4.72-95.36, P < 0.001). As multivariate regression analysis showed, significantly increased cumulative ox-LDL exposure was relevant to poor functional prognosis at 90 days (OR = 9.92, 95% CI, 1.23-79.76, P = 0.031), but not with neurological worsening at discharge (P = 0.414). ROC curve revealed that cumulative ox-LDL exposure had a higher predictive value (AUC = 0.843, P < 0.001) for functional prognosis of AIS than cumulative LDL exposure (AUC = 0.629, P = 0.023).CONCLUSION:Cumulative ox-LDL exposure has a positive correlation with poor prognosis at 90 days of AIS, and has a more accurate predictive ability than cumulative LDL exposure.

Background The performance of intravenous tenecteplase in patients who had an acute ischaemic stroke with large/medium vessel occlusion or severe stenosis in an extended time window remains unknown. We investigated the promise of efficacy and safety of different doses of tenecteplase manufactured in China, in patients who had an acute ischaemic stroke with large/medium vessel occlusion beyond 4.5-hour time window. Methods The CHinese Acute tissue-Based imaging selection for Lysis In Stroke-Tenecteplase was an investigator-initiated, umbrella phase IIa, open-label, blinded-endpoint, Simon’s two-stage randomised clinical trial in 13 centres across mainland China. Participants who had salvageable brain tissue on automated perfusion imaging and presented within 4.5–24 hours from time of last seen well were randomised to receive 0.25 mg/kg tenecteplase or 0.32 mg/kg tenecteplase, both with a bolus infusion over 5–10 s. The primary outcome was proportion of patients with promise of efficacy and safety defined as reaching major reperfusion without symptomatic intracranial haemorrhage at 24–48 hours after thrombolysis. Assessors were blinded to treatment allocation. All participants who received tenecteplase were included in the analysis. Results A total of 86 patients who had an acute ischaemic stroke identified with anterior large/medium vessel occlusion or severe stenosis were included in this study from November 2019 to December 2021. All of the 86 patients enrolled either received 0.25 mg/kg (n=43) or 0.32 mg/kg (n=43) tenecteplase, and were available for primary outcome analysis. Fourteen out of 43 patients in the 0.25 mg/kg tenecteplase group and 10 out of 43 patients in the 0.32 mg/kg tenecteplase group reached the primary outcome, providing promise of efficacy and safety for both doses based on Simon’s two-stage design. Discussion Among patients with anterior large/medium vessel occlusion and significant penumbral mismatch presented within 4.5–24 hours from time of last seen well, tenecteplase 0.25 mg/kg and 0.32 mg/kg both provided sufficient promise of efficacy and safety. Trial registration number ClinicalTrials.gov Registry ( NCT04086147 , https://clinicaltrials.gov/ct2/show/NCT04086147 ).

ObjectivesThis study aims to investigate whether circulating ADAMTS13 activity can offer insights into the mechanism of pathophysiological changes in deep medullary veins (DMVs).MethodsThis study was conducted on a community cohort of elderly individuals in Shanghai. Plasma von Willebrand factor (VWF) levels and ADAMTS13 activity were measured. A validated DMV score described the overall burden of DMV on the brain. Through ordinal regression models, we investigated the correlation between VWF levels, ADAMTS13 activity, and increasing severity of DMV score while adjusting for demographics and cardiovascular risk factors.ResultsThe study enrolled 262 subjects according to the inclusion criteria. The mean VWF level (1.35 ± 0.25) was higher in the DMV group than in the group without DMV (1.25 ± 0.30) (p = 0.025), and ADAMTS13 activity (83.76 ± 7.96) was relatively lower. After adjusting for age, sex, alcohol consumption, smoking, hypertension, and diabetes, reduced ADAMTS13 activity [β = -7.78; 95% CI (-10.21, -5.35) p < 0.01] was associated with DMV. Moreover, correlation analysis indicated that ADAMTS13 activity was negatively correlated with the DMV score (Kendall's tau-b = -0.53, p < 0.001).DiscussionIn summary, there was an inverse correlation observed between ADAMTS13 activity and the DMV score, which may provide some clinical clues for exploring the potential pathogenesis of DMV.