Estimating the potential value of MSM-focused evidence-based implementation interventions in three Ending the HIV Epidemic jurisdictions in the United States: a model-based analysis.

INTRODUCTION: Improving the delivery of existing evidence-based interventions to prevent and diagnose HIV is key to Ending the HIV Epidemic in the United States. Structural barriers in the access and delivery of related health services require municipal or state-level policy changes; however, suboptimal implementation can be addressed directly through interventions designed to improve the reach, effectiveness, adoption or maintenance of available interventions. Our objective was to estimate the cost-effectiveness and potential epidemiological impact of six real-world implementation interventions designed to address these barriers and increase the scale of delivery of interventions for HIV testing and pre-exposure prophylaxis (PrEP) in three US metropolitan areas. METHODS: We used a dynamic HIV transmission model calibrated to replicate HIV microepidemics in Atlanta, Los Angeles (LA) and Miami. We identified six implementation interventions designed to improve HIV testing uptake ("Academic detailing for HIV testing," "CyBER/testing," "All About Me") and PrEP uptake/persistence ("Project SLIP," "PrEPmate," "PrEP patient navigation"). Our comparator scenario reflected a scale-up of interventions with no additional efforts to mitigate implementation and structural barriers. We accounted for potential heterogeneity in population-level effectiveness across jurisdictions. We sustained implementation interventions over a 10-year period and evaluated HIV acquisitions averted, costs, quality-adjusted life years and incremental cost-effectiveness ratios over a 20-year time horizon (2023-2042). RESULTS: Across jurisdictions, implementation interventions to improve the scale of HIV testing were most cost-effective in Atlanta and LA (CyBER/testing cost-saving and All About Me cost-effective), while interventions for PrEP were most cost-effective in Miami (two of three were cost-saving). We estimated that the most impactful HIV testing intervention, CyBER/testing, was projected to avert 111 (95% credible interval: 110-111), 230 (228-233) and 101 (101-103) acquisitions over 20 years in Atlanta, LA and Miami, respectively. The most impactful implementation intervention to improve PrEP engagement, PrEPmate, averted an estimated 936 (929-943), 860 (853-867) and 2152 (2127-2178) acquisitions over 20 years, in Atlanta, LA and Miami, respectively. CONCLUSIONS: Our results highlight the potential impact of interventions to enhance the implementation of existing evidence-based interventions for the prevention and diagnosis of HIV.

Improved quantification of tumor adhesion in meningiomas using MR elastography-based slip interface imaging.

Meningiomas, the most prevalent primary benign intracranial tumors, often exhibit complicated levels of adhesion to adjacent normal tissues, significantly influencing resection and causing postoperative complications. Surgery remains the primary therapeutic approach, and when combined with adjuvant radiotherapy, it effectively controls residual tumors and reduces tumor recurrence when complete removal may cause a neurologic deficit. Previous studies have indicated that slip interface imaging (SII) techniques based on MR elastography (MRE) have promise as a method for sensitively determining the presence of tumor-brain adhesion. In this study, we developed and tested an improved algorithm for assessing tumor-brain adhesion, based on recognition of patterns in MRE-derived normalized octahedral shear strain (NOSS) images. The primary goal was to quantify the tumor interfaces at higher risk for adhesion, offering a precise and objective method to assess meningioma adhesions in 52 meningioma patients. We also investigated the predictive value of MRE-assessed tumor adhesion in meningioma recurrence. Our findings highlight the effectiveness of the improved SII technique in distinguishing the adhesion degrees, particularly complete adhesion. Statistical analysis revealed significant differences in adhesion percentages between complete and partial adherent tumors (p = 0.005), and complete and non-adherent tumors (p<0.001). The improved technique demonstrated superior discriminatory ability in identifying tumor adhesion patterns compared to the previously described algorithm, with an AUC of 0.86 vs. 0.72 for distinguishing complete adhesion from others (p = 0.037), and an AUC of 0.72 vs. 0.67 for non-adherent and others. Aggressive tumors exhibiting atypical features showed significantly higher adhesion percentages in recurrence group compared to non-recurrence group (p = 0.042). This study validates the efficacy of the improved SII technique in quantifying meningioma adhesions and demonstrates its potential to affect clinical decision-making. The reliability of the technique, coupled with potential to help predict meningioma recurrence, particularly in aggressive tumor subsets, highlights its promise in guiding treatment strategies.

Construction of oral squamous cell carcinoma organoids in vitro 3D-culture for drug screening.

OBJECTIVE: Patient-derived organoids are potent pre-chemotherapy models. Due to limited research on diverse types of oral squamous cell carcinoma (OSCC) and construction efficiency, our goal was to optimize OSCC organoid models from various sites and assess drug responsiveness. METHODS: We screened and optimized culture media, employing three-dimensional techniques to construct human-derived oral squamous cell carcinoma (OSCC) organoid models in vitro. Morphological validation, immunofluorescence analysis, tissue origin verification, and Short Tandem Repeat (STR) sequencing confirmed the consistency between organoids and source tissues. These organoid models were then subjected to varying concentrations of anticancer drugs, with subsequent assessment of cell viability to calculate IC50 values. RESULTS: Twenty-nine surgical specimens yielded an 86.2% success rate in culturing 25 organoids in vitro. Morphological consistency confirmed nuclear atypia and positive expression of K5, P40, and E-cadherin, indicating squamous epithelial origin. Cultured complex organoids included α-SMA+ tumour-associated fibroblasts and tumour stem cells expressing CD44 and Ki67. STR sequencing affirmed genomic homogeneity between cultured organoids and source tissues. Drug sensitivity testing revealed diverse responses among organoids, highlighting their value for assessing drug sensitivity. CONCLUSIONS: An efficient OSCC organoid culture system for personalized in vitro drug sensitivity screening was established, laying the foundation for precise treatment development.

Sex Differences in Aging-related Myocardial Stiffening Quantitatively Measured with MR Elastography.

Purpose To investigate the feasibility of using quantitative MR elastography (MRE) to characterize the influence of aging and sex on left ventricular (LV) shear stiffness. Materials and Methods In this prospective study, LV myocardial shear stiffness was measured in 109 healthy volunteers (age range: 18-84 years; mean age, 40 years ± 18 [SD]; 57 women, 52 men) enrolled between November 2018 and September 2019, using a 5-minute MRE acquisition added to a clinical MRI protocol. Linear regression models were used to estimate the association of cardiac MRI and MRE characteristics with age and sex; models were also fit to assess potential age-sex interaction. Results Myocardial shear stiffness significantly increased with age in female (age slope = 0.03 kPa/year ± 0.01, P = .009) but not male (age slope = 0.008 kPa/year ± 0.009, P = .38) volunteers. LV ejection fraction (LVEF) increased significantly with age in female volunteers (0.23% ± 0.08 per year, P = .005). LV end-systolic volume (LVESV) decreased with age in female volunteers (-0.20 mL/m2 ± 0.07, P = .003). MRI parameters, including T1, strain, and LV mass, did not demonstrate this interaction (P > .05). Myocardial shear stiffness was not significantly correlated with LVEF, LV stroke volume, body mass index, or any MRI strain metrics (P > .05) but showed significant correlations with LV end-diastolic volume/body surface area (BSA) (slope = -3 kPa/mL/m2 ± 1, P = .004, r2 = 0.08) and LVESV/BSA (-1.6 kPa/mL/m2 ± 0.5, P = .003, r2 = 0.08). Conclusion This study demonstrates that female, but not male, individuals experience disproportionate LV stiffening with natural aging, and these changes can be noninvasively measured with MRE. Keywords: Cardiac, Elastography, Biological Effects, Experimental Investigations, Sexual Dimorphisms, MR Elastography, Myocardial Shear Stiffness, Quantitative Stiffness Imaging, Aging Heart, Myocardial Biomechanics, Cardiac MRE Supplemental material is available for this article. Published under a CC BY 4.0 license.

Establishment of genome-editing system and assembly of a near-complete genome in broomcorn millet.

The ancient crop broomcorn millet (Panicum miliaceum L.) is an indispensable orphan crop in semi-arid regions due to its short life cycle and excellent abiotic stress tolerance. These advantages make it an important alternative crop to increase food security and achieve the goal of zero hunger, particularly in light of the uncertainty of global climate change. However, functional genomic and biotechnological research in broomcorn millet has been hampered due to a lack of genetic tools such as transformation and genome-editing techniques. Here, we successfully performed genome editing of broomcorn millet. We identified an elite variety, Hongmi, that produces embryogenic callus and has high shoot regeneration ability in in vitro culture. We established an Agrobacterium tumefaciens-mediated genetic transformation protocol and a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated genome-editing system for Hongmi. Using these techniques, we produced herbicide-resistant transgenic plants and edited phytoene desaturase (PmPDS), which is involved in chlorophyll biosynthesis. To facilitate the rapid adoption of Hongmi as a model line for broomcorn millet research, we assembled a near-complete genome sequence of Hongmi and comprehensively annotated its genome. Together, our results open the door to improving broomcorn millet using biotechnology.

The Role of Astrocytes in Migraine with Cortical Spreading Depression: Protagonists or Bystanders? A Narrative Review.

Cortical spreading depression (CSD) is a slow wave of cortical depolarization closely associated with migraines with an aura. Previously, it was thought that CSD depolarization was mainly driven by neurons, with characteristic changes in neuronal swelling and increased extracellular potassium (K+) and glutamate. However, the role of astrocytes, a member of the neurovascular unit, in migraine with CSD has recently received increasing attention. In the early stages of CSD, astrocytes provide neurons with energy support and clear K+ and glutamate from synaptic gaps. However, in the late stages of CSD, astrocytes release large amounts of lactic acid to exacerbate hypoxia when the energy demand exceeds the astrocytes' compensatory capacity. Astrocyte endfoot swelling is a characteristic of CSD, and neurons are not similarly altered. It is primarily due to K+ influx and abnormally active calcium (Ca2+) signaling. Aquaporin 4 (AQP-4) only mediates K+ influx and has little role as an aquaporin. Astrocytes endfoot swelling causes perivascular space closure, slowing the glymphatic system flow and exacerbating neuroinflammation, leading to persistent CSD. Astrocytes are double-edged swords in migraine with CSD and may be potential targets for CSD interventions.

Targeting Super-Enhancer-Driven Transcriptional Dependencies Suppresses Aberrant Hedgehog Pathway Activation and Overcomes Smoothened Inhibitor Resistance.

Aberrant activation of the Hedgehog (Hh) signaling pathway plays important roles in oncogenesis and therapeutic resistance in several types of cancer. The clinical application of FDA-approved Hh-targeted Smoothened inhibitors (SMOi) is hindered by the emergence of primary or acquired drug resistance. Epigenetic and transcriptional targeted therapies represent a promising direction for developing improved anti-Hh therapies. In this study, we integrated epigenetic/transcriptional-targeted small-molecule library screening with CRISPR/Cas9 knockout library screening and identified CDK9 and CDK12, two transcription elongation regulators, as therapeutic targets for antagonizing aberrant Hh activation and overcoming SMOi resistance. Inhibition of CDK9 or CDK12 potently suppressed Hh signaling and tumor growth in various SMOi responsive or resistant Hh-driven tumor models. Systemic epigenomic profiling elucidated the Hh-driven super-enhancer (SE) landscape and identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the IGF pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target in Hh-driven tumor models. Collectively, this study identifies SE-driven transcriptional dependencies that represent promising therapeutic vulnerabilities for suppressing the Hh pathway and overcoming SMOi resistance. As CDK9 and IRS inhibitors have already entered human clinical trials for cancer treatment, these findings provide comprehensive preclinical support for developing trials for Hh-driven cancers.

Powder Synthesis and Characterization of Al0.5CoCrFeNi High-Entropy Alloy for Additive Manufacturing Prepared by the Plasma Rotating Electrode Process.

The Al0.5CoCrFeNi high-entropy alloy powder was produced by using a plasma rotating electrode process. The morphology, microstructure, and physical properties of the powder were characterized. The powder exhibited a smooth surface and a narrow particle size distribution with a single peak. The relationships between particle size and secondary dendrite arm space as well as cooling rate were evaluated as follows: λ = 0.0105d + 0.062 and vc = 4.34 × 10-5d-2 + 2.62 × 10-2d-3/2, respectively. The Al0.5CoCrFeNi powder mainly consisted of fcc + bcc phases. As the powder particle size decreased, the microstructure of the powder changed from dendritic to columnar or equiaxed, along with a decrease in the fcc content and an increase in the bcc content. The tap density (4.76 g cm-3), flowability (15.01 s × 50 g-1), oxygen content (<300 ppm), and sphericity (>94%) of the powder indicated suitability for additive manufacturing.

A computational study of cell membrane damage and intracellular delivery in a cross-slot microchannel.

We propose a three-dimensional computational framework to simulate the flow-induced cell membrane damage and the resulting enhanced intracellular mass transport in a cross-slot microchannel. We model the cell as a liquid droplet enclosed by a viscoelastic membrane and solve the cell deformation using a well-tested immersed-boundary lattice-Boltzmann method. The cell membrane damage, which is directly related to the membrane permeability, is considered using continuum damage mechanics. The transport of the diffusive solute into the cell is solved by a lattice-Boltzmann model. After validating the computational framework against several benchmark cases, we consider a cell flowing through a cross-slot microchannel, focusing on the effects of the flow strength, channel fluid viscosity and cell membrane viscosity on the membrane damage and enhanced intracellular transport. Interestingly, we find that under a comparable pressure drop across the device, for cells with low membrane viscosity, the inertial flow regime, which can be achieved by driving a low-viscosity liquid at a high speed, often leads to much larger membrane damage, compared with the high-viscosity low-speed viscous flow regime. However, the enhancement can be significantly reduced or even reversed by an increase of the cell membrane viscosity, which limits cell deformation, particularly in the inertial flow regime. Our computational framework and simulation results may guide the design and optimisation of microfluidic devices, which use cross-slot geometry to disrupt cell membranes to enhance intracellular delivery of solutes.

Correlation between NGS panel-based mutation results and clinical information in colorectal cancer patients.

Early mutation identification guides patients with colorectal cancer (CRC) toward targeted therapies. In the present study, 414 patients with CRC were enrolled, and amplicon-based targeted next-generation sequencing (NGS) was then performed to detect genomic alterations within the 73 cancer-related genes in the OncoAim panel. The overall mutation rate was 91.5 % (379/414). Gene mutations were detected in 38/73 genes tested. The most frequently mutated genes were TP53 (60.9 %), KRAS (46.6 %), APC (30.4 %), PIK3CA (15.9 %), FBXW7 (8.2 %), SMAD4 (6.8 %), BRAF (6.5 %), and NRAS (3.9 %). Compared with the wild type, TP53 mutations were associated with low microsatellite instability/microsatellite stability (MSI-L/MSS) (P = 0.007), tumor location (P = 0.043), and histological grade (P = 0.0009); KRAS mutations were associated with female gender (P = 0.026), distant metastasis (P = 0.023), TNM stage (P = 0.013), and histological grade (P = 0.004); APC mutations were associated with patients <64 years of age at diagnosis (P = 0.04); PIK3CA mutations were associated with tumor location (P = 4.97e-06) and female gender (P = 0.018); SMAD4 mutations were associated with tumor location (P = 0.033); BRAF mutations were associated with high MSI (MSI-H; P = 6.968e-07), tumor location (P = 1.58e-06), and histological grade (P = 0.04). Mutations in 164 individuals were found to be pathogenic or likely pathogenic. A total of 26 patients harbored MSI-H tumors and they all had at least one detected gene mutation. Mutated genes were enriched in signaling pathways associated with CRC. The present findings have important implications for improving the personalized treatment of patients with CRC in China.

MR elastography-based slip interface imaging (SII) for functional assessment of myofascial interfaces: A feasibility study.

PURPOSE: Abnormal adherence at functional myofascial interfaces is hypothesized as an important phenomenon in myofascial pain syndrome. This study aimed to investigate the feasibility of MR elastography (MRE)-based slip interface imaging (SII) to visualize and assess myofascial mobility in healthy volunteers. METHODS: SII was used to assess local shear strain at functional myofascial interfaces in the flexor digitorum profundus (FDP) and thighs. In the FDP, MRE was performed at 90 Hz vibration to each index, middle, ring, and little finger. Two thigh MRE scans were performed at 40 Hz with knees flexed and extended. The normalized octahedral shear strain (NOSS) maps were calculated to visualize myofascial slip interfaces. The entropy of the probability distribution of the gradient NOSS was computed for the two knee positions at the intermuscular interface between vastus lateralis and vastus intermedius, around rectus femoris, and between vastus intermedius and vastus medialis. RESULTS: NOSS map depicted distinct functional slip interfaces in the FDP for each finger. Compared to knee flexion, clearer slip interfaces and larger gradient NOSS entropy at the vastus lateralis-vastus intermedius interface were observed during knee extension, where the quadriceps are not passively stretched. This suggests the optimal position for using SII to visualize myofascial slip interface in skeletal muscles is when muscles are not subjected to any additional force. CONCLUSION: The study demonstrated that MRE-based SII can visualize and assess myofascial interface mobility in extremities. The results provide a foundation for investigating the hypothesis that myofascial pain syndrome is characterized by changes in the mobility of myofascial interfaces.

Freeze-Thaw Damage Characterization of Cement-Stabilized Crushed Stone Base with Skeleton Dense Gradation.

The skeleton dense graded cement-stabilized crushed stone base is a widely used material for road construction. However, this material is susceptible to freeze-thaw damage, which can lead to degradation and failure, for which there is still a lack of an in-depth understanding of the freeze-thaw damage characteristics. This study aims to assess the mechanical performance and the freeze-thaw damage characteristics of the cement-stabilized crushed stone base with skeleton dense gradation based on a mechanical test and acoustic technology in a laboratory. There is a gradually increasing trend in the mass loss rate of the base material with an increase in freeze-thaw cycles. The curve steepens significantly after 15 cycles, following a parabola-fitting pattern relationship. The compressive strength of the cement-stabilized crushed stone base also decreased with a parabola-fitting pattern, and the decrease rate may accelerate as the freeze-thaw cycles increase. The resilience modulus of the base material decreased with increasing freeze-thaw cycles, following a parabolic trend. This suggests that the material's resistance to freeze-thaw damage decreases with increasing cycles. The ultrasonic wave velocity decreased with increasing freeze-thaw cycles, exhibiting a parabolic trend. This decline can be attributed to microcracks and defects developing within the material, offering insights for monitoring and predicting its service life. The damage progression of the cement-stabilized crushed stone base was found to occur in three stages: initial, stationary, and failure. The duration of stage I increased with freeze-thaw cycles, while the duration of stage III decreased. The findings provide valuable insights into the mechanisms and processes of freeze-thaw damage in a cement-stabilized crushed stone base with skeleton dense gradation.

Implementation of low-intensity thrombolysis monitoring care in routine practice: process evaluation of the Optimal Post rtPA-IV Monitoring in Acute Ischemic Stroke (OPTIMISTmain) study in the United States.

INTRODUCTION: The ongoing OPTIMISTmain study, an international, multicenter, stepped-wedge cluster randomized trial, aims to determine effectiveness and safety of low-intensity versus standard monitoring in thrombolysis-treated patients with mild-to-moderate acute ischemic stroke (AIS). An embedded process evaluation explored integration and impact of the intervention on care processes at participating US sites. METHODS: A mixed-methods approach with quantitative and qualitative data were collected between September 2021 and November 2022. Implementer surveys were undertaken at pre- and post-intervention phases to understand the perceptions of low-intensity monitoring strategy. A sample of stroke care nurses were invited to participate in semi-structured interviews at an early stage of post-intervention. Qualitative data were analyzed deductively using the normalization process theory; quantitative data were tabulated. RESULTS: Interviews with 21 nurses at 8 hospitals have shown low-intensity monitoring was well accepted, as there were less time constraints and reduced workload for each patient. There were initial safety concerns over missing deteriorating patients and difficulties in changing established routines. Proper training, education, and communication, and changing the habits and culture of care, were key elements to successfully adopting the new monitoring care into routine practice. Similar results were found in the post-intervention survey (42 nurses from 13 hospitals). Nurses reported time being freed up to provide patient education (56%), daily living care (50%), early mobilization (26%), mood/cognition assessment (44%), and other aspects (i.e. communication, family support). CONCLUSIONS: Low-intensity monitoring for patients with mild-to-moderate acute ischemic stroke, facilitated by appropriate education and organizational support, appears feasible and acceptable at US hospitals.

Diagnostic Performance of Carotid Ring Sign on CT-Angiography in Internal Carotid True Occlusion.

BACKGROUND: To differentiate between pseudo occlusion (PO) and true occlusion (TO) of internal carotid artery (ICA) is important in thrombectomy treatment planning for patients with acute ischemic stroke. Although delayed contrast filling has been differentiated carotid PO from TO, its application has been limited by the implementations of multiphasic computed tomography angiography. In this study, we hypothesized that carotid ring sign, which is readily acquired from single-phasic CTA, can sufficiently differentiate carotid TO from PO. METHODS: One thousand four hundred and twenty patients with anterior circulation stroke receiving endovascular therapy were consecutively recruited through a hospital- and web-based registry. Two hundred patients with nonvisualization of the proximal ICA were included in the analysis after a retrospective screening. Diagnosis of PO or TO of the cervical segment of ICA was made based on digital subtraction angiography. Diagnostic performances of carotid ring sign on arterial-phasic CTA and delayed contrast filling on multiphasic computed tomography angiography were evaluated and compared. RESULTS: One-hundred twelve patients had ICA PO and 88 had TO. Carotid ring sign was more common in patients with TO (70.5% versus 6.3%; P<0.001), whereas delayed contrast filling was more common in PO (94.9% versus 7.7%; P<0.001). The sensitivity and specificity of carotid ring sign in diagnosing carotid TO were 0.70 and 0.94, respectively, whereas sensitivity and specificity of delayed contrast filling was 0.95 and 0.92 in judging carotid PO. CONCLUSIONS: Carotid ring sign is a potent imaging marker in diagnosing ICA TO. Carotid ring sign could be complementary to delayed contrast filling sign in differentiating TO from PO, in particular in centers with only single-phasic CTA.

Intravenous Alteplase Versus Best Medical Therapy for Patients With Minor Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: The efficacy of thrombolysis (IVT) in minor stroke (National Institutes of Health Stroke Scale score, 0-5) remains inconclusive. The aim of this study is to compare the effectiveness and safety of IVT with best medical therapy (BMT) by means of a systematic review and meta-analysis of randomized controlled trials and observational studies. METHODS: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases to obtain articles related to IVT in minor stroke from inception until August 10, 2023. The primary outcome was an excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days. The associations were calculated for the overall and preformulated subgroups by using the odds ratios (ORs). This study was registered with PROSPERO (CRD42023445856). RESULTS: A total of 20 high-quality studies, comprised of 13 397 patients with acute minor ischemic stroke, were included. There were no significant differences observed in the modified Rankin Scale scores of 0 to 1 (OR, 1.10 [95% CI, 0.89-1.37]) and 0 to 2 (OR, 1.16 [95% CI, 0.95-1.43]), mortality rates (OR, 0.67 [95% CI, 0.39-1.15]), recurrent stroke (OR, 0.89 [95% CI, 0.57-1.38]), and recurrent ischemic stroke (OR, 1.09 [95% CI, 0.68-1.73]) between the IVT and BMT group. There were differences between the IVT group and the BMT group in terms of early neurological deterioration (OR, 1.81 [95% CI, 1.17-2.80]), symptomatic intracranial hemorrhage (OR, 7.48 [95% CI, 3.55-15.76]), and hemorrhagic transformation (OR, 4.73 [95% CI, 2.40-9.34]). Comparison of modified Rankin Scale score of 0 to 1 remained unchanged in subgroup patients with nondisabling deficits or compared with those using antiplatelets. CONCLUSIONS: These findings indicate that IVT does not yield significant improvement in the functional prognosis of patients with acute minor ischemic stroke. Additionally, it is associated with an increased risk of symptomatic intracranial hemorrhage when compared with the BMT. Moreover, IVT may not have superiority over BMT in patients with nondisabling deficits or those using antiplatelets.

CTP-Defined Large Core Is a Better Predictor of Poor Outcome for Endovascular Treatment Than ASPECTS-Defined Large Core.

BACKGROUND: Recent trials confirmed the effectiveness of endovascular therapy in patients with large ischemic cores. Yet the optimal neuroimaging modalities to define large core remains unclear. We tried to address this question by comparing the functional outcomes in patients receiving thrombectomy selected by either noncontrast computed tomography Alberta Stroke Program Early Computed Tomography Score (ASPECTS) or computed tomography perfusion (CTP). METHODS: This study retrospectively selected patients enrolled in the International Stroke Perfusion Registry between August 2011 and April 2022. Patients with acute stroke with large vessel occlusion in anterior circulation treated with endovascular therapy were included. All received both CTP and noncontrast computed tomography. The primary outcome was defined as poor functional outcome represented by a modified Rankin Scale score of 5 to 6 at 3 months. Large cores were defined in terms of either (1) noncontrast computed tomography ASPECTS ≤5 or (2) core volume ≥70 mL on CTP. RESULTS: A total of 1115 patients were included in the analysis, of which 90 patients had ASPECTS ≤5 (8.1%) and 97 patients CTP core ≥70 mL (8.7%). A fair agreement between ASPECTS and CTP with a κ value of 0.31 (0.21-0.40) was found. Compared with patients with neither CTP nor ASPECTS large cores, those with only ASPECTS-defined large cores (ie, ASPECTS ≤5; n=56) did not have a higher adjusted odds of poor outcome (29%; odds ratio, 1.84 [0.91-3.73]; P=0.089). However, patients with CTP large core but not ASPECTS-defined large core (n=63) had a higher adjusted odds of poor outcome (60%; odds ratio, 3.91 [2.01-7.60]; P<0.001). In time-stratified subgroup analysis (>6 versus ≤6 hours), ASPECTS showed no discriminative difference between ≤5 and >5 in poor outcome for patients receiving endovascular therapy within 6 hours. CONCLUSIONS: CTP core ≥70 mL-defined large cores are more predictive of poor outcome than ASPECTS ≤5-defined core in endovascular therapy patients, particularly within 6 hours after stroke onset.

Synthesis, biological activities and mechanism studies of 1,3,4-oxadiazole analogues of petiolide A as anticancer agents.

In order to develop new natural product-based anticancer agents, a series of 1,3,4-oxadiazole analogues based on petiolide A were prepared and evaluated for their anticancer activities by MTT method. The structures of all analogues were characterized by various spectral analyses, and B9 was further confirmed by X-ray crystallography. Among all the synthesized compounds, B1 displayed the most promising growth inhibitory effect on colon cancer cells (HCT116) with the IC50 value of 8.53 µM. Flow cytometric analysis exhibited that B1 arrested the cell cycle at G2 phase and induced apoptosis. Additionally, network pharmacology analysis calculated that B1 might target several key proteins, including AKT serine/threonine kinase 1 (AKT1), SRC proto-oncogene, non-receptor tyrosine kinase (SRC) and epidermal growth factor receptor (EGFR). Furthermore, molecular docking study indicated that B1 had potentially high binding affinity to these three target proteins. Given these results, analogue B1 could be deeply developed as potential anticancer agents.

Sublingual Edaravone Dexborneol for the Treatment of Acute Ischemic Stroke: The TASTE-SL Randomized Clinical Trial.

Importance: Sublingual edaravone dexborneol, which can rapidly diffuse and be absorbed through the oral mucosa after sublingual exposure, is a multitarget brain cytoprotection composed of antioxidant and anti-inflammatory ingredients edaravone and dexborneol. Objective: To investigate the efficacy and safety of sublingual edaravone dexborneol on 90-day functional outcome in patients with acute ischemic stroke (AIS). Design, Setting, and Participants: This was a double-blind, placebo-controlled, multicenter, parallel-group, phase 3 randomized clinical trial conducted from June 28, 2021, to August 10, 2022, with 90-day follow-up. Participants were recruited from 33 centers in China. Patients randomly assigned to treatment groups were aged 18 to 80 years and had a National Institutes of Health Stroke Scale score between 6 and 20, a total motor deficit score of the upper and lower limbs of 2 or greater, a clinically diagnosed AIS symptom within 48 hours, and a modified Rankin Scale (mRS) score of 1 or less before stroke. Patients who did not meet the eligibility criteria or declined to participate were excluded. Intervention: Patients were assigned, in a 1:1 ratio, to receive sublingual edaravone dexborneol (edaravone, 30 mg; dexborneol, 6 mg) or placebo (edaravone, 0 mg; dexborneol, 60 µg) twice daily for 14 days and were followed up until 90 days. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with mRS score of 1 or less on day 90 after randomization. Results: Of 956 patients, 42 were excluded. A total of 914 patients (median [IQR] age, 64.0 [56.0-70.0] years; 608 male [66.5%]) were randomly allocated to the edaravone dexborneol group (450 [49.2%]) or placebo group (464 [50.8%]). The edaravone dexborneol group showed a significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization compared with the placebo group (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P = .003). The rate of adverse events was similar between the 2 groups (89.8% [405 of 450] vs 90.1% [418 of 464]). Conclusion and Relevance: Among patients with AIS within 48 hours, sublingual edaravone dexborneol could improve the proportion of those achieving a favorable functional outcome at 90 days compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04950920.

Tenecteplase thrombolysis for stroke up to 24 hours after onset with perfusion imaging selection: the umbrella phase IIa CHABLIS-T randomised clinical trial.

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).

Paroxysmal Sympathetic Hyperactivity After Acquired Brain Injury: An Integrative Review of Diagnostic and Management Challenges.

Paroxysmal sympathetic hyperactivity (PSH) mainly occurs after acquired brain injury (ABI) and often presents with high fever, hypertension, tachycardia, tachypnea, sweating, and dystonia (increased muscle tone or spasticity). The pathophysiological mechanisms of PSH are not fully understood. Currently, there are several views: (1) disconnection theory, (2) excitatory/inhibitory ratio, (3) neuroendocrine function, and (4) neutrophil extracellular traps. Early diagnosis of PSH remains difficult, given the low specificity of its diagnostic tools and unclear pathogenesis. According to updated case analyses in recent years, PSH is now more commonly observed in patients with stroke, with tachycardia and hypertension as the main clinical manifestations, which is not fully consistent with previous data. To date, the PSH Assessment Measure tool is optimal for the early identification of PSH and stratification of symptom severity. Clinical strategies for the management of PSH are divided into three main points: (1) reduction of stimulation, (2) reduction of sympathetic excitatory afferents, and (3) inhibition of the effects of sympathetic hyperactivity on target organs. However, use of drugs and standards have not yet been harmonized. Further investigation on the relationship between PSH severity and long-term neurological prognosis in patients with ABI is required. This review aimed to determine the diagnostic and management challenges encountered in PSH after ABI.