Quantifying irregular pulsation of intracranial aneurysms using 4D-CTA.

Recent studies have suggested that irregular pulsation of intracranial aneurysm during the cardiac cycle may be potentially associated with aneurysm rupture risk. However, there is a lack of quantification method for irregular pulsations. This study aims to quantify irregular pulsations by the displacement and strain distribution of the intracranial aneurysm surface during the cardiac cycle using four-dimensional CT angiographic image data. Four-dimensional CT angiography was performed in 8 patients. The image data of a cardiac cycle was divided into approximately 20 phases, and irregular pulsations were detected in four intracranial aneurysms by visual observation, and then the displacement and strain of the intracranial aneurysm was quantified using coherent point drift and finite element method. The displacement and strain were compared between aneurysms with irregular and normal pulsations in two different ways (total and stepwise). The stepwise first principal strain was significantly higher in aneurysms with irregular than normal pulsations (0.20±0.01 vs 0.16±0.02, p=0.033). It was found that the irregular pulsations in intracranial aneurysms usually occur during the consecutive ascending or descending phase of volume changes during the cardiac cycle. In addition, no statistically significant difference was found in the aneurysm volume changes over the cardiac cycle between the two groups. Our method can successfully quantify the displacement and strain changes in the intracranial aneurysm during the cardiac cycle, which may be proven to be a useful tool to quantify intracranial aneurysm deformability and aid in aneurysm rupture risk assessment.

CuCo2O4/CuO Heterostructure with Oxygen Vacancies Induced by Plasma for Electrocatalytic Nitrate Reduction to Ammonia.

Electrochemical nitrate reduction (NO3RR) to ammonia production is regarded as one of the potential alternatives for replacing the Haber-Bosch technology for realizing artificial ammonia synthesis. In this study, a CuCo2O4/CuO-Ar heterostructure in the shape of dandelion nanospheres formed by nanoarrays has been successfully constructed, demonstrating excellent NO3RR performance. Experimental results indicate that Ar plasma etching of CuCo2O4/CuO-Ar significantly increases the content of oxygen vacancies compared to the sample of CuCo2O4/CuO-Air etched by air plasma, resulting in improved NO3RR performance. Density functional theory calculations further confirm that the existence of more oxygen vacancies effectively decreases the energy barrier of nitrate adsorption, which is due to the generation of more oxygen vacancies facilitating nitrate adsorption and weakening the N-O bonds of nitrate after plasma treatment. As a result, CuCo2O4/CuO-Ar exhibits a high NH3 yield of 0.55 mmol h-1 cm-2 and a Faraday efficiency of 95.07% at the optimal potential of -0.9 V (vs RHE) in a neutral medium. Importantly, CuCo2O4/CuO-Ar also showcases excellent electrocatalytic stability. This study presents new views on the design and structure regulation of NO3RR electrocatalysts and their potential applications in the future.

[Effects of Luhong Yixin Granules on myocardial fibrosis in heart failure rats based on TGF-ß1/Smads signaling pathway].

To investigate the effects of Luhong Yixin Granules on myocardial fibrosis in rats with heart failure and its possible mechanism, a total of 60 male Wistar rats were randomly divided into the control group, model group, and low-, medium-and high-dose Luhong Yixin Granules groups, with 12 rats in each group. Except for those in the control group, rats in the other groups were induced by intraperitoneal injection of doxorubicin(DOX) into a rat model. After the Luhong Yixin Granules were dissolved in the same amount of normal saline, they were given by gavage at low, medium and high doses(2.8, 5.6, 11.2 g·kg~(-1)·d~(-1)), and the control group and the model group were given the same amount of normal saline by gavage for 40 days. After the end of dosing, echocardiography was used to measure left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS). Rat body weight(BW) and heart weight(HW) were calculated as HW/BW. Enzyme-linked immunosorbent assay was used to measure the levels of interleukin-6(IL-6), interleukin-17(IL-17), tumor necrosis factor-α(TNF-α), transforming growth factor-ß1(TGF-ß1), growth stimulation expressed gene 2 protein(ST2), N-terminal pro-B-type natriuretic peptide(NT-proBNP), galectin-3(Gal-3) and creatine kinase isoenzyme(CK-MB) in serum. Hematoxylin-eosin(HE) staining and Masson staining were used to observe the pathological morphology of myocardial tissue. Western blot and quantitative real-time polymerase chain reaction were used to detect the protein and mRNA expression levels of IL-6, IL-17, TNF-α, TGF-ß1, Smad3, Smad7, α-smooth muscle actin(α-SMA), and collagen Ⅰ(COL-Ⅰ), respectively. RESULTS:: showed that compared with those in the control group, LVEF, LVFS, and HW/BW in the model group were decreased(P<0.05), and the levels of IL-6, IL-17, TNF-α, TGF-ß1, ST2, NT-proBNP, Gal-3, and CK-MB were increased(P<0.05). HE staining showed inflammatory changes in myocardial tissue; Masson staining showed decreases in the cross-sectional area and ventricular cavity area of the heart, and myocardial fibrosis of varying degrees(P<0.05). The protein and mRNA expression of IL-6, IL-17, TNF-α, TGF-ß1, Smad3, α-SMA, and COL-Ⅰ were increased(P<0.05), and the protein and mRNA expression of Smad7 protein was decreased(P<0.01). Compared with those in the model group, LVEF, LVFS and HW/BW of the low-, medium-and high-dose Luhong Yixin Granules groups were increased(P<0.05), and the levels of IL-6, IL-17, TNF-α, TGF-ß1, ST2, NT-proBNP, Gal-3 and CK-MB were decreased(P<0.05). HE staining showed gradually reduced inflammatory changes of myocardial tissue, and Masson staining showed increased cross-sectional area and ventricular cavity area of the heart and decreased area of myocardial fibrosis(P<0.05). The protein and mRNA expression levels of IL-6, IL-17, TNF-α, TGF-ß1, Smad3, α-SMA, and COL-Ⅰ were decreased(P<0.05), while the protein and mRNA expression levels of Smad7 were increased(P<0.05). Luhong Yixin Granules may be of great value in the treatment of heart failure by regulating the TGF-ß1/Smads signaling pathway, inhibiting the expression of inflammation-related proteins, reducing the deposition of extracellular matrix, and alleviating myocardial fibrosis.

Biofilm-producing ability of methicillin-resistant Staphylococcus aureus clinically isolated in China.

BACKGROUND: Staphylococcus aureus, a commensal bacterium, colonizes the skin and mucous membranes of approximately 30% of the human population. Apart from conventional resistance mechanisms, one of the pathogenic features of S. aureus is its ability to survive in a biofilm state on both biotic and abiotic surfaces. Due to this characteristic, S. aureus is a major cause of human infections, with Methicillin-Resistant Staphylococcus aureus (MRSA) being a significant contributor to both community-acquired and hospital-acquired infections. RESULTS: Analyzing non-repetitive clinical isolates of MRSA collected from seven provinces and cities in China between 2014 and 2020, it was observed that 53.2% of the MRSA isolates exhibited varying degrees of ability to produce biofilm. The biofilm positivity rate was notably high in MRSA isolates from Guangdong, Jiangxi, and Hubei. The predominant MRSA strains collected in this study were of sequence types ST59, ST5, and ST239, with the biofilm-producing capability mainly distributed among moderate and weak biofilm producers within these ST types. Notably, certain sequence types, such as ST88, exhibited a high prevalence of strong biofilm-producing strains. The study found that SCCmec IV was the predominant type among biofilm-positive MRSA, followed by SCCmec II. Comparing strains with weak and strong biofilm production capabilities, the positive rates of the sdrD and sdrE were higher in strong biofilm producers. The genetic determinants ebp, icaA, icaB, icaC, icaD, icaR, and sdrE were associated with strong biofilm production in MRSA. Additionally, biofilm-negative MRSA isolates showed higher sensitivity rates to cefalotin (94.8%), daptomycin (94.5%), mupirocin (86.5%), teicoplanin (94.5%), fusidic acid (81.0%), and dalbavancin (94.5%) compared to biofilm-positive MRSA isolates. The biofilm positivity rate was consistently above 50% in all collected specimen types. CONCLUSIONS: MRSA strains with biofilm production capability warrant increased vigilance.

Helicobacter pylori East Asian type CagA hijacks more SHIP2 by its EPIYA-D motif to potentiate the oncogenicity.

CagA is a significant oncogenic factor injected into host cells by Helicobacter pylori, which is divided into two subtypes: East Asian type (CagAE), characterized by the EPIYA-D motif, and western type (CagAW), harboring the EPIYA-C motif. CagAE has been reported to have higher carcinogenicity than CagAW, although the underlying reason is not fully understood. SHIP2 is an intracellular phosphatase that can be recruited by CagA to perturb the homeostasis of intracellular signaling pathways. In this study, we found that SHIP2 contributes to the higher oncogenicity of CagAE. Co-Immunoprecipitation and Pull-down assays showed that CagAE bind more SHIP2 than CagAW. Immunofluorescence staining showed that a higher amount of SHIP2 recruited by CagAE to the plasma membrane catalyzes the conversion of PI(3,4,5)P3 into PI(3,4)P2. This alteration causes higher activation of Akt signaling, which results in enhanced IL-8 secretion, migration, and invasion of the infected cells. SPR analysis showed that this stronger interaction between CagAE and SHIP2 stems from the higher affinity between the EPIYA-D motif of CagAE and the SH2 domain of SHIP2. Structural analysis revealed the crucial role of the Phe residue at the Y + 5 position in EPIYA-D. After mutating Phe of CagAE into Asp (the corresponding residue in the EPIYA-C motif) or Ala, the activation of downstream Akt signaling was reduced and the malignant transformation of infected cells was alleviated. These findings revealed that CagAE hijacks SHIP2 through its EPIYA-D motif to enhance its carcinogenicity, which provides a better understanding of the higher oncogenic risk of H. pylori CagAE.

Optimizing timing for quantification of intracranial aneurysm enhancement: a multi-phase contrast-enhanced vessel wall MRI study.

OBJECTIVES: Aneurysm wall enhancement (AWE) on high-resolution contrast-enhanced vessel wall MRI (VWMRI) is an emerging biomarker for intracranial aneurysms (IAs) stability. Quantification methods of AWE in the literature, however, are variable. We aimed to determine the optimal post-contrast timing to quantify AWE in both saccular and fusiform IAs. MATERIALS AND METHODS: Consecutive patients with unruptured IAs were prospectively recruited. VWMRI was acquired on 1 pre-contrast and 4 consecutive post-contrast phases (each phase was 9 min). Signal intensity values of cerebrospinal fluid (CSF) and aneurysm wall on pre- and 4 post-contrast phases were measured to determine the aneurysm wall enhancement index (WEI). AWE was also qualitatively analyzed on post-contrast images using previous grading criteria. The dynamic changes of AWE grade and WEI were analyzed for both saccular and fusiform IAs. RESULTS: Thirty-four patients with 42 IAs (27 saccular IAs and 15 fusiform IAs) were included. The changes in AWE grade occurred in 8 (30%) saccular IAs and 6 (40%) in fusiform IAs during the 4 post-contrast phases. The WEI of fusiform IAs decreased 22.0% over time after contrast enhancement (p = 0.009), while the WEI of saccular IAs kept constant during the 4 post-contrast phases (p > 0.05). CONCLUSIONS: When performing quantitative analysis of AWE, acquiring post-contrast VWMRI immediately after contrast injection achieves the strongest AWE for fusiform IAs. While the AWE degree is stable for 36 min after contrast injection for saccular IAs. CLINICAL RELEVANCE STATEMENT: The standardization of imaging protocols and analysis methods for AWE will be helpful for imaging surveillance and further treatment decisions of patients with unruptured IAs. KEY POINTS: Imaging protocols and measurements of intracranial aneurysm wall enhancement are reported heterogeneously. Aneurysm wall enhancement for fusiform intracranial aneurysms (IAs) is strongest immediately post-contrast, and stable for 36 min for saccular IAs. Future multi-center studies should investigate aneurysm wall enhancement as an emerging marker of aneurysm growth and rupture.

A dual-energy computed tomography-based radiomics nomogram for predicting time since stroke onset: a multicenter study.

OBJECTIVES: We aimed to develop and validate a radiomics nomogram based on dual-energy computed tomography (DECT) images and clinical features to classify the time since stroke (TSS), which could facilitate stroke decision-making. MATERIALS AND METHODS: This retrospective three-center study consecutively included 488 stroke patients who underwent DECT between August 2016 and August 2022. The eligible patients were divided into training, test, and validation cohorts according to the center. The patients were classified into two groups based on an estimated TSS threshold of ≤ 4.5 h. Virtual images optimized the visibility of early ischemic lesions with more CT attenuation. A total of 535 radiomics features were extracted from polyenergetic, iodine concentration, virtual monoenergetic, and non-contrast images reconstructed using DECT. Demographic factors were assessed to build a clinical model. A radiomics nomogram was a tool that the Rad score and clinical factors to classify the TSS using multivariate logistic regression analysis. Predictive performance was evaluated using receiver operating characteristic (ROC) analysis, and decision curve analysis (DCA) was used to compare the clinical utility and benefits of different models. RESULTS: Twelve features were used to build the radiomics model. The nomogram incorporating both clinical and radiomics features showed favorable predictive value for TSS. In the validation cohort, the nomogram showed a higher AUC than the radiomics-only and clinical-only models (AUC: 0.936 vs 0.905 vs 0.824). DCA demonstrated the clinical utility of the radiomics nomogram model. CONCLUSIONS: The DECT-based radiomics nomogram provides a promising approach to predicting the TSS of patients. CLINICAL RELEVANCE STATEMENT: The findings support the potential clinical use of DECT-based radiomics nomograms for predicting the TSS. KEY POINTS: Accurately determining the TSS onset is crucial in deciding a treatment approach. The radiomics-clinical nomogram showed the best performance for predicting the TSS. Using the developed model to identify patients at different times since stroke can facilitate individualized management.

Injectable 2D Material-Based Sensor Array for Minimally Invasive Neural Implants.

Intracranial implants for diagnosis and treatment of brain diseases have been developed over the past few decades. However, the platform of conventional implantable devices still relies on invasive probes and bulky sensors in conjunction with large-area craniotomy and provides only limited biometric information. Here, an implantable multi-modal sensor array that can be injected through a small hole in the skull and inherently spread out for conformal contact with the cortical surface is reported. The injectable sensor array, composed of graphene multi-channel electrodes for neural recording and electrical stimulation and MoS2-based sensors for monitoring intracranial temperature and pressure, is designed based on a mesh structure whose elastic restoring force enables the contracted device to spread out. It is demonstrated that the sensor array injected into a rabbit's head can detect epileptic discharges on the surface of the cortex and mitigate it by electrical stimulation while monitoring both intracranial temperature and pressure. This method provides good potential for implanting a variety of functional devices via minimally invasive surgery.

Whitening and antioxidant activities of Inonotus sanghuang Extract and development of primary whitening gel products.

Polysaccharides and flavonoids have excellent antioxidant properties and tyrosinase inhibitory effects. In this paper, the antioxidant capacity of Inonotus sanghuang extract and its inhibition kinetics on mushroom tyrosinase were investigated to determine the preparation process of Inonotus sanghuang primary whitening gel. By conducting experimental studies on the effects of water extract and alcohol extract of Inonotus sanghuang on antioxidant capacity and tyrosinase activity, their inhibitory ability and types of inhibitory effects were determined. The single factor experiment was used to determine the preparation process of Sanghuang primary whitening gel. This study has proven that the extract of Inonotus sanghuang possesses antioxidant and tyrosinase inhibitory capabilities. It also identified the preparation process for the primary whitening gel of Inonotus sanghuang, thereby providing a theoretical and experimental basis for the development of whitening products utilising Inonotus sanghuang.

Two natural compounds as potential inhibitors against the Helicobacter pylori and Acinetobacter baumannii IspD enzymes.

In a vast majority of bacteria, protozoa and plants, the methylerythritol phosphate (MEP) pathway is utilized for the synthesis of isopentenyl diphosphate (IDP) and dimethylallyl diphosphate (DMADP), which are precursors for isoprenoids. Isoprenoids, such as cholesterol and coenzyme Q, play a variety of crucial roles in physiological activities, including cell-membrane formation, protein degradation, cell apoptosis, and transcription regulation. In contrast, humans employ the mevalonate (MVA) pathway for the production of IDP and DMADP, rendering proteins in the MEP pathway appealing targets for antimicrobial agents. This pathway consists of seven consecutive enzymatic reactions, of which 4-diphosphocytidyl-2C-methyl-D-erythritol synthase (IspD) and 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF) catalyze the third and fifth steps, respectively. In this study, we characterized the enzymatic activities and protein structures of Helicobacter pylori IspDF and Acinetobacter baumannii IspD. Then, using the direct interaction-based thermal shift assay, we conducted a compound screening of an approved drug library and identified 27 hit compounds potentially binding to AbIspD. Among them, two natural products, rosmarinic acid and tanshinone IIA sodium sulfonate, exhibited inhibitory activities against HpIspDF and AbIspD, by competing with one of the substrates, MEP. Moreover, tanshinone IIA sodium sulfonate also demonstrated certain antibacterial effects against H. pylori. In summary, we identified two IspD inhibitors from approved ingredients, broadening the scope for antibiotic discovery targeting the MEP pathway.

Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection.

BACKGROUND: SHP1 has been documented as a tumor suppressor and it was thought to play an antagonistic role in the pathogenesis of Helicobacter pylori infection. In this study, the exact mechanism of this antagonistic action was studied. MATERIALS AND METHODS: AGS, MGC803, and GES-1 cells were infected with H. pylori, intracellular distribution changes of SHP1 were first detected by immunofluorescence. SHP1 overexpression and knockdown were then constructed in these cells to investigate its antagonistic roles in H. pylori infection. Migration and invasion of infected cells were detected by transwell assay, secretion of IL-8 was examined via ELISA, the cells with hummingbird-like alteration were determined by microexamination, and activation of JAK2/STAT3, PI3K/Akt, and ERK pathways were detected by immunoblotting. Mice infection model was established and gastric pathological changes were evaluated. Finally, the SHP1 activator sorafenib was used to analyze the attenuating effect of SHP1 activation on H. pylori pathogenesis in vitro and in vivo. RESULTS: The sub-localization of SHP1 changed after H. pylori infection, specifically that the majority of the cytoplasmic SHP1 was transferred to the cell membrane. SHP1 inhibited H. pylori-induced activation of JAK2/STAT3 pathway, PI3K/Akt pathway, nuclear translocation of NF-κB, and then reduced EMT, migration, invasion, and IL-8 secretion. In addition, SHP1 inhibited the formation of CagA-SHP2 complex by dephosphorylating phosphorylated CagA, reduced ERK phosphorylation and the formation of CagA-dependent hummingbird-like cells. In the mice infection model, gastric pathological changes were observed and increased IL-8 secretion, indicators of cell proliferation and EMT progression were also detected. By activating SHP1 with sorafenib, a significant curative effect against H. pylori infection was obtained in vitro and in vivo. CONCLUSIONS: SHP1 plays an antagonistic role in H. pylori pathogenesis by inhibiting JAK2/STAT3 and PI3K/Akt pathways, NF-κB nuclear translocation, and CagA phosphorylation, thereby reducing cell EMT, migration, invasion, IL-8 secretion, and hummingbird-like changes.

Delayed Enhancement of Intracranial Atherosclerotic Plaque Can Better Differentiate Culprit Lesions: A Multiphase Contrast-Enhanced Vessel Wall MRI Study.

BACKGROUND AND PURPOSE: Intracranial plaque enhancement (IPE) identified by contrast-enhanced vessel wall MR imaging (VW-MR imaging) is an emerging marker of plaque instability related to stroke risk, but there was no standardized timing for postcontrast acquisition. We aim to explore the optimal postcontrast timing by using multiphase contrast-enhanced VW-MR imaging and to test its performance in differentiating culprit and nonculprit lesions. MATERIALS AND METHODS: Patients with acute ischemic stroke due to intracranial plaque were prospectively recruited to undergo VW-MR imaging with 1 precontrast phase and 4 consecutive postcontrast phases (9 minutes and 13 seconds for each phase). The signal intensity (SI) values of the CSF and intracranial plaque were measured on 1 precontrast and 4 postcontrast phases to determine the intracranial plaque enhancement index (PEI). The dynamic changes of the PEI were compared between culprit and nonculprit plaques on the postcontrast acquisitions. RESULTS: Thirty patients with acute stroke (aged 59 ± 10 years, 18 [60%] men) with 113 intracranial plaques were included. The average PEI of all intracranial plaques significantly increased (up to 14%) over the 4 phases. There was significantly increased PEI over the 4 phases for culprit plaques (an average increase of 23%), but this was not observed for nonculprit plaques. For differentiating culprit and nonculprit plaques, we observed that the performance of IPE in the second postcontrast phase (cutoff = 0.83, AUC = 0.829 [0.746-0.893]) exhibited superior accuracy when compared with PEI in the first postcontrast phase (cutoff = 0.48; AUC = 0.768 [0.680-0.843]) (P = .022). CONCLUSIONS: A 9-minute delay of postcontrast acquisition can maximize plaque enhancement and better differentiate between culprit and nonculprit plaques. In addition, culprit and nonculprit plaques have different enhancement temporal patterns, which should be evaluated in future studies.

Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction.

INTRODUCTION: Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis. OBJECTIVE: This study was aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution. METHODS: An HFpEF mouse model was induced by a high-fat diet with N-nitro-L-arginine methyl ester. Cells from the hearts were subjected to single-cell sequencing. The key protein expression was measured with Immunohistochemistry and immunofluorescence staining. RESULTS: In HFpEF hearts, myocardial fibroblasts exhibited higher levels of fibrosis. Furthermore, an increased number of fibroblasts differentiated into high-metabolism and high-fibrosis phenotypes. The expression levels of genes encoding certain pro-angiogenic secreted proteins were decreased in the HFpEF group, as confirmed by bulk RNA sequencing. Additionally, the proportion of the endothelial cell (EC) lineages in the HFpEF group was significantly downregulated, with low angiogenesis and high apoptosis phenotypes observed in these EC lineages. Interestingly, the fibroblasts in the HFpEF heart might cross-link with the EC lineages via over-secretion of ANGPTL4, thus displaying an anti-angiogenic function. Immunohistochemistry and immunofluorescence staining then revealed the downregulation of vascular density and upregulation of ANGPTL4 expression in HFpEF hearts. Finally, we predicted ANGPTL4as a potential druggable target using DrugnomeAI. CONCLUSION: In conclusion, this study comprehensively characterized the angiogenesis impairment in HFpEF hearts at single-cell resolution and proposed that ANGPTL4 secretion by fibroblasts may be a potential mechanism underlying this angiogenic abnormality.

Associations between atherosclerotic luminal stenosis in the distal internal carotid artery and diffuse wall thickening in its upstream segment.

OBJECTIVES: Significant atherosclerotic stenosis or occlusion in the distal internal carotid artery (ICA) may induce diffuse wall thickening (DWT) in the upstream arterial wall. This study aimed to assess the association of atherosclerotic steno-occlusive diseases in the distal ICA with DWT in the upstream ipsilateral ICA. METHODS: Individuals with atherosclerotic stenosis in the distal ICA, detected by carotid MR vessel wall imaging using 3D pre- and post-contrast T1 volume isotropic turbo spin-echo acquisition (T1-VISTA) sequence, were enrolled. The associations of vessel wall thickening, the longitudinal extent of DWT, enhancement of the upstream ipsilateral ICA, and stenosis degree in the distal ICA were examined. RESULTS: Totally 64 arteries in 55 patients with atherosclerotic steno-occlusive distal ICAs were included. Significant correlations were found between distal ICA stenosis and DWT in the petrous ICA (r = 0.422, p = 0.001), DWT severity (r = 0.474, p < 0.001), the longitudinal extent of DWT in the ICA (r = 0.671, p < 0.001), enhancement in the petrous ICA (r = 0.409, p = 0.001), and enhancement degree (r = 0.651, p < 0.001). In addition, high degree of enhancement was correlated with both increased wall thickness and increased prevalence of DWT in the petrous ICA (both p < 0.001). CONCLUSIONS: DWT of the petrous ICA is commonly detected in patients with atherosclerotic steno-occlusive disease in the distal ICA. The degree of stenosis in the distal ICA is associated with wall thickening and its longitudinal extent in the upstream segments. CLINICAL RELEVANCE STATEMENT: Diffuse wall thickening is a common secondary change in atherosclerotic steno-occlusive disease in the intracranial carotid. This phenomenon constitutes a confounding factor in the distinction between atherosclerosis and inflammatory vasculopathies, and could be reversed after alleviated atherosclerotic stenosis. KEY POINTS: • Diffuse wall thickening of the petrous internal carotid artery is commonly detected in patients with atherosclerotic steno-occlusive disease in the distal internal carotid artery. • The phenomenon of diffuse wall thickening could be reversed after stenosis alleviation. • Carotid artery atherosclerosis with diffuse wall thickening should warrant a differential diagnosis from other steno-occlusive diseases, including moyamoya diseases and Takayasu aortitis.

Novel small-molecule compound YH7 inhibits the biofilm formation of Staphylococcus aureus in a sarX-dependent manner.

The emergence of antibiotic-resistant and biofilm-producing Staphylococcus aureus isolates presents major challenges for treating staphylococcal infections. Biofilm inhibition is an important anti-virulence strategy. In this study, a novel maleimide-diselenide hybrid compound (YH7) was synthesized and demonstrated remarkable antimicrobial activity against methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) in both planktonic cultures and biofilms. The minimum inhibitory concentration (MIC) of YH7 for S. aureus isolates was 16 µg/mL. Quantification of biofilms demonstrated that the sub-MIC (4 µg/mL) of YH7 significantly inhibits biofilm formation in both MSSA and MRSA. Confocal laser scanning microscopy analysis further confirmed the biofilm inhibitory potential of YH7. YH7 also significantly suppressed bacterial adherence to A549 cells. Moreover, YH7 treatment significantly inhibited S. aureus colonization in nasal tissue of mice. Preliminary mechanistic studies revealed that YH7 exerted potent biofilm-suppressing effects by inhibiting polysaccharide intercellular adhesin (PIA) synthesis, rather than suppressing bacterial autolysis. Real-time quantitative PCR data indicated that YH7 downregulated biofilm formation-related genes (clfA, fnbA, icaA, and icaD) and the global regulatory gene sarX, which promotes PIA synthesis. The sarX-dependent antibiofilm potential of YH7 was validated by constructing S. aureus NCTC8325 sarX knockout and complementation strains. Importantly, YH7 demonstrated a low potential to induce drug resistance in S. aureus and exhibited non-toxic to rabbit erythrocytes, A549, and BEAS-2B cells at antibacterial concentrations. In vivo toxicity assays conducted on Galleria mellonella further confirmed that YH7 is biocompatible. Overall, YH7 demonstrated potent antibiofilm activity supports its potential as an antimicrobial agent against S. aureus biofilm-related infections. IMPORTANCE Biofilm-associated infections, characterized by antibiotic resistance and persistence, present a formidable challenge in healthcare. Traditional antibacterial agents prove inadequate against biofilms. In this study, the novel compound YH7 demonstrates potent antibiofilm properties by impeding the adhesion and the polysaccharide intercellular adhesin production of Staphylococcus aureus. Notably, its exceptional efficacy against both methicillin-resistant and methicillin-susceptible strains highlights its broad applicability. This study highlights the potential of YH7 as a novel therapeutic agent to address the pressing issue of biofilm-driven infections.

Emergence of KPC-2 and NDM-5-coproducing hypervirulent carbapenem-resistant Klebsiella pneumoniae with high-risk sequence types ST11 and ST15.

The emergence of Klebsiella pneumoniae carbapenemase-2 (KPC-2) and New Delhi metallo-ß-lactamase (NDM)-coproducing hypervirulent carbapenem-resistant Klebsiella pneumoniae (KPC-2-NDM-hv-CRKP) poses a certain threat to public health. Currently, only a few sporadic reports of such double-positive hv-CRKPs were available. In this study, we isolated two KPC-2-NDM-5-hv-CRKPs from elderly patients with serious underlying diseases and poor prognoses. We found both FK3122 and FK3127 were typical multidrug-resistant (MDR) isolates, exhibiting high-level resistance to both carbapenems and novel ß-lactamase inhibitors ceftazidime/avibactam. Notably, FK3122 is even resistant to cefiderocol due to multiple blaNDM-5 elements. Besides the MDR phenotype, A549 human lung epithelial cells and Galleria mellonella infection model all indicated that FK3122 and FK3127 were highly pathogenic. According to the whole-genome sequencing analysis, we observed over 10 resistant elements, and the uncommon co-existence of blaKPC-2, blaNDM-5, and virulence plasmids in both two isolates. Both virulence plasmids identified in FK3122 and FK3127 shared a high identity with classical virulence plasmid pK2044, harboring specific hypervirulent factors: rmpA and iuc operon. We also found that the resistance and virulence plasmids in FK3127 could not only be transferred to Escherichia coli EC600 independently but also together as a co-transfer, which was additionally confirmed by the S1-pulsed-field gel electrophoresis plasmid profile. Moreover, polymorphic mobile genetic elements were found surrounding resistance genes, which may stimulate the mobilization of resistance genes and result in the duplication of these elements. Considering the combination of high pathogenicity, limited therapy options, and easy transmission of KPC-2-NDM-5-hv-CRKP, our study emphasizes the need for underscores the imperative for ongoing surveillance of these pathogens.IMPORTANCEHypervirulent Klebsiella pneumoniae drug resistance has increased gradually with the emergence of carbapenem-resistant hypervirulent K. pneumoniae (hv-CRKP). However, little information is available on the virulence characteristics of the New Delhi metallo-ß-lactamase (NDM) and Klebsiella pneumoniae carbapenemase-2 (KPC-2) co-producing K. pneumoniae strains. In this study, we obtained two KPC-2-NDM-hv-CRKPs from elderly patients, each with distinct capsule types and sequence types: ST11-KL64 and ST15-KL24; these ST-type lineages are recognized as classical multidrug-resistant (MDR) K. pneumoniae. We found these KPC-2-NDM-hv-CRKPs were not only typical MDR isolates, including resistance to ceftazidime/avibactam and cefiderocol, but also displayed exceptionally high levels of pathogenicity. In addition, these high-risk factors can also be transferred to other isolates. Consequently, our study underscores the need for ongoing surveillance of these isolates due to their heightened pathogenicity, limited therapeutic options, and potential for easy transmission.

Atherosclerotic plaque characteristics in extracranial carotid artery may indicate closer association with white matter hyperintensities than intracranial arteries: A CARE-II study.

PURPOSE: This study aimed to investigate the associations of atherosclerotic plaque characteristics in intracranial and extracranial carotid arteries with severity of white matter hyperintensities (WMHs) in symptomatic patients using magnetic resonance (MR) imaging. METHOD: Patients with cerebrovascular symptoms and carotid plaque were recruited from the cross-sectional, multicenter study of CARE-II. Luminal stenosis of intracranial and extracranial carotid arteries, carotid plaque compositional features, and WMHs were evaluated by brain structural and vascular MR imaging. The atherosclerotic plaque characteristics in intracranial and extracranial carotid arteries were compared between patients with and without moderate-to-severe WMHs (Fazekas score > 2), and their associations with severity of WMHs were analyzed using logistic regression. RESULTS: Of the recruited 622 patients (mean age, 58.7 ± 10.9 years; 422 males), 221 (35.5 %) had moderate-to-severe WMHs with higher prevalence of moderate-to-severe luminal stenosis (17.0 % vs. 10.4 %), intraplaque hemorrhage (15.7 % vs. 9.0 %), thin/ruptured fibrous cap (30.2 % vs. 20.4 %), calcification (44.4 % vs. 22.2 %) and lipid-rich necrotic core (63.8 % vs. 51.1 %) in carotid artery compared to those without (all P < 0.05). Multivariate logistic regression showed that carotid calcification (OR, 1.854; 95 % CI, 1.187-2.898; P = 0.007) was independently associated with moderate-to-severe WMHs after adjusting for confounding factors. No significant association was found between intracranial atherosclerotic stenosis and moderate-to-severe WMHs (P > 0.05). CONCLUSION: Carotid atherosclerotic plaque features, particularly presence of calcification, were independently associated with severity of WMHs, but such association was not found in intracranial atherosclerotic stenosis, suggesting that carotid atherosclerotic plaque characteristics may have closer association with severity of WMHs compared to intracranial atherosclerosis.

Gadolinium-enhanced intracranial aneurysm wall imaging and risk of aneurysm growth and rupture: a multicentre longitudinal cohort study.

OBJECTIVES: In patients with an unruptured intracranial aneurysm, gadolinium enhancement of the aneurysm wall is associated with growth and rupture. However, most previous studies did not have a longitudinal design and did not adjust for aneurysm size, which is the main predictor of aneurysm instability and the most important determinant of wall enhancement. We investigated whether aneurysm wall enhancement predicts aneurysm growth and rupture during follow-up and whether the predictive value was independent of aneurysm size. MATERIALS AND METHODS: In this multicentre longitudinal cohort study, individual patient data were obtained from twelve international cohorts. Inclusion criteria were as follows: 18 years or older with ≥ 1 untreated unruptured intracranial aneurysm < 15 mm; gadolinium-enhanced aneurysm wall imaging and MRA at baseline; and MRA or rupture during follow-up. Patients were included between November 2012 and November 2019. We calculated crude hazard ratios with 95%CI of aneurysm wall enhancement for growth (≥ 1 mm increase) or rupture and adjusted for aneurysm size. RESULTS: In 455 patients (mean age (SD), 60 (13) years; 323 (71%) women) with 559 aneurysms, growth or rupture occurred in 13/194 (6.7%) aneurysms with wall enhancement and in 9/365 (2.5%) aneurysms without enhancement (crude hazard ratio 3.1 [95%CI: 1.3-7.4], adjusted hazard ratio 1.4 [95%CI: 0.5-3.7]) with a median follow-up duration of 1.2 years. CONCLUSIONS: Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not independent of aneurysm size. CLINICAL RELEVANCE STATEMENT: Gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, since it appears to have no additional value to conventional predictors. KEY POINTS: • Although aneurysm wall enhancement is associated with aneurysm instability in cross-sectional studies, it remains unknown whether it predicts risk of aneurysm growth or rupture in longitudinal studies. • Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not when adjusting for aneurysm size. • While gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, it may hold potential for aneurysms smaller than 7 mm.

Constrained estimation of intracranial aneurysm surface deformation using 4D-CTA.

BACKGROUND AND OBJECTIVE: Intracranial aneurysms are relatively common life-threatening diseases, and assessing aneurysm rupture risk and identifying the associated risk factors is essential. Parameters such as the Oscillatory Shear Index, Pressure Loss Coefficient, and Wall Shear Stress are reliable indicators of intracranial aneurysm development and rupture risk, but aneurysm surface irregular pulsation has also received attention in aneurysm rupture risk assessment. METHODS: The present paper proposed a new approach to estimate aneurysm surface deformation. This method transforms the estimation of aneurysm surface deformation into a constrained optimization problem, which minimizes the error between the displacement estimated by the model and the sparse data point displacements from the four-dimensional CT angiography (4D-CTA) imaging data. RESULTS: The effect of the number of sparse data points on the results has been discussed in both simulation and experimental results, and it shows that the proposed method can accurately estimate the surface deformation of intracranial aneurysms when using sufficient sparse data points. CONCLUSIONS: Due to a potential association between aneurysm rupture and surface irregular pulsation, the estimation of aneurysm surface deformation is needed. This paper proposed a method based on 4D-CTA imaging data, offering a novel solution for the estimation of intracranial aneurysm surface deformation.

Cortical surface plasticity promotes map remodeling and alleviates tinnitus in adult mice.

Tinnitus induced by hearing loss is caused primarily by irreversible damage to the peripheral auditory system, which results in abnormal neural responses and frequency map disruption in the central auditory system. It remains unclear whether and how electrical rehabilitation of the auditory cortex can alleviate tinnitus. We hypothesize that stimulation of the cortical surface can alleviate tinnitus by enhancing neural responses and promoting frequency map reorganization. To test this hypothesis, we assessed and activated cortical maps using our newly designed graphene-based electrode array with a noise-induced tinnitus animal model. We found that cortical surface stimulation increased cortical activity, reshaped sensory maps, and alleviated hearing loss-induced tinnitus behavior in adult mice. These effects were likely due to retained long-term synaptic potentiation capabilities, as shown in cortical slices from the mice model. These findings suggest that cortical surface activation can be used to facilitate practical functional recovery from phantom percepts induced by sensory deprivation. They also provide a working principle for various treatment methods that involve electrical rehabilitation of the cortex.