Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease.

Mitochondrial dysfunction is a well-established hallmark of Alzheimer's disease (AD). Despite recent documentation of transcellular mitochondrial transfer, its role in the pathogenesis of AD remains unclear. In this study, we report an impairment of mitochondrial quality within the astrocytes and neurons of adult 5 × FAD mice. Following treatment with mitochondria isolated from aged astrocytes induced by exposure to amyloid protein or extended cultivation, cultured neurons exhibited an excessive generation of reactive oxygen species and underwent neurite atrophy. Notably, aerobic exercise enhanced mitochondrial quality by upregulating CD38 within hippocampal astrocytes of 5 × FAD mice. Conversely, the knockdown of CD38 diminished astrocytic-neuronal mitochondrial transfer, thereby abolishing the ameliorative effects of aerobic exercise on neuronal oxidative stress, ß-amyloid plaque deposition, and cognitive dysfunction in 5 × FAD mice. These findings unveil an unexpected mechanism through which aerobic exercise facilitates the transference of healthy mitochondria from astrocytes to neurons, thus countering the AD-like progression.

Unveiling the Role of Sik1 in Osteoblast Differentiation: Implications for Osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative disease characterized by subchondral osteosclerosis, mainly due to osteoblast activity. This research investigates the function of Sik1, a member of the AMP-activated protein kinase family, in OA. Proteomic analysis was conducted on clinical samples from 30 OA patients, revealing a negative correlation between Sik1 expression and OA. In vitro experiments utilized BMSCs to examine the effect of Sik1 on osteogenic differentiation. BMSCs were cultured and induced toward osteogenesis with specific media. Sik1 overexpression was achieved through lentiviral transfection, followed by analysis of osteogenesis-associated proteins using Western blotting, RT-qPCR, and alkaline phosphate staining. In vivo experiments involved destabilizing the medial meniscus in mice to establish an OA model, assessing the therapeutic potential of Sik1. The CT scans and histological staining were used to analyze subchondral bone alterations and cartilage damage. The findings show that Sik1 downregulation correlates with advanced OA and heightened osteogenic differentiation in BMSCs. Sik1 overexpression inhibits osteogenesis-related markers in vitro and reduces cartilage damage and subchondral osteosclerosis in vivo. Mechanistically, Sik1 modulates osteogenesis and subchondral bone changes through Runx2 activity regulation. The research emphasizes Sik1 as a promising target for treating OA, suggesting its involvement in controlling bone formation and changes in the subchondral osteosclerosis.

Unveiling the role of RhoA and ferroptosis in vascular permeability: Implications for osteoarthritis.

Abnormal angiogenesis and increased vascular permeability of subchondral bone are key mechanisms related to osteoarthritis (OA). However, the precise mechanisms responsible for heightened vascular permeability in OA remain unclear. The present study used proteomics to identify protein expression in damaged subchondral bone compared with normal subchondral bone. The results suggest that Ras homolog family member A (RhoA) may be associated with the vascular permeability of subchondral bone and ferroptosis in OA. The results of analysis of clinical samples indicated a significant increase in expression of RhoA in the subchondral bone of OA. This were consistent with the proteomics findings. We found through western blotting, RT­PCR, and immunofluorescence that RhoA significantly increased the permeability of endothelial cells (ECs) by inhibiting inter­EC adhesion proteins (zona occludens­1, connexin 43 and Vascular endothelial­Cadherin) and actin filaments. Furthermore, RhoA induced ferroptosis core proteins (glutathione peroxidase 4,  solute carrier family 7 member 11 and acyl­CoA synthase long­chain family member 4, ACSL4) by influencing lipid peroxidation and mitochondrial function, leading to ferroptosis of ECs. This suggested an association between RhoA, ferroptosis and vascular permeability. Ferroptosis significantly increased permeability of ECs by inhibiting inter­EC adhesion proteins. RhoA increased vascular permeability by inducing ferroptosis of ECs. In vivo, inhibition of RhoA and ferroptosis significantly mitigated progression of OA by alleviating cartilage degeneration and subchondral bone remodeling in mice with destabilization of the medial meniscus. In conclusion, the present findings indicated that RhoA enhanced vascular permeability in OA by inducing ferroptosis. This may serve as a novel strategy for the early prevention and treatment of OA.

Comparison of targeted next-generation sequencing and the Xpert MTB/RIF assay for detection of Mycobacterium tuberculosis in clinical isolates and sputum specimens.

Targeted next-generation sequencing (tNGS) can be used to perform Mycobacterium tuberculosis (MTB) complex-specific amplification or target capture directly from sputum samples, yielding simultaneous coverage of many genes and DNA regions associated with antimicrobial resistance (AMR). Performance comparisons of tNGS and another molecular testing tool, Xpert MTB/rifampicin (RIF), have been empirical. Here, using a dilution series of a RIF-resistant clinical isolate of MTB, we found that tNGS had a slightly lower limit of bacterial detection (102 CFU/mL) compared with Xpert MTB/RIF (103 CFU/mL) in culture medium. However, the minimum detection limit of the rpoB S450L mutation in this isolate was significantly lower with tNGS (102 CFU/mL) than with Xpert MTB/RIF (106 CFU/mL). Sputum samples collected from 129 suspected pulmonary tuberculosis patients were also prospectively studied with the clinical diagnosis as a reference, revealing that the sensitivity of tNGS (48.6%) was higher than those of culture (46.8%), Xpert MTB/RIF (39.4%), and smear microscopy (34.9%) testing. Notably, AMR analysis of 56 MTB-positive samples as determined by tNGS revealed high mutation frequencies of 96.4%, 35.7%, 26.8%, and 19.6% in the following AMR-associated genes: rrs, rpoB, katG, and pncA, respectively. The findings of this study provide theoretical support for the differential clinical application of tNGS and Xpert MTB/RIF and suggest that tNGS has greater application value in tuberculosis drug resistance monitoring and prevention.IMPORTANCETargeted next-generation sequencing (tNGS) can be used to perform Mycobacterium tuberculosis (MTB) complex-specific amplification or target capture directly from sputum samples, yielding simultaneous coverage of genes and DNA regions associated with antimicrobial resistance (AMR). Performance comparisons of tNGS and Xpert MTB/rifampicin (RIF) have been empirical. The Xpert MTB/RIF assay is a commercial system that uses the nucleic acid amplification detection method for rapid (2 hours) diagnosis of tuberculosis (TB). The cost of the tNGS and Xpert MTB/RIF assays in this study was similar, at USD 98 and USD 70-104 per sample, respectively, but the time required for tNGS (3 days) was much longer than that required for the Xpert MTB/RIF assay. However, tNGS yielded more accurate results and a larger number of AMR-associated gene mutations, which compensated for the extra time and highlighted the greater application value of tNGS in TB drug resistance monitoring and prevention.

Functional aspects of the brain lymphatic drainage system in aging and neurodegenerative diseases.

The phenomenon of an aging population is advancing at a precipitous rate. Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common age-associated neurodegenerative diseases, both of which are primarily characterized by the accumulation of toxic proteins and the progressive demise of neuronal structures. Recent discoveries about the brain lymphatic drainage system have precipitated a growing body of investigations substantiating its novel roles, including the clearance of macromolecular waste and the trafficking of immune cells. Notably, aquaporin 4-mediated glymphatic transport, crucial for maintaining neural homeostasis, becomes disrupted during the aging process and is further compromised in the pathogenesis of AD and PD. Functional meningeal lymphatic vessels, which facilitate the drainage of cerebrospinal fluid into the deep cervical lymph nodes, are integral in bridging the central nervous system with peripheral immune responses. Dysfunction in these meningeal lymphatic vessels exacerbates pathological trajectory of the age-related neurodegenerative disease. This review explores modulatory influence of the glymphatic system and meningeal lymphatic vessels on the aging brain and its associated neurodegenerative disorders. It also encapsulates the insights of potential mechanisms and prospects of the targeted non-pharmacological interventions.

A deep learning framework for intracranial aneurysms automatic segmentation and detection on magnetic resonance T1 images.

OBJECTIVES: To design a deep learning-based framework for automatic segmentation and detection of intracranial aneurysms (IAs) on magnetic resonance T1 images and test the robustness and performance of framework. METHODS: A retrospective diagnostic study was conducted based on 159 IAs from 136 patients who underwent the T1 images. Among them, 127 cases were randomly selected for training and validation, and 32 cases were used to assess the accuracy and consistency of our algorithm. We developed and assembled three convolutional neural networks for the segmentation and detection of IAs. The segmentation and detection performance of the model were compared with the ground truth, and various metrics were calculated at the voxel level, IAs level, and patient level to show the performance of our framework. RESULTS: Our assembled model achieved overall Dice, voxel-level sensitivity, specificity, balanced accuracy, and F1 score of 0.802, 0.874, 0.9998, 0.937, and 0.802, respectively. A coincidence greater than 0.7 between the aneurysms predicted by the model and the ground truth was considered as a true positive. For IAs detection, the sensitivity reached 90.63% with 0.58 false positives per case. The volume of IAs segmented by our model showed a high agreement and consistency with the volume of IAs labeled by experts. CONCLUSION: The deep learning framework is achievable and robust for IAs segmentation and detection. Our model offers more clinical application opportunities compared to digital subtraction angiography (DSA)-based, CTA-based, and MRA-based methods. CLINICAL RELEVANCE STATEMENT: Our deep learning framework effectively detects and segments intracranial aneurysms using clinical routine T1 sequences, showing remarkable effectiveness and offering great potential for improving the detection of latent intracranial aneurysms and enabling early identification. KEY POINTS: •There is no segmentation method based on clinical routine T1 images. Our study shows that the proper deep learning framework can effectively localize the intracranial aneurysms. •The T1-based segmentation and detection method is more universal than other angiography-based detection methods, which can potentially reduce missed diagnoses caused by the absence of angiography images. •The deep learning framework is robust and has the potential to be applied in a clinical setting.

Contamination of neonicotinoid insecticides in source water and their fate during drinking water treatment in the Dongguan section of the Pearl River.

Neonicotinoid insecticides (NEOs) as well as their metabolites are highly mobile on the subsurface and can potentially contaminate drinking water sources; however, their pollution status and fate in the drinking water system remains ambiguous. In this study, six parent NEOs and two characteristic metabolites were measured in drinking water source protection area (source water, n = 52) and two related drinking water treatment plants (DWTPs) (n = 88) located in the Dongguan section of the Pearl River. The ubiquitous of NEOs was observed in source water with the mean concentration of total NEOs (ΣNEOs) at 240 ng/L. Although advanced DWTP (A-DWTP; range: 26 % to 100 %) showed better removals of ΣNEOs and all individual NEOs rather than those in conventional DWTP (C-DWTP; range: -53 % to 28 %), the removals were still low for acetamiprid (ACE, 26 %), thiacloprid (THD, 59 %), thiamethoxam (THM, 56 %) and N-desmethyl-acetamiprid (N-dm-ACE, 45 %) in A-DWTP. Removal rates were positive in chlorination (48 %), final stage of sedimentation (F-Sed, 24 %), and granular activated carbon (GAC) filter effluent (19 %) in A-DWTP. It worthy to note that ΣNEOs has high negative removal rates at the start stage of sedimentation (S-Sed, -83 %), middle stage of sedimentation (M-Sed, -47 %), and sand filter effluent (-42 %) water in C-DWTP, which resulted in negative removals of ΣNEOs (-9.6 %), imidacloprid (IMI, -22 %), clothianidin (CLO, -37 %), flupyradifurone (FLU, -76 %), and N-dm-ACE (-29 %) in C-DWTP. Residual levels of NEOs were high in source water, and their low or negative removals in DWTPs should be highly concerning. Results would fill the existing knowledge gap of NEOs in aquatic environment and provide a scientific dataset for policy-making on pollution control and environmental protection.

Decreased miR-451a in cerebrospinal fluid, a marker for both cognitive impairment and depressive symptoms in Alzheimer's disease.

Background: Alzheimer's disease (AD) patients are often accompanied by depressive symptoms, but its underlying mechanism remains unclear. The present study aimed to explore the potential role of microRNAs in the comorbidity of AD and depression. Methods: The miRNAs associated with AD and depression were screened from databases and literature and then confirmed in the cerebrospinal fluid (CSF) of AD patients and different ages of transgenic APP/PS1 mice. AAV9-miR-451a-GFP was injected into the medial prefrontal cortex (mPFC) of APP/PS1 mice at seven months, and four weeks later, a series of behavioral and pathological analyses were performed. Results: AD patients had low CSF levels of miR-451a, which was positively correlated with the cognitive assessment score, but negatively with their depression scale. In the mPFC of APP/PS1 transgenic mice, the miR-451a levels also decreased significantly in the neurons and microglia. Specific virus vector-induced overexpression of miR-451a in the mPFC of APP/PS1 mice ameliorated AD-related behavior deficits and pathologies, including long-term memory defects, depression-like phenotype, ß-amyloid load, and neuroinflammation. Mechanistically, miR-451a decreased the expression of neuronal ß-secretase 1 of neurons through inhibiting Toll-like receptor 4/Inhibitor of kappa B Kinase ß/ Nuclear factor kappa-B signaling pathway and microglial activation by inhibiting activation of NOD-like receptor protein 3, respectively. Conclusion: This finding highlighted miR-451a as a potential target for diagnosing and treating AD, especially for those with coexisting symptoms of depression.

Three-dimensional aneurysm wall enhancement in fusiform intracranial aneurysms is associated with aneurysmal symptoms.

Background and purpose: Aneurysm wall enhancement (AWE) in high-resolution magnetic resonance imaging (HR-MRI) is a potential biomarker for evaluating unstable aneurysms. Fusiform intracranial aneurysms (FIAs) frequently have a complex and curved structure. We aimed to develop a new three-dimensional (3D) aneurysmal wall enhancement (AWE) characterization method to enable comprehensive FIA evaluation and to investigate the ability of 3D-AWE to predict symptomatic FIA. Methods: We prospectively recruited patients with unruptured FIAs and received 3 T HR-MRI imaging from September 2017 to January 2019. 3D models of aneurysms and parent arteries were generated. Boundaries of the FIA were determined using 3D vessel diameter measurements. Dmax was the greatest diameter in the cross-section, while Lmax was the length of the centerline of the aneurysm. Signal intensity of the FIA was normalized to the pituitary stalk and then mapped onto the 3D model, then the average enhancement (3D-AWEavg), maximum enhancement (3D-AWEmax), enhancement area (AWEarea), and enhancement ratio (AWEratio) were calculated as AWE indicators, and the surface area of the entire aneurysm (Aarea) was also calculated. Areas with high AWE were defined as those with a value >0.9 times the signal intensity of the pituitary stalk. Multivariable logistic regression analyses were performed to determine independent predictors of aneurysm-related symptoms. FIA subtypes were defined as fusiform, dolichoectasia, and transitional. Differences between the three FIA subtypes were also examined. Results: Forty-seven patients with 47 FIAs were included. Mean patient age was 55 ± 12.62 years and 74.5% were male. Twenty-nine patients (38.3%) were symptomatic. After adjusting for baseline differences in age, hypertension, Lmax, and FIA subtype, the multivariate logistics regression models showed that 3D-AWEavg (odds ratio [OR], 4.029; p = 0.019), 3D-AWEmax (OR, 3.437; p = 0.022), AWEarea (OR, 1.019; p = 0.008), and AWEratio (OR, 2.490; p = 0.045) were independent predictors of aneurysm-related symptoms. Dmax and Aarea were larger and 3D-AWEavg, 3D-AWEmax, AWEarea, and AWEratio were higher with the transitional subtype than the other two subtypes. Conclusion: The new 3D AWE method, which enables the use of numerous new metrics, can predict symptomatic FIAs. Different 3D-AWE between the three FIA subtypes may be helpful in understanding the pathophysiology of FIAs.

Aneurysm wall enhancement, atherosclerotic proteins, and aneurysm size may be related in unruptured intracranial fusiform aneurysms.

OBJECTIVE: This cross-sectional study aimed to investigate the associations between aneurysm wall enhancement (AWE), atherosclerotic protein levels, and aneurysm size in unruptured intracranial fusiform aneurysms (IFAs). METHODS: Patients with IFAs underwent high-resolution magnetic resonance imaging (HR-MRI) and atherosclerotic protein examinations from May 2015 to December 2021 were collected. A CRstalk (signal intensity [SI] of IFA wall/SI of pituitary stalk) > 0.60 was considered to indicate AWE. Atherosclerotic protein data was obtained from the peripheral blood. Aneurysmal characteristics included the maximal diameter of the cross-section (Dmax), location, type of IFA, presence of mural thrombus, and mural clots. Statistical analyses were performed with univariate analysis, logistic regression analysis, and Spearman's correlation coefficient. RESULTS: Seventy-one IFAs from 71 patients were included in the study. Multivariate analysis revealed statin use (OR = 0.189, p = 0.026) and apolipoprotein B (Apo-B) level (OR = 6.019, p = 0.026) were the independent predictors of AWE in IFAs. In addition, statin use (OR = 0.813, p = 0.036) and Apo-B level (OR = 1.610, p = 0.003) were also the independent predictors of CRstalk. Additionally, we found that CRstalk and AWE were significantly positively associated with Dmax (rs = 0.409 and 0.349, respectively; p < 0.001 and p = 0.003, respectively). CONCLUSIONS: There may be correlations between AWE, atherosclerotic protein levels, and aneurysm size in patients with IFAs. Apo-B and statin use were independent predictors of AWE in IFAs, which have the potential to be new therapeutic targets for IFAs. KEY POINTS: • There may be correlations between aneurysm wall enhancement, atherosclerotic protein levels in the peripheral blood, and aneurysm size in patients with intracranial fusiform aneurysms. • Apolipoprotein B and statin use were independent predictors of aneurysm wall enhancement in intracranial fusiform aneurysms.

Systemic immune-inflammation index is associated with aneurysmal wall enhancement in unruptured intracranial fusiform aneurysms.

Introduction: Inflammation plays a key role in the progression of intracranial aneurysms. Aneurysmal wall enhancement (AWE) correlates well with inflammatory processes in the aneurysmal wall. Understanding the potential associations between blood inflammatory indices and AWE may aid in the further understanding of intracranial aneurysm pathophysiology. Methods: We retrospectively reviewed 122 patients with intracranial fusiform aneurysms (IFAs) who underwent both high-resolution magnetic resonance imaging and blood laboratory tests. AWE was defined as a contrast ratio of the signal intensity of the aneurysmal wall to that of the pituitary stalk ≥ 0.90. The systemic immune-inflammation (SII) index (neutrophils × platelets/lymphocytes) was calculated from laboratory data and dichotomized based on whether or not the IFA had AWE. Aneurysmal symptoms were defined as sentinel headache or oculomotor nerve palsy. Multivariable logistic regression and receiver operating characteristic curve analyses were performed to determine how well the SII index was able to predict AWE and aneurysmal symptoms. Spearman's correlation coefficients were used to explore the potential associations between variables. Results: This study included 95 patients, of whom 24 (25.3%) presented with AWE. After adjusting for baseline differences in neutrophil to lymphocyte ratios, leukocytes, and neutrophils in the multivariable logistic regression analysis, smoking history (P = 0.002), aneurysmal symptoms (P = 0.047), maximum diameter (P = 0.048), and SII index (P = 0.022) all predicted AWE. The SII index (P = 0.038) was the only independent predictor of aneurysmal symptoms. The receiver operating characteristic curve analysis revealed that the SII index was able to accurately distinguish IFAs with AWE (area under the curve = 0.746) and aneurysmal symptoms (area under the curve = 0.739). Discussion: An early elevation in the SII index can independently predict AWE in IFAs and is a potential new biomarker for predicting IFA instability.

Inflow Angle Impacts Morphology, Hemodynamics, and Inflammation of Side-wall Intracranial Aneurysms.

BACKGROUND: Aneurysm inflow angle has been shown to be associated with hemodynamic changes by computational fluid dynamics. However, these studies were based on single aneurysm model and were limited to side-wall aneurysms. PURPOSE: To investigate the association between inflow angle and morphology, hemodynamic, and inflammation of intracranial side-wall and bifurcation aneurysms. STUDY TYPE: Prospective. POPULATION: A total of 62 patients (aged 58.34 ± 12.39, 44 female) with 59 unruptured side-wall aneurysms and 17 unruptured bifurcation aneurysms were included. FIELD STRENGTH/SEQUENCE: A 3.0 T; 3D fast field echo sequence (TOF-MRA); free-breathing, 3D radio-frequency-spoiled, multi-shot turbo field echo sequence (4D-flow MRI); 3D black-blood T1-weighted volumetric turbo spin echo acquisition sequence (T1 -VISTA) ASSESSMENT: Two neuroradiologists assessed the inflow angle and size for intracranial aneurysms in 3D space with TOF-MRA images. The average and maximum inflow velocity (Vavg-IA , Vmax-IA ), blood flow (Flowavg-IA , Flowmax-IA ), and average wall shear stress (WSSavg-IA ) for aneurysms were assessed from 4D-flow MRI in regions of interest drawn by two neuroradiologists. The aneurysmal wall enhancement (AWE) grades between precontrast and postcontrast T1 -VISTA images were evaluated by three neuroradiologists. STATISTICAL TESTS: Kruskal-Wallis H test, χ2 test, Pearson's correlation coefficient, scatter plots and regression lines, multivariate logistic regression analysis (partial correlation r) were performed. A P < 0.05 was considered statistically significant. RESULTS: The WSSavg-IA (0.52 ± 0.34 vs. 0.27 ± 0.22) and AWE grades (1.38 ± 1.04 vs. 2.02 ± 0.68) between the two inflow angle subgroups of side-wall aneurysms were significantly different. The aneurysm size (rs  = 0.31), WSSavg-IA (rs  = -0.45), and AWE grades (rs  = 0.45) were significantly correlated with inflow angle in side-wall aneurysms. While in bifurcation aneurysms, there were no significant associations between inflow angle and size (P = 0.901), Vavg-IA (P = 0.699), Vmax-IA (P = 0.482), Flowavg-IA (P = 0.550), Flowmax-IA (P = 0.689), WSSavg-IA (P = 0.573), and AWE grades (P = 0.872). DATA CONCLUSION: A larger aneurysm size, a lower WSS and a higher AWE grade were correlated with a larger inflow angle in side-wall aneurysms. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

[Analysis on medical care seeking of local and non-local pulmonary tuberculosis patients reported in Beijing, 2016-2021].

Objective: To analyze the medical care seeking of local and non-local pulmonary tuberculosis (TB) patients in Beijing from 2016 to 2021 and provide evidence for TB prevention and control in Beijing. Methods: The reported pulmonary TB data from 2016 to 2021 were collected from tuberculosis management information system and standard code management system of Chinese information system for disease control and prevention. The map data were obtained from the Institute of Geographic Sciences and Natural Resources Research. Excel 2016, SPSS 19.0, Python 3.9 and ArcGIS 10.6 softwares were used for data analysis and visualization for the inter-provincial mobility and inter-district mobility of pulmonary TB patient's medical care seeking in Beijing. Results: Among the reported pulmonary TB patients in Beijing from 2016 to 2021, 35.27%(24 307/68 926) were from 30 provinces (autonomous regions, municipalities) and Xinjiang Production and Construction Corps. The top 5 provinces with pulmonary TB patients medical care seeking in Beijing were Hebei (39.58%,9 620/24 307), Shanxi (8.82%,2 145/24 307), Inner Mongolia Autonomous Region (8.66%,2 105/24 307), Heilongjiang (6.95%,1 690/24 307) and Henan (6.88%,1 672/24 307). Patients from these 5 provinces accounted for 70.89% (17 232/24 307) of total pulmonary TB patients from other provinces. The pulmonary TB patients from other provinces mainly flowed to Tongzhou district of Beijing, accounting for 46.72% (11 356/24 307). These pulmonary TB patients mainly visited grade Ⅲ (A) hospitals, such as Beijing Chest Hospital of Capital Medical University with the highest proportion of 44.76% (10 880/24 307). Among pulmonary TB patients with current residence in Beijing, those sought medical care in other districts accounted for 55.06% (24 566/44 619). The outflow and inflow of TB cases' medical care seeking occurred in 16 districts of Beijing. The median proportion of cross district medical care seeking in 16 districts was 59.30% (56.05%, 65.13%). The inflow of the medical care seeking in Tongzhou, Haidian and Xicheng district was greater than the outflow, and the outflow was greater than the inflow in the other 13 districts. The pulmonary TB patients in Beijing mainly went to Beijing Chest Hospital in Tongzhou for medical care seeking, accounting for 42.18%(18 822/44 619). Conclusions: The proportions of non-local pulmonary TB patients seeking medical care in Beijing from 2016 to 2021 and local pulmonary TB patients seeking medical care in other districts in Beijing were high, and the hospitals where non-local pulmonary TB patients and local pulmonary TB patients sought medical care respectively belonged to grade Ⅲ (A) and municipal designated medical institutions of TB.

Transmission of multidrug-resistant tuberculosis in Beijing, China: An epidemiological and genomic analysis.

Background: Understanding multidrug-resistant tuberculosis (MDR-TB) transmission patterns is crucial for controlling the disease. We aimed to identify high-risk populations and geographic settings of MDR-TB transmission. Methods: We conducted a population-based retrospective study of MDR-TB patients in Beijing from 2018 to 2020, and assessed MDR-TB recent transmission using whole-genome sequencing of isolates. Geospatial analysis was conducted with kernel density estimation. We combined TransPhylo software with epidemiological investigation data to construct transmission networks. Logistic regression analysis was utilized to identify risk factors for recent transmission. Results: We included 241 MDR-TB patients, of which 146 (60.58%) were available for genomic analysis. Drug resistance prediction showed that resistance to fluoroquinolones (FQs) was as high as 39.74% among new cases. 36 (24.66%) of the 146 MDR strains were grouped into 12 genome clusters, suggesting recent transmission of MDR strains. 44.82% (13/29) of the clustered patients lived in the same residential community, adjacent residential community or the same street as other cases. The inferred transmission chain found a total of 6 transmission events in 3 clusters; of these, 4 transmission events occurred in residential areas and nearby public places. Logistic regression analysis revealed that being aged 25-34 years-old was a risk factor for recent transmission. Conclusions: The recent transmission of MDR-TB in Beijing is severe, and residential areas are common sites of transmission; high levels of FQs drug resistance suggest that FQs should be used with caution unless resistance can be ruled out by laboratory testing.

Locomotor Hyperactivity in the Early-Stage Alzheimer's Disease-like Pathology of APP/PS1 Mice: Associated with Impaired Polarization of Astrocyte Aquaporin 4.

Non-cognitive behavioral and psychological symptoms often occur in Alzheimer's disease (AD) patients and mouse models, although the exact neuropathological mechanism remains elusive. Here, we report hyperactivity with significant inter-individual variability in 4-month-old APP/PS1 mice. Pathological analysis revealed that intraneuronal accumulation of amyloid-ß (Aß), c-Fos expression in glutamatergic neurons and activation of astrocytes were more evident in the frontal motor cortex of hyperactive APP/PS1 mice, compared to those with normal activity. Moreover, the hyperactive phenotype was associated with mislocalization of perivascular aquaporin 4 (AQP4) and glymphatic transport impairment. Deletion of the AQP4 gene increased hyperactivity, intraneuronal Aß load and glutamatergic neuron activation, but did not influence working memory or anxiety-like behaviors of 4-month-old APP/PS1 mice. Together, these results demonstrate that AQP4 mislocalization or deficiency leads to increased intraneuronal Aß load and neuronal hyperactivity in the motor cortex, which in turn causes locomotor over-activity during the early pathophysiology of APP/PS1 mice. Therefore, improving AQP4 mediated glymphatic clearance may offer a new strategy for early intervention of hyperactivity in the prodromal phase of AD.

Independent predictors and risk score for intraprocedural rupture during endovascular treatment of small ruptured intracranial aneurysms (<5 mm).

Background and purpose: Intraprocedural rupture (IPR) is a devastating complication of endovascular treatment (EVT). Small-sized and ruptured aneurysms are independent predictors of IPR, which presents a technical challenge during EVT. We aimed to develop a score to quantify the individual patient risk of IPR in the EVT of small (<5 mm) ruptured aneurysms (SRAs). Methods: A retrospective review was conducted to interrogate databases prospectively maintained at two academic institutions in China from January 2009 to October 2016. We collected intraoperative angiograms and medical records to identify independent predictors of IPR using univariate and multivariable analyses. A risk score for IPR was derived using multivariable logistic regression analyses. Results: Of the 290 enrolled patients, IPR occurred in 16 patients (5.5%). The univariate analysis showed that the rate of IPR was significantly higher in patients having aneurysms with a small basal outpouching (SBO), in patients having aneurysms concomitant with adjacent moderate atherosclerotic stenosis (ACAMAS), and in former or current smokers. Multivariate analyses showed that SBO [odds ratio (OR): 3.573; 95% confidence interval (CI): 1.078-11.840; p = 0.037], vascular eloquence (VE; OR: 3.780; 95% CI: 1.080-13.224; p = 0.037), and ACAMAS (OR: 6.086; 95% CI: 1.768-20.955; p = 0.004) were significantly and independently associated with IPR. A three-point risk score (S-V-A) was derived to predict IPR [SBO (yes = 1), VE (yes = 1), and ACAMAS (yes = 1)]. Conclusions: Intraprocedural rupture occurred in 5.5% of the patients during EVT of SRA. SBO, VE, and ACAMAS were independent risk factors of IPR in the EVT of SRA. Based on these variables, the S-V-A score may be useful in predicting IPR daily, but more confirmation studies are required.

Comparisons between cross-section and long-axis-section in the quantification of aneurysmal wall enhancement of fusiform intracranial aneurysms in identifying aneurysmal symptoms.

Background: To investigate the quantification of aneurysmal wall enhancement (AWE) in fusiform intracranial aneurysms (FIAs) and to compare AWE parameters based on different sections of FIAs in identifying aneurysm symptoms. Methods: Consecutive patients were prospectively recruited from February 2017 to November 2019. Aneurysm-related symptoms were defined as sentinel headache and oculomotor nerve palsy. All patients underwent high resolution magnetic resonance imaging (HR-MRI) protocol, including both pre and post-contrast imaging. CRstalk (signal intensity of FIAs' wall divided by pituitary infundibulum) was evaluated both in the cross-section (CRstalk-cross) and the long-axis section (CRstalk-long) of FIAs. Aneurysm characteristics include the maximal diameter of the cross-section (D max), the maximal length of the long-axis section (L max), location, type, and mural thrombus. The performance of parameters for differentiating symptomatic and asymptomatic FIAs was obtained and compared by a receiver operating characteristic (ROC) curve. Results: Forty-three FIAs were found in 43 patients. Eighteen (41.9%) patients who presented with aneurysmal symptoms were classified in the symptomatic group. In univariate analysis, male sex (P = 0.133), age (P = 0.013), FIAs type (P = 0.167), mural thrombus (P = 0.130), L max (P = 0.066), CRstalk-cross (P = 0.027), and CRstalk-long (P = 0.055) tended to be associated with aneurysmal symptoms. In the cross-section model of multivariate analysis, male (P = 0.038), age (P = 0.018), and CRstalk-cross (P = 0.048) were independently associated with aneurysmal symptoms. In the long-axis section model of multivariate analysis, male (P = 0.040), age (P = 0.010), CRstalk-long (P = 0.046), and L max (P = 0.019) were independently associated with aneurysmal symptoms. In the combination model of multivariate analysis, male (P = 0.027), age (P = 0.011), CRstalk-cross (P = 0.030), and L max (P = 0.020) were independently associated with aneurysmal symptoms. CRstalk-cross has the highest accuracy in predicting aneurysmal symptoms (AUC = 0.701). The combination of CRstalk-cross and L max exhibited the highest performance in discriminating symptomatic from asymptomatic FIAs (AUC = 0.780). Conclusion: Aneurysmal wall enhancement is associated with symptomatic FIAs. CRstalk-cross and L max were independent risk factors for aneurysmal symptoms. The combination of these two factors may improve the predictive performance of aneurysmal symptoms and may also help to stratify the instability of FIAs in future studies.

Aneurysmal wall enhancement and hemodynamics: pixel-level correlation between spatial distribution.

Background: Inflammation and hemodynamics are interrelated risk factors for intracranial aneurysm rupture. This study aimed to identify the relationship between these risk factors from an individual-patient perspective using biomarkers of aneurysm wall enhancement (AWE) derived from high-resolution magnetic resonance imaging (HR-MRI) and hemodynamic parameters by four-dimensional flow MRI (4D-flow MRI). Methods: A total of 29 patients with 29 unruptured intracranial aneurysms larger than 4 mm were included in this prospective cross-sectional study. A total of 24 aneurysms had AWE and 5 did not have AWE. A three-dimensional (3D) vessel model of each individual aneurysm was generated with 3D time-of-flight magnetic resonance angiography (3D TOF-MRA). Quantification of AWE was sampled with HR-MRI. Time-averaged wall shear stress (WSS) and oscillatory shear index (OSI) were calculated from the 4D-flow MRI. The correlation between spatial distribution of AWE and hemodynamic parameters measured at pixel-level was evaluated for each aneurysm. Results: In aneurysms with AWE, the spatial distribution of WSS was negatively correlated with AWE in 100% (24/24) of aneurysms, though 2 had an absolute value of the correlation coefficient <0.1. The OSI was positively correlated with AWE in 91.7% (22/24) of aneurysms; the other 2 aneurysms showed a negative correlation with AWE. In aneurysms with no AWE, there was no correlation between WSS (100%, 5/5), OSI (80%, 4/5), and wall inflammation. Conclusions: The spatial distribution of WSS was negatively correlated with AWE in aneurysms with AWE, and OSI was positively correlated with AWE in most aneurysms with AWE. While aneurysms that did not contain AWE showed no correlation between hemodynamics and wall inflammation.

Quantification of aneurysm wall enhancement in intracranial fusiform aneurysms and related predictors based on high-resolution magnetic resonance imaging: a validation study.

Background: Aneurysm wall enhancement (AWE) in high-resolution magnetic resonance imaging (HR-MRI) has emerged as a new imaging biomarker of intracranial aneurysm instability. Objective: To determine a standard method of AWE quantification for predicting fusiform intracranial aneurysms (FIAs) stability by comparing the sensitivity of each parameter in identifying symptomatic FIAs. The predictors of AWE and FIA types were also identified. Methods: We retrospectively analyzed consecutive fusiform aneurysm patients who underwent HR-MRI from two centers. The aneurysm-to-pituitary stalk contrast ratio (CRstalk), aneurysm enhancement ratio, and aneurysm enhancement index were extracted, and their sensitivities in discriminating aneurysm symptoms were compared using the receiver-operating characteristic curve. Morphological parameters of fusiform aneurysm were extracted based on 3D vessel model. Uni- and multivariate analyses of related predictors for AWE, CRstalk, and FIA types were performed, respectively. Results: Overall, 117 patients (mean age, 53.3 ± 11.7 years; male, 75.2%) with 117 FIAs underwent HR-MRI were included. CRstalk with the maximum signal intensity (CRstalk-max) had the highest sensitivity in identifying symptomatic FIAs with an area under the curve value (0.697) and a cut-off value of 0.90. The independent predictors of AWE were aneurysm symptoms [(odds ratio) OR = 3.754, p = 0.003], aspirin use (OR = 0.248, p = 0.037), and the maximum diameter of the cross-section (OR = 1.171, p = 0.043). The independent predictors of CRstalk-max were aneurysm symptoms (OR = 1.289, p = 0.003) and posterior circulation aneurysm (OR = 1.314, p = 0.001). Transitional-type showed higher rates of hypertension and mural thrombus over both dolichoectatic- and fusiform-type FIAs. Conclusion: CRstalk-max may be the most reliable parameter to quantify AWE to distinguish symptomatic FIAs. It also has the potential to identify unstable FIAs. Several factors contribute to the complex pathophysiology of FIAs and need further validation in a larger cohort.

Quantitative detection of trace VBNC Cronobacter sakazakii by immunomagnetic separation in combination with PMAxx-ddPCR in dairy products.

One immunomagnetic separation (IMS) assay based on immunomagnetic beads (IMBs) has been evaluated as a potential pretreatment tool for the separation and enrichment of target bacteria. In this study, we successfully immobilized antibodies onto magnetic bead surfaces to form IMBs through biotin and a streptavidin (SA) system to capture viable but nonculturable (VBNC) Cronobacter sakazakii (C. sakazakii) from dairy products. Various parameters that affected the capture efficiency (CE) of IMS, including the number of antibodies, IMBs dose, incubation time, magnetic separation time, and immunoreaction temperature, were systematically investigated. We further determined the optimal enrichment conditions for different dairy substrates to ensure maximum enrichment of target pathogens in the system. An IMS technique combining improved propidium monoazide (PMAxx) and droplet digital PCR (ddPCR) was established to detect the pathogenic VBNC C. sakazakii. The IMS-PMAxx-ddPCR method after IMBs enrichment showed higher accuracy when the VBNC C. sakazakii was under 1 Log10 copies/g. The detection limit for this method in a background of powdered infant formula (PIF) was 5.6 copies/g. In summary, the developed IMS-PMAxx-ddPCR method has great potential for the analysis and detection of VBNC bacteria in food.