Pulsatile Flow Increases METTL14-induced m6A modification and attenuates septic cardiomyopathy: an experimental study.

INTRODUCTION: Septic cardiomyopathy is a sepsis-mediated cardiovascular complication with severe microcirculatory malperfusion. Emerging evidence has highlighted the protective effects of pulsatile flow in case of microcirculatory disturbance, yet the underlying mechanisms are still elusive. The objective of this study was to investigate the mechanisms of N6-methyladenosine (m6A) modification in the alleviation of septic cardiomyopathy associated with extracorporeal membrane oxygenation (ECMO)-generated pulsatile flow. METHODS: Rat model with septic cardiomyopathy was established and was supported under ECMO either with pulsatile or non-pulsatile flow. Peripheral perfusion index (PPI) and cardiac function parameters were measured using ultrasonography. Dot blot assay was applied to examine the m6A level, while qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry were used to measure the expressions of related genes. RNA immunoprecipitation assay was performed to validate the interaction between molecules. RESULTS: The ECMO-generated pulsatile flow significantly elevates microcirculatory PPI, improves myocardial function, protects the endothelium, and prolongs survival in rat models with septic cardiomyopathy. The pulsatile flow mediates the METTL14-mediated m6A modification to zonula occludens- (ZO-) 1 mRNA which stabilizes the ZO-1 mRNA depending on the presence of YTHDF2. The pulsatile flow suppresses the PI3K-Akt signaling pathway, of which the downstream molecule Foxo1, a negative transcription factor of METTL14, binds to the METTL14 promoter and inhibits the METTL14-induced m6A modification. CONCLUSION: The ECMO-generated pulsatile flow increases METTL14-induced m6A modification in ZO-1 and attenuates the progression of septic cardiomyopathy, suggesting that pulsatility might be a new therapeutic strategy in septic cardiomyopathy by alleviating microcirculatory disturbance.

Effect of temperature and air pressure on the incidence of Bell's palsy in Hangzhou: a distributed lag non-linear analysis.

The etiology of Bell's palsy (BP) is currently unknown, and the findings from previous studies examining the association between seasonal or meteorological factors and BP have been inconsistent. This research aims to clarify this relationship by analyzing a larger dataset and employing appropriate statistical methods. Data from 5387 patients with BP treated at Zhejiang Provincial Hospital of Traditional Chinese Medicine in Hangzhou, Zhejiang Province, from May 1, 2018, to June 30, 2023, was gathered. We assessed the temporal distribution of meteorological factors and the incidence of BP across seasons and months. A distributed lag non-linear model was used to further investigate the lagged and overall effects of temperature and air pressure on the onset of BP. The temporal distribution of BP incidence revealed the highest average number of cases occurring in December and the lowest in June. A correlation existed between BP episodes and temperature or air pressure. The model revealed a higher relative risk during periods of low temperature and high air pressure, characterized by a time lag effect. This correlation was notably more pronounced in female patients and individuals in the young and middle-aged groups. Our findings suggest that exposure to low temperatures and high air pressure constitute risk factors for BP development.

Evaluating Upstaging in Ductal Carcinoma In Situ Using Preoperative MRI-Based Radiomics.

BACKGROUND: About 20%-40% of patients diagnosed with ductal carcinoma in situ (DCIS) by core needle biopsy (CNB) will develop invasive cancer at the time of excision. Improving the preoperative diagnosis of DCIS is important for surgical planning. PURPOSE: To establish an MRI-based radiomics nomogram for preoperatively evaluating the upstaging of DCIS patients and help with risk stratification. STUDY TYPE: Retrospective. POPULATION: A total of 227 patients (50.5 ± 9.7 years; 67 upstaged DCIS) were divided into training (n = 109), internal (n = 47), and external (n = 71) validation cohort. FIELD STRENGTH/SEQUENCE: 1.5-T or 3-T, dynamic contrast-enhanced (DCE) imaging, and diffusion-weighted imaging (DWI). ASSESSMENT: DCIS lesions were manually segmented using ITK-SNAP software and 1304 radiomic features were extracted from DCE, DWI, and apparent diffusion coef-ficient (ADC) maps, respectively. A radscore was calculated by a random forest algo-rithm based on DCIS upstaging-related radiomic features, which selected by a coarse-to-fine method including interclass correlation coefficient, single-factor anal-ysis, and the least absolute shrinkage and selection operator (LASSO) method. Uni-variate and multivariate logistic regression was used to analyze the independent risk factors, including age, location, lesion size, estrogen receptor (ER) status, and other clinico-pathologic factors. Finally, Mann-Whitney U tests were performed to com-pare the differences in radscore between low/intermediate and high nuclear grade groups for pure DCIS patients. STATISTICAL TESTS: Student's t-tests or Mann-Whitney U tests, chi-square-tests, or Fisher's-tests, univariate and multivariate logistic regression analysis, calibration curve, Youden index, the area under the curve (AUC), Delong test, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses. RESULTS: Eight important radiomic features (two from ADC, three from DWI, and three from DCE) were selected for calculating radscore. Clinical model including age and ER was established with AUCs of 0.747 and 0.738 in the internal and external validation cohorts, respectively. A combined model integrating age, estrogen receptor (ER), and radscore were also constructed with AUCs of 0.887 and 0.881. Further subgroup analysis showed that pure DCIS patients with different nuclear grade have significant differences in radscore. DATA CONCLUSION: Multisequence MRI radiomics may preoperatively evaluate the upstaging of DCIS and might provide personalized image-based clinical decision support. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Circular RNA UBAP2 (hsa_circ_0007367) Correlates with Microcirculatory Perfusion and Predicts Outcomes of Cardiogenic Shock Patients Undergoing Extracorporeal Membrane Oxygenation Support.

BACKGROUND: Severe microcirculatory disturbance is common in patients with cardiogenic shock necessitating extracorporeal membrane oxygenation (ECMO), however, biomarkers linked to microcirculation and clinical outcome are scarce. Herein we identified a circular RNA, hsa_circ_0007367, rooted from the ubiquitin-associated protein 2 (UBAP2) gene, namely circUBAP2, and evaluated its biological function and the associations with microcirculation and the prognosis. METHODS: Patients on ECMO with cardiogenic shock were included if qualified sublingual microcirculation parameters could be obtained and were categorized into the survivor group or non-survivor group. Macro-circulatory, microcirculatory data, cytokine levels, and relative circUBAP2 expressions were collected before, at 24 h, and at ECMO weaning off, respectively. The effects of circUBAP2 on the migration, polarization, cytokine productions, and inflammatory pathways in macrophage NR8383 cells were investigated using in vitro methods. RESULTS: Thirty-three patients with an average age of 58.0 years were enrolled, including 19 survivors and 14 non-survivors. The survivors had higher small vessel density, perfused small vessel density (PSVD), and microvascular flow index (MFI) throughout the ECMO course than did the non-survivors. Relative expression of circUBAP2 (hsa_circ_0007367) correlated with the microcirculatory parameters and satisfactorily predicted the 30-day in-hospital mortality. A multivariable logistic model was developed, showing following four predictors: age (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.00-1.12), time from shock to ECMO (OR 1.10, 95% CI 1.01-1.20), PVSD (OR 0.14, 95% CI 0.02-0.89), and the circUBAP2 expression (OR 0.25, 95% CI 0.08-0.78). In addition, circUBAP2 inhibited the migratory activity and promoted M2 polarization in macrophages, declining the productions of cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1ß, and monocyte chemotactic protein [MCP]-1) and the PI3K/Akt/mTOR pathway. CONCLUSION: The expression of circUBAP2 correlates with microcirculatory perfusion and has the potential in predicting outcomes for on-ECMO patients with cardiogenic shock.

Arterial Pulsatility Augments Microcirculatory Perfusion and Maintains the Endothelial Integrity during Extracorporeal Membrane Oxygenation via hsa_circ_0007367 Upregulation in a Canine Model with Cardiac Arrest.

BACKGROUND: The impairment of microcirculation is associated with the unfavorable outcome for extracorporeal membrane oxygenation (ECMO) patients. Studies revealed that pulsatile modification improves hemodynamics and attenuates inflammation during ECMO support. However, whether flow pattern impacts microcirculation and endothelial integrity is rarely documented. The objective of this work was to explore how pulsatility affects microcirculation during ECMO. METHODS: Canine animal models with cardiac arrest were supported by ECMO, with the i-Cor system used to generate nonpulsatile or pulsatile flow. The sublingual microcirculation parameters were examined using the CytoCam microscope system. The expression of hsa_circ_0007367, a circular RNA, was measured during ECMO support. In vitro validation was performed in pulmonary vascular endothelial cells (PMVECs) exposed to pulsatile or nonpulsatile flow, and the expressions of hsa_circ_0007367, endothelial tight junction markers, endothelial adhesive molecules, endothelial nitric oxide synthases (eNOS), and NF-κB signaling activity were analyzed. RESULTS: The pulsatile modification of ECMO enhanced microcirculatory perfusion, attenuated pulmonary inflammation, and stabilized endothelial integrity in animal models; meanwhile, the expression of hsa_circ_0007367 was significantly upregulated both in animals and PMVECs exposed to pulsatile flow. In particular, upregulation of hsa_circ_0007367 stabilized the expressions of endothelial tight junction markers zonula occludens- (ZO-) 1 and occludin, followed by modulating the endothelial nitric oxide synthases (eNOS) activity and inhibiting the NF-κB signaling pathway. CONCLUSION: The modification of pulsatility contributes to microcirculatory perfusion and endothelial integrity during ECMO. The expression of hsa_circ_0007367 plays a pivotal role in this protective mechanism.

Effect of Lithium-Slag in the Performance of Slag Cement Mortar Based on Least-Squares Support Vector Machine Prediction.

There is a universally accepted view that environmental pollution should be controlled while improving cement mortar natural abilities. The purpose of this study is to develop a green cement mortar that has better compressive strength and anti-chloride ion permeability. Two industrial wastes, lithium-slag and slag, were added to cement mortar, and the role of lithium-slag was to activate slag. In addition, to save economic and time costs, this paper also used the least-squares support vector machine (LS-SVM) method to predict the property changes of cementitious-based materials. Then multiple natural abilities of samples, including compressive strength, anti-chloride ion permeability, and fluidity, were tested. In addition, LS-SVM and traditional support vector machine (SVM) were used to train and forecast the performance, including compressive strength. The results show that lithium-slag can activate slag to improve the compressive strength, anti-chloride ion permeability of mortar, and LS-SVM sharpens accuracy by 11% compared to SVM.