Trial of Endovascular Therapy for Acute Ischemic Stroke with Large Infarct.

BACKGROUND: The role of endovascular therapy for acute stroke with a large infarction has not been extensively studied in differing populations. METHODS: We conducted a multicenter, prospective, open-label, randomized trial in China involving patients with acute large-vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 3 to 5 (range, 0 to 10, with lower values indicating larger infarction) or an infarct-core volume of 70 to 100 ml. Patients were randomly assigned in a 1:1 ratio within 24 hours from the time they were last known to be well to undergo endovascular therapy and receive medical management or to receive medical management alone. The primary outcome was the score on the modified Rankin scale at 90 days (scores range from 0 to 6, with higher scores indicating greater disability), and the primary objective was to determine whether a shift in the distribution of the scores on the modified Rankin scale at 90 days had occurred between the two groups. Secondary outcomes included scores of 0 to 2 and 0 to 3 on the modified Rankin scale. The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours after randomization. RESULTS: A total of 456 patients were enrolled; 231 were assigned to the endovascular-therapy group and 225 to the medical-management group. Approximately 28% of the patients in both groups received intravenous thrombolysis. The trial was stopped early owing to the efficacy of endovascular therapy after the second interim analysis. At 90 days, a shift in the distribution of scores on the modified Rankin scale toward better outcomes was observed in favor of endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval, 1.11 to 1.69; P = 0.004). Symptomatic intracranial hemorrhage occurred in 14 of 230 patients (6.1%) in the endovascular-therapy group and in 6 of 225 patients (2.7%) in the medical-management group; any intracranial hemorrhage occurred in 113 (49.1%) and 39 (17.3%), respectively. Results for the secondary outcomes generally supported those of the primary analysis. CONCLUSIONS: In a trial conducted in China, patients with large cerebral infarctions had better outcomes with endovascular therapy administered within 24 hours than with medical management alone but had more intracranial hemorrhages. (Funded by Covidien Healthcare International Trading [Shanghai] and others; ANGEL-ASPECT ClinicalTrials.gov number, NCT04551664.).

Enhancing generalizability and performance in drug-target interaction identification by integrating pharmacophore and pre-trained models.

MOTIVATION: In drug discovery, it is crucial to assess the drug-target binding affinity (DTA). Although molecular docking is widely used, computational efficiency limits its application in large-scale virtual screening. Deep learning-based methods learn virtual scoring functions from labeled datasets and can quickly predict affinity. However, there are three limitations. First, existing methods only consider the atom-bond graph or one-dimensional sequence representations of compounds, ignoring the information about functional groups (pharmacophores) with specific biological activities. Second, relying on limited labeled datasets fails to learn comprehensive embedding representations of compounds and proteins, resulting in poor generalization performance in complex scenarios. Third, existing feature fusion methods cannot adequately capture contextual interaction information. RESULTS: Therefore, we propose a novel DTA prediction method named HeteroDTA. Specifically, a multi-view compound feature extraction module is constructed to model the atom-bond graph and pharmacophore graph. The residue concat graph and protein sequence are also utilized to model protein structure and function. Moreover, to enhance the generalization capability and reduce the dependence on task-specific labeled data, pre-trained models are utilized to initialize the atomic features of the compounds and the embedding representations of the protein sequence. A context-aware nonlinear feature fusion method is also proposed to learn interaction patterns between compounds and proteins. Experimental results on public benchmark datasets show that HeteroDTA significantly outperforms existing methods. In addition, HeteroDTA shows excellent generalization performance in cold-start experiments and superiority in the representation learning ability of drug-target pairs. Finally, the effectiveness of HeteroDTA is demonstrated in a real-world drug discovery study. AVAILABILITY AND IMPLEMENTATION: The source code and data are available at https://github.com/daydayupzzl/HeteroDTA.

Mitochondrial genome undergoes de novo DNA methylation that protects mtDNA against oxidative damage during the peri-implantation window.

Mitochondrial remodeling during the peri-implantation stage is the hallmark event essential for normal embryogenesis. Among the changes, enhanced oxidative phosphorylation is critical for supporting high energy demands of postimplantation embryos, but increases mitochondrial oxidative stress, which in turn threatens mitochondrial DNA (mtDNA) stability. However, how mitochondria protect their own histone-lacking mtDNA, during this stage remains unclear. Concurrently, the mitochondrial genome gain DNA methylation by this stage. Its spatiotemporal coincidence with enhanced mitochondrial stress led us to ask if mtDNA methylation has a role in maintaining mitochondrial genome stability. Herein, we report that mitochondrial genome undergoes de novo mtDNA methylation that can protect mtDNA against enhanced oxidative damage during the peri-implantation window. Mitochondrial genome gains extensive mtDNA methylation during transition from blastocysts to postimplantation embryos, thus establishing relatively hypermethylated mtDNA from hypomethylated state in blastocysts. Mechanistic study revealed that DNA methyltransferase 3A (DNMT3A) and DNMT3B enter mitochondria during this process and bind to mtDNA, via their unique mitochondrial targeting sequences. Importantly, loss- and gain-of-function analyses indicated that DNMT3A and DNMT3B are responsible for catalyzing de novo mtDNA methylation, in a synergistic manner. Finally, we proved, in vivo and in vitro, that increased mtDNA methylation functions to protect mitochondrial genome against mtDNA damage induced by increased mitochondrial oxidative stress. Together, we reveal mtDNA methylation dynamics and its underlying mechanism during the critical developmental window. We also provide the functional link between mitochondrial epigenetic remodeling and metabolic changes, which reveals a role for nuclear-mitochondrial crosstalk in establishing mitoepigenetics and maintaining mitochondrial homeostasis.

MetDIT: Transforming and Analyzing Clinical Metabolomics Data with Convolutional Neural Networks.

Clinical metabolomics is growing as an essential tool for precision medicine. However, classical machine learning algorithms struggle to comprehensively encode and analyze the metabolomics data due to their high dimensionality and complex intercorrelations. This article introduces a new method called MetDIT, designed to analyze intricate metabolomics data effectively using deep convolutional neural networks (CNN). MetDIT comprises two components: TransOmics and NetOmics. Since CNN models have difficulty in processing one-dimensional (1D) sequence data efficiently, we developed TransOmics, a framework that transforms sequence data into two-dimensional (2D) images while maintaining a one-to-one correspondence between the sequences and images. NetOmics, the second component, leverages a CNN architecture to extract more discriminative representations from the transformed samples. To overcome the overfitting due to the small sample size and class imbalance, we introduced a feature augmentation module (FAM) and a loss function to improve the model performance. Furthermore, we systematically optimized the model backbone and image resolution to balance the model parameters and computational costs. To demonstrate the performance of the proposed MetDIT, we conducted extensive experiments using three different clinical metabolomics data sets and achieved better classification performance than classical machine learning methods used in metabolomics, including Random Forest, SVM, XGBoost, and LightGBM. The source code is available at the GitHub repository at https://github.com/Li-OmicsLab/MetDIT, and the WebApp can be found at http://metdit.bioinformatics.vip/.

Syntrophic microbes involved in the oxidation of short-chain fatty acids in continuous-flow anaerobic digesters treating waste activated sludge with hydrochar.

The rapid degradation of short-chain fatty acids (SCFAs) is an essential issue of anaerobic digestion (AD), in which SCFA oxidizers could generally metabolize in syntrophy with methanogens. The dynamic responses of active metagenome-assembled genomes to low concentrations of propionate and acetate were analyzed to identify specific syntrophic SCFA oxidizers and their metabolic characteristics in continuous-flow AD systems treating waste activated sludge with and without hydrochar. In this study, hydrochar increased methane production by 19%, possibly due to hydrochar enhancing acidification and methanogenesis processes. A putative syntrophic propionate oxidizer and two acetate oxidizers contributed substantially to the syntrophic degradation of SCFAs, and hydrochar positively regulated their functional gene expressions. A significant relationship was established between the replication rate of SCFA oxidizers and their stimulation-related transcriptional activity. Acetate was degraded in the hydrochar group, which might be mainly through the syntrophic acetate oxidizer from the genus Desulfallas and methanogens from the genus Methanosarcina.IMPORTANCEShort-chain fatty acid (SCFA) degradation is an important process in the methanogenic ecosystem. However, current knowledge of this microbial mechanism is mainly based on studies on a few model organisms incubated as mono- or co-cultures or in enrichments, which cannot provide appropriate evidence in complex environments. Here, this study revealed the microbial mechanism of a hydrochar-mediated anaerobic digestion (AD) system promoting SCFA degradation at the species level and identified key SCFA oxidizing bacteria. Our analysis provided new insights into the SCFA oxidizers involved in the AD of waste activated sludge facilitated by hydrochar.

Genetic identification of familial hypercholesterolemia within whole genome sequences in 6820 newborns.

Familial hypercholesterolemia (FH) is defined as a monogenic disease, characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels. FH remains underdiagnosed and undertreated in Chinese. We whole-genome sequenced 6820 newborns from Qingdao of China to investigate the FH-related gene (LDLR, APOB, PCSK9) mutation types, carrier ratio and genotype-phenotype correlation. In this study, the prevalence of FH in Qingdao of China was 0.47% (95% CI: 0.32%-0.66%). The plasma lipid levels of FH-related gene mutation carriers begin to increase as early as infant. T-CHO and LDL-C of FH infants was higher by 48.1% (p < 0.001) and 42.9% (p < 0.001) relative to non-FH infants. A total of 22 FH infants and their parent participate in further studies. The results indicated that FH infant parent noncarriers have the normal plasma lipid level, while T-CHO and LDL-C increased in FH infants and FH infant parent carriers, but no difference between the groups. This highlights the importance of genetic factors. In conclusion, the spectrum of FH-causing mutations in the newborns of Qingdao, China was described for the first time. These data can serve as a considerable dataset for next-generation sequencing analysis of the Chinese population with FH and potentially helping reform regional policies for early detection and prevention of FH.

Neutrophil extracellular traps promote proliferation of pulmonary smooth muscle cells mediated by CCDC25 in pulmonary arterial hypertension.

BACKGROUND: Previous studies have indicated that neutrophil extracellular traps (NETs) play a pivotal role in pathogenesis of pulmonary arterial hypertension (PAH). However, the specific mechanism underlying the impact of NETs on pulmonary artery smooth muscle cells (PASMCs) has not been determined. The objective of this study was to elucidate underlying mechanisms through which NETs contribute to progression of PAH. METHODS: Bioinformatics analysis was employed in this study to screen for potential molecules and mechanisms associated with occurrence and development of PAH. These findings were subsequently validated in human samples, coiled-coil domain containing 25 (CCDC25) knockdown PASMCs, as well as monocrotaline-induced PAH rat model. RESULTS: NETs promoted proliferation of PASMCs, thereby facilitating pathogenesis of PAH. This phenomenon was mediated by the activation of transmembrane receptor CCDC25 on PASMCs, which subsequently activated ILK/ß-parvin/RAC1 pathway. Consequently, cytoskeletal remodeling and phenotypic transformation occur in PASMCs. Furthermore, the level of NETs could serve as an indicator of PAH severity and as potential therapeutic target for alleviating PAH. CONCLUSION: This study elucidated the involvement of NETs in pathogenesis of PAH through their influence on the function of PASMCs, thereby highlighting their potential as promising targets for the evaluation and treatment of PAH.

Verteporfin attenuates trauma-induced heterotopic ossification of Achilles tendon by inhibiting osteogenesis and angiogenesis involving YAP/ß-catenin signaling.

Heterotopic ossification occurs as a pathological ossification condition characterized by ectopic bone formation within soft tissues following trauma. Vascularization has long been established to fuel skeletal ossification during tissue development and regeneration. However, the feasibility of vascularization as a target of heterotopic ossification prevention remained to be further clarified. Here, we aimed to identify whether verteporfin as a widely used FDA-approved anti-vascularization drug could effectively inhibit trauma-induced heterotopic ossification formation. In the current study, we found that verteporfin not only dose dependently inhibited the angiogenic activity of human umbilical vein endothelial cells (HUVECs) but also the osteogenic differentiation of tendon stem cells (TDSCs). Moreover, YAP/ß-catenin signaling axis was downregulated by the verteporfin. Application of lithium chloride, an agonist of ß-catenin, recovered TDSCs osteogenesis and HUVECs angiogenesis that was inhibited by verteporfin. In vivo, verteporfin attenuated heterotopic ossification formation by decelerating osteogenesis and the vessels densely associated with osteoprogenitors formation, which could also be readily reversed by lithium chloride, as revealed by histological analysis and Micro-CT scan in a murine burn/tenotomy model. Collectively, this study confirmed the therapeutic effect of verteporfin on angiogenesis and osteogenesis in trauma-induced heterotopic ossification. Our study sheds light on the anti-vascularization strategy with verteporfin as a candidate treatment for heterotopic ossification prevention.

Hepatocyte growth factor is protective in early stage but bone-destructive in late stage of experimental periodontitis.

BACKGROUND AND OBJECTIVE: Clinical studies found high levels of hepatocyte growth factor (HGF) expression in patients with periodontitis. Studies suggest that HGF plays an important role in periodontitis, is involved in inflammation, and modulates alveolar bone integrity in periodontitis. This study aims to investigate the effects and mechanisms of HGF in the progression of experimental periodontitis. METHODS: We used silk thread ligation to induce periodontitis in HGF-overexpressing transgenic (HGF-Tg) and wild-type C57BL/6J mice. The effects of HGF overexpression on alveolar bone destruction were assessed by microcomputed tomography imaging at baseline and on days 7, 14, 21, and 28. We analyzed the cytokines (IL-6 and TNF-α) and lymphocytes in periodontitis tissues by enzyme-linked immunosorbent assay and flow cytometry. The effects of HGF on alveolar bone destruction were further tested by quantifying the systemic bone metabolism markers CTXI and PINP and by RNA sequencing for the signaling pathways involved in bone destruction. Western blotting and immunohistochemistry were performed to further elucidate the involved signaling pathways. RESULTS: We found that experimental periodontitis increased HGF production in periodontitis tissues; however, the effects of HGF overexpression were inconsistent with disease progression. In the early stage of periodontitis, periodontal inflammation and alveolar bone destruction were significantly lower in HGF-Tg mice than in wild-type mice. In the late stage, HGF-Tg mice showed higher inflammatory responses and progressively aggravated bone destruction with continued stimulation of inflammation. We identified the IL-17/RANKL/TRAF6 pathway as a signaling pathway involved in the HGF effects on the progression of periodontitis. CONCLUSION: HGF plays divergent effects in the progression of experimental periodontitis and accelerates osteoclastic activity and bone destruction in the late stage of inflammation.

Residual networks models detection of atrial septal defect from chest radiographs.

OBJECT: The purpose of this study was to explore a machine learning-based residual networks (ResNets) model to detect atrial septal defect (ASD) on chest radiographs. METHODS: This retrospective study included chest radiographs consecutively collected at our hospital from June 2017 to May 2022. Qualified chest radiographs were obtained from patients who had finished echocardiography. These chest radiographs were labeled as positive or negative for ASD based on the echocardiographic reports and were divided into training, validation, and test dataset. Six ResNets models were employed to examine and compare by using the training dataset and was tuned using the validation dataset. The area under the curve, recall, precision and F1-score were taken as the evaluation metrics for classification result in the test dataset. Visualizing regions of interest for the ResNets models using heat maps. RESULTS: This study included a total of 2105 chest radiographs of children with ASD (mean age 4.14 ± 2.73 years, 54% male), patients were randomly assigned to training, validation, and test dataset with an 8:1:1 ratio. Healthy children's images were supplemented to three datasets in a 1:1 ratio with ASD patients. Following the training, ResNet-10t and ResNet-18D have a better estimation performance, with precision, recall, accuracy, F1-score, and the area under the curve being (0.92, 0.93), (0.91, 0.91), (0.90, 0.90), (0.91, 0.91) and (0.97, 0.96), respectively. Compared to ResNet-18D, ResNet-10t was more focused on the distribution of the heat map of the interest region for most chest radiographs from ASD patients. CONCLUSION: The ResNets model is feasible for identifying ASD through children's chest radiographs. ResNet-10t stands out as the preferable estimation model, providing exceptional performance and clear interpretability.

Hypoxia-responsive lncRNA G077640 promotes ESCC tumorigenesis via the H2AX-HIF1α-glycolysis axis.

Long noncoding RNAs (lncRNAs) contribute to esophageal squamous cell carcinoma (ESCC) progression, but the underlying mechanisms remain elusive. In this study, we verified a hitherto uncharacterized hypoxia-responsive lncRNA, G077640, which is upregulated in human ESCC cells and tissues, supporting the proliferation and migration of ESCC cells. Mechanistically, G077640 prevented hypoxia-inducible factor-1α (HIF1α) from being degraded by directly interacting with histone H2AX and further modulated the interaction of HIF1α and H2AX. In addition, G077640 reprogrammed glycolytic metabolism by regulating the expression of glucose transporter 4 (GLUT4), hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1) for ESCC proliferation and migration. Clinically, G077640 was associated with poor prognosis in ESCC patients. Taken together, our findings identified a hypoxia-responsive lncRNA that contributes to ESCC cells proliferation and migration, and targeting G077640 and its pathway might be a potential therapeutic strategy for ESCC.

STING contributes to trauma-induced heterotopic ossification through NLRP3-dependent macrophage pyroptosis.

Trauma-induced heterotopic ossification (HO) is featured by aberrant bone formation at extra-skeletal site. STING is a master adaptor protein linking cellular damage to immune responses, while its role in HO remains elusive. A murine burn/tenotomy model was used to mimic trauma-induced HO in vivo. We demonstrated elevated STING expression in macrophages in inflammatory stage after burn/tenotomy, and STING inhibition significantly alleviated HO formation. Activated NLRP3-dependent macrophage pyroptosis was also found in inflammatory stage after burn/tenotomy. Either STING or NLRP3 suppression reduced mature HO by weakening macrophage pyroptotic inflammation, while protective effects of STING were abolished by NLRP3 overexpression. Further, in vitro, we also found a prominent STING level in pyroptotic BMDMs. STING suppression relieved macrophage pyroptotic inflammation, while abolished by NLRP3 overexpression. Our results reveal that STING poses regulatory effects on trauma-induced HO formation, via modulating NLRP3-dependent macrophage pyroptosis. Targeting STING-NLRP3 axis represents an attractive approach for trauma-induced HO prevention.

CircGNB1 facilitates the malignant phenotype of GSCs by regulating miR-515-5p/miR-582-3p-XPR1 axis.

Glioma is the most common and aggressive primary malignant brain tumor. Circular RNAs (circRNAs) and RNA-binding proteins (RBPs) have been verified to mediate diverse biological behaviors in various human cancers. Therefore, the aim of this study was to explore a novel circRNA termed circGNB1 and elucidate relative molecular mechanism in functional phenotypes, which might be a potential prognostic biomarker and therapeutic approach for glioma. CircGNB1 was upregulated in glioma and closely associated with the low poor prognosis. Functional assays demonstrated that circGNB1 overexpression promoted glioma stem cells (GSCs) viability proliferation, invasion, and neurosphere formation. Mechanistically, circGNB1 upregulated the expression of oncogene XPR1 via sponging miR-515-5p and miR-582-3p. The following experiments proved XPR1 could promote the malignant phenotype of GSCs via upregulating IL6 expression and activating JAK2/STAT3 signaling. Moreover, the RNA binding protein IGF2BP3 could bind to and maintain the stability of circGNB1, thus promoting the effects of circGNB1 on GSCs. Our study reveals that circGNB1 plays a crucial role in promoting tumorigenesis and malignant progression in glioma, which provides a promising cancer biomarker.

Enhancement of recombinant human interleukin-22 production by fusing with human serum albumin and supplementing N-acetylcysteine in Pichia Pastoris.

Interleukin-22 (IL-22) plays an important role in the treatment of organ failure, which can induce anti-apoptotic and proliferative signaling pathways; Nevertheless, the practical utilization of IL-22 is hindered by the restricted efficacy of its production. Pichia pastoris presents a viable platform for both industrial and pharmaceutical applications. In this study, we successfully generated a fusion protein consisting of truncated human serum albumin and human IL-22 (HSA-hIL-22) using P. pastoris, and examined the impact of antioxidants on HSA-hIL-22 production. We have achieved the production of HSA-hIL-22 in the culture medium at a yield of approximately 2.25 mg/ml. Moreover, 0-40 mM ascorbic acid supplementation did not significantly affect HSA-hIL-22 production or the growth rate of the recombinant strain. However, 80 mM ascorbic acid treatment had a detrimental effect on the expression of HSA-hIL-22. In addition, 5-10 mM N-acetyl-l-cysteine (NAC) resulted in an increase of HSA-hIL-22 production, accompanied by a reduction in the growth rate of the recombinant strain. Conversely, 20-80 mM NAC supplementation inhibited the growth of the recombinant strains and reduced intact HSA-hIL-22 production. However, neither NAC nor ascorbic acid exhibited any effect on superoxide dismutase (SOD) and malondialdehyde (MDA) levels, except that NAC increased GSH content. Furthermore, our findings indicate that recombinant HSA-hIL-22, which demonstrated the ability to stimulate the proliferation of HepG2 cells, possesses bioactivity. In addition, NAC did not affect HSA-hIL-22 bioactivity. In conclusion, our study demonstrates that NAC supplementation can enhance the secretion of functional HSA-hIL-22 proteins produced in P. pastoris without compromising their activity.

Ropivacaine Promotes Axon Regeneration by Regulating Nav1.8-mediated Macrophage Signaling after Sciatic Nerve Injury in Rats.

BACKGROUND: Continuous nerve block with ropivacaine is commonly performed after repair surgery for traumatic peripheral nerve injuries. After peripheral nerve injury, tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 is upregulated and contributes to macrophage inflammation. This study investigated whether ropivacaine promotes peripheral nerve regeneration through Nav1.8-mediated macrophage signaling. METHODS: A sciatic nerve transection-repair (SNT) model was established in adult Sprague-Dawley rats of both sexes. The rats received 0.2% ropivacaine or 10 µM Nav1.8-selective inhibitor A-803467 around the injured site or near the sacrum for 3 days. Nerve regeneration was evaluated using behavioral, electrophysiologic, and morphological examinations. Moreover, myelin debris removal, macrophage phenotype, Nav1.8 expression, and neuropeptide expression were assessed using immunostaining, enzyme-linked immunosorbent assay, and Western blotting. RESULTS: Compared to the SNT-plus-vehicle group, the sensory, motor, and sensory-motor coordination functions of the two ropivacaine groups were significantly improved. Electrophysiologic (mean ± SD: recovery index of amplitude, vehicle 0.43 ± 0.17 vs. ropivacaine 0.83 ± 0.25, n = 11, P < 0.001) and histological analysis collectively indicated that ropivacaine significantly promoted axonal regrowth (percentage of neurofilament 200 [NF-200]-positive area: vehicle 19.88 ± 2.81 vs. ropivacaine 31.07 ± 2.62, n = 6, P < 0.001). The authors also found that, compared to the SNT-plus-vehicle group, the SNT-plus-ropivacaine group showed faster clearance of myelin debris, accompanied by significantly increased macrophage infiltration and transition from the M1 to M2 phenotype. Moreover, ropivacaine significantly attenuated Nav1.8 upregulation at 9 days after sciatic nerve transection (vehicle 4.12 ± 0.30-fold vs. ropivacaine 2.75 ± 0.36-fold, n = 5, P < 0.001), which coincided with the increased expression of chemokine ligand 2 and substance P. Similar changes were observed when using the selective Nav1.8 channel inhibitor A-803467. CONCLUSIONS: Continuous nerve block with ropivacaine promotes the structural and functional recovery of injured sciatic nerves, possibly by regulating Nav1.8-mediated macrophage signaling.

Predictive value of D-dimer and fibrinogen degradation product for splanchnic vein thrombosis in patients with severe acute pancreatitis: a single-center retrospective study.

BACKGROUND AND AIM: Early diagnosis of splanchnic vein thrombosis (SVT) after severe acute pancreatitis (SAP) remains difficult because of its insidious onset. Common serum markers for thrombosis such as D-dimer (D-D) have lost their diagnostic value due to their elevation in non-thrombotic patients with SAP. The aim of this study is to predict SVT after SAP using common serum indicators of thrombosis by establishing a new cut-off value. METHODS: 177 SAP patients were included in a retrospective cohort study from September 2019 to September 2021. Patient demographics, dynamic changes of coagulation and fibrinolysis indicators were collected. Univariate analyses and binary logistic regression analyses were applied to assess potential risk factors for the development of SVT in SAP patients. A receiver operating characteristic (ROC) curve was generated to assess the predictive value of independent risk factors. Moreover, clinical complications and outcomes were compared between two groups. RESULTS: Among 177 SAP patients, 32 (18.1%) developed SVT. The most common cause of SAP was biliary (49.8%), followed by hypertriglyceridemia (21.5%). Multivariate logistic regression analyses showed that D-D (OR, 1.135; 95%CI, 1.043-1.236; p = 0.003) and fibrinogen degradation product (FDP) (OR, 1.037; 95%CI, 1.015-1.060; p = 0.001) were independent risk factors for SVT development in patients with SAP. The area under ROC curve for D-D was 0.891 (p = 0.003, sensitivity= 95.3%, specificity = 74.1%) at a cut-off value of 6.475, and the area under ROC curve for FDP was 0.858 (p = 0.001, sensitivity = 89.4%, specificity = 72.4%) at a cut-off value of 23.155. CONCLUSION: D-D and FDP are significant independent risk factors with high predictive value for SVT in patients with SAP.

Association Between Loop Diuretics and Mortality in Patients With Cardiac Surgery-Associated Acute Kidney Injury: A Retrospective Propensity Score-Weighted Analysis.

BACKGROUND: Although loop diuretics (LDs) have been widely used in clinical practice, their effect on mortality when administered to patients experiencing cardiac surgery-associated acute kidney injury (CS-AKI) remains unknown. The study aimed to investigate the effectiveness of LD use in patients with CS-AKI. METHODS: Patients who underwent cardiac surgery with AKI were identified from the Medical Information Mart for Intensive Care III. Postoperative LD use in intensive care units (ICUs) was exposure. There were 2 primary outcome measures, the in-hospital mortality and ICU mortality; both were treated as time-to-event data and were analyzed via multivariable Cox proportional hazard models. Inverse probability weighting (IPW) was used to minimize bias. RESULTS: The study enrolled a total of 5478 patients, with a median age of 67 years, among which 2205 (40.3%) were women. The crude in-hospital and ICU mortality rates were significantly lower in the LD use group (525 of 4150 [12.7%] vs 434 of 1328 [32.7%], P < .001; 402 of 4150 [9.69%] vs 333 of 1328 [25.1%], P < .001). Adjusted hazard ratios suggested significant reductions in both in-hospital (hazard ratio [HR], 0.428; 95% confidence interval [CI], 0.374-0.489) and ICU mortality (HR, 0.278; 95% CI, 0.238-0.327). The IPW data showed a similar reduction, in-hospital mortality (HR, 0.434; 95% CI, 0.376-0.502) and ICU mortality (HR, 0.296; 95% CI, 0.251-0.349). Such association may act differently for patients with different fluid balance (P value for interaction < .001). CONCLUSIONS: LD use is associated with lower hospital and ICU mortality in CS-AKI patients in general. Patients under different conditions showed diverse responses toward such treatment indicating that personalized management is needed.

Complex wave and phase retrieval from a single off-axis interferogram.

Single-frame off-axis holographic reconstruction is promising for quantitative phase imaging. However, reconstruction accuracy and contrast are degraded by noise, frequency spectrum overlap of the interferogram, severe phase distortion, etc. In this work, we propose an iterative single-frame complex wave retrieval based on an explicit model of object and reference waves. We also develop a phase restoration algorithm that does not resort to phase unwrapping. Both simulation and real experiments demonstrate higher accuracy and robustness compared to state-of-the-art methods, for both complex wave estimation and phase reconstruction. Importantly, the allowed bandwidth for the object wave is significantly improved in realistic experimental conditions (similar amplitudes for object and reference waves), which makes it attractive for large field-of-view and high-resolution imaging applications.

Development and validation of a practical prognostic nomogram for evaluating inpatient mortality of cirrhotic patients with acute variceal hemorrhage.

INTRODUCTION AND OBJECTIVES: Cirrhotic patients with acute variceal hemorrhage (AVH) have high short-term mortality. Established prognostic scores are seldom applicable clinically, partially because they need external validation or contain subjective variables. We aimed to develop and validate a practical prognostic nomogram based on objective predictors to predict prognosis for cirrhotic patients with AVH. PATIENTS AND METHODS: We enrolled 308 AVH patients with cirrhosis from our center as the derivation cohort to develop a new nomogram using logistic regression and validated it in cohorts of patients from Medical Information Mart for Intensive Care (MIMIC) III (n = 247) and IV (n = 302). RESULTS: International normalized ratio (INR), albumin (ALB) and estimated glomerular filtration rate (eGFR) were identified as predictors for inpatient mortality and a nomogram was constructed based on them. The nomogram discriminated well in both derivation and MIMIC-III/-IV validation cohorts with the area under the receiver operating characteristic curves (AUROCs) of 0.846 and 0.859/0.833, respectively and showed a better agreement between expected and observed outcomes (Hosmer-Lemeshow tests, all comparisons, P > 0.05) than other scores in all cohorts. Our nomogram had the lowest Brier scores (0.082/0.114/0.119 in training/MIMIC-III/MIMIC-IV) and highest R2 (0.367/0.393/0.346 in training/MIMIC-III/MIMIC-IV) compared to the recalibrated model for end-stage liver disease (MELD), MELD-hepatic encephalopathy (MELD-HE) and cirrhosis acute gastrointestinal bleeding (CAGIB) scores in all cohorts. CONCLUSIONS: We developed a practical prognostic nomogram using easily verified indicators available in initial patient evaluation, which may serve as a reliable tool to accurately predict inpatient mortality for cirrhotic patients with AVH.

FUNDC2, a mitochondrial outer membrane protein, mediates triple-negative breast cancer progression via the AKT/GSK3ß/GLI1 pathway.

Triple-negative breast cancer (TNBC) lacks effective therapeutic targets and has a poor prognosis, easy recurrence and metastasis. It is urgent and important to explore TNBC treatment targets. Through mass spectrometry combined with qRT-PCR validation in luminal A cells and TNBC cells, high-content screening and clinical sample analysis, FUNDC2 was discovered as a novel target. The function of the outer mitochondrial membrane protein FUNDC2 in breast cancer is still unclear. In this study, we find that FUNDC2 expression in TNBC tissues is significantly higher than that in luminal subtype breast cancer tissues. FUNDC2 silencing in TNBC cells significantly reduces cell proliferation, migration and invasion. As demonstrated in vivo using subcutaneous tumor xenografts in mice, FUNDC2 suppression significantly inhibits tumor growth. The underlying mechanism might be mediated by inactivating its downstream signal AKT/GSK3ß and GLI1, a key factor of the Hedgehog signaling pathway. Therefore, FUNDC2 may promote TNBC progression and provide a therapeutic target for treating TNBC.