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The application of Convolutional Neural Network (CNN) on the detection of COVID-19 infection has yielded favorable results. However, with excessive model parameters, the CNN detection of COVID-19 is low in recall, highly complex in computation. In this paper, a novel lightweight CNN model, CodnNet is proposed for quick detection of COVID-19 infection. CodnNet builds a more effective dense connections based on DenseNet network to make features highly reusable and enhances interactivity of local and global features. It also uses depthwise separable convolution with large convolution kernels instead of traditional convolution to improve the range of receptive field and enhances classification performance while reducing model complexity. The 5-Fold cross validation results on Kaggle's COVID-19 Dataset showed that CodnNet has an average precision of 97.9%, recall of 97.4%, F1score of 97.7%, accuracy of 98.5%, mAP of 99.3%, and mAUC of 99.7%. Compared to the typical CNNs, CodnNet with fewer parameters and lower computational complexity has achieved better classification accuracy and generalization performance. Therefore, the CodnNet model provides a good reference for quick detection of COVID-19 infection.
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Photochemical enantioselective nickel-catalyzed cross-coupling reactions are difficult to implement. We report a visible-light-mediated strategy that successfully couples symmetrical anhydrides and 4-alkyl dihydropyridines (DHPs) to afford enantioenriched α-substituted ketones under mild conditions. The chemistry does not require exogenous photocatalysts. It is triggered by the direct excitation of DHPs, which act as a radical source and as a reductant, facilitating the turnover of the chiral catalytic nickel complex.
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Transition-metal-free radical α-perfluoroalkylation with the accompanying vicinal ß-alkenylation of unactivated alkenes is presented. These radical cascades proceed by means of 1,4- or 1,5-alkenyl migration by electron catalysis on readily accessed allylic alcohols. The reactions comprise a regioselective perfluoroalkyl radical addition with subsequent alkenyl migration and concomitant deprotonation to generate a ketyl radical anion that sustains the chain as a single-electron-transfer reducing reagent.
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The well-established A(3) coupling reaction of terminal alkynes, aldehydes, and amines provides the most straightforward approach to propargylic amines. However, the related reaction of ketones, especially aromatic ketones, is still a significant challenge. A highly efficient catalytic protocol has been developed for the coupling of aromatic ketones with amines and terminal alkynes, in which Cu(I) , generated in situ from the reduction of CuBr2 with sodium ascorbate, has been identified as the highly efficient catalyst. Since propargylic amines are versatile synthetic intermediates and important units in pharmaceutical products, such an advance will greatly stimulate research interest involving the previously unavailable propargylic amines.
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Tetrahydroisoquinoline alkaloids with a C1 stereogenic center are a common unit in many natural and non-natural compounds of biological importance. Herein we describe a novel Cu(I) -catalyzed highly chemo- and enantioselective synthesis of chiral tetrahydroisoquinoline-alkaloid derivatives from readily available unsubstituted tetrahydroisoquinolines, aldehydes, and terminal alkynes in the presence of the ligand (R,R)-N-pinap. This synthetic operation installs two substituents in the 1- and 2-positions.
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Aldehídos/química , Alquinos/síntesis química , Cobre/química , Isoquinolinas/síntesis química , Catálisis , Isoquinolinas/química , Estructura Molecular , EstereoisomerismoRESUMEN
Photochemical generation of radicals is a powerful way to construct various molecules. But most of these methods rely on initiators or the redox properties of radical precursors. Herein, we report a photochemical organic catalyst that reacts with benzyl halide to generate carbon radical via an SN2 pathway. This nucleophilic catalyst can be easily prepared and is bench-stable. The SN2 process does not rely on the redox properties of halides, showing potential synthetic utility. Control experiments and UV-vis spectroscopic analysis indicate that the SN2 substitution adduct is the key intermediate.
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This study conducted dynamic triaxial tests on a typical poured asphalt concrete material of core walls in Xinjiang, exploring the dynamic characteristics of poured asphalt concrete under various confining pressures, principal stress ratios, and vibration frequencies. On this basis, the dynamic constitutive relationship of poured asphalt concrete was investigated using the Hardin-Drnevich model. The results indicate that under different confining pressures, principal stress ratios, and vibration frequencies, the variation patterns of the backbone lines of dynamic stress-strain of poured asphalt concrete are basically identical, consistent with a hyperbolic curve. The confining pressure and principal stress ratio significantly affect the backbone line of dynamic stress-strain. By comparison, frequency has a minimal effect. The changing trends of dynamic elasticity modulus and damping ratio of poured asphalt concrete under various factors are almost the same. When the material has high dynamic stress and strain, the hysteresis loop is large. When the curve of the damping ratio becomes flat, the asymptotic constant can be used as the maximum damping ratio. The relationship between the reciprocal of the dynamic elasticity modulus and the dynamic strain of poured asphalt concrete exhibits a linear distribution. Under different ratios of confining pressure to principal stress, there are large discrepancies between the calculated values from the formula and the experimental fitting values of the maximum dynamic elasticity modulus, and the maximum relative errors reach 16.65% and 18.15%, respectively. Therefore, the expression for the maximum dynamic elasticity modulus was modified, and the calculated values using the modified formula were compared with the experimental fitting values. The relative errors are significantly reduced, and the maximum relative errors are 3.02% and 2.04%, respectively, in good agreement with the fitting values of the experimental data. The findings of this article render a theoretical basis and reference for the promotion and application of poured asphalt concrete.
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Circulating neutrophil extracellular trap (NET) formation is an adaptive process during acute lung injury (ALI). The important role of plasminogen activator inhibitor (PAI)-1 in NET formation during ALI remains unclear. This research intends to examine the impacts of the decrease in PAI-1 levels on NET formation and the underlying mechanism. We found a relative association between the increase in plasma NET levels and thromboinflammation-induced lung damage in patients with ARDS. PAI-1 knockout (KO) mice exhibited significant increases in Pseudomonas aeruginosa (PAO1 strain)-induced ALI, inflammation, inflammatory cell accumulation, and proinflammatory cytokine secretion, and wild-type mice exhibited the opposite changes. During PAO1-induced ALI, PAI-1 KO increased NET release and the levels of prothrombotic markers in mice. PAI-1 deficiency also promoted NET formation and NET-mediated pyroptosis and ferroptosis by activating the PI3K/MAPK/AKT pathway in a PAO1-induced ALI mouse model. In conclusion, PAI-1 KO exacerbated PAO1-induced pneumonia-associated injury and contributed to NET-mediated pyroptosis and ferroptosis through PI3K/MAPK/AKT pathway activation. Thus, targeting PAI-1 and NETs may be a promising therapeutic approach for ameliorating pneumonia and thromboinflammation-associated ALI.
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PURPOSE: Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of fibrinolytic systems. The effect of PAI-1 on inflammatory response is still inconsistent. Our study was conducted to investigate its effects on inflammation to clarify the role of PAI-1 in acute lung injury (ALI) induced by lipopolysaccharide (LPS). MATERIAL AND METHODS: ALI models were established in wild-type (WT) and PAI-1 knockout (KO) mice by LPS intervention for 48 âh. Lung histopathology, wet-dry ratio, total cell count and TNF-α concentration in bronchoalveolar lavage fluid (BALF), and inflammation related proteins were detected. Flow cytometry was used to sort neutrophils, macrophages, regulatory T cells (Treg) and T helper cell 17 (Th17). RNA sequencing was performed to find differentially expressed genes. Masson staining and immunohistochemistry were used to analyze pulmonary fiber deposition and proliferation. RESULTS: Compared with ALI (WT) group, the wet-dry ratio, the total number of BALF cells, the concentration of TNF-α in BALF, and the expression of pp65 in the lung tissue was increased in ALI (PAI-1 KO) group, with increased proportion of neutrophils, decreased proportion of macrophages and decreased proportion of Treg/Th17 in the lung tissue. Collagen fiber deposition and PCNA expression were lighter in ALI (PAI-1 KO) group than ALI (WT) group. PPI analysis showed that PAI-1 was closely related to TNF, IL-6, IL-1ß, Smad2/3 and mainly concentrated in the complement and coagulation system, TNF-α and IL-17 signaling pathways. CONCLUSIONS: PAI-1 KO could aggravate ALI induced by LPS at 48 âh. PAI-1 may be an important target to improve the prognosis of ALI.
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Lesión Pulmonar Aguda , Lipopolisacáridos , Ratones Noqueados , Inhibidor 1 de Activador Plasminogénico , Animales , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/inducido químicamente , Ratones , Inhibidor 1 de Activador Plasminogénico/metabolismo , Inhibidor 1 de Activador Plasminogénico/genética , Masculino , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/inmunologíaRESUMEN
BACKGROUND: Adjuvant Xuebijing therapy exhibited a protective effect on severe community-acquired pneumonia (SCAP) in previous studies. Blood inflammatory biomarkers related to the disease subtype and severity of SCAP might be associated with the effects of Xuebijing on clinical outcomes of SCAP. PURPOSE: To investigate whether neutrophils or lymphocytes are a useful biomarker of the therapeutic effect of Xuebijing on mortality and inflammation damage index. STUDY DESIGN: A post hoc analysis of a randomized, placebo-controlled and double-blinded clinical trial of Xuebijing in patients with SCAP (Clinical Trial Registration: ChiCTR-TRC-13003534). METHODS: We compared 28-day mortality (primary outcome) and four clinical scores (secondary outcome), including pneumonia severity index (PSI) score, sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE II) score, and systemic inflammatory response syndrome (SIRS) score, according to the baseline strata of neutrophil count and lymphocyte count. RESULTS: A total of 675 patients were included in the analyses, of which 334 received Xuebijing and 341 received the placebo. Xuebijing was more effective in SCAP patients with higher lymphocyte counts and lower neutrophil counts. In the lymphocyte-dominated inflammation (LDI) subgroup, defined as neutrophil count <13 × 109 cells/l and lymphocyte count ≥0.65 × 109 cells/l, Xuebijing reduced 28-day mortality by 15% while mortality of the neutrophil-dominated inflammation (NDI) subgroup decreased by 4.7% (p = 0.050). There was also greater improvement in the PSI, SOFA, APACHE II, and SIRS scores following Xuebijing treatment in the LDI subgroup compared with the NDI subgroup. CONCLUSIONS: Xuebijing treatment shows stronger protective effects in SCAP patients with higher lymphocyte and lower neutrophil counts. Our findings may facilitate the selection of the most appropriate treatments for individual patients with SCAP, including who will receive Xuebijing injections.
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Neutrófilos , Neumonía , Humanos , Neumonía/tratamiento farmacológico , Recuento de Linfocitos , Síndrome de Respuesta Inflamatoria Sistémica , Adyuvantes Inmunológicos/uso terapéutico , Adyuvantes Farmacéuticos/uso terapéuticoRESUMEN
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is characterized by diffuse alveolar injury primarily caused by an excessive inflammatory response. Regrettably, the lack of effective pharmacotherapy currently available contributes to the high mortality rate in patients with this condition. Xuebijing (XBJ), a traditional Chinese medicine recognized for its potent anti-inflammatory properties, exhibits promise as a potential therapeutic agent for ALI/ARDS. This study aimed to explore the preventive effects of XBJ on ALI and its underlying mechanism. To this end, we established an LPS-induced ALI model and treated ALI mice with XBJ. Our results demonstrated that pre-treatment with XBJ significantly alleviated lung inflammation and increased the survival rate of ALI mice by 37.5%. Moreover, XBJ substantially suppressed the production of TNF-α, IL-6, and IL-1ß in the lung tissue. Subsequently, we performed a network pharmacology analysis and identified identified 109 potential target genes of XBJ that were mainly involved in multiple signaling pathways related to programmed cell death and anti-inflammatory responses. Furthermore, we found that XBJ exerted its inhibitory effect on gasdermin-E-mediated pyroptosis of lung cells by suppressing TNF-α production. Therefore, this study not only establishes the preventive efficacy of XBJ in ALI but also reveals its role in protecting alveolar epithelial cells against gasdermin-E-mediated pyroptosis by reducing TNF-α release.
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Lesión Pulmonar Aguda , Síndrome de Dificultad Respiratoria , Animales , Ratones , Células Epiteliales Alveolares , Piroptosis , Gasderminas , Lipopolisacáridos/efectos adversos , Factor de Necrosis Tumoral alfa , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológicoRESUMEN
Purpose At present, though the application of Convolution Neural Network (CNN) to detect COVID-19 infection significantly enhance the detection performance and efficiency, it often causes low sensitivity and poor generalization performance. Methods In this article, an effective CNN, CrodenseNet is proposed for COVID-19 detection. CrodenseNet consists of two parallel DenseNet Blocks, each of which contains dilated convolutions with different expansion scales and traditional convolutions. We employ cross-dense connections and one-sided soft thresholding to the layers for filtering of noise-related features, and increase information interaction of local and global features. Results Cross-validation experiments on COVID-19x dataset shows that via CrodenseNet the COVID-19 detection attains the precision of 0.967 ± 0.010, recall of 0.967 ± 0.010, F1-score of 0.973 ± 0.005, AP (area under P-R curve) of 0.991 ± 0.002, and AUC (area under ROC curve) of 0.996 ± 0.001. Conclusion CrodenseNet outperforms a variety of state-of-the-art models in terms of evaluation metrics so it assists clinicians to prompt diagnosis of COVID-19 infection.
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INTRODUCTION: Pulmonary infections are frequent in immunocompromised hosts (ICH), and microbial detection is difficult. As a new method, next-generation sequencing (NGS) may offer a solution. OBJECTIVES: This study aimed to assess the impact of NGS-assisted pathogenic detection on the diagnosis, treatment, and outcomes of ICH complicated by pulmonary infection and radiographic evidence of bilateral diffuse lesions. METHODS: This study enrolled 356 patients with ICH complicated by pulmonary infection that were admitted to Zhongshan Hospital, Fudan University, from November 17, 2017, to November 23, 2018, including 102 and 254 in the NGS and non-NGS groups, respectively. Clinical characteristics, detection time, rough positive rate, effective positive rate, impact on anti-infective treatment plan, 30-day/60-day mortality, and in-hospital mortality were compared. RESULTS: NGS-assisted pathogenic detection reduced detection time (28.2 h [interquartile range (IQR) 25.9-29.83 h] vs. 50.50 h [IQR 47.90-90.91 h], P < 0.001), increased positive rate, rate of mixed infection detected, effective positive rate, and proportion of antibiotic treatment modification (45.28% vs. 89.22%, 4.72% vs. 51.96%, 21.65% vs. 64.71%, 16.54% vs. 46.08%, P < 0.001). The NGS group had a significantly lower 60-day mortality rate (18.63% vs. 33.07%, P = 0.007). The difference in the Kaplan-Meier survival curve was significant (P = 0.029). After multivariate logistic regression, NGS-assisted pathogenic detection remained a significant predictor of survival (OR 0.189, confidence interval [CI], 0.068-0.526). CONCLUSION: NGS-assisted pathogenic detection may improve detection efficiency and is associated with better clinical outcomes in these patients.
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Secuenciación de Nucleótidos de Alto Rendimiento , Huésped Inmunocomprometido , Humanos , Estudios RetrospectivosRESUMEN
Background: Immune checkpoint inhibitors (ICIs) have led to dramatic improvements in survival a subset of patients with non-small cell lung cancer (NSCLC); however, they have been shown to cause life-threatening toxicity such as immune checkpoint inhibitor-related pneumonitis (CIP). Our previous studies have shown that chronic obstructive pulmonary disease (COPD) and circulating cytokines are associated with clinical outcomes in NSCLC patients receiving ICIs. However, the relationship between these factors and the development of CIP is unclear. In this study, we retrospectively assessed NSCLC patients receiving ICIs to identify CIP risk factors. Methods: This retrospective cohort study reviewed medical records of NSCLC patients receiving ICIs targeting programmed cell death 1 (PD-1) or its ligand PD-L1 between March 2017 and December 2020 at Zhongshan Hospital Fudan University. CIP was diagnosed by the treating investigator. Clinical characteristics and baseline plasma cytokines were collected. Logistic regression was used to compare clinical characteristics and circulating cytokine levels between patients with and without CIP to identify CIP risk factors. Results: Of 164 NSCLC patients who received ICIs, CIP developed in 20 cases (12.2%). The presence of COPD [odds ratio (OR), 7.194; 95% confidence interval (CI): 1.130 to 45.798; P=0.037] and PD-L1 expression of ≥50% (OR, 7.184; 95% CI: 1.154 to 44.721; P=0.035) were independently associated with a higher incidence of CIP, whereas a higher baseline level of interleukin-8 (IL-8) was associated with a lower incidence of CIP (OR, 0.758; 95% CI: 0.587 to 0.978; P=0.033). The independent risk factors from final multivariate analysis were incorporated into a nomogram to predict the incidence of CIP. The nomogram model receiver operating characteristic (ROC) curve had a good predictive accuracy of 0.883 (95% CI: 0.806 to 0.959). Conclusions: Increased risk of CIP independently associated with history of COPD, tumor PD-L1 expression ≥50%, and low baseline IL-8 level. The nomogram may hold promise for CIP risk assessment in the administration of ICIs.
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We report a photochemical method for the chemoselective radical functionalization of tryptophan (Trp)-containing peptides. The method exploits the photoactivity of an electron donor-acceptor complex generated between the tryptophan unit and pyridinium salts. Irradiation with weak light (390 nm) generates radical intermediates right next to the targeted Trp amino acid, facilitating a proximity-driven radical functionalization. This protocol exhibits high chemoselectivity for Trp residues over other amino acids and tolerates biocompatible conditions.
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Materiales Biomiméticos/química , Péptidos/química , Triptófano/química , Alquilación , Estructura MolecularRESUMEN
INTRODUCTION: Coronavirus Disease 2019 (COVID-19) has spread worldwide, and it has reached to more than 14.5 million cases. Although Hubei province is the epicenter of China, little is known about epidemiological and clinical features of COVID-19 in other areas in Hubei province around Wuhan. In addition, the virological data, particularly the factors associated with viral shedding of COVID-19 has not been well described. OBJECTIVE: To describe the epidemiological and clinical features of patients with COVID-19 in Tianmen city, and identify risk factors associated with prolonged viral shedding of COVID-19. METHODS: Inpatients with COVID-19 admitted before February 9, 2020 were included. Characteristics were compared between patients with early and late viral RNA shedding. Multivariate cox regression model was used to investigate variables associated with prolonged viral shedding. RESULTS: One hundred and eighty-three patients were included. About 8.2% patients were categorized as critical degree of severity. All patients received antiviral therapy, with arbidol and interferon being the commonest. About 38.3% and 16.9% patients were treated with corticosteroid and immunoglobulin, respectively. Time from onset to admission (HR = 0.829, P < 0.001), and administration of corticosteroid (HR = 0.496, P = 0.002), arbidol (HR = 2.605, P = 0.008) and oseltamivir (HR = 0.416, P < 0.001) were independently associated with duration of viral shedding. CONCLUSION: Symptoms of patients from Tianmen are relatively mild. Treatment should be started as early as possible, but corticosteroid and oseltamivir should be initiated with caution. In addition, clinical trials on arbidol should be conducted to demonstrate its effectiveness.
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Corticoesteroides/uso terapéutico , Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Hospitalización/estadística & datos numéricos , Oseltamivir/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Esparcimiento de Virus/efectos de los fármacos , Adulto , Betacoronavirus , COVID-19 , China/epidemiología , Infecciones por Coronavirus/epidemiología , Femenino , Humanos , Inmunoglobulinas/uso terapéutico , Indoles/uso terapéutico , Interferones/uso terapéutico , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/epidemiología , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2 , Factores de TiempoRESUMEN
BACKGROUND: Acinetobacter baumannii (A. baumannii) ventilator-associated pneumonia (VAP) in intensive care unit (ICU) is associated with high morbidity and mortality in patients with critical illness. However, the literatures that focused on the short-term prognosis and the risk factors for mortality are limited. The aim of this study was to evaluate the risk factors for mortality in ICU patients with A. baumannii VAP. METHODS: A retrospective cohort study was conducted in the medical/surgical ICU at Zhongshan Hospital in Shanghai, China. Adult patients meeting the criteria of A. baumannii VAP from January 2012 to October 2015 were enrolled. Apart from collecting clinical and microbiologic data, we performed biofilm-formation and cytotoxicity testing using A. baumannii strains which are isolated from patients. Multivariate logistic regression analysis was used to determine the independent risk factors for 30-day mortality in ICU. RESULTS: Seventy-eight patients were included in this study. The 30-day mortality rate in ICU for the patients was 37.2%. Multivariate analysis revealed that short-term mortality was significantly associated with prior surgery [OR, 0.277; 95% confidence interval (CI), 0.089-0.866; P=0.027], higher APACHEII score (OR, 1.140; 95% CI, 1.007-1.291; P=0.038) and an increased bacterial cytotoxicity (OR, 1.029 ; 95% CI, 1.001-1.058; P=0.047). CONCLUSIONS: The main finding of our study was that increased bacterial cytotoxicity might be a risk factor for short-term mortality in ICU patients with A. baumannii VAP.
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BACKGROUND: Acute respiratory distress syndrome (ARDS) is the leading cause of high mortality in intensive care units (ICUs) worldwide. An effective marker for prognosis in ARDS is particularly important given the absence of effective treatment strategies aside from small tidal volume ventilation. Previous studies identified an association between the neutrophil-to-lymphocyte ratio (NLR) and prognosis in critical patients. In this study, we explored the prognostic and predictive value of the NLR in ARDS patients. METHODS: We retrospectively included 275 ARDS patients treated at a single institute from 2008 to 2015. After excluding patients with chronic lung disease, acute myocardial infarction and missing data, 247 patients were ultimately included in the analysis. Clinical characteristics and experimental test data, including the NLR, were collected from medical records at 24 hours after the ARDS diagnosis. Independent prognostic factors were determined by multivariate Cox regression analysis. Subgroup stratification was performed according to different factors, and the continuous factors were divided according to the median values. RESULTS: The NLR in survivors was significantly lower than that in non-survivors (P<0.001). We took the median NLR value as the cut-off point and further divided all patients into a high NLR group (NLR >14) and a low NLR group (NLR ≤14). We found that an NLR >14 was associated with a shorter overall survival (OS) (P=0.005). In the multivariate Cox regression model, we further identified an NLR >14 as an independent prognostic factor for OS [hazard ratio (HR) 1.532, (95% CI, 1.095-2.143), P=0.013]. Subgroup analysis showed that the prognostic value of the NLR was higher in hypertensive patients (P=0.009) and in patients with low red blood cell specific volume (P=0.013), high sodium (P=0.002) and high creatinine levels (P=0.017). CONCLUSIONS: The NLR is potentially a predictive prognostic biomarker in ARDS patients.