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[This corrects the article DOI: 10.3389/fcell.2021.793073.].
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Non-precious metal-based nitrogen-doped carbon (M-Nx/C) shows great potential as a substitute for precious metal Pt-based catalysts. However, the conventional pyrolytic methods for forming M-Nx/C active sites are prone to issues such as the lack of synergistic interactions among bimetallic atoms and the potential encasement of active sites, leading to compromised catalytic efficiency and hindered mass transfer. In this work, a highly active FeCo-N-C@U-AC electrocatalyst is developed with a high density of active sites, adequate exposure of catalytic sites, and robust mass transfer capability using the chemical vapor-phase deposition (CVD) technique. The resulting catalyst demonstrates impressive oxygen reduction reaction (ORR) catalytic performance and stability, with half-wave potentials of 0.820 V (0.1 M HClO4) and 0.911 V (0.1 M KOH), respectively. It also exhibits significantly enhanced stability, retaining 93.25% and 98.38% of current after continuous 50 000 s of durability testing, surpassing the retention rates of Pt/C (80.31% in HClO4 and 84.96% in KOH electrolytes). Notably, when employed as a cathode catalyst in proton exchange membrane fuel cells (PEMFCs) and zinc-air flow batteries (ZAFBs), the FeCo-N-C@U-AC catalyst delivers peak power densities of 859 and 162 mW·cm-2, respectively, showcasing competitive performance comparable to benchmark Pt/C.
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Phyllanthus emblica L. offers promising therapeutic potential for inflammatory diseases. This study revealed the molecular structure of a homogeneous polysaccharide purified from Phyllanthus emblica L. (PEP-1) and evaluated its anti-inflammatory effects on ulcerative colitis (UC) in mice. In the in vivo experiment, administered in varying dosages to dextran sulfate sodium (DSS)-induced UC models, PEP-1 significantly alleviated colonic symptoms, histological damages and reshaped the gut microbiota. Notably, it adjusted the Firmicutes/Bacteroidetes ratio and reduced pro-inflammatory species, closely aligning with shifts in the fecal metabolites and metabolic pathways such as the metabolism of pyrimidine, beta-alanine, and purine. These findings underscore the potential of PEP-1 as a therapeutic agent for UC, providing insights into the mechanisms through gut microbiota and metabolic modulation.
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Heterocyclic amines (HAs) are a group of mutagenic and carcinogenic compounds produced from the processing of high-protein foods, which include 2-amino-3-methylimidazo[4, 5-f]quinoline (IQ) showing the strongest carcinogenic effect. Camels are able to digest HAs in foods, which provide rich microbial resources for the study. Thus, camel rumen and intestinal microbiota were used to degrade IQ, and the dominant microorganisms and their degradation characteristics were investigated. After three generations of culture with IQ as the sole carbon source, the highest abundance in rumen and intestinal microbes was found in the Proteobacteria phylum. The strains of third generation of the rumen contents were mainly attributed to the genera Brevundimonas and Pseudomonas, and the dominant genera in intestine were Ochrobactrum, Bacillus, and Pseudomonas. Microorganisms were further isolated and purified from the third generation cultures. These 27 strains from the rumen (L1-L27) and 23 strains from the intestine (C1-C23) were obtained. Among them, four strains with the most effective degrading abilities were as follows: L6 (28.55% of IQ degrading rate) and C1 (25.19%) belonged to the genus Ochrobactrum, L15 (23.41%) belonged to the genus Pseudomonas, and C16 (20.89%) were of the genus Bacillus. This study suggested the application of abundant microbial resources from camels' digestive tract to biodegrade foodborne toxins.
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This study analyzed neonicotinoid insecticides (NEOs) and metabolite (m-NEOs) residues in 136 Panax notoginseng samples via ultra-performance liquid chromatography-tandem mass spectrometry. Imidacloprid was the most detected NEO (88.24% of samples), ranging from 1.50 to 2850 µg/kg. To the best of our knowledge, some novel NEOs were detected in P. notoginseng for the first time. NEO clustering patterns varied among plant parts, with higher contamination in leaves and flowers. Fourteen NEO/m-NEOs, including cycloxaprid and acetamiprid, showed site-specific behavior, indicating the possibility of using multiple NEOs simultaneously during planting, resulting in formation of distinct metabolites in different plant parts. Transfer rates in decoction and infusion ranged from 10.06 to 32.33%, reducing residues postprocessing. Dietary risk assessment showed low hazard quotients (HQa: 7.05 × 10-7 to 2.09 × 10-2; HQc: 3.74 × 10-7 to 2.38 × 10-3), but risk-ranking scores indicated potential hazards with imidacloprid and acetamiprid in flowers and leaves. The findings are expected to promote safety assessment and distribution research of NEOs in plants.
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Contaminação de Alimentos , Inseticidas , Neonicotinoides , Panax notoginseng , Resíduos de Praguicidas , Folhas de Planta , Inseticidas/análise , Neonicotinoides/análise , Panax notoginseng/química , Resíduos de Praguicidas/análise , Contaminação de Alimentos/análise , Folhas de Planta/química , Medição de Risco , Espectrometria de Massas em Tandem , Flores/química , Nitrocompostos/análise , Cromatografia Líquida de Alta PressãoRESUMO
The dosing of fluconazole for young infants remains empirical because of the limited pharmacokinetic (PK) data. We aimed to establish a population PK model and assess the systematic exposure-response of commonly used regimens of fluconazole in Chinese infants. We included infants with a postnatal age of less than 120 days and received intravenous fluconazole. Both scheduled and scavenged plasma samples were collected, and fluconzaole concentration was determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using Phoenix NLME, and then Monte Carlo simulation was conducted to predict the probability of target attainment (PTA) of empirically used regimens of both prophylactic and therapeutic purposes. Based on 304 plasma samples from 183 young infants, fluconazole concentration data was best described by a one-compartment model with first-order elimination. Gestational Age (GA), postnatal age (PNA), and body weight (BW) were included in the final model as CL = 0.02*(GA/214)2.77*(PNA/13)0.24*exp(nCL); V = 1.56*(BW/1435)0.90*exp(nV). Model validation revealed the final model had qualified stability and acceptable predictive properties. Monte Carlo simulation indicated that under the same minimum inhibitory concentration (MIC) value and administration regimen, PTA decreased with GA and PNA. The commonly used prophylactic regimens can meet the clinical need, while higher doses might be needed for treatment of invasive candidiasis. This population PK model of fluconazole discriminated the impact of GA and PNA on CL and BW on V. Dosing adjustment was needed according to the GA and PNA of infants to achieve targeted exposures.
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BACKGROUND: No trial of supramolecular salicylic acid (SSA) for chloasma is available yet. OBJECTIVE: The purpose of this study was to assess the efficacy and safety of Bole DA 30% supramolecular salicylic acid (SSA) combined with 10% niacinamide in treating chloasma. METHODS: This multicenter (n=15), randomized, double-blind, parallel placebo-controlled trial randomized the subjects (1:1) to Bole DA 30% SSA or placebo. The primary endpoint was the effective rate after 16 weeks using the modified melasma area severity index (mMASI) [(pretreatment-posttreatment)/pretreatment×100%]. RESULTS: This study randomized 300 subjects (150/group in the full analysis set, 144 and 147 in the per-protocol set). The total mMASI score, overall Griffiths 10 score, left Griffiths 10 score, and right Griffiths 10 score were significantly lower in the Bole DA 30% SSA group than in the placebo group (all P<0.001). One study drug-related AE and one study drug-unrelated adverse events (AE) were reported in the Bole DA 30% SSA group. No AE was reported in the placebo group. CONCLUSION: Bole DA 30% SSA combined with 10% niacinamide is effective and safe for treating chloasma. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR2200065346.
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BACKGROUND: Noninvasive energy-based device (NI-EBD) aesthetic procedures has recently gained widespread usage for treating various skin conditions, enhancing skin texture and performing rejuvenation-related procedures. However, practically all NI-EBD procedures result in variable degrees of damage to the skin barrier, inducing pathological and physiological processes such as oxidative stress and inflammation, and only a small percentage of individuals possess the innate ability to restore it. OBJECTIVE: To introduce the concept of integrated skincare and establish standardized operational procedures for perioperative integrated skincare, and furnish a theoretical basis for clinical diagnosis and treatment performed by professional medical aestheticians. METHODS: The author leveraged domestic and international guidelines, clinical practice expertise and evidence-based research, adapting them to suit the specific circumstances in China. RESULTS: The consensus were provided four parts, including concept and essence of integrated skincare, integrated skincare significance during the perioperative phase of NI-EBD procedures, active ingredients and functions of effective skincare products, standardized perioperative skincare procedure for NI-EBD procedures and precautions. For the standardized perioperative skincare procedure, four recommendations were listed according to different stages during NI-EBD procedures. CONCLUSION: These recommendations create the 'Expert Consensus on Perioperative Integrated Skincare for Noninvasive Energy-Based Device Aesthetic Procedures in Clinical Practice in China'.
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Técnicas Cosméticas , Humanos , China , Assistência Perioperatória , Consenso , Rejuvenescimento , Higiene da Pele/métodos , Envelhecimento da Pele , EstéticaRESUMO
ConspectusOxygen electrode catalysis is crucial for the efficient operation of clean energy devices, such as proton exchange membrane fuel cells (PEMFCs) and Zn-air batteries (ZABs). However, sluggish oxygen electrocatalysis kinetics in these infrastructures put forward impending requirements toward seeking efficient oxygen-electrode catalytic materials with a clear active-site configuration and geometrical morphology to study in depth the structure-property relationship of materials. Although transition-metal-nitrogen-carbon (M-N-C) electrocatalysts have shown great prospects currently and potential in oxygen electrocatalysis as promising platinum group metal-free catalysts, the universal pyrolysis operation in the preparation process often inevitably brings about randomness and diversity of active sites, for which it is difficult to determine the structure-activity relationship, understand the catalytic mechanism, and further improve facilities performance.Covalent organic polymers (COPs) are a class of molecular geometric constructs linked by irreversible kinetic covalent bonds through reticular chemistry. Unique structural tailorability, diverse design principles, and inherent well-defined construction in pristine COPs naturally provide a great platform to study the structure-property relationship of active sites and exhibit unique features for application. In this Account, we afford an overview of our recent attempts toward the utilization of COP materials as free-pyrolysis oxygen electrode catalysts, enabling accurate construction of oxygen electrodes with clear active site and geometrical morphology characteristics in PEMFC and ZAB devices yet without enduring any high-temperature pyrolysis treatments. Starting from the needs of modern electrocatalysis, we discussed the unique properties for the design and development of pyrolysis-free pristine COPs as high-performance oxygen electrode catalytic materials in terms of intrinsic electronic structure properties and membrane-electrode-assembly (MEA) application distinguished from pyrolysis M-N-C catalysts. First, the pyrolysis-free COP catalysts provide a viable molecular model catalyst platform, which is conducive to mechanism comprehension for the relationship between catalyst activity and structure. Second, the simple and low-energy consumption synthesis process for pyrolysis-free catalysts lays the foundation for the large-scale production of catalysts, oxygen electrodes, and even the entire stack assembly without considering numerous complicated factors as traditional pyrolytic catalysts. Besides, most traditional COPs are difficult to dissolve and solution process due to their cross-linked skeleton. Our newly developed COP materials with solution processability bring about new opportunities to the process and assemble oxygen electrodes into device. These properties are unparalleled and have not been systematically reviewed and analyzed by any research reports so far. Here, we have clarified the specific advantage and potential of pyrolysis-free COP materials as oxygen electrodes applied in PEMFC and ZAB devices in response to the latest progress and requirements of current electrocatalytic research.
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Multiple tyrosine kinase inhibitors (TKIs) are often developed for the same indication. However, their relative overall efficacy is frequently incompletely understood and they may harbor unrecognized targets that cooperate with the intended target. We compared several ROS1 TKIs for inhibition of ROS1-fusion-positive lung cancer cell viability, ROS1 autophosphorylation and kinase activity, which indicated disproportionately higher cellular potency of one TKI, lorlatinib. Quantitative chemical and phosphoproteomics across four ROS1 TKIs and differential network analysis revealed that lorlatinib uniquely impacted focal adhesion signaling. Functional validation using pharmacological probes, RNA interference, and CRISPR-Cas9 knockout uncovered a polypharmacology mechanism of lorlatinib by dual targeting ROS1 and PYK2, which form a multiprotein complex with SRC. Rational multi-targeting of this complex by combining lorlatinib with SRC inhibitors exhibited pronounced synergy. Taken together, we show that systems pharmacology-based differential network analysis can dissect mixed canonical/non-canonical polypharmacology mechanisms across multiple TKIs enabling the design of rational drug combinations.
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Carcinoma Pulmonar de Células não Pequenas , Lactamas , Neoplasias Pulmonares , Proteínas Tirosina Quinases , Pirazóis , Humanos , Aminopiridinas/farmacologia , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quinase 2 de Adesão Focal/antagonistas & inibidores , Lactamas Macrocíclicas , Neoplasias Pulmonares/tratamento farmacológico , Polifarmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-OncogênicasRESUMO
Objective: This study aims to compare the efficacy and safety of drug-coated balloon (DCB) and standard angioplasty balloon (SAB) in the treatment of intrastent restenosis (ISR) after lower extremity ASO following rotarex thrombus removal. Methods: 94 patients with ISR after lower extremity ASO were selected and divided into DCB group (47 cases) and SAB group (47 cases). After patients were treated with DCB and SAB methods, six months after discharge care, the therapeutic effect, lower extremity dorsal arterial blood flow, ankle-brachial index, lameness distance, hemorheology, endothelial function indexes, and lipid levels were measured. Results: DCB group showed significantly higher effective rate compared to SAB group (P < .05). After treatment, post-treatment improvements in dorsalis arterial blood flow, ankle-brachial index intermittent claudicity distance, high-density lipoprotein cholesterol (HDL-C) and nitric oxide (NO) contents were more pronounced in the DCB group than SAB group (P < .05).Indexes of hemorheology and the contents of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and endothelin-1 (ET-1) levels significantly decreased after treatment, with greater reduction observed in DCB group (P < .05). In addition, No significant change in adverse reactions between groups, but DCB group had lower adverse drug reaction rate. Conclusions: Overall, DCB demonstrated superior efficacy in treating ISR after lower extremity ASO, offering a promising option for improving patient outcomes.
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Angioplastia com Balão , Trombose , Humanos , Idoso , Resultado do Tratamento , Angioplastia com Balão/efeitos adversos , Extremidade Inferior , Colesterol , Trombose/etiologiaRESUMO
OBJECTIVE: Secreted phospholipase A2 Group IB (sPLA2GIB) regulates the release of arachidonic acid, prostaglandins, and other inflammatory lipid mediators. Although it has been well involved in extensive inflammatory diseases, its specific mechanism in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear. In this study, we investigated the role of sPLA2GIB in the pathophysiology of CRSwNP. METHODS: Quantitative PCR, immunofluorescence staining, western blotting, and enzyme-linked immunosorbent assay (ELISA) were used to analyze the expression of sPLA2s, phospholipase A2 receptor (PLA2R), and prostaglandin D2 (PGD2) in nasal samples. Human nasal epithelial cells (HNECs) were cultured at an air-liquid interface (ALI) and stimulated with various cytokines. The human mast cell line HMC-1 was stimulated with sPLA2GIB, and the expression of PGD2 and cytokines in the culture supernatant was detected by ELISA. RESULTS: The mRNA and protein levels of sPLA2GIB were significantly higher in eosinophilic CRSwNP than in control tissues. sPLA2GIB was predominantly expressed in the nasal epithelial cells. PLA2R mRNA and protein levels were upregulated in both eosinophilic and non-eosinophilic CRSwNP compared with the control groups. IL-4, IL-13, TNF-α, and IL-1ß upregulated the expression of sPLA2GIB in ALI-cultured HNECs. sPLA2GIB induced PGD2 and IL-13 production in HMC-1 cells in a hydrolytic activity-independent manner. PGD2 protein expression was elevated in tissue homogenates of eosinophilic CRSwNP, and PGD2 upregulated the expression of IL-13 in HMC-1 cells. CONCLUSION: Increased secretion of sPLA2GIB by epithelial cells may promote eosinophilic inflammation in CRSwNP by enhancing PGD2 and IL-13 production in mast cells via binding to PLA2R. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:1107-1117, 2024.
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Pólipos Nasais , Rinite , Rinossinusite , Sinusite , Humanos , Pólipos Nasais/complicações , Prostaglandina D2 , Interleucina-13 , Rinite/complicações , Rinite/genética , Sinusite/complicações , Sinusite/genética , Citocinas/metabolismo , RNA Mensageiro/metabolismo , Doença CrônicaRESUMO
[This corrects the article on p. 714 in vol. 9, PMID: 31105998.].
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Heavy computational load inhibits the application of groundwater contaminant numerical model to groundwater pollution source identification, remediation design, and uncertainty analysis, since a large number of model runs are required for these applications. Machine learning-based surrogate models are an effective approach to enhance the efficiency of the numerical models, and have recently attracted considerable attention in the field of groundwater contaminant modeling. Here, we review 120 research articles on machine learning-based surrogate models for groundwater contaminant modeling that were published between 1994 and 2022. We outline the state of the art method, identify the most significant research challenges, and suggest potential future directions. The six major applications of machine learning-based surrogate models are groundwater pollution source identification, groundwater remediation design, coastal aquifer management, uncertainty analysis of groundwater, groundwater monitoring network design, and groundwater transport parameters inversion. Together, these account for more than 90% of the studies we review. Latin hypercube sampling (LHS) is the most widely used sampling method, and artificial neural networks (ANNs) and Kriging are the two most widely used methods for constructing surrogate model. No method is universally superior, the advantages and disadvantages of different methods, as well as the applicability of these methods for different application purposes of groundwater contaminant modeling were analyzed. Some recommendations on the method selection for various application fields are given based on the reviews and experiences. Based on our review of the state-of-the-art, we suggest several future research directions to enhance the feasibility of the machine learning-based surrogate models of groundwater contaminant modeling: the alleviation of the curse of dimensionality, enhancing transferability, practical applications for real case studies, multi-source dada fusion, and real-time monitoring and prediction.
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Água Subterrânea , Modelos Teóricos , Aprendizado de Máquina , Poluição Ambiental , Redes Neurais de ComputaçãoRESUMO
Background: Hepatitis E virus (HEV) is a zoonotic pathogen. HEV has been found to be widely prevalent in rabbits. Its isolates are classified into HEV-3, rabbit subgenotype (HEV-3ra). The routes of human infection with HEV-3ra remain unclear; however, foodborne transmission is possible when asymptomatically infected animals enter the food chain. The prevalence of HEV infection in slaughtered rabbits and the presence of HEV in rabbit meat were evaluated in this study. Materials and Methods: In three slaughterhouses in Hebei province, China, samples of rabbit blood were collected during the slaughter process, and muscle, liver, and cavity juice were collected from the rabbit carcasses. Anti-HEV antibody in serum samples was detected using enzyme-linked immunosorbent assay. HEV RNA was tested in all samples by reverse transcription nested PCR (RT-nested PCR). The final amplicons of RT-nested PCR were sequenced and phylogenetically analyzed. Results: Of the 459 serum samples, 50 [10.9%, 95% confidence interval (CI): 8.1-13.7] were positive for anti-HEV antibody, and 17 (3.7%, 95% CI: 2.0-5.4) were positive for HEV RNA. HEV RNA was detected in 7 of 60 liver samples (11.7%, 95% CI: 3.3-20) and 2 cavity juice samples from semi-eviscerated carcasses, but was not detected in any muscle sample from either the eviscerated or semi-eviscerated carcasses. All the detected HEV strains belonged to HEV-3ra and related most closely with the rabbit HEV sequence previously reported in China. Conclusion: A portion of rabbits were in the viremia period of HEV infection at the slaughter age, resulting in the possibility of HEV carriage by rabbit carcass, particularly semi-eviscerated carcass containing liver. These findings suggest a potential risk of HEV transmission from raw rabbit products entering the food chain, whereas the presence of HEV appeared to be lower in the eviscerated carcass than in the semi-eviscerated carcass.
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Vírus da Hepatite E , Hepatite E , Humanos , Animais , Coelhos , Vírus da Hepatite E/genética , Matadouros , RNA Viral/genética , Hepatite E/epidemiologia , Hepatite E/veterinária , Anticorpos Anti-Hepatite/genética , Carne , China/epidemiologia , FilogeniaRESUMO
Neuroelectrical signals transmitted onto the skin tend to decay to an extremely weak level, making them highly susceptible to interference from the environment and body movement. Meanwhile, for comprehensively understanding cognitive nerve conduction, multimodal sensing of neural signals, such as magnetic resonance imaging (MRI) and functional near-infrared spectroscopy (fNIRS), is highly required. Previous metal or polymer conductors cannot either provide a seamless on-skin feature for accurate sensing of neuroelectrical signals or be compatible with multimodal imaging techniques without opto- and magnet- artifacts. Herein, a ≈20 nm thick MXene film that is able to simultaneously detect electrophysiological signals and perform imaging by MRI and fNIRS with high fidelity is reported. The ultrathin film is made of crosslinked Ti3 C2 Tx film via poly (3,4-ethylene dioxythiophene): polystyrene sulfonate (PEDOT: PSS), showing a record high electroconductivity and transparency combination (11 000 S cm-1 @89%). Among them, PEDOT: PSS not only plays a cross-linking role to stabilize MXene film but also shortens the interlayer distance for effective charge transfer and high transparency. Thus, it can achieve a low interfacial impedance with skin or neural surfaces for accurate recording of electrophysiological signals with low motion artifacts. Besides, the high transparency originating from the ultrathin feature leads to good compatibility with fNIRS and MRI without optical and magnetic artifacts, enabling multimodal cognitive neural monitoring during prolonged use.
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Artefatos , Imãs , Movimento (Física) , MovimentoRESUMO
The anti-inflammatory effect of ellagic acid (EA) and its possible underlying mechanism in dextran sulfate sodium (DSS)-induced mouse chronic colonic inflammation were studied. It was observed that EA administration significantly alleviated the colonic inflammation phenotypes, including decreasing the disease activity index (DAI), enhancing the body weight loss, and improving the shortened length of the colon and pathological damage of colon tissue. Additionally, EA reshaped the constitution of the gut microbiota by elevating the ratio of Bacteroidetes along with Bacteroides and Muribaculaceae, while decreasing the proportion of Firmicutes. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2) revealed that the metabolic function of the gut microbiota was also changed. Furthermore, mouse colon transcriptome analysis showed that the tight junction and peroxisome proliferator-activated receptor (PPAR) signaling pathways were activated and the expressions of related genes were upregulated after EA intervention. These results showed that EA could remodel the gut bacterial composition, change the intestinal epithelial cell gene expressions in mice, and consequently improve the colonic inflammatory symptoms.
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Colite , Microbioma Gastrointestinal , Animais , Camundongos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Colo/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Ácido Elágico/farmacologia , Ácido Elágico/metabolismo , Células Epiteliais/metabolismo , Expressão Gênica , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , FilogeniaRESUMO
BACKGROUND: Aspirin is recommended for secondary stroke prevention in patients with moderate-to-severe ischaemic stroke but can lead to gastrointestinal intolerance and bleeding. Indobufen is used as an alternative antiplatelet agent in some countries, despite an absence of large-scale clinical trials for this indication. We tested the hypothesis that indobufen is non-inferior to aspirin in reducing the risk of new stroke at 90 days in patients with moderate-to-severe ischaemic stroke. METHODS: We conducted a randomised, double-blind, double-dummy, active control, non-inferiority trial at 163 tertiary and district general hospitals in China. Eligible participants were aged 18-80 years with acute moderate-to-severe ischaemic stroke (National Institutes of Health Stroke Scale score 4-18). We randomly assigned (1:1) participants within 72 h of the onset of symptoms to receive either indobufen (100 mg tablet twice per day) or aspirin (100 mg tablet once per day) for 90 days. The randomisation sequence was computer generated centrally and stratified by local participating centres. Masked local investigators assigned the random code to patients in ascending order and provided a treatment kit corresponding to the random code. The primary efficacy outcome was new stroke and the primary safety outcome was severe or moderate bleeding, both within 90 days. This primary efficacy outcome was assessed in all randomly assigned and consenting patients and in a per-protocol group (ie, all patients finishing the treatment without major violation of the trial protocol). Safety analyses were done in the safety-analysis population (ie, all patients who received at least one dose of the study drug and had a safety assessment available). We assessed the non-inferiority of indobufen versus aspirin using the one-sided upper limit of the 95% CI of the hazard ratio (HR) with a prespecified non-inferiority margin of 1·25. This trial is registered with ClinicalTrials.gov (NCT03871517). FINDINGS: This trial took place between June 2, 2019, and Nov 28, 2021. Of 84 093 patients screened, 5438 patients were randomly assigned to receive either indobufen (n=2715) or aspirin (n=2723), all of whom were included in the primary analyses. Median age was 64·2 years (IQR 56·1-70·6); 1921 (35·3%) were women and 3517 (64·7%) were men. Stroke occurred within 90 days in 213 (7·9%) patients in the indobufen group versus 175 (6·4%) in the aspirin group (HR 1·23, 95% CI 1·01-1·50; pnon-inferiority=0·44). Moderate or severe bleeding occurred in 18 (0·7%) patients in the indobufen group and in 28 (1·0%) in the aspirin group (0·63, 95% CI 0·35 to 1·15; p=0·13). Adverse events within 90 days occurred in 666 (24·5%) patients in the indobufen group and 679 (24·9%) patients in the aspirin group (p=0·73). INTERPRETATION: In patients with acute moderate-to-severe ischaemic stroke, indobufen was not non-inferior to aspirin because the upper limit of the 95% CI was greater than 1·25. Furthermore, indobufen seemed to be inferior to aspirin in reducing the risk of recurrent stroke at 90 days because the lower limit of the 95% CI was greater than 1·00. Although moderate or severe bleeding did not differ between groups, these findings do not support the use of indobufen for secondary stroke prevention in patients with moderate-to-severe ischaemic stroke. FUNDING: Hangzhou Zhongmei Huadong Pharmaceutical and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Aspirina/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Isquemia Encefálica/complicações , Resultado do Tratamento , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/complicações , Método Duplo-CegoRESUMO
Some agronomic practices not only promote the development of crop roots and increase overall plant performance but also affect colonisation by rhizosphere microorganisms. However, the composition and temporal dynamics of the tobacco rhizosphere microbiota under different root-promoting practices are poorly understood. Here, we characterised the tobacco rhizosphere microbiota at the knee-high, vigorous growing, and maturity stages under the application of potassium fulvic acid (PFA), γ-Polyglutamic acid (PGA), soymilk root irrigation (SRI), and conventional fertilization (CK) and its correlation with root characteristics and soil nutrients. The results showed that three root-promoting practices notably improved the dry and fresh root weights. Total nitrogen and phosphorus, available phosphorus and potassium, and organic matter contents in the rhizosphere markedly increased at the vigorous growing stage. The rhizosphere microbiota was changed through root-promoting practices. However, with tobacco growth, the change of rhizosphere microbiota showed a pattern of slow first and then fast and the microbiota of different treatments gradually approached. SRI reduced plant-pathogenic fungi but increased chemoheterotrophic and phototrophic bacteria, and arbuscular mycorrhizal fungi. PFA and PGA markedly increased arbuscular mycorrhizal and ectomycorrhizal fungi at the knee-high stage, which benefitted tobacco nutrient absorption. The correlation between rhizosphere microorganisms and environmental factors varied at different growth stages. Notably, the rhizosphere microbiota was more sensitive to environmental factors at the vigorous growing stage, and the interactions were more complex than in other stages. Furthermore, a variance partitioning analysis showed that the influence of root-soil interaction on the rhizosphere microbiota increased with tobacco growth. Overall, all three root-promoting practices could improve root characteristics, rhizosphere nutrient, and rhizosphere microbiota to varying degrees and increase the tobacco biomass, among which PGA had the most obvious effect and most suitable for tobacco cultivation. Our findings revealed the role of root-promoting practices in shaping the rhizosphere microbiota during plant growth and elucidated the assembly patterns and environmental drivers of crop rhizosphere microbiota driven by the application of root-promoting practices in agricultural production.
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Micorrizas , Nicotiana , Raízes de Plantas/microbiologia , Rizosfera , Solo , Plantas , Microbiologia do Solo , FósforoRESUMO
BACKGROUND. Abbreviated protocols could allow wider adoption of MRI in patients undergoing breast cancer neoadjuvant chemotherapy (NAC). However, abbreviated MRI has been explored primarily in screening settings. OBJECTIVE. The purpose of this article was to compare diagnostic performance of abbreviated MRI and full-protocol MRI for evaluation of breast cancer NAC response, stratifying by radiologists' breast imaging expertise. METHODS. This retrospective study included 203 patients with breast cancer (mean age, 52.1 ± 11.2 [SD] years) from two hospitals who underwent MRI before NAC initiation and after NAC completion before surgical resection from March 2017 to April 2021. Abbreviated MRI was extracted from full-protocol MRI and included the axial T2-weighted sequence and precontrast and single early postcontrast T1-weighted sequences. Three general radiologists and three breast radiologists independently interpreted abbreviated and full-protocol MRI in separate sessions, identifying enhancing lesions to indicate residual tumor and measuring lesion size. The reference standard was presence and size of residual tumor on pathologic assessment of post-NAC surgical specimens. RESULTS. A total of 50 of 203 patients had pathologic complete response (pCR). Intraobserver and interobserver agreement for abbreviated and full-protocol MRI for general and breast radiologists ranged from substantial to nearly perfect (κ = 0.70-0.81). Abbreviated MRI compared with full-protocol MRI showed no significant difference for general radiologists in sensitivity (54.7% vs 57.3%, p > .99), specificity (92.8% vs 95.6%, p = .29), or accuracy (83.4% vs 86.2%, p = .30), nor for breast radiologists in sensitivity (60.0% vs 61.3%, p > .99), specificity (94.6% vs 97.4%, p = .22), or accuracy (86.0% vs 88.5%, p = .30). Sensitivity, specificity, and accuracy were not significantly different between protocols for any reader individually (p > .05). Mean difference in residual tumor size on MRI relative to pathology for abbreviated protocol ranged for general radiologists from -0.19 to 0.03 mm and for breast radiologists from -0.15 to -0.05 mm, and for full protocol ranged for general radiologists from 0.57 to 0.65 mm and for breast radiologists from 0.66 to 0.79 mm. CONCLUSION. Abbreviated compared with full-protocol MRI showed similar intraobserver and interobserver agreement and no significant difference in diagnostic performance. Full-protocol MRI but not abbreviated MRI slightly overestimated pathologic tumor sizes. CLINICAL IMPACT. Abbreviated protocols may facilitate use of MRI for post-NAC response assessment by general and breast radiologists.