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1.
IEEE Trans Med Imaging ; PP2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33798076

RESUMO

An effective presymptomatic diagnosis and treatment of Alzheimer's disease (AD) would have enormous public health benefits. Sparse coding (SC) has shown strong potential for longitudinal brain image analysis in preclinical AD research. However, the traditional SC computation is time-consuming and does not explore the feature correlations that are consistent over the time. In addition, longitudinal brain image cohorts usually contain incomplete image data and clinical labels. To address these challenges, we propose a novel two-stage Multi-Resemblance Multi-Target Low-Rank Coding (MMLC) method, which encourages that sparse codes of neighboring longitudinal time points are resemblant to each other, favors sparse code low-rankness to reduce the computational cost and is resilient to both source and target data incompleteness. In stage one, we propose an online multi-resemblant low-rank SC method to utilize the common and task-specific dictionaries in different time points to immune to incomplete source data and capture the longitudinal correlation. In stage two, supported by a rigorous theoretical analysis, we develop a multi-target learning method to address the missing clinical label issue. To solve such a multi-task low-rank sparse optimization problem, we propose multi-task stochastic coordinate coding with a sequence of closed-form update steps which reduces the computational costs guaranteed by a theoretical convergence proof. We apply MMLC on a publicly available neuroimaging cohort to predict two clinical measures and compare it with six other methods. Our experimental results show our proposed method achieves superior results on both computational efficiency and predictive accuracy and has great potential to assist the AD prevention.

2.
J Alzheimers Dis ; 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33749642

RESUMO

BACKGROUND: Besides their other roles, brain imaging and other biomarkers of Alzheimer's disease (AD) have the potential to inform a cognitively unimpaired (CU) person's likelihood of progression to mild cognitive impairment (MCI) and benefit subject selection when evaluating promising prevention therapies. We previously described that among baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD, hippocampal volume was the best predictor of incident MCI within 2 years (79%sensitivity/78%specificity), using standard automated MRI volumetric algorithmic programs, binary logistic regression, and leave-one-out procedures. OBJECTIVE: To improve the same prediction by using different hippocampal features and machine learning methods, cross-validated via two independent and prospective cohorts (Arizona and ADNI). METHODS: Patch-based sparse coding algorithms were applied to hippocampal surface features of baseline TI-MRIs from 78 CU adults who subsequently progressed to amnestic MCI in approximately 2 years ("progressors") and 80 matched adults who remained CU for at least 4 years ("nonprogressors"). Nonprogressors and progressors were matched for age, sex, education, and apolipoprotein E4 allele dose. We did not include amyloid or tau biomarkers in defining MCI. RESULTS: We achieved 92%prediction accuracy in the Arizona cohort, 92%prediction accuracy in the ADNI cohort, and 90%prediction accuracy when combining the two demographically distinct cohorts, as compared to 79%(Arizona) and 72%(ADNI) prediction accuracy using hippocampal volume. CONCLUSION: Surface multivariate morphometry and sparse coding, applied to individual MRIs, may accurately predict imminent progression to MCI even in the absence of other AD biomarkers.

3.
J Diabetes Complications ; 35(5): 107888, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33640264

RESUMO

AIMS: This study aimed to evaluate the long-term outcomes of peritoneal dialysis (PD) patients with and without diabetes in southern China. METHODS: This retrospective and observational cohort study included all adult patients with end-stage renal disease (ESRD) who received PD in our center from January 2009 to December 2017 and were followed until December 2019. Clinical outcomes were compared by Kaplan-Meier survival analysis and cumulative incidence function, and risk factors were estimated using Cox regression analyses and competing risk models. RESULTS: Of 401 patients receiving PD, 120 (29.9%) had type 2 diabetes mellitus (DM), and 281 (70.1%) did not have diabetes mellitus (NDM). Patients with DM were older and had more cardiovascular disease (CVD) morbidities than patients without DM. Kaplan-Meier analysis showed that patients with DM had shorter survival (Log-rank 3.215, P < 0.0001) compared with patients without DM. Patients with DM had a lower death-censored technique survival (Log-rank 2.029, P = 0.0180), however, there was no significant difference in peritonitis-free period (Log rank 1.375, P = 0.1133). These results were reproduced after taking competing events into account. Both on multivariate Cox analysis and on multivariate competing risk regression, diabetes was an independent predictor for increased mortality and technique failure, but not for peritonitis-free survival. CONCLUSIONS: Patients undergoing PD with DM had increased risk of mortality and technique failure, and closer monitoring and additional focus in patients with DM treated by PD are, therefore, warranted.

4.
J Environ Manage ; 282: 111964, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33485034

RESUMO

Coastal aquifer management (CAM) considering conjunctive optimization of pumping and injection system for seawater intrusion (SI) mitigation poses significant decision-making challenges. CAM needs to pose multiple objectives and massive decision variables to explore tradeoff strategies between the conflicting resources, economic, and environmental requirements. Here, we investigate a joint artificial injection scheme for ameliorating SI by establishing an evolutionary multi-objective decision-making framework that combines simulation-optimization (S-O) modelling with a cost-benefit analysis, and demonstrate the framework on a large-scale CAM case in Baldwin County, Alabama. First, a SI numerical model, using SEAWAT, was configured to predict the vulnerable region as an SI encroachment area with the scenarios of minimum and maximum pumping capacity. As a result, a smaller number of candidate sites were selected in the SI encroachment area for implementing groundwater injection to avoid the computationally infeasible SI optimization with an inordinate number of injection related decision variables. Second, the effective S-O methodology of niched Pareto tabu search combined with a genetic algorithm (NPTSGA), which considers the moving-well option, was applied to discover optimal pumping/injection (P/I) strategies (including P/I rates and injection well locations) between three conflicting management objectives under complicated SI constraints. Third, for practical operation of the P/I schemes, a cost-benefit analysis provides judgment criteria to allow decision-makers to implement more sustainable P/I strategies to capture the different realistic preferences. The implementation of three extreme optimization solutions for the case study indicates that, compared to the initial unoptimized scheme, a maximum increase of a factor of 3 in groundwater extraction rates, a maximum reduction of 17% in extent of SI, and a maximum 82.3 million US dollars in comprehensive benefits are specifically achieved by conjunctive P/I optimization. The robustness in the decision alternatives attributed to the uncertainty in physical parameters of hydraulic conductivity was discovered through global sensitivity analysis. The proposed framework provides a decision support system for multi-objective CAM with combined pumping control and engineering measures for SI mitigation.


Assuntos
Água Subterrânea , Análise Custo-Benefício , Objetivos , Água do Mar , Incerteza
5.
Talanta ; 224: 121852, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33379068

RESUMO

Reduced glutathione (GSH) and the oxidized glutathione (GSSG) are well-known biomolecules in the main constituents of intracellular redox homeostasis system. A rapid, accurate measurement of cellular GSH and GSSG is quite needed in investigating important biochemical events. In this work, we present a novel and sensitive method to monitor intracellular GSH and GSSG concentrations by a portable surface-enhanced Raman spectroscopy (SERS) technique. We introduced a reduction-sensitive reaction-type Raman probe, 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) to initiate GSH reduction, itself concomitantly converts to 2-nitro-5-thiobenzoic acid (TNB) to release a strong SERS signal. In a convenient way of inorganic salt MgSO4 induced aggregation of silver nanoparticles substrate, we easily implemented a good discrimination between DTNB and TNB, and a quantitative measurement of GSH and GSSG with a high sensitivity of 10 nM. This SERS method proved its feasible applicability in rapidly and sensitively monitoring GSH depletion behaviors of some notorious alkylating agents, i.e., sulfur mustard and nitrogen mustards in ex vitro or in vitro (cellular response). This SERS method may be very worthwhile in cellular detoxication event via the GSH approach and other GSH involved biomedical researches.

6.
Int J Food Microbiol ; 337: 108951, 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33202299

RESUMO

Pit mud microbiota plays a key role in flavour production for Chinese strong-aroma type liquor. However, the pit mud microbiota cannot be cultured in laboratory. In this study, an oligotrophic medium with acetate as carbon source was used to enrich pit mud microbiota. The 16S rRNA gene amplicon sequencing was applied to examine the microbial dynamics of the enrichment consortia. Both methanogens and bacteria were simultaneously enriched. Euryarchaeota, Bacteroidetes and Firmicutes were the top 3 enriched phyla, and 31 genera were successfully enriched. More specifically, 11 genera (65%) out of the 17 dominant genera in pit mud were successfully enriched, including Petrimonas, Proteiniphilum, Anaerocella, Hydrogenispora, Methanosarcina, Fermentimonas, LNR_A2-18, Sedimentibacter, Lutispora, Syntrophomonas and Aminobacterium. Furthermore, 20 rare genera in the analyzed pit mud samples were also enriched. Aceticlastic Methanosaeta and Methanosarcina were found to be dominant methanogens in the enrichment consortia. Metagenomic sequencing was then applied to the enriched microbial consortia to explore the metabolic potentials of pit mud microbes. Aceticlastic methanogenesis pathway of Methanosaeta was reconstructed. Furthermore, 26 high-quality metagenome-assembled genomes (MAGs) were obtained based on the metagenomic binning analysis. Moreover, nutrients in pit mud were found to be crucial to sustain the methanogenesis of the enriched microbial consortia. These results suggested that the enrichment approach by using oligotrophic culturing can effectively cultivate the pit mud microbiota. Combined with metagenomics, the oligotrophic culturing will be greatly helpful to decipher the community composition and metabolic potentials of pit mud microbiota.


Assuntos
Bebidas Alcoólicas/microbiologia , Microbiota , Acetatos/análise , Acetatos/metabolismo , Archaea/classificação , Archaea/genética , Archaea/isolamento & purificação , Archaea/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , China , Meios de Cultura/química , Fermentação , Humanos , Microbiota/genética , RNA Ribossômico 16S/genética
7.
Med Image Anal ; 67: 101877, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33166772

RESUMO

Cognitive decline due to Alzheimer's disease (AD) is closely associated with brain structure alterations captured by structural magnetic resonance imaging (sMRI). It supports the validity to develop sMRI-based univariate neurodegeneration biomarkers (UNB). However, existing UNB work either fails to model large group variances or does not capture AD dementia (ADD) induced changes. We propose a novel low-rank and sparse subspace decomposition method capable of stably quantifying the morphological changes induced by ADD. Specifically, we propose a numerically efficient rank minimization mechanism to extract group common structure and impose regularization constraints to encode the original 3D morphometry connectivity. Further, we generate regions-of-interest (ROI) with group difference study between common subspaces of Aß+AD and Aß-cognitively unimpaired (CU) groups. A univariate morphometry index (UMI) is constructed from these ROIs by summarizing individual morphological characteristics weighted by normalized difference between Aß+AD and Aß-CU groups. We use hippocampal surface radial distance feature to compute the UMIs and validate our work in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. With hippocampal UMIs, the estimated minimum sample sizes needed to detect a 25% reduction in the mean annual change with 80% power and two-tailed P=0.05are 116, 279 and 387 for the longitudinal Aß+AD, Aß+mild cognitive impairment (MCI) and Aß+CU groups, respectively. Additionally, for MCI patients, UMIs well correlate with hazard ratio of conversion to AD (4.3, 95% CI = 2.3-8.2) within 18 months. Our experimental results outperform traditional hippocampal volume measures and suggest the application of UMI as a potential UNB.

8.
Dalton Trans ; 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33295909

RESUMO

The anion-adaptive self-assembly described here not only offers a facile approach to produce large single-molecule magnets without the need for precise manipulation of the stoichiometry of ligand-metal centers but also provides an understanding of how structural factors affect the magnetic properties. X-ray diffraction analysis reveals that a rare hexagonal metallacycle with a diameter approaching 23 Å was obtained. Magnetic investigation shows that the resulting hexagonal metallacycle behaves as a typical single-molecule magnet with double relaxation under dc field thanks to the different coordination geometry of the DyIII centers.

9.
Sci Transl Med ; 12(572)2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268508

RESUMO

Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) has reached epidemic proportions with no pharmacological therapy approved. Lower circulating glycine is consistently reported in patients with NAFLD, but the causes for reduced glycine, its role as a causative factor, and its therapeutic potential remain unclear. We performed transcriptomics in livers from humans and mice with NAFLD and found suppression of glycine biosynthetic genes, primarily alanine-glyoxylate aminotransferase 1 (AGXT1). Genetic (Agxt1 -/- mice) and dietary approaches to limit glycine availability resulted in exacerbated diet-induced hyperlipidemia and steatohepatitis, with suppressed mitochondrial/peroxisomal fatty acid ß-oxidation (FAO) and enhanced inflammation as the underlying pathways. We explored glycine-based compounds with dual lipid/glucose-lowering properties as potential therapies for NAFLD and identified a tripeptide (Gly-Gly-L-Leu, DT-109) that improved body composition and lowered circulating glucose, lipids, transaminases, proinflammatory cytokines, and steatohepatitis in mice with established NASH induced by a high-fat, cholesterol, and fructose diet. We applied metagenomics, transcriptomics, and metabolomics to explore the underlying mechanisms. The bacterial genus Clostridium sensu stricto was markedly increased in mice with NASH and decreased after DT-109 treatment. DT-109 induced hepatic FAO pathways, lowered lipotoxicity, and stimulated de novo glutathione synthesis. In turn, inflammatory infiltration and hepatic fibrosis were attenuated via suppression of NF-κB target genes and TGFß/SMAD signaling. Unlike its effects on the gut microbiome, DT-109 stimulated FAO and glutathione synthesis independent of NASH. In conclusion, impaired glycine metabolism may play a causative role in NAFLD. Glycine-based treatment attenuates experimental NAFLD by stimulating hepatic FAO and glutathione synthesis, thus warranting clinical evaluation.

10.
ACS Biomater Sci Eng ; 6(10): 5857-5865, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33320563

RESUMO

Identifying severe acute pancreatitis (SAP) as soon as possible is critical for achieving optimal outcomes and saving lives. In this study, a novel P-selectin-targeted, NIR fluorescent dye (Cy 5.5)-labeled dual-modal nanoprobe based on diethylenetriaminepentaacetic chelates (Gd-DTPA-Cy5.5-PsLmAb) was constructed for the bimodal imaging of SAP at the early stage. Gd-DTPA-Cy5.5-PsLmAb was prepared, and its structure was characterized by Fourier transform infrared spectroscopy, UV-vis spectroscopy, and fluorescence spectroscopy, and its stability was evaluated. Biocompatibility was evaluated by the hemolysis and cytotoxicity assays. The enzyme-linked immunosorbent assay was used to detect and evaluate the expression of P-selectin in the peripheral blood of 11 patients with acute pancreatitis (AP) and 5 healthy volunteers. The bimodal imaging ability of Gd-DTPA-Cy5.5-PsLmAb nanoprobes was evaluated via near-infrared fluorescence (NIRF) and magnetic resonance imaging (MRI) in AP animal models in vivo. Gd-DTPA-Cy5.5-PsLmAb showed low toxicity to human embryonic kidney cells (293T cells) and good blood compatibility. The P-selectin levels of humans and rats in the mild acute pancreatitis (MAP)/SAP stage were significantly higher than those in the control group and reached the highest level at the SAP stage. Furthermore, Gd-DTPA-Cy5.5-PsLmAb nanoprobes showed clear NIRF imaging of mouse pancreas at the MAP stage and SAP stage by a fluorescence signal at 6.09 × 108 and 1.95 × 109, respectively. Meanwhile, Gd-DTPA-Cy5.5-PsLmAb nanoprobes also successfully showed the T1-weighted MR signal of rat pancreas at the MAP stage, but Gd-DTPA seldom showed any signal increase at the MAP stage; Gd-DTPA-Cy5.5-PsLmAb and Gd-DTPA could show an increasing MR signal of rat pancreas at the SAP stage. Gd-DTPA-Cy5.5-PsLmAb proved to offer a stronger signal than Gd-DTPA.Our findings indicate that Gd-DTPA-Cy5.5-PsLmAb is an effective and specific MR/NIRF dual nanoprobe for bimodal imaging, providing a promising diagnostic approach for early SAP in clinic.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33250550

RESUMO

Collectively, vast quantities of brain imaging data exist across hospitals and research institutions, providing valuable resources to study brain disorders such as Alzheimer's disease (AD). However, in practice, putting all these distributed datasets into a centralized platform is infeasible due to patient privacy concerns, data restrictions and legal regulations. In this study, we propose a novel federated feature selection framework that can analyze the data at each individual institution without data-sharing or accessing private patient information. In this framework, we first propose a federated group lasso optimization method based on block coordinate descent. We employ stability selection to determine statistically significant features, by solving the group lasso problem with a sequence of regularization parameters. To accelerate the stability selection, we further propose a federated screening rule, which can identify and exclude the irrelevant features before solving the group lasso. Here, we use this framework for patch based feature selection on hippocampal morphometry. Shape is characterized through two different kinds of local measures, the radial distance and the surface area determined via tensor-based morphometry (TBM). The method is tested on 1,127 T1-weighted brain magnetic resonance images (MRI) of AD, mild cognitive impairment (MCI) and elderly control subjects, randomly assigned to five independent hypothetical institutions for testing purpose. We examine the association of MRI-based anatomical measures with general cognitive assessment and amyloid burden to identify the morphometry changes related to AD deterioration and plaque accumulation. Finally, we visualize the significance of the association on the hippocampal surfaces. Our experimental results successfully demonstrate the efficiency and effectiveness of our method.

12.
Gastroenterology ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33217448

RESUMO

BACKGROUND & AIMS: RNA N6-methyladenosine (m6A) modification has recently emerged as a new regulatory mechanism in cancer progression. We aimed to explore the role of m6A regulatory enzyme METTL3 in colorectal cancer (CRC) pathogenesis and its potential as a therapeutic target. METHODS: The expression and clinical implication of METTL3 were investigated in multiple human CRC cohorts. The underlying mechanisms of METTL3 in CRC were investigated by integrative m6A-sequencing, RNA-sequencing and ribosome profiling analyses. The efficacy of targeting METTL3 in CRC treatment was elucidated in CRC cell lines, patient-derived CRC organoids and Mettl3 knockout mouse models. RESULTS: Using targeted CRISPR/Cas9 dropout screening, we identified METTL3 as the top essential m6A regulatory enzyme in CRC. METTL3 was overexpressed in 62.2% (79/127) and 88.0% (44/50) of primary CRC from two independent cohorts. High METTL3 expression predicted poor survival in CRC patients (n=374, P < .01). Functionally, silencing METTL3 suppressed tumorigenesis in CRC cells, human-derived primary CRC organoids and Mettl3 knockout mouse models. We discovered the novel functional m6A methyltransferase domain of METTL3 in CRC cells by domain-focused CRISPR screen and mutagenesis assays. Mechanistically, METTL3 directly induced m6A-GLUT1-mTORC1 axis as identified by integrated m6A-sequencing, RNA-sequencing, Ribosome-sequencing and functional validation. METTL3 induced GLUT1 translation in m6A-dependent manner, which subsequently promoted glucose uptake and lactate production, leading to the activation of mTORC1 signaling and CRC development. Furthermore, inhibition of mTORC1 potentiated the anticancer effect of METTL3 silencing in CRC patient-derived organoids and METTL3 transgenic mouse models. CONCLUSIONS: METTL3 promotes CRC by activating m6A-GLUT1-mTORC1 axis. METTL3 is a promising therapeutic target for the treatment of CRC.

13.
Biomed Res Int ; 2020: 3049302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33145344

RESUMO

The present study was to investigate the effect of mesenteric lymph duct drainage on lung inflammatory response, histological alteration, and endothelial cell apoptosis in septic rats. Animals were randomly assigned into four groups: control, sham surgery, sepsis, and sepsis plus mesenteric lymph drainage. We used the colon ascendens stent peritonitis (CASP) procedure to induce the septic model in rats, and mesenteric lymph drainage was performed with a polyethylene (PE) catheter inserted into mesenteric lymphatic. The animals were sacrificed at the end of CASP in 6 h. The mRNA expression levels of inflammatory mediators were measured by qPCR, and the histologic damage were evaluated by the pathological score method. It was found that mesenteric lymph drainage significantly reduced the expression of TNF-α, IL-1ß, and IL-6 mRNA in the lung. Pulmonary interstitial edema and infiltration of inflammatory cells were alleviated by mesenteric lymph drainage. Moreover, increased mRNA levels of TNF-α, IL-1ß, IL-6 mRNA, and apoptotic rate were observed in PMVECs treated with septic lymph. These results indicate that mesenteric lymph duct drainage significantly attenuated lung inflammatory injury by decreasing the expression of pivotal inflammatory mediators and inhibiting endothelial apoptosis to preserve the pulmonary barrier function in septic rats.

14.
Microb Drug Resist ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33085931

RESUMO

Background: Helicobacter pylori prevalence and gastric cancer rates are remarkably high in Peru. Effective antimicrobial regimens are essential for successful H. pylori eradication. We aimed at assessing antimicrobial resistance rates to first- and second-line therapeutic agents in H. pylori strains detected in gastric biopsy samples. Materials and Methods: Gastric biopsy samples (antrum and corpus) were collected from therapy-naive patients (n = 154). H. pylori presence in the samples was confirmed by histopathology. Genotypic resistance to clarithromycin and quinolones was determined by real-time PCR. Results: Histology results were 100% concordant with PCR results (97/154; 63% H. pylori-positive in both). In 6% (6/97) of the patients, we found discordant results of H. pylori infection in antrum and corpus samples from the same patient. Resistance rates to clarithromycin and quinolone were 34% (33/97) and 68% (56/82), respectively. Antimicrobial resistance to both antimicrobials was 30% (25/82). Conclusion: Antimicrobial resistance rates of H. pylori to clarithromycin and quinolones are very high in Lima, Peru. Many first- and second-line, empiric eradication regimens may not be recommended for Peruvian patients.

15.
Mol Cell ; 80(2): 296-310.e6, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32979304

RESUMO

Necroptosis induction in vitro often requires caspase-8 (Casp8) inhibition by zVAD because pro-Casp8 cleaves RIP1 to disintegrate the necrosome. It has been unclear how the Casp8 blockade of necroptosis is eliminated naturally. Here, we show that pro-Casp8 within the necrosome can be inactivated by phosphorylation at Thr265 (pC8T265). pC8T265 occurs in vitro in various necroptotic cells and in the cecum of TNF-treated mice. p90 RSK is the kinase of pro-Casp8. It is activated by a mechanism that does not need ERK but PDK1, which is recruited to the RIP1-RIP3-MLKL-containing necrosome. Phosphorylation of pro-Casp8 at Thr265 can substitute for zVAD to permit necroptosis in vitro. pC8T265 mimic T265E knockin mice are embryonic lethal due to unconstrained necroptosis, and the pharmaceutical inhibition of RSK-mediated pC8T265 diminishes TNF-induced cecum damage and lethality in mice by halting necroptosis. Thus, phosphorylation of pro-Casp8 at Thr265 by RSK is an intrinsic mechanism for passing the Casp8 checkpoint of necroptosis.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Caspase 8/metabolismo , Necroptose , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais , Animais , Ceco/lesões , Ceco/patologia , Linhagem Celular , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Mutação/genética , Necroptose/efeitos dos fármacos , Especificidade de Órgãos , Fosforilação/efeitos dos fármacos , Fosfotreonina/metabolismo , Proteínas Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia
16.
ACS Appl Mater Interfaces ; 12(40): 44475-44484, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32931236

RESUMO

The use of tunneled dialysis catheters (TDCs) for patients in need of hemodialysis treatments (HDs) causes a significant number of bloodstream infections (BSIs), with very few viable preventative/treatment methods. Use of antibiotics is relatively ineffective due to the development of multidrug-resistant bacterial strains and the inability to penetrate bacterial biofilms. Nitric oxide (NO) is an endogenous gas molecule that has broad-spectrum antimicrobial/antibiofilm activity. In this study, the potential of creating a NO-releasing insert device that is attached onto the hub region cap of TDCs and locally releases NO within the TDC hub is evaluated for its antimicrobial/antibiofilm effectiveness. The NO-releasing insert contains the natural NO donor S-nitrosoglutathione (GSNO), along with zinc oxide (ZnO) nanoparticles to accelerate NO release from the GSNO, within a short silicone tube that is sealed at both ends and attached to the catheter cap. An in vitro 3-d-long antimicrobial study using catheter hubs yielded >6.6 log reductions of both Pseudomonas aeruginosa and Staphylococcus aureus for the NO-releasing insert device compared to controls. Two 14-d-long sheep studies demonstrated that the NO-releasing insert devices are exceptionally potent at preventing bacteria/biofilm growth on the inner lumen walls of TDCs compared to controls that have no preventative treatment devices as well as implanted TDCs that have commercially available chlorhexidine-treated insert devices placed within the hub regions.

17.
J Clin Endocrinol Metab ; 105(12)2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32880390

RESUMO

BACKGROUND: Systemic corticosteroids are now recommended in many treatment guidelines, although supporting evidence is limited to 1 randomized controlled clinical trial (RECOVERY). OBJECTIVE: To identify whether corticosteroids were beneficial to COVID-19 patients. METHODS: A total of 1514 severe and 249 critical hospitalized COVID-19 patients from 2 medical centers in Wuhan, China. Multivariable Cox models, Cox model with time-varying exposure and propensity score analysis (inverse-probability-of-treatment-weighting [IPTW] and propensity score matching [PSM]) were used to estimate the association of corticosteroid use with risk of in-hospital mortality in severe and critical cases. RESULTS: Corticosteroids were administered in 531 (35.1%) severe and 159 (63.9%) critical patients. Compared to the non-corticosteroid group, systemic corticosteroid use was not associated with beneficial effect in reducing in-hospital mortality in either severe cases (HR = 1.77; 95% CI, 1.08-2.89; P = 0.023), or critical cases (HR = 2.07; 95% CI, 1.08-3.98; P = 0.028). Findings were similar in time-varying Cox analysis. For patients with severe COVID-19 at admission, corticosteroid use was not associated with improved or harmful outcome in either PSM or IPTW analysis. For critical COVID-19 patients at admission, results were consistent with multivariable Cox model analysis. CONCLUSION: Corticosteroid use was not associated with beneficial effect in reducing in-hospital mortality for severe or critical cases in Wuhan. Absence of the beneficial effect in our study in contrast to that observed in the RECOVERY clinical trial may be due to biases in observational data, in particular prescription by indication bias, differences in clinical characteristics of patients, choice of corticosteroid used, timing of initiation of treatment, and duration of treatment.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Mortalidade Hospitalar/tendências , Hospitalização/estatística & dados numéricos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/mortalidade , Corticosteroides/uso terapêutico , Idoso , Infecções por Coronavirus/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
18.
Infect Drug Resist ; 13: 2053-2061, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32636658

RESUMO

Purpose: Although immune dysfunction has been investigated in adult septic patients, early immune status remains unclear. In this study, our primary aim was to assess early immune status in adult patients with sepsis stratified by age and its relevance to hospital mortality. Patients and Methods: A post hoc analysis of a multicenter, randomized controlled trial was conducted; 273 patients whose immune status was evaluated within 48 hours after onset of sepsis were enrolled. Early immune status was evaluated by the percentage of monocyte human leukocyte antigen-DR (mHLA-DR) in total monocytes within 48 hours after onset of sepsis and it was classified as immunoparalysis (mHLA-DR ≤30%) or non-immunoparalysis (>30%). Three logistic regression models were conducted to explore the associations between early immunoparalysis and hospital mortality. We also developed two sensitivity analyses to find out whether the definition of early immune status (24 hours vs 48 hours after onset of sepsis) and immunotherapy affect the primary outcome. Results: Of the 181 elderly (≥60yrs) and 92 non-elderly (<60yrs) septic patients, 71 (39.2%) and 25 (27.2%) died in hospital, respectively. The percentage of early immunoparalysis in the elderly was twice of that in the non-elderly patients (32% vs 16%, p=0.006). For the elderly, hospital mortality was higher in the immunoparalysis ones than the non-immunoparalysis ones (53.4% vs 32.5%, p=0.009). But there was no significant difference in hospital mortality between immunoparalysis non-elderly patients and non-immunoparalysis non-elderly ones (33.5% vs 26.0%, p=0.541). By means of logistic regression models, we found that early immunoparalysis was independently associated with increased hospital mortality in elderly, but not in non-elderly patients. Sensitivity analysis further confirmed the definition of early immune status and immunotherapy did not affect the outcomes. Conclusion: The elderly were more susceptible to early immunoparalysis after onset of sepsis. Early immunoparalysis was independently associated with poor prognosis in elderly, but not in non-elderly patients.

19.
Cancer Med ; 9(17): 6166-6172, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32657029

RESUMO

BACKGROUND: This study aimed to compare the efficacy and toxicity of raltitrexed (Saiweijian® ) plus cisplatin (SP regimen) and 5-fluorouracil plus cisplatin (FP regimen) as concurrent chemoradiotherapy (CCRT) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: Eligible patients (N = 135) were allocated randomly in a ratio of 1:1 to receive CCRT with either SP or FP. At least 2 cycles of chemotherapy was administrated during radiotherapy. Progression free survival (PFS) was primary endpoint. Secondary endpoints included overall survival (OS), loco-regional relapse free survival (LRRFS), distant metastasis free survival (DMFS) and toxicity. RESULTS: In this study, 68 patients received SP as CCRT, and 67 received FP. Objective responses were noted in 97.1% of the patients in the SP group and in 97.0% of the patients in the FP group (P = 1.00). At the end of a median 36 months follow-up period, the estimated 3-year PFS rates were 70.1% for SP and 66.6% for FP, respectively. The 3-year LRRFS, DMFS and OS rates were 88.9%, 74.7% and 84.0%, respectively, for the SP group, and 92.3%, 71.0% and 73.7%, respectively, for the FP group. Overall, there was no difference between treatment groups with regard to response or survival. The most frequent acute toxicities monitored in both groups were bone marrow suppression, gastrointestinal side effects and oral mucositis (OM). The overall incidence of grade 3-4 OM in the FP group (47.8%) was higher than in the SP group (11.8%). However, the incidence of other adverse effects observed in both groups was similar (P > .05). CONCLUSIONS: These data indicate that SP and FP therapies have similar efficacy in treating LA-NPC. The SP regimen showed a tolerable safety profile along with a lower frequency of severe OM and therefore, an improved life quality. In conclusion, SP was a well tolerated, effective, regimen for LA-NPC treatment.

20.
Ann Transl Med ; 8(12): 785, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32647710

RESUMO

Background: Transesophageal echocardiography (TEE) performed by intensivists is increasingly used in critically ill patients. However, TEE is usually not the preferred monitoring tool, especially when transthoracic echocardiography (TTE) appears to have addressed the clinical problems. As a result, it remains largely unknown whether TEE is a clinically valuable replacement or supplement for TTE as a primary tool in evaluating haemodynamic problems in critically ill surgical patients. The purpose of this study was to assess the diagnostic and therapeutic value of TEE instead or in addition to TTE in critically ill surgical patients with hemodynamic instability. Methods: A prospective observational study was conducted. A total of 68 consecutive patients were enrolled from December 2016 to February 2018. TEE was routinely performed in addition to TTE, and the imaging data from TTE and TEE were successively disclosed to two different primary physicians, who reported any resulting changes in management. The two physicians were required to reach a consensus if there was any disagreement. The results of the additional TEE examination were compared with the clinical findings and TTE information. The image quality of TTE views was classified as a good (score 2), suboptimal (score 1) or poor view (score 0). According to the scores of TTE images, the patients were divided into two groups: patients with adequate TTE views (score ≥6) and inadequate TTE views (score <6). Results: The results of additional TEE examination were classified into four categories. TEE failed to provide additional information about the initial diagnosis and therapy (class 1) in 26 patients (38.2%). Of the remaining 42 patients (61.8%), TEE instead or in addition to TTE revealed new findings or led to significant changes in therapy, as TTE supplied inadequate information. TEE used in addition to TTE led to a new diagnosis without therapeutic implications (class 2) in 11 patients (16.2%) and made a major clinical contribution leading to a therapeutic change (class 3) in 23 patients (33.8%). TEE used instead of TTE determined the diagnosis and therapy in 8 patients (11.8%) whose haemodynamic problems could not be addressed by TTE (class 4). In total, TEE had critical therapeutic benefits (class 3 and 4) that was not provided by TTE in 31 patients (45.6%). Of particular concern was that TEE had a higher proportion of therapeutic benefits to patients with inadequate TTE views than those with adequate TTE views (54.3% vs. 27.3%, P=0.036). Conclusions: TEE as a feasible clinical tool is useful for critically ill surgical patients with hemodynamic instability, especially for the patients with inadequate TTE views. TEE instead or in addition to TTE could provide valuable information for diagnosis, which may bring significant therapeutic benefits.

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