Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain ...unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score-matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease. This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January-April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15. Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval CI, 0.388-0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio HR, 1.758; 95% CI, 1.323-2.337; p < 0.001), regardless of baseline clinical status. The duration of invasive mechanical ventilation was shorter in corticosteroid versus non-corticosteroid group (HR, 1.466; 95% CI, 0.841-2.554; p = 0.177). Of the 106 patients who received methylprednisolone, the duration of invasive mechanical ventilation was significantly shorter in the pulse/semi-pulse versus standard dose group (HR, 2.831; 95% CI, 1.347-5.950; p = 0.006). In conclusion, corticosteroids for hospitalized patients with COVID-19 did not improve clinical status on Day 15, but reduced the time to improvement in radiological findings for all patients regardless of disease severity and also reduced the duration of invasive mechanical ventilation in patients who required intubation.Trial registration: This study was registered in the University hospital Medical Information Network Clinical Trials Registry on April 21, 2020 (ID: UMIN000040211).
Aim: Neopterin is an activation marker for monocytes/macrophages. We prospectively investigated the predictive value of plasma neopterin levels on 2-year and long-term cardiovascular events in ...patients with stable angina pectoris (SAP) undergoing coronary stent implantation.Methods: We studied 123 consecutive patients with SAP who underwent primary coronary stenting (44 patients with bare metal stent: BMS group and 79 with drug-eluting stent: DES group). Plasma neopterin levels were measured on admission using HPLC. Moreover, one frozen coronary artery specimen after DES and three frozen coronary specimens after BMS were obtained by autopsy or endarterectomy, followed by immunohistochemical staining for neopterin.Results: Plasma neopterin levels were significantly higher in patients with cardiovascular events than in those without them (P＜0.001). In subgroup analyses, higher levels of plasma neopterin in patients with cardiovascular events (P＜0.001) and a positive correlation between neopterin levels and late lumen loss after stenting (P =0.008) were observed in the BMS group but not in the DES group (P=0.53 and P=0.17, respectively). In long-term cardiovascular events, multivariate Cox regression analysis identified the significance of the high-neopterin group as independent determinants of cardiovascular events (hazard ratio, 2.225; 95% CI, 1.283–3.857; P =0.004). Immunohistochemical staining showed abundant neopterin-positive macrophages in the neointima after BMS implantation but no neopterin-positive macrophages in the neointima after DES implantation.Conclusion: These findings suggest that neopterin is associated with cardiovascular events after coronary stent implantation in patients with SAP. However, there might be a strong association between neopterin and cardiovascular events after BMS but not after DES in these patients.
Reactive oxygen species (ROS) play important roles as root growth regulators. We previously reported a comprehensive transcriptomic atlas, which we named ROS-map, that revealed ROS-responsible genes ...in Arabidopsis root tips. By using ROS-map, we have characterised an early ROS response key transcription factor, MYB30, as a regulator of root cell elongation under ROS signals. However, there are other ROS-responsible transcription factors which have the potential to regulate root growth. In the present study, we characterised the function of another early ROS-responsible transcription factor, ANAC032, that was selected from ROS-map. Overexpression of ANAC032 fused with the transcriptional activation domain, VP16, inhibited root growth, especially decreasing cell elongation. By transcriptome analysis, we revealed that ANAC032 regulated many stress-responsible genes in the roots. Intriguingly, ANAC032 upregulated MYB30 and its target genes. The upregulation of MYB30 target genes was completely abolished in the ANAC032-VP16x2 OX and ANAC032 estradiol-inducible line in myb30-2 mutants. Moreover, root growth inhibition was alleviated in ANAC032-OX in myb30-2 mutants. Overall, we characterised an upstream transcription factor, ANAC032, of the MYB30 transcriptional cascade which is a key regulator for root cell elongation under ROS signalling.
Abstract
Various measures in two-way contingency table analysis have been proposed to express the strength of association between row and column variables in contingency tables. Tomizawa et al. ...(2004) proposed more general measures, including Cramér’s coefficient, using the power-divergence. In this paper, we propose measures using the
f
-divergence that has a wider class than the power-divergence. Unlike statistical hypothesis tests, these measures provide quantification of the association structure in contingency tables. The contribution of our study is proving that a measure applying a function that satisfies the condition of the
f
-divergence has desirable properties for measuring the strength of association in contingency tables. With this contribution, we can easily construct a new measure using a divergence that has essential properties for the analyst. For example, we conducted numerical experiments with a measure applying the
$$\theta$$
θ
-divergence. Furthermore, we can give further interpretation of the association between the row and column variables in the contingency table, which could not be obtained with the conventional one. We also show a relationship between our proposed measures and the correlation coefficient in a bivariate normal distribution of latent variables in the contingency tables.
In the analysis of two-way contingency tables, the degree of departure from independence is measured using measures of association between row and column variables (e.g., Yule’s coefficients of ...association and of colligation, Cramér’s coefficient, and Goodman and Kruskal’s coefficient). On the other hand, in the analysis of square contingency tables with the same row and column classifications, we are interested in measuring the degree of departure from symmetry rather than independence. Over past years, many studies have proposed various types of indexes based on their power divergence (or diversity index) to represent the degree of departure from symmetry. This study proposes a two-dimensional index to measure the degree of departure from symmetry in terms of the log odds of each symmetric cell with respect to the main diagonal of the table. By measuring the degree of departure from symmetry in terms of the log odds of each symmetric cell, the analysis results are easier to interpret than existing indexes. Numerical experiments show the utility of the proposed two-dimensional index. We show the usefulness of the proposed two-dimensional index by using real data.
In contingency table analysis, one is interested in testing whether a model of interest (e.g., the independent or symmetry model) holds using goodness-of-fit tests. When the null hypothesis where the ...model is true is rejected, the interest turns to the degree to which the probability structure of the contingency table deviates from the model. Many indexes have been studied to measure the degree of the departure, such as the Yule coefficient and Cramér coefficient for the independence model, and Tomizawa’s symmetry index for the symmetry model. The inference of these indexes is performed using sample proportions, which are estimates of cell probabilities, but it is well known that the bias and mean square error (MSE) values become large without a sufficient number of samples. To address the problem, this study proposes a new estimator for indexes using Bayesian estimators of cell probabilities. Assuming the Dirichlet distribution for the prior of cell probabilities, we asymptotically evaluate the value of MSE, when plugging the posterior means of cell probabilities into the index, and propose an estimator of the index using the Dirichlet hyperparameter that minimizes the value. Numerical experiments show that when the number of samples per cell is small, the proposed method has smaller values of bias and MSE than other methods of correcting estimation accuracy. We also show that the values of bias and MSE are smaller than those obtained by using the uniform and Jeffreys priors.
Expression of human protein kinase C delta (PKCδ) protein has been linked to many types of cancers. PKCδ is known to be a multifunctional PKC family member and has been rigorously studied as an ...intracellular signaling molecule. Here we show that PKCδ is a secretory protein that regulates cell growth of liver cancer. Full-length PKCδ was secreted to the extracellular space in living liver cancer cells under normal cell culture conditions and in xenograft mouse models. Patients with liver cancer showed higher levels of serum PKCδ than patients with chronic hepatitis or liver cirrhosis or healthy individuals. In liver cancer cells, PKCδ secretion was executed in an endoplasmic reticulum (ER)-Golgi-independent manner, and the inactivation status of cytosolic PKCδ was required for its secretion. Furthermore, colocalization studies showed that extracellular PKCδ was anchored on the cell surface of liver cancer cells via association with glypican 3, a liver cancer-related heparan sulfate proteoglycan. Addition of exogenous PKCδ activated IGF-1 receptor (IGF1R) activation and subsequently enhanced activation of ERK1/2, which led to accelerated cell growth in liver cancer cells. Conversely, treatment with anti-PKCδ antibody attenuated activation of both IGF1R and ERK1/2 and reduced cell proliferation and spheroid formation of liver cancer cells and tumor growth in xenograft mouse models. This study demonstrates the presence of PKCδ at the extracellular space and the function of PKCδ as a growth factor and provides a rationale for the extracellular PKCδ-targeting therapy of liver cancer. SIGNIFICANCE: PKCδ secretion from liver cancer cells behaves as a humoral growth factor that contributes to cell growth via activation of proliferative signaling molecules, which may be potential diagnostic or therapeutic targets.
Objective Several studies have shown an increased risk of bullous pemphigoid (BP) when receiving dipeptidyl pepitidase-4 inhibitor (DPP-4i) treatment. The present study explored the associations of ...DPP-4i treatment with the clinical phenotypes and clinical course of BP. Methods We analyzed data of 146 patients with BP at Tokai University School of Medicine from December 1, 2009, to December 31, 2021. We obtained data by a retrospective medical record review and compared the bullous pemphigoid disease area index (BPDAI) between diabetes patients receiving DPP-4i treatment and those not receiving DPP-4i treatment. We employed multivariable linear regression models to explore the association between the DPP-4i treatment and the BPDAI scores. Results Among 53 BP patients with diabetes, 33 had developed BP during treatment with DPP-4i agents, among which vildagliptin was the most frequently used. The urticaria/erythema scores of the BPDAI were significantly lower in patients who developed BP while receiving DPP-4i treatment than among others. Of note, 69.2% of the patients who stopped DPP-4i treatment experienced complete remission, and the clinical course was more favorable in patients with lower scores for urticaria/erythema than among others. Conclusion These findings suggest that, in patients who developed BP while receiving DPP-4i treatment, a noninflammatory phenotype may indicate a high likelihood that DPP-4i treatment contributes to the development of BP. The discontinuation of DPP-4i should be carefully considered in close consultation with dermatologists.
Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits ...associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were used in the discovery phase (Stage I); two datasets from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center 2 (HERPACC2) study were used in the replication phases (Stages II and III) and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel false discovery rate (FDR) = 0.011, 0.230 and 7.2 × 10-7, respectively. The single variant-based GWAS revealed that nine PSCA single nucleotide polymorphisms (SNPs) fulfilled the genome-wide significance level (P < 5 × 10-8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31 × 10-27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans.
α-Alkylation of ketones was successfully achieved by the reaction of ketones with alcohols catalyzed by iridium complexes in the presence of a small amount of base. For example, 2-octanone was ...allowed to react with butanol under the influence of Ir(cod)Cl2/PPh3/KOH to give 6-dodecanone in good yield. The reaction was found to proceed by using a 1:1 mixture of ketone and alcohol without use of any solvent.
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