We investigated whether combining the pre-arrest serum albumin level could improve the performance of the Good Outcome Following Attempted Resuscitation (GO-FAR) score for predicting neurologic ...outcomes in in-hospital cardiac arrest patients. Adult patients who were admitted to a tertiary care hospital between 2013 and 2017 were assessed. Their pre-arrest serum albumin levels were measured within 24 h before the cardiac arrest. According to albumin levels, the patients were divided into quartiles and were assigned 1, 0, 0, and, - 2 points. Patients were allocated to the derivation (n = 419) and validation (n = 444) cohorts. The proportion of favorable outcome increased in a stepwise manner across increasing quartiles (p for trend < 0.018). Area under receiver operating characteristic curve (AUROC) of the albumin-added model was significantly higher than that of the original GO-FAR model (0.848 vs. 0.839; p = 0.033). The results were consistent in the validation cohort (AUROC 0.799 vs. 0.791; p = 0.034). Net reclassification indices of the albumin-added model were 0.059 (95% confidence interval CI - 0.037 to 0.094) and 0.072 (95% CI 0.013-0.132) in the derivation and validation cohorts, respectively. An improvement in predictive performance was found by adding the ordinal scale of pre-arrest albumin levels to the original GO-FAR score.
Chemotherapy plus trastuzumab is standard of care for HER2-positive advanced gastric cancer (AGC). However, not all patients with HER2-positive AGC seem to benefit from trastuzumab. We evaluated the ...association between treatment outcomes with trastuzumab and HER2 status in patients with HER2-positive AGC.
We enrolled 126 patients with HER2-positive AGC treated with trastuzumab plus chemotherapy in a training cohort. HER2 IHC (N = 126), HER2/CEP17 ratio (N = 66), and HER2 gene copy number (GCN; N = 59) were analyzed, and the optimal values for discriminating overall survival (OS) were determined using receiver operating characteristic (ROC) curve analysis. We validated the findings from the training cohort using an independent validation cohort (N = 72).
Patients with HER2 IHC 3+ showed significantly longer OS (29 vs. 15.3 months; P = 0.025) than patients with IHC ≤ 2+. An HER2/CEP17 ratio of 4.48 was the optimal cutoff for predicting longer OS (26.9 vs. 14.7 months; P = 0.027). In subgroup analysis, treatment outcomes of patients with IHC 3+ were not influenced by the level of HER2 gene amplification. However, in patients with IHC ≤ 2+, an HER2/CEP17 ratio more than 3.69 and HER2 GCN more than 7.75 were positive predictive factors for better outcomes with trastuzumab-based chemotherapy. These findings were confirmed in both the validation cohort and the combined cohort.
HER2 IHC status, HER2/CEP17 ratio, and HER2 GCN were correlated with clinical outcomes of trastuzumab-based treatment in HER2-positive AGC. Clinical outcomes of patients with IHC ≤ 2+ were strongly dependent on the HER2/CEP17 ratio and HER2 GCN.
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been shown to exert a synergistic antitumor effect when combined with fluoropyrimidine. This synergy may be attributable to ...the downregulation of thymidylate synthase (TS), which is frequently overexpressed in fluoropyrimidine-resistant cancer cells. However, the molecular mechanism underlying the downregulation of TS has yet to be clearly elucidated.
In this study, we demonstrate that lapatinib, a dual TKI of EGFR and HER2 downregulates TS via inhibition of the nuclear translocation of EGFR and HER2. From our cDNA microarray experiments, we determined that a variety of nucleotide synthesis-related genes, including TS, were downregulated with lapatinib, and this was apparent in HER2-amplified cells. Targeted and pharmacologic inhibition assays confirmed that the dual inhibition of EGFR and HER2 is required for the more effective reduction of TS as compared to what was observed with gefitinib or trasutuzumab alone. Additionally, we determined that co-transfected EGFR and HER2 activate the TS gene promoter more profoundly than do either EGFR or HER2 alone. The translocation of EGFR and HER2 into the nucleus and the subsequent activation of the TS promoter were inhibited by lapatinib.
These results demonstrate that lapatinib inhibits the nuclear translocation of EGFR and HER2 and downregulates TS, thus sensitizing cancer cells to fluoropyrimidine.
Although accumulating evidence suggests a more extensive reduction of low-density lipoprotein cholesterol (LDL-C), it is unclear whether a higher statin dose is more effective and cost-effective in ...the Asian population. This study compared the efficacy, safety, and cost-effectiveness of atorvastatin 20 and 10 mg in high-risk Asian patients with hypercholesterolemia.
A 12-week, open-label, parallel, multicenter, Phase IV randomized controlled trial was conducted at ten hospitals in the Republic of Korea between October 2017 and May 2019. High-risk patients with hypercholesterolemia, defined according to 2015 Korean guidelines for dyslipidemia management, were eligible to participate. We randomly assigned 250 patients at risk of atherosclerotic cardiovascular disease to receive 20 mg (n = 124) or 10 mg (n = 126) of atorvastatin. The primary endpoint was the difference in the mean percentage change in LDL-C levels from baseline after 12 weeks. Cost-effectiveness was measured as an exploratory endpoint.
LDL-C levels were reduced more significantly by atorvastatin 20 mg than by 10 mg after 12 weeks (42.4% vs. 33.5%, p < 0.0001). Significantly more patients achieved target LDL-C levels (<100 mg/dL for high-risk patients, <70 mg/dL for very high-risk patients) with atorvastatin 20 mg than with 10 mg (40.3% vs. 25.6%, p < 0.05). Apolipoprotein B decreased significantly with atorvastatin 20mg versus 10 mg (-36.2% vs. -29.9%, p < 0.05). Lipid ratios also showed greater improvement with atorvastatin 20 mg than with 10 mg (total cholesterol/high-density lipoprotein cholesterol ratio, -33.3% vs. -29.4%, p < 0.05; apolipoprotein B/apolipoprotein A1 ratio, -36.7% vs. -31.4%, p < 0.05). Atorvastatin 20 mg was more cost-effective than atorvastatin 10 mg in terms of both the average and incremental cost-effectiveness ratios. Safety and tolerability of atorvastatin 20 mg were comparable to those of atorvastatin 10 mg.
In high-risk Asian patients with hypercholesterolemia, atorvastatin 20 mg was both efficacious in reducing LDL-C and cost-effective compared with atorvastatin 10 mg.
The current early warning scores may be insufficient for medical emergency teams (METs) to use in assessing the severity and the prognosis of activated patients. We evaluated the predictive powers of ...the Modified Early Warning Score (MEWS) and the National Early Warning Score (NEWS) for 28-day mortality and to analyze predictors of 28-day mortality in general ward patients who activate the MET.
Adult general ward inpatients who activated the MET in a tertiary referral teaching hospital between March 2009 and December 2016 were included. The demographic and clinical characteristics and physiologic parameters at the time of MET activation were collected, and MEWS and NEWS were calculated.
A total of 6,729 MET activation events were analyzed. Patients who died within 28 days were younger (mean age 60 vs 62 years), were more likely to have malignancy (72% vs 53%), were more likely to be admitted to the medical department rather than the surgical department (93% vs 80%), had longer intervals from admission to MET activation (median, 7 vs 5 days), and were less likely to activate the MET during nighttime hours (5 PM to 8 AM) (61% vs 66%) compared with those who did not die within 28 days (P < 0.001 for all comparisons). The areas under the receiver operating characteristic curves of MEWS and NEWS for 28-day mortality were 0.58 (95% CI, 0.56-0.59) and 0.60 (95% CI, 0.59-0.62), which were inferior to that of the logistics regression model (0.73; 95% CI, 0.72-0.74; P < 0.001 for both comparisons).
Both the MEWS and NEWS had poor predictive powers for 28-day mortality in patients who activated the MET. A new scoring system is needed to stratify the severity and prognosis of patients who activated the MET.
Complicated intra-abdominal infection (cIAI) is infection that extends beyond the hollow viscus of origin into the peritoneal space, and is associated with either abscess formation or peritonitis. ...There are few studies that have assessed the actual costs and outcomes associated with failure of initial antibiotic therapy for cIAI. The aims of this study were to evaluate risk factors and impact on costs and outcomes of failure of initial antibiotic therapy for community-onset cIAI.
A retrospective study was performed at eleven tertiary-care hospitals. Hospitalized adults with community-onset cIAI who underwent an appropriate source control procedure between August 2008 and September 2011 were included. Failure of initial antibiotic therapy was defined as a change of antibiotics due to a lack of improvement of the clinical symptoms and signs associated with cIAI in the first week.
A total of 514 patients hospitalized for community-onset cIAI were included in the analysis. The mean age of the patients was 53.3 ± 17.6 years, 72 patients (14%) had health care-associated infection, and 48 (9%) experienced failure of initial antibiotic therapy. Failure of initial antibiotic therapy was associated with increased costs and morbidity. After adjustment for covariates, patients with unsuccessful initial therapy received an additional 2.9 days of parenteral antibiotic therapy, were hospitalized for an additional 5.3 days, and incurred $3,287 in additional inpatient charges. Independent risk factors for failure of initial antibiotic therapy were health care-associated infection, solid cancer, and APACHE II ≥13.
To improve outcomes and costs in patients with community-onset cIAI, rapid assessment of health care-associated risk factors and severity of disease, selection of an appropriate antibiotic regimen accordingly, and early infection source control should be performed.
•MC-LR was dose-dependently accumulated from 1μgL−1, threshold concentration, in the digestive glands of Pacific oyster and blue mussel.•Accumulated MC-LR concentrations in the digestive gland ...decreased during the depuration phase.•MC-LR exposure induced parallel dynamics of GSH and MDA at 10 and 20μgL−1.•Antioxidant enzyme activities (GST, CAT, SOD, GPx, and GR) showed similar, bell-shaped dynamics.•Slightly different dynamics in accumulation patterns of MC-LR and the intracellular markers were observed in both marine bivalves.
Microcystins (MCs) are a major group of potent cyanobacterial toxins found in freshwater and even brackish waterbodies. To understand the putative correlation between bioconcentration of MCs and antioxidant responses of the digestive gland of bivalves, Pacific oyster Crassostrea gigas and blue mussel Mytilus edulis were exposed to different concentrations (0.1, 1, 10 and 20μgL−1) of MC-Leucine-Arginine (LR) for seven days. MC-LR bioconcentrated in the digestive glands of both bivalves during exposure period. The levels were slightly reduced when the bivalves were exposed to seawater during depuration (7days), while approximately 0.1μgL−1 of MC-LR was observed in the 10 and 20μgL−1 exposed bivalves at the end of depuration. Intracellular malondialdehyde (MDA) and glutathione (GSH) levels were significantly elevated in the 10 and 20μgL−1 exposed bivalves at 7day, and the levels were maintained during depuration in both bivalves. Overall, significant higher levels of enzymatic activities of antioxidant defense systems such as glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) were observed in the 10 and 20μgL−1 exposed bivalves. Interestingly, most of higher levels of Pacific oyster were detected at exposure period, while blue mussel showed higher levels at depuration phase, suggesting a species-specific sensitivity upon MC-LR. These patterns were correlated with the bioconcentration patterns of MC-LR as Pacific oyster was highly accumulated by MC-LR during exposure period, but blue mussel showed prolonged high levels of MC-LR for depuration phase. Our results will be useful to understand species-specific bioconcentration of MC-LR in bivalves and their effects on intracellular oxidative status via accumulation.
High-fat and high-salt diets are risk factors for metabolic syndrome development. However, gochujang, which has a high salt content, possesses antiobesity properties in cell and animal models. We ...aimed to evaluate the effects of Sunchang traditional and modern factory produced gochujang on metabolic syndrome factors in high-fat diet (HFD)-induced obese mice. For 14 weeks, 4-week-old C57BL/6J male mice were separated into five groups and fed a normal diet (ND), a high-fat diet only (HD), a HD with salt (SALT), a HD with traditional Sunchang gochujang (TS), and HD with modern factory made Sunchang gochujang (FS). Compared to HD and SALT groups, the gochujang groups had lower body weight, blood leptin, and insulin levels with reduced Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index and improved serum and liver lipid profiles. In addition, gochujang supplemented groups exhibited a significant reduction in mRNA expression of anabolic lipid metabolism related factors;
,
, and
, and a significant increase in mRNA expression of energy expenditure-related factors;
and
. Protein expressions of
were downregulated in the gochujang fed groups. TS and FS intakes improved obesity in HFD-induced obese mice. Compared to the gochujang groups, the SALT group did not exhibit any of those benefits suggesting that the high salt content of gochujang has different effects compared with added salt alone. Our findings provide evidence that gochujang could be a functional food to attenuate metabolic syndrome.
The prognostic significance of ataxia‐telangiectasia‐mutated (ATM) expression in gastric cancer remains unclear. The functional loss of ATM gene exhibits a biologic correlation with microsatellite ...instability (MSI). In this study, we investigated the significance of ATM expression with MSI by evaluating gastric cancer patients who had underwent curative resection. ATM expression was classified into low ATM expression (−, ±, +) and high ATM expression (++, +++) using immunohistochemistry analysis. MSI status was classified as MSI‐negative (MSS, MSI‐low) and MSI‐positive (MSI‐high). Of 321 patients, 205 (63.9%) exhibited low ATM expression and 116 (36.1%) exhibited high ATM expression. Low ATM expression was more frequently identified in patients of older age, more advanced stage and with MSI‐positive tumor (p = 0.025, p = 0.001 and p = 0.014, respectively). The probability of 5‐year disease‐free survival (DFS) and overall survival (OS) was lower in low ATM expression group compared with the high ATM expression group (DFS: 62.5%, 76.4%, p = 0.017, OS: 65.9%, 78.5%, p = 0.027, respectively). According to MSI status, a subgroup of MSI‐negative and low ATM expression cases exhibited the worst prognosis for DFS and OS; this subgroup also exhibited poorer DFS according to multivariable analysis (hazard radio = 1.8, 95% confidence interval, 1.2–2.8, p = 0.010), although prognostic value of ATM expression alone did not remain in the multivariable analysis. Taken together, these findings indicate that ATM expression with MSI status is an independent factor for gastric cancer prognosis in gastric cancer patients who received curative surgery.
What's new?
ATM is a protein kinase that controls the repair of double‐stranded breaks in DNA. Defective ATM has been reported in several types of tumors. Defects in a different type of DNA‐repair, mismatch repair, have been associated with microsatellite instability (MSI). In this study, however, the authors confirmed that MSI can also be associated with defective ATM function. In addition, they found that ATM expression plus MSI status may be a useful prognostic biomarker in gastric cancer. These results may be beneficial for further studies of agents that target the DNA‐repair pathways controlled by ATM.
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