All-oral combinations of direct-acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin-based regimens. In this open-label, phase 3 study, 135 interferon-ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary endpoint was sustained virologic response 24 weeks after treatment (SVR24). This study is registered with http://ClinicalTrials.gov (NCT01497834). SVR24 was achieved by 87.4% of interferon-ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhosis (90.9%) and noncirrhosis (84.0%) patients, and in patients with IL28B CC (84.5%) or non-CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol-defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), headache, diarrhea, and pyrexia. Conclusion: Interferon-free, ribavirin-free all-oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon-based therapy. (Hepatology 2014;59:2083–2091)

There is a Blood Commentary on this article in this issue.

Background-Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. Methods and Results-We profiled platelet mRNA from patients with acute ST-segment-elevation myocardial infarction (STEMI, nϭ16) or stable coronary artery disease (nϭ44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated 1 candidate gene product by performing a prospective, nested case-control study (nϭ255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, PϽ0.001) and myeloid-related protein-14 (MRP-14; odds ratio 3.3, Pϭ0.002). Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (17.0 versus 8.0 g/mL, PϽ0.001). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (P trend Ͻ0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (PϽ0.001).Risks were independent of standard risk factors and C-reactive protein. Conclusions-The

Our results suggest that transcriptional profiling has the potential to identify a gene expression pattern in breast cancer that may lead to clinically useful predictors of pCR to T/FAC neoadjuvant therapy.

An epidemic rise in asthma has occurred concurrently with a rise in overweight among United States children, but it is unclear whether body weight affects the risk of incident childhood asthma. We studied the prospective relation of body-mass index (BMI) to incident asthma in a longitudinal study of 9,828 children aged 6-14 years, examined annually over a median follow-up time of 5 years in six US cities. An increased risk of a new asthma diagnosis in girls was associated with higher BMI at entry into the study (P=0.009) and greater increase in BMI during follow-up (P=0.0003). Compared with girls in the leanest quintile of BMI at entry (age taken into account), girls in the top quintile of adiposity had 2.2 times greater risk of incident asthma with any wheeze in subsequent years. Girls with the largest annual rate of increase in BMI (top compared to bottom quintile, age taken into account) had 1.5 times the risk of asthma with any wheeze, and 2.2 times the risk of asthma with persistent wheeze. Boys with the largest and smallest annual changes in BMI also had an increased risk of asthma. For girls, overweight contributes to development of asthma. For boys and girls, extremes of annual BMI growth rates increase the risk of asthma.

We examined the respiratory health effects of exposure to acidic air pollution among 13,369 white children 8 to 12 years old from 24 communities in the United States and Canada between 1988 and 1991. Each child's parent or guardian completed a questionnaire. Air quality and meteorology were measured in each community for a 1-year period. We used a two-stage logistic regression model to analyze the data, adjusting for the potential confounding effects of sex, history of allergies, parental asthma, parental education, and current smoking in the home. Children living in the community with the highest levels of particle strong acidity were significantly more likely [odds ratio (OR) = 1.66; 95% confidence interval (CI) 1.11-2.48] to report at least one episode of bronchitis in the past year compared to children living in the least-polluted community. Fine particulate sulfate was also associated with higher reporting of bronchitis (OR = 1.65; 95% CI 1.12-2.42). No other respiratory symptoms were significantly higher in association with any of the air pollutants of interest. No sensitive subgroups were identified. Reported bronchitis, but neither asthma, wheeze, cough, nor phlegm, were associated with levels of particle strong acidity for these children living in a nonurban environment. Images Figure 1. Figure 2. Figure 3.

Purpose: Women with advanced epithelial ovarian cancer are routinely treated with platinum-paclitaxel chemotherapy following cytoreductive surgery, yet only f20% achieve long-term disease-free survival. We hypothesized that differences in gene expression before treatment could distinguish patients with short versus long time to recurrence after administration of platinum-paclitaxel combination chemotherapy.Experimental Design: To test this hypothesis, gene expression profiling of 79 primary surgically resected tumors from women with advanced-stage, high-grade epithelial ovarian cancer was done using cDNA microarrays containing 30,721 genes. Supervised learning algorithms were applied in an effort to develop a binary classifier that could discriminate women at risk for early (V 21 months) versus late (>21 months) relapse after initial chemotherapy.Results: A 14-gene predictive model was developed using a set of training samples (n = 51) and subsequently tested using an independent set of test samples (n = 28). This model correctly predicted the outcome of 24 of the 28 test samples (86% accuracy) with 95% positive predictive value for early relapse.Conclusions: Predictive markers for early recurrence can be identified for platinum-paclitaxel combination chemotherapy in primary ovarian carcinoma. The proposed 14-gene model requires further validation.

JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) andBrogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives.We examined the respiratory health effects of exposure to acidic air pollution among 13,369 white children 8 to 12 years old from 24 communities in the United States and Canada between 1988 and 1991. Each child's parent or guardian completed a questionnaire. Air quality and meteorology were measured in each community for a 1-year period. We used a two-stage logistic regression model to analyze the data, adjusting for the potential confoulnding effects of sex, history of allergies, parental asthma, parental education, and current smoking in the home. Children living in the community with the highest levels of partice strong acidity were significanty more likely [odds ratio (OR) = 1.66; 95% confidence interval (CI) 1.11-2.48] to report at least one episode of bronchitis in the past year compared to children living in the least-polluted community. Fine particulate sulfate was also associated with higher reporting of bronchitis (OR = 1.65; 95% CI 1.12-2.42). No other respiratory symptoms were significantly higher in association with any of the air pollutants of interest. No sensitive subgroups were identified. Reported bronchitis, but neither asthma, wheeze, cough, nor phlegm, were associated with levels of partice strong acidity for these children living in a nonurban environment.