Ability of a novel shock index that incorporates invasive hemodynamics to predict mortality in patients with ST-elevation myocardial infarction.

OBJECTIVE: To determine whether the use of invasively measured hemodynamics improves the prognostic ability of a shock index (SI). BACKGROUND: SI such as Admission-SI, Age-SI, Modified SI (MSI), and Age-MSI predict short-term mortality in ST-elevation myocardial infarction (STEMI). METHODS: Single-center study of 510 patients who underwent primary percutaneous coronary intervention. STEMI SI was defined as age × heart rate (HR) divided by coronary perfusion pressure (CPP). RESULTS: The mean age was 62 ± 14 years, 66% were males with hypertension (69%), tobacco use (38%), diabetes (28%) and chronic kidney disease (6%). The mean HR, systolic blood pressure (SBP), and CPP were 81 ± 18 bpm, 124 ± 28 mmHg, and 52.8 ± 16.3 mmHg, respectively. Patients with STEMI SI ≥182 (n = 51) were more likely to experience a cardiac arrest in the catheterization laboratory (9.8% vs. 2.0%; p = .001), require mechanical circulatory support (47.1% vs. 8.5%; p < .0001) and be treated with vasopressors (56.9% vs. 10.7%; p < .0001) compared to STEMI SI < 182 (n = 459). After multivariate adjustment, patients with STEMI SI ≥182 were 10, 10.1 and 4.8 times more likely to die during hospitalization, at 30 days and at 5 years, respectively. The C statistic of STEMI SI was 0.870, similar to GRACE score (AUC = 0.902; p = .29) and TIMI STEMI score (AUC = 0.895; p = .36). CONCLUSION: STEMI SI is an easy to calculate risk score that identifies STEMI patients at high risk of in-hospital death.

Relationships between airflow obstruction and quantitative CT measurements of emphysema, air trapping, and airways in subjects with and without chronic obstructive pulmonary disease.

OBJECTIVE: This study evaluates the relationships between quantitative CT (QCT) and spirometric measurements of disease severity in cigarette smokers with and without chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Inspiratory and expiratory CT scans of 4062 subjects in the Genetic Epidemiology of COPD (COPDGene) Study were evaluated. Measures examined included emphysema, defined as the percentage of low-attenuation areas≤-950 HU on inspiratory CT, which we refer to as "LAA-950I"; air trapping, defined as the percentage of low-attenuation areas≤-856 HU on expiratory CT, which we refer to as "LAA-856E"; and the inner diameter, inner and outer areas, wall area, airway wall thickness, and square root of the wall area of a hypothetical airway of 10-mm internal perimeter of segmental and subsegmental airways. Correlations were determined between spirometry and several QCT measures using statistics software (SAS, version 9.2). RESULTS: QCT measurements of low-attenuation areas correlate strongly and significantly (p<0.0001) with spirometry. The correlation between LAA-856E and forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) (r=-0.77 and -0.84, respectively) is stronger than the correlation between LAA-950I and FEV1 and FEV1/FVC (r=-0.67 and r=-0.76). Inspiratory and expiratory volume changes decreased with increasing disease severity, as measured by the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) staging system (p<0.0001). When airway variables were included with low-attenuation area measures in a multiple regression model, the model accounted for a statistically greater proportion of variation in FEV1 and FEV1/FVC (R2=0.72 and 0.77, respectively). Airway measurements alone are less correlated with spirometric measures of FEV1 (r=0.15 to -0.44) and FEV1/FVC (r=0.19 to -0.34). CONCLUSION: QCT measurements are strongly associated with spirometric results showing impairment in smokers. LAA-856E strongly correlates with physiologic measurements of airway obstruction. Airway measurements can be used concurrently with QCT measures of low-attenuation areas to accurately predict lung function.

The characterization of twenty sequenced human genomes.

We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.

IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C.

UNLABELLED: Genetic variation in the IL28B (interleukin 28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC) who were treated with peginterferon-α and ribavirin. We hypothesized that IL28B polymorphism is associated with intrahepatic expression of interferon-stimulated genes (ISGs), known to influence treatment outcome. IL28B genotyping (rs12979860) and whole-genome RNA expression were performed using liver biopsies from 61 North American patients with CHC. After correction for multiple testing (false discovery rate < 0.10), 164 transcripts were found to be differentially expressed by IL28B-type. The interferon signaling pathway was the most enriched canonical pathway differentially expressed by IL28B-type (P < 10(-5)), with most genes showing higher expression in livers of individuals carrying the poor-response IL28B-type. In 25 patients for which treatment response data were available, IL28B-type was associated with SVR (P = 0.0054). ISG expression was also associated with SVR; however, this was not independent of IL28B-type. Analysis of miR-122 expression in liver biopsies showed reduced miR-122 levels associated with poorer treatment outcome, independently of IL28B-type. No association was observed between IL28B-type and levels of liver IL28B or IL28A messenger RNA expression. IL28B protein sequence variants associated with rs12979860 were therefore investigated in vitro: no differences in ISG induction or inhibition of HCV replication were observed in Huh7.5 cells. CONCLUSION: The good response IL28B variant was strongly associated with lower level ISG expression. The results suggest that IL28B genotype may explain the relationship between hepatic ISG expression and HCV treatment outcome, and this is independent of miR-122 expression. IL28B-type was not associated with intrahepatic IL28B messenger RNA expression in vivo. Further investigation of the precise molecular mechanism(s) by which IL28B genetic variation influences HCV outcomes is warranted.

cGMP modulates responses to queen mandibular pheromone in worker honey bees.

Responses to social cues, such as pheromones, can be modified by genotype, physiology, or environmental context. Honey bee queens produce a pheromone (queen mandibular pheromone; QMP) which regulates aspects of worker bee behavior and physiology. Forager bees are less responsive to QMP than young bees engaged in brood care, suggesting that physiological changes associated with behavioral maturation modulate response to this pheromone. Since 3',5'-cyclic guanosine monophosphate (cGMP) is a major regulator of behavioral maturation in workers, we examined its role in modulating worker responses to QMP. Treatment with a cGMP analog resulted in significant reductions in both behavioral and physiological responses to QMP in young caged workers. Treatment significantly reduced attraction to QMP and inhibited the QMP-mediated increase in vitellogenin RNA levels in the fat bodies of worker bees. Genome-wide analysis of brain gene expression patterns demonstrated that cGMP has a larger effect on expression levels than QMP, and that QMP has specific effects in the presence of cGMP, suggesting that some responses to QMP may be dependent on an individual bees' physiological state. Our data suggest that cGMP-mediated processes play a role in modulating responses to QMP in honey bees at the behavioral, physiological, and molecular levels.

Usefulness of a Novel Risk Score to Predict In-Hospital Mortality in Patients ≥ 60 Years of Age with ST Elevation Myocardial Infarction.

Numerous algorithms are available to predict short-term mortality in ST elevation myocardial infarction (STEMI) but none are focused on elderly patients or include invasive hemodynamics. A simplified risk score (LASH score) including left ventricular end diastolic pressure > 20 mm Hg, age > 75 years, systolic blood pressure < 100 mm Hg and heart rate > 100 bpm was tested in a retrospective, single-center study of 346 patients ≥ 60 years old who underwent primary percutaneous coronary intervention (PPCI). The median age was 70 years [IQR: 64, 79], 60.1% were men, and 77.8% identified as White. In-hospital all-cause mortality was 10.1%. Patients with a LASH score ≥ 3 (n = 34) had an in-hospital mortality rate of 44.1% compared to 6.4% for LASH score ≤ 2 (p < 0.0001). The odds ratio for in-hospital mortality for patients with LASH score ≥ 3 was 13.2 (95% CI 5.3-33.1) compared to patients with a LASH score ≤ 2 when adjusted for sex, cardiac arrest, heart failure, and prior cerebrovascular event. The LASH score had an area under the ROC curve for predicting in-hospital mortality of 0.795 [CI 0.716-0.872], as compared to TIMI-STEMI (0.881, CI 0.829-0.931; p = 0.01), GRACE (0.849, CI 0.778-0.920; p = 0.19), shock index (0.769, CI 0.667-0.871; p = 0.51) and modified shock index (0.765, CI 0.716-0.873; p = 0.48). In summary, a simplified, easy to calculate risk score that incorporates age and invasive hemodynamics predicts in-hospital mortality in patients ≥ 60 years old undergoing PPCI for STEMI.

Visual Assessment of CT Findings in Smokers With Nonobstructed Spirometric Abnormalities in The COPDGene® Study.

Within the COPD Genetic Epidemiology (COPDGene®) study population of cigarette smokers, 9% were found to be unclassifiable by the Global Initiative for chronic Obstructive Lung Disease (GOLD) criteria. This study was to identify the differences in computed tomography (CT) findings between this nonobstructed (GOLDU) group and a control group of smokers with normal lung function. This research was approved by the institutional review board of each institution. CT images of 400 participants in the COPDGene® study (200 GOLDU, 200 smokers with normal lung function) were retrospectively evaluated in a blinded fashion. Visual CT assessment included lobar analysis of emphysema (type, extent), presence of paraseptal emphysema, airway wall thickening, expiratory air trapping, centrilobular nodules, atelectasis, non-fibrotic and fibrotic interstitial lung disease (ILD), pleural thickening, diaphragmatic eventration, vertebral body changes and internal thoracic diameters (in mm). Univariate comparisons of groups for each CT parameter and multiple logistic regression were performed to determine the imaging features associated with GOLDU. When compared with the control group, GOLDU participants had a significantly higher prevalence of unilateral diaphragm eventration (30% vs. 16%), airway wall thickening, centrilobular nodules, reticular abnormality, paraseptal emphysema (33% vs. 17%), linear atelectasis (60% vs. 35.6%), kyphosis (12% vs. 4%), and a smaller internal transverse thoracic diameter (255 ± 22.5 [standard deviation] vs. 264.8 ± 22.4, mm) (all p<0.05). With multiple logistic regression, all of these CT parameters, except non-fibrotic ILD and kyphosis, remained significantly associated with GOLDU status (p<0.05). In cigarette smokers, chest wall abnormalities and parenchymal lung disease, which contribute to restrictive physiologic impairment, are associated with GOLD-nonobstructed status.