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The risk difference is an intelligible measure for comparing disease incidence in two exposure or treatment groups. Despite its convenience in interpretation, it is less prevalent in epidemiological and clinical areas where regression models are required in order to adjust for confounding. One major barrier to its popularity is that standard linear binomial or Poisson regression models can provide estimated probabilities out of the range of (0,1), resulting in possible convergence issues. For estimating adjusted risk differences, we propose a general framework covering various constraint approaches based on binomial and Poisson regression models. The proposed methods span the areas of ordinary least squares, maximum likelihood estimation, and Bayesian inference. Compared to existing approaches, our methods prevent estimates and confidence intervals of predicted probabilities from falling out of the valid range. Through extensive simulation studies, we demonstrate that the proposed methods solve the issue of having estimates or confidence limits of predicted probabilities out of (0,1), while offering performance comparable to its alternative in terms of the bias, variability, and coverage rates in point and interval estimation of the risk difference. An application study is performed using data from the Prospective Registry Evaluating Myocardial Infarction: Event and Recovery (PREMIER) study. [ABSTRACT FROM AUTHOR]

The TOPCAT database was obtained and queried for cumulative events for the primary outcome of heart failure hospitalization, aborted cardiac arrest, and death from cardiovascular causes. To be enrolled in the trial, patients needed to have symptoms of heart failure, a left ventricular ejection fraction >=45%, and either a hospitalization for heart failure within the previous 12 months or an elevated natriuretic peptide level. For example, TOPCAT evaluated the effect of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction using a composite of death from cardiovascular causes, aborted cardiac arrest, and heart failure hospitalization.1 This TOPCAT analysis demonstrated that spironolactone did not significantly reduce the time-to-first composite events. [Extracted from the article]

Smoking exerts strong dose-dependent increases in cardiovascular risk and mortality, and quitting can profoundly decrease these risks. Varenicline attenuates nicotine addiction by reducing withdrawal symptoms and cravings. A meta-analysis performed addressed whether a longer duration of varenicline is associated with better abstinence rates than shorter courses of treatment. For this meta-analysis, a literature search was performed to identify randomized controlled trials investigating the efficacy of the smoking cessation agent varenicline. The association between abstinence and duration of treatment was analyzed using fixed-effect meta-regression. Five randomized controlled trials were identified and included in this meta-analysis. A highly significant relationship (P<.001) was found between the length of exposure to varenicline and abstinence rate. Cessation rates were approximately twice as high with varenicline treatment of 24 weeks compared to 6 weeks. In conclusion, a meta-analysis of randomized controlled trials suggests that longer duration of varenicline therapy improves long-term abstinence rates. [ABSTRACT FROM AUTHOR]

Elevated plasma levels of remnant lipoproteins and small, dense low-density lipoprotein (LDL) particles increase the risk of atherosclerosis. This prospective, placebo-controlled, crossover trial evaluated the effect of atorvastatin on various lipid parameters including remnant lipoproteins and small, dense-LDL cholesterol levels. Forty-five subjects were enrolled in the study. These subjects fell into three distinct lipid patterns: atherogenic dyslipidemia, isolated hypercholesterolemia, and mixed dyslipidemia. Regardless of the baseline lipid profile, atorvastatin (10 mg q.d.) reduced levels of remnant lipoproteins by 25%, LDL-cholesterol by 27%, and the three LDL subfractions by 23%-28% (p<0.0001 for all). Combining all patients, atorvastatin did not significantly alter the overall LDL subfraction pattern; however, in the isolated hypercholesterolemia group, the proportion of LDL present as the small, dense fraction increased by 23% (p=0.01) with treatment, whereas it did not change significantly in the other two groups. Overall, atorvastatin reduced triglycerides by 18% and apolipoprotein-B100 by 23% and increased high-density lipoproteins by 6.2% (p<0.001 all). Since atorvastatin is known to reduce the risk for coronary heart disease events and these data suggest that it does not appear to alter the LDL subfraction pattern, it is unclear whether or not the latter is an important risk predictor independent of LDL-cholesterol concentrations. Increased attention should be paid to absolute concentrations of LDL subfraction cholesterol, which may be a more sensitive indicator of coronary heart disease risk than total LDL or an LDL pattern. [ABSTRACT FROM AUTHOR]

Abstract: Regulator of G protein signaling (RGS) proteins are GTPase-activating proteins that modulate neurotransmitter and G protein signaling. RGS7 and its binding partners Gα and Gβ5 are enriched in brain, but biochemical mechanisms governing RGS7/Gα/Gβ5 interactions and membrane association are poorly defined. We report that RGS7 exists as one cytosolic and three biochemically distinct membrane-bound fractions (salt-extractable, detergent-extractable, and detergent-insensitive) in brain. To define factors that determine RGS7 membrane attachment, we examined the biochemical properties of recombinant RGS7 and Gβ5 synthesized in Spodoptera frugiperda insect cells. We have found that membrane-bound but not cytosolic RGS7 is covalently modified by the fatty acid palmitate. Gβ5 is not palmitoylated. Both unmodified (cytosolic) and palmitoylated (membrane-derived) forms of RGS7, when complexed with Gβ5, are equally effective stimulators of Gαo GTPase activity, suggesting that palmitoylation does not prevent RGS7/Gαo interactions. The isolated core RGS domain of RGS7 selectively binds activated Gαi/o in brain extracts and is an effective stimulator of both Gαo and Gαi1 GTPase activities in vitro. In contrast, the RGS7/Gβ5 complex selectively interacts with Gαo only, suggesting that features outside the RGS domain and/or Gβ5 association dictate RGS7-Gα interactions. These findings define previously unrecognized biochemical properties of RGS7, including the first demonstration that RGS7 is palmitoylated. [ABSTRACT FROM AUTHOR]

Abstract: The cell bodies of ascending noradrenergic neurons in the brain are located predominantly in the locus coeruleus. An in vitro model of locus coeruleus neurons could prove to be a useful tool in the investigation of noradrenergic neural networks and their associated pathophysiologies. The CATH.a cell line demonstrates some of the properties expected of locus coeruleus neurons, and the present study investigated the neurotransmitter uptake and release properties of the CATH.a cells. It was surprising that the CATH.a cells failed to accumulate [3H]noradrenaline ([3H]NA), suggesting the lack of a functional NA transporter. RT-PCR supported this finding by demonstrating the absence of NA transporter mRNA. Treatment of CATH.a cells with various differentiating agents failed to increase the [3H]NA uptake. Endogenous NA release was studied using HPLC detection, which revealed a lack of depolarisation-induced increases in endogenous NA release. A human NA transporter-transfected CATH.a cell line was generated (termed RUNT), and a study of the [3H]NA uptake revealed that the RUNT cells displayed significant uptake that could be blocked by cocaine (10 μM). Furthermore, the uptake capacity could be dramatically increased by differentiation of the cells with dibutyryl cyclic AMP (1 mM) for 24 h. Using dibutyryl cyclic AMP-differentiated RUNT cells, high K+ concentrations (50 mM) significantly increased [3H]NA release above basal levels. [ABSTRACT FROM AUTHOR]

Abstract: Regulators of G protein signaling (RGS) proteins serve aspotent GTPase-activating proteins for the heterotrimeric G proteins αi/oand αq/11. This study describes the immunohistochemical distribution ofRGS7 throughout the adult rat brain and its cellular colocalization withGαq/11, an important G protein-coupled receptor signal transducer forphospholipase Cβ-mediated activity. In general, both RGS7 andGαq/11 displayed a heterogeneous and overlapping regional distribution.RGS7 immunoreactivity was observed in cortical layers I-VI, being most intensein the neuropil of layer I. In the hippocampal formation, RGS7immunoreactivity was concentrated in the strata oriens, strata radiatum, mossyfibers, and polymorphic cells, with faint to nondetectable immunolabelingwithin the dentate gyrus granule cells and CA1-CA3 subfield pyramidal cells.Numerous diencephalic and brainstem nuclei also displayed dense RGS7immunostaining. Dual immunofluorescence labeling studies with the twoprotein-specific antibodies indicated a cellular selectivity in thecolocalization between RGS7 and Gαq/11 within many discrete brainregions, such as the superficial cortical layer I, hilus area of thehippocampal formation, and cerebellar Golgi cells. To assess the ability ofGαq/11-mediated signaling pathways to modulate dynamically RGSexpression, primary cortical neuronal cultures were incubated with phorbol12,13-dibutyrate, a selective protein kinase C activator. A time-dependentincrease in levels of mRNA for RGS7, but not RGS4, was observed. Our resultsprovide novel information on the region- and cell-specific pattern ofdistribution of RGS7 with the transmembrane signal transducer, Gαq/11.We also describe a possible RGS7-selective neuronal feedback adaptation onGαq/11-mediated pathway function, which may play an important role insignaling specificity in the brain. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) and heart failure with reduced ejection fraction frequently coexist. The AATAC (Ablation versus Amiodarone for Treatment of persistent Atrial fibrillation in patients with Congestive heart failure and an implantable device) trial suggests that catheter ablation may benefit these patients. However, applicability to contemporary ambulatory cardiology practice is unknown., Methods and Results: Using the outpatient National Cardiovascular Data Registry ® Practice Innovation and Clinical Excellence Registry, we identified participants meeting AATAC enrollment criteria between 2013 and 2014. Treatment with medications and procedures was assessed at registry inclusion. From 164 166 patients with AF and heart failure, 8483 (7%) patients potentially met AATAC inclusion criteria. Eligible subjects, compared to AATAC trial participants, were older (mean age, 71.2±11.4 years) and had greater comorbidity (coronary artery disease 79.2%, hypertension 82.4%, and diabetes mellitus 31.8%). AF was predominantly paroxysmal (65.5%), rather than persistent/permanent (16.7%) or new onset (17.8%), whereas all patients in the AATAC trial had persistent AF. Commonly used atrioventricular-nodal blocking agents were carvedilol (71.2%), digoxin (31.9%), and metoprolol (27.1%). Rhythm control with anti-arrhythmic drugs was reported in 29.0% of AATAC eligible patients (predominantly amiodarone [24.6%]) and 9.3% had undergone catheter ablation. Patients who underwent ablation were more likely to be younger and have less comorbidities than those who did not., Conclusions: Among the contemporary ambulatory AF/heart failure with reduced ejection fraction population, treatment is predominantly rate control with few catheter ablations. Application of AATAC findings has the potential to markedly increase the use of catheter ablation in this population, although significant differences in clinical profiles might influence ablation outcomes in practice., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)