Atrial Fibrillation Management Strategies in Routine Clinical Practice: Insights from the International RealiseAF Survey

Background

Atrial fibrillation (AF) can be managed with rhythm- or rate-control strategies. There are few data from routine clinical practice on the frequency with which each strategy is used and their correlates in terms of patients’ clinical characteristics, AF control, and symptom burden.

Methods

RealiseAF was an international, cross-sectional, observational survey of 11,198 patients with AF. The aim of this analysis was to describe patient profiles and symptoms according to the AF management strategy used. A multivariate logistic regression identified factors associated with AF management strategy at the end of the visit.

Results

Among 10,497 eligible patients, 53.7% used a rate-control strategy, compared with 34.5% who used a rhythm-control strategy. In 11.8% of patients, no clear strategy was stated. The proportion of patients with AF-related symptoms (EHRA Class > = II) was 78.1% (n = 4396/5630) for those using a rate-control strategy vs. 67.8% for those using a rhythm-control strategy (p<0.001). Multivariate logistic regression analysis revealed that age <75 years or the paroxysmal or persistent form of AF favored the choice of a rhythm-control strategy. A change in strategy was infrequent, even in patients with European Heart Rhythm Association (EHRA) Class > = II.

Conclusions

In the RealiseAF routine clinical practice survey, rate control was more commonly used than rhythm control, and a change in strategy was uncommon, even in symptomatic patients. In almost 12% of patients, no clear strategy was stated. Physician awareness regarding optimal management strategies for AF may be improved.     

Electroencephalographic Patterns in Chronic Pain: A Systematic Review of the Literature

The main objective of this study is to review and summarize recent findings on electroencephalographic patterns in individuals with chronic pain. We also discuss recent advances in the use of quantitative Electroencephalography (qEEG) for the assessment of pathophysiology and biopsychosocial factors involved in its maintenance over time. Data collection took place from February 2014 to July 2015 in PubMed, SciELO and PEDro databases. Data from cross-sectional studies and longitudinal studies, as well as clinical trials involving chronic pain participants were incorporated into the final analysis. Our primary findings related to chronic pain were an increase of theta and alpha EEG power at rest, and a decrease in the amplitude of evoked potentials after sensory stimulation and cognitive tasks. This review suggests that qEEG could be considered as a simple and objective tool for the study of brain mechanisms involved in chronic pain, as well as for identifying the specific characteristics of chronic pain condition. In addition, results show that qEEG probably is a relevant outcome measure for assessing changes in therapeutic studies.     

Effects of MDMA Injections on the Behavior of Socially-Housed Long-Tailed Macaques (Macaca fascicularis)

3,4-methylenedioxy-N-methyl amphetamine (MDMA) is one of the few known molecules to increase human and rodent prosocial behaviors. However, this effect has never been assessed on the social behavior of non-human primates. In our study, we subcutaneously injected three different doses of MDMA (1.0, 1.5 or 2.0mg/kg) to a group of three, socially housed, young male long-tailed macaques. More than 200 hours of behavioral data were recorded, during 68 behavioral sessions, by an automatic color-based video device that tracked the 3D positions of each animal and of a toy. This data was then categorized into 5 exclusive behaviors (resting, locomotion, foraging, social contact and object play). In addition, received and given social grooming was manually scored. Results show several significant dose-dependent behavioral effects. At 1.5mg/kg only, MDMA induces a significant increase in social grooming behavior, thus confirming the prosocial effect of MDMA in macaques. Additionally, at 1.5 and 2.0 mg/kg MDMA injection substantially decreases foraging behavior, which is consistent with the known anorexigenic effect of this compound. Furthermore, at 2.0 mg/kg MDMA injection induces an increase in locomotor behavior, which is also in accordance with its known stimulant property. Interestingly, MDMA injected at 1.0mg/kg increases the rate of object play, which might be interpreted as a decrease of the inhibition to manipulate a unique object in presence of others, or, as an increase of the intrinsic motivation to manipulate this object. Together, our results support the effectiveness of MDMA to study the complex neurobiology of primates’ social behaviors.     

Degree of Hybridization in Seed Stands of Pinus engelmannii Carr. In the Sierra Madre Occidental,Durango, Mexico

Hybridization is an important evolutionary force, because interspecific gene transfer can introduce more new genetic material than is directly generated by mutations. Pinus engelmannii Carr. is one of the nine most common pine species in the pine-oak forest ecoregion in the state of Durango, Mexico. This species is widely harvested for lumber and is also used in reforestation programmes. Interspecific hybrids between P.engelmannii and Pinus arizonica Engelm. have been detected by morphological analysis. The presence of hybrids in P. engelmannii seed stands may affect seed quality and reforestation success. Therefore, the goals of this research were to identify introgressive hybridization between P. engelmannii and other pine species in eight seed stands of this species in Durango, Mexico, and to examine how hybrid proportion is related to mean genetic dissimilarity between trees in these stands, using Amplified Fragment Length Polymorphism (AFLP) markers and morphological traits. Differences in the average current annual increment of putative hybrids and pure trees were also tested for statistical significance. Morphological and genetic analyses of 280 adult trees were carried out. Putative hybrids were found in all the seed stands studied. The hybrids did not differ from the pure trees in vigour or robustness. All stands with putative P. engelmannii hybrids detected by both AFLPs and morphological traits showed the highest average values of the Tanimoto distance, which indicates: i) more heterogeneous genetic material, ii) higher genetic variation and therefore iii) the higher evolutionary potential of these stands, and iv) that the morphological differentiation (hybrid/not hybrid) is strongly associated with the Tanimoto distance per stand. We conclude that natural pairwise hybrids are very common in the studied stands. Both morphological and molecular approaches are necessary to confirm the genetic identity of forest reproductive material.     

Confirmatory Factor Analysis and Differential Relationships of the Two Subdomains of Negative Symptoms in Chronically Ill Psychotic Patients

Research suggests a two factor structure for negative symptoms in patients with psychotic disorders: social amotivation (SA) and expressive deficits (ED). Applying this two-factor structure in clinical settings may provide valuable information with regard to outcomes and to target treatments. We aimed to investigate 1) whether the factor structure is also supported in chronically ill patients with a psychotic disorder and 2) what the relationship is between these factors and functioning (overall functioning and living situation), depressive symptoms and quality of life. 1157 Patients with a psychotic disorder and a duration of illness of 5 years or more were included in the analysis (data selected from the Pharmacotherapy Monitoring Outcome Survey; PHAMOUS). A confirmatory factor analysis was performed using items of the Positive and Negative Syndrome Scale that were previously identified to reflect negative symptoms (N1-4, N6, G5, G7, G13, G16). Subsequently, regression analysis was performed on outcomes. The results confirmed the distinction between SA (N2, N4, G16) and ED (N1, N3, N6, G5, G7, G13) in chronically ill patients. Both factors were related to worse overall functioning as measured with the Health of the Nation Outcome Scales, ED was uniquely associated with residential living status. Higher scores for SA were associated with more depressive symptoms and worse quality of life. Thus, SA is most strongly related to level of social-emotional functioning, while ED are more related to living situation and thereby are indicative of level of everyday functioning. This subdivision may be useful for research purposes and be a valuable additional tool in clinical practice and treatment development.     

Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project

Background

Venous thromboembolism (VTE) is a common disease where known genetic risk factors explain only a small portion of the genetic variance. Then, the analysis of intermediate phenotypes, such as thrombin generation assay, can be used to identify novel genetic risk factors that contribute to VTE.

Objectives

To investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE.

Patients/Methods

Lag time, thrombin peak and endogenous thrombin potential (ETP) were measured in the families of the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project. This sample consisted of 935 individuals in 35 extended families selected through a proband with idiopathic thrombophilia. We performed also genome wide association studies (GWAS) with thrombin generation phenotypes.

Results

The results showed that 67% of the variation in the risk of VTE is attributable to genetic factors. The heritabilities of lag time, thrombin peak and ETP were 49%, 54% and 52%, respectively. More importantly, we demonstrated also the existence of positive genetic correlations between thrombin peak or ETP and the risk of VTE. Moreover, the major genetic determinant of thrombin generation was the F2 gene. However, other suggestive signals were observed.

Conclusions

The thrombin generation phenotypes are strongly genetically determined. The thrombin peak and ETP are significantly genetically correlated with the risk of VTE. In addition, F2 was identified as a major determinant of thrombin generation. We reported suggestive signals that might increase our knowledge to explain the variability of this important phenotype. Validation and functional studies are required to confirm GWAS results.     

In silico Identification and Validation of a Linear and Naturally Immunogenic B-Cell Epitope of the Plasmodium vivax Malaria Vaccine Candidate Merozoite Surface Protein-9

Synthetic peptide vaccines provide the advantages of safety, stability and low cost. The success of this approach is highly dependent on efficient epitope identification and synthetic strategies for efficacious delivery. In malaria, the Merozoite Surface Protein-9 of Plasmodium vivax (PvMSP9) has been considered a vaccine candidate based on the evidence that specific antibodies were able to inhibit merozoite invasion and recombinant proteins were highly immunogenic in mice and humans. However the identities of linear B-cell epitopes within PvMSP9 as targets of functional antibodies remain undefined. We used several publicly-available algorithms for in silico analyses and prediction of relevant B cell epitopes within PMSP9. We show that the tandem repeat sequence EAAPENAEPVHENA (PvMSP9_E795-A808) present at the C-terminal region is a promising target for antibodies, given its high combined score to be a linear epitope and located in a putative intrinsically unstructured region of the native protein. To confirm the predictive value of the computational approach, plasma samples from 545 naturally exposed individuals were screened for IgG reactivity against the recombinant PvMSP9-RIRII_729-972 and a synthetic peptide representing the predicted B cell epitope PvMSP9_E795-A808. 316 individuals (58%) were responders to the full repetitive region PvMSP9-RIRII, of which 177 (56%) also presented total IgG reactivity against the synthetic peptide, confirming it validity as a B cell epitope. The reactivity indexes of anti-PvMSP9-RIRII and anti-PvMSP9_E795-A808 antibodies were correlated. Interestingly, a potential role in the acquisition of protective immunity was associated with the linear epitope, since the IgG1 subclass against PvMSP9_E795-A808 was the prevalent subclass and this directly correlated with time elapsed since the last malaria episode; however this was not observed in the antibody responses against the full PvMSP9-RIRII. In conclusion, our findings identified and experimentally confirmed the potential of PvMSP9_E795-A808 as an immunogenic linear B cell epitope within the P. vivax malaria vaccine candidate PvMSP9 and support its inclusion in future subunit vaccines.     

Dasatinib Reduces Lung Inflammation and Fibrosis in Acute Experimental Silicosis

Silicosis is an occupational lung disease with no effective treatment. We hypothesized that dasatinib, a tyrosine kinase inhibitor, might exhibit therapeutic efficacy in silica-induced pulmonary fibrosis. Silicosis was induced in C57BL/6 mice by a single intratracheal administration of silica particles, whereas the control group received saline. After 14 days, when the disease was already established, animals were randomly assigned to receive DMSO or dasatinib (1 mg/kg) by oral gavage, twice daily, for 14 days. On day 28, lung morphofunction, inflammation, and remodeling were investigated. RAW 264.7 cells (a macrophage cell line) were incubated with silica particles, followed by treatment or not with dasatinib, and evaluated for macrophage polarization. On day 28, dasatinib improved lung mechanics, increased M2 macrophage counts in lung parenchyma and granuloma, and was associated with reduction of fraction area of granuloma, fraction area of collapsed alveoli, protein levels of tumor necrosis factor-α, interleukin-1β, transforming growth factor-β, and reduced neutrophils, M1 macrophages, and collagen fiber content in lung tissue and granuloma in silicotic animals. Additionally, dasatinib reduced expression of iNOS and increased expression of arginase and metalloproteinase-9 in silicotic macrophages. Dasatinib was effective at inducing macrophage polarization toward the M2 phenotype and reducing lung inflammation and fibrosis, thus improving lung mechanics in a murine model of acute silicosis.