Hepatitis E virus RNA-dependent RNA polymerase is involved in RNA replication and infectious particle production.

Hepatitis E virus (HEV) is one of the most common causes of acute hepatitis worldwide. Its positive-strand RNA genome encodes three open reading frames (ORF). ORF1 is translated into a large protein composed of multiple domains and is known as the viral replicase. The RNA-dependent RNA polymerase (RDRP) domain is responsible for the synthesis of viral RNA. Here, we identified a highly conserved α-helix located in the RDRP thumb subdomain. Nuclear magnetic resonance demonstrated an amphipathic α-helix extending from amino acids 1628 to 1644 of the ORF1 protein. Functional analyses revealed a dual role of this helix in HEV RNA replication and virus production, including assembly and release. Mutations on the hydrophobic side of the amphipathic α-helix impaired RNA replication and resulted in the selection of a second-site compensatory change in the RDRP palm subdomain. Other mutations enhanced RNA replication but impaired virus assembly and/or release. Structure-function analyses identified a conserved amphipathic α-helix in the thumb subdomain of the HEV RDRP with a dual role in viral RNA replication and infectious particle production. This study provides structural insights into a key segment of the ORF1 protein and describes the successful use of reverse genetics in HEV, revealing functional interactions between the RDRP thumb and palm subdomains. On a broader scale, it demonstrates that the HEV replicase, similar to those of other positive-strand RNA viruses, is also involved in virus production

The decompression of the outer neutron star crust and r-process nucleosynthesis

The rapid neutron-capture process, or r-process, is known to be fundamental for explaining the origin of approximately half of the A>60 stable nuclei observed in nature. In recent years nuclear astrophysicists have developed more and more sophisticated r-process models, by adding new astrophysical or nuclear physics ingredients to explain the solar system composition in a satisfactory way. Despite these efforts, the astrophysical site of the r-process remains unidentified. The composition of the neutron star outer crust material is investigated after the decompression that follows its possible ejection. The composition of the outer crust of a neutron star is estimated before and after decompression. Two different possible initial conditions are considered, namely an idealized crust composed of cold catalyzed matter and a crust initially in nuclear statistical equilibrium at temperatures around 10 GK. We show that in this second case before decompression and at temperatures typically corresponding to 8 GK, the Coulomb effect due to the high densities in the crust leads to an overall composition of the outer crust in neutron-rich nuclei with a mass distribution close to the solar system r-abundance distribution. Such distributions differ, however, from the solar one due to a systematic shift in the second peak to lower values. After decompression, the capture of the few neutrons per seed nucleus available in the hot outer crust leads to a final distribution of stable neutron-rich nuclei with a mass distribution of 80 < A < 140 nuclei in excellent agreement with the solar distribution, provided the outer crust is initially at temperatures around 8 GK and all layers of the outer crust are ejected. The decompression of the neutron star matter from the outer crust provides suitable conditions for a robust r-processing of the light species, i.e., r-nuclei with A < 140.Comment: 11 pages, 16 figures; Accepted in A&A main Journa

Cardiac outcomes after pregnancy in women with congenital heart disease

Objective: Women with congenital heart disease (CHD) are at risk for adverse cardiac events during pregnancy; however, the risk of events late after pregnancy (late cardiac events; LCE) has not been well studied. A study was undertaken to examine the frequency and determinants of LCE in a large cohort of women with CHD. Design: Baseline characteristics and pregnancy were prospectively recorded. LCE (\u3e6 months after delivery) were determined by chart review. Survival analysis was used to determine the risk factors for LCE. Setting: A tertiary care referral hospital. Patients: The outcomes of 405 pregnancies were studied (318 women; median follow-up 2.6 years). Main outcome measures: LCE included cardiac death/ arrest, pulmonary oedema, arrhythmia or stroke. Results: LCE occurred after 12% (50/405) of pregnancies. The 5-year rate of LCE was higher in women with adverse cardiac events during pregnancy than in those without (27±9% vs 15±3%, HR 2.2, p=0.02). Women at highest risk for LCE were those with functional limitations/cyanosis (HR 3.9, 95% CI 1.2 to 13.0), subaortic ventricular dysfunction (HR 3.0, 95% CI 1.4 to 6.6), subpulmonary ventricular dysfunction and/or significant pulmonary regurgitation (HR 3.2, 95% CI 1.6 to 6.6), left heart obstruction (HR 2.6, 95% CI 1.2 to 5.2) and cardiac events before or during pregnancy (HR 2.6, 95% CI 1.3 to 4.9). In women with 0, 1 or \u3e1 risk predictors the 5-year rate of LCE was 762%, 2365% and 44610%, respectively (p\u3c0.001). Conclusions: In women with CHD, pre-pregnancy maternal characteristics can help to identify women at increased risk for LCE. Adverse cardiac events during pregnancy are important and are associated with an increased risk of LCE

Self-efficacy as a predictor of patient-reported outcomes in adults with congenital heart disease

OBJECTIVE: Self-efficacy is a known predictor of patient-reported outcomes in individuals with acquired diseases. With an overall objective of better understanding patient-reported outcomes in adults with congenital heart disease, this study aimed to: (i) assess self-efficacy in adults with congenital heart disease, (ii) explore potential demographic and medical correlates of self-efficacy and (iii) determine whether self-efficacy explains additional variance in patient-reported outcomes above and beyond known predictors. METHODS: As part of a large cross-sectional international multi-site study (APPROACH-IS), we enrolled 454 adults (median age 32 years, range: 18-81) with congenital heart disease in two tertiary care centres in Canada and Switzerland. Self-efficacy was measured using the General Self-Efficacy (GSE) scale, which produces a total score ranging from 10 to 40. Variance in the following patient-reported outcomes was assessed: perceived health status, psychological functioning, health behaviours and quality of life. Hierarchical multivariable linear regression analysis was performed. RESULTS: Patients' mean GSE score was 30.1 ± 3.3 (range: 10-40). Lower GSE was associated with female sex ( p = 0.025), not having a job ( p = 0.001) and poorer functional class ( p = 0.048). GSE positively predicted health status and quality of life, and negatively predicted symptoms of anxiety and depression, with an additional explained variance up to 13.6%. No associations between self-efficacy and health behaviours were found. CONCLUSIONS: GSE adds considerably to our understanding of patient-reported outcomes in adults with congenital heart disease. Given that self-efficacy is a modifiable psychosocial factor, it may be an important focus for interventions targeting congenital heart disease patients' well-being

Mass Ejection by Strange Star Mergers and Observational Implications

We determine the Galactic production rate of strangelets as a canonical input to calculations of the measurable cosmic ray flux of strangelets by performing simulations of strange star mergers and combining the results with recent estimates of stellar binary populations. We find that the flux depends sensitively on the bag constant of the MIT bag model of QCD and disappears for high values of the bag constant and thus more compact strange stars. In the latter case strange stars could coexist with ordinary neutron stars as they are not converted by the capture of cosmic ray strangelets. An unambiguous detection of an ordinary neutron star would then not rule out the strange matter hypothesis.Comment: 5 pages, 2 eps figures; referee comments included, accepted by Phys. Rev. Let

Cardiac outcomes in adults with supravalvar aortic stenosis

Aims Supravalvar aortic stenosis is a rare form of left ventricular outflow tract obstruction that is often progressive in childhood. Little data are available on outcomes in the adult population. Our aim was to define cardiac outcomes in adults with supravalvar aortic stenosis. Methods and results This is a multicentre retrospective study of cardiac outcomes in adults (≥18 years) with supravalvar aortic stenosis. We examined: (i) adverse cardiac events (cardiovascular death, myocardial infarction, stroke, heart failure, sustained arrhythmias, and infective endocarditis) and (ii) the need for cardiac surgery in adulthood. One hundred and thirteen adults (median age at first visit 19 years; 55% with Williams-Beuren syndrome; 67% with surgical repair in childhood) were identified. Adults without Williams-Beuren syndrome had more severe supravalvar aortic stenosis and more often associated left ventricular outflow tract obstructions (P < 0.001). In contrast, mitral valve regurgitation was more common in patients with Williams-Beuren syndrome. Eighty-five per cent of adults (96/113) had serial follow-up information (median follow-up 6.0 years). Of these patients, 13% (12/96) had an adverse cardiac event and 13% (12/96) had cardiac operations (7 valve repair or replacements, 4 supravalvar aortic stenosis repairs, 1 other). Cardiac surgery was more common in adults without Williams-Beuren syndrome (P = 0.007). Progression of supravalvar aortic stenosis during adulthood was rare. Conclusion Adults with supravalvar aortic stenosis remain at risk for cardiac complications and reoperations, while progression of supravalvar aortic stenosis in adulthood is rare. Valve surgery is the most common indication for cardiac surgery in adulthoo

Strangeness in Astrophysics and Cosmology

Some recent developments concerning the role of strange quark matter for astrophysical systems and the QCD phase transition in the early universe are addressed. Causality constraints of the soft nuclear equation of state as extracted from subthreshold kaon production in heavy-ion collisions are used to derive an upper mass limit for compact stars. The interplay between the viscosity of strange quark matter and the gravitational wave emission from rotation-powered pulsars are outlined. The flux of strange quark matter nuggets in cosmic rays is put in perspective with a detailed numerical investigation of the merger of two strange stars. Finally, we discuss a novel scenario for the QCD phase transition in the early universe, which allows for a small inflationary period due to a pronounced first order phase transition at large baryochemical potential.Comment: 8 pages, invited talk given at the International Conference on Strangeness in Quark Matter (SQM2009), Buzios, Brasil, September 28 - October 2, 200

Temperate Prophages Increase Bacterial Adhesin Expression and Virulence in an Experimental Model of Endocarditis Due to Staphylococcus aureus From the CC398 Lineage.

Until 2007, Staphylococcus aureus from clonal complex 398 (CC398) was exclusively associated with livestock species and companion animals. Recently, several studies described the emergence of S. aureus CC398 as etiologies of severe infections in humans living in an animal-free environment. Recent sequencing efforts showed that the mobile genetic elements found in CC398 isolates were specific for each population and enabled differentiation of strains responsible for asymptomatic colonization from strains involved in bloodstream infections. We mobilized prophages from a human CC398 isolate and introduced them into two naïve ancestral isolates devoid of prophages that exclusively colonize animals. These lysogenized ancestral CC398 isolates acquired features related to virulence, such as an increased capacity to adhere to human extracellular matrix proteins and the ability to invade and survive within non-phagocytic cells. Pathogenicity of several clinical isolates from the CC398 lineage as well as ancestral and in vitro lysogenized ancestral counterparts was assessed in a model of infectious endocarditis in rats. Natural and artificial lysogens were not only more invasive than their prophage-free parent but also showed an increased capacity to multiply within aortic vegetations. This study identified prophages as mediators of bacterial virulence in a model of infectious endocarditis, probably through promotion of interaction with extracellular matrix components. Further studies are needed to identify mechanisms leading to promotion of intrinsic virulence

Identification of patients at risk of sudden cardiac death in congenital heart disease:The PRospEctiVE study on implaNTable cardlOverter defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease (PREVENTION-ACHD)

BACKGROUND Sudden cardiac death (SCD) is the main preventable cause of death in patients with adult congenital heart disease (ACHD). Since robust risk stratification methods are lacking, we developed a risk score model to predict SCD in patients with ACHD: the PRospEctiVE study on implaNTable cardlOverter defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease (PREVENTION-ACHD) risk score model. OBJECTIVE The purpose of this study was to prospectively study predicted SCD risk using the PREVENTION-ACHD risk score model and actual SCD and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) rates in patients with ACHD. METHODS The PREVENTION-ACHD risk score model assigns 1 point each to coronary artery disease, New York Heart Association class II/III heart failure, supraventricular tachycardia, systemic ejection fraction = 120 ms, and QT dispersion >= 70 ms. SCD risk was calculated for each patient. An annual predicted risk of >= 3% constituted high risk. The primary outcome was SCD or VT/VF after 2 years. The secondary outcome was SCD. RESULTS The study included 783 consecutive patients with ACHD (n=239 (31%) left-sided lesions; n=138 (18%) tetralogy of Fallot; n=108 (14%) dosed atrial septal defect; median age 36 years; interquartile range 28-47 years; n=401 (51%) men). The PREVENTION-ACHD risk score modelidentified 58 high-risk patients. Eight patients (4 at high risk) experienced the primary outcome. The Kaplan-Meier estimates were 7% (95% confidence interval [CI] 0.1%-13.3%) in the high-risk group and 0.6% (95% CI 0.0%-1.1%) in the low-risk group (hazard ratio 12.5; 95% CI 3.1-50.9; P < .001). The risk score model's sensitivity was 0.5 and specificity 93, resulting in a C-statistic of 0.75 (95% CI 0.57-0.90). The hazard ratio for SCD was 12.4 (95% CI 1.8-88.1) (P = .01); the sensitivity and specificity were 0.5 and 0.92, and the C-statistic was 0.81 (95% CI 0.67-0.95). CONCLUSION The PREVENTION-ACHD risk score model provides greater accuracy in SCD or VT/VF risk stratification as compared with current guideline indications and identifies patients with ACHD who may benefit from preventive implantable cardioverterdefibrillator implantation