A comprehensive review of the PARTNER trial

ObjectivePercutaneous transcatheter aortic valve replacement was introduced in 2002, but its effectiveness remained to be assessed.MethodsA prospective, randomized trial (the Placement of Aortic Transcatheter Valves, or PARTNER) was designed with 2 arms: PARTNER A (n = 699) for high-risk surgical patients (Society of Thoracic Surgeons score >10%, surgeon assessed risk of mortality >15%) and PARTNER B (n = 358, patients inoperable by assessment of 2 surgeons). PARTNER A patients were divided into femoral artery access transcatheter aortic valve replacement or none (n = 207), and then randomized to open aortic valve replacement (n = 351) or device (n = 348). Inclusion criteria included valve area <0.8 cm2, gradient >40 mm Hg or peak >64 mm Hg, and survival >1 year. The end point of the study was 1-year mortality.ResultsThirty-day mortality for PARTNER A was 3.4% for transcatheter aortic valve replacement and 6.5% for aortic valve replacement; 1-year mortality was 24.2% and 26.8%, respectively (P = .001 for noninferiority). The respective prevalence of stroke was 3.8% and 2.1% (P = .2), although for all neurologic events, the difference between transcatheter aortic valve replacement and aortic valve replacement was significant (P = .04), including 4.6% for femoral artery access transcatheter aortic valve replacement versus 1.4% for open aortic valve replacement (P = .05). For PARTNER B—transcatheter aortic valve replacement versus medical treatment—30-day mortality was 5.0% versus 2.8% (P = .41), and at 1 year, mortality was 30.7% versus 50.7% (P < .001), respectively. Hospitalization cost of transcatheter aortic valve replacement for PARTNER B was $78,542, or$50,200 per year of life gained. Analysis of PARTNER A strokes showed that hazard with transcatheter aortic valve replacement peaked early, but thereafter remained constant in relation to aortic valve replacement. Two-year PARTNER A data showed paravalvular regurgitation was associated with increased mortality, even when mild (P < .001). Continued access to transapical transcatheter aortic valve replacement (n = 853) showed a mortality of 8.2% and decline in strokes to 2.0%. Of the 1801 Cleveland Clinic patients reviewed to December 2010, 214 (12%) underwent transcatheter aortic valve replacement with a mortality of 1%; in 2011, 105 underwent transcatheter aortic valve replacement: 34 transapical aortic valve replacement, with no deaths, and 71 femoral artery access aortic valve replacement with 1 death.ConclusionsThe PARTNER A and B trials showed that survival has been remarkably good, but stroke and perivalvular leakage require further device development

Glycan shifting on hepatitis C virus (HCV) E2 glycoprotein is a mechanism for escape from broadly neutralizing antibodies

Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma. Glycan shielding has been proposed to be a mechanism by which HCV masks broadly neutralizing epitopes on its viral glycoproteins. However, the role of altered glycosylation in HCV resistance to broadly neutralizing antibodies is not fully understood. Here, we have generated potent HCV neutralizing antibodies hu5B3.v3 and MRCT10.v362 that, similar to the previously described AP33 and HCV1, bind to a highly conserved linear epitope on E2. We utilize a combination of in vitro resistance selections using the cell culture infectious HCV and structural analyses to identify mechanisms of HCV resistance to hu5B3.v3 and MRCT10.v362. Ultra deep sequencing from in vitro HCV resistance selection studies identified resistance mutations at asparagine N417 (N417S, N417T and N417G) as early as 5 days post treatment. Comparison of the glycosylation status of soluble versions of the E2 glycoprotein containing the respective resistance mutations revealed a glycosylation shift from N417 to N415 in the N417S and N417T E2 proteins. The N417G E2 variant was glycosylated neither at residue 415 nor at residue 417 and remained sensitive to MRCT10.v362. Structural analyses of the E2 epitope bound to hu5B3.v3 Fab and MRCT10.v362 Fab using X-ray crystallography confirmed that residue N415 is buried within the antibody–peptide interface. Thus, in addition to previously described mutations at N415 that abrogate the β-hairpin structure of this E2 linear epitope, we identify a second escape mechanism, termed glycan shifting, that decreases the efficacy of broadly neutralizing HCV antibodies

Effectiveness of early intervention programs for parents of preterm infants: a meta-review of systematic reviews

Background: Various intervention programs exist for parents of preterm babies and some systematic reviews (SRs) have synthesised the evidence of their effectiveness. These reviews are, however, limited to specific interventions, components, or outcomes, and a comprehensive evidence base is lacking. The aim of this meta-review was to appraise and meta-synthesise the evidence from existing SRs to provide a comprehensive evidence base on the effectiveness of interventions for parents of preterm infants on parental and infant outcomes. Methods: We conducted a comprehensive search of the following databases to identify relevant SRs: Cochrane library, Web of science, EMBASE, CINAHL, British Nursing Index, PsycINFO, Medline, ScienceDirect, Scopus, IBSS, DOAJ, ERIC, EPPI-Centre, PROSPERO, WHO Library. Additional searches were conducted using authors’ institutional libraries, Google Scholar, and the reference lists of identified reviews. Identified articles were screened in two stages against an inclusion criteria with titles and abstracts screened first followed by full-text screening. Selected SRs were appraised using the AMSTAR tool. Extracted data using a predesigned tool were synthesised narratively examining the direction of impact on outcomes. Results: We found 11 SRs eligible for inclusion that synthesised a total of 343 quantitative primary studies. The average quality of the SRs was ‘medium’. Thirty four interventions were reported across the SRs with considerable heterogeneity in the structural framework and the targeted outcomes that included maternal-infant dyadic, maternal/parental, and infant outcomes. Among all interventions, Kangaroo Care (KC) showed the most frequent positive impact across outcomes (n = 19) followed by Mother Infant Transaction Program (MITP) (n = 14). Other interventions with most consistent positive impact on infant outcomes were Modified-Mother Infant Transaction Program (M-MITP) (n = 6), Infant Health and Development Program (IHDP) (n = 5) and Creating Opportunities for Parent Empowerment (COPE) (n = 5). Overall, interventions with both home and facility based components showed the most frequent positive impact across outcomes. Conclusions: Neonatal care policy and planning for preterm babies should consider the implementation of interventions with most positive impact on outcomes. The heterogeneity in interventions and outcomes calls for the development and implementation of an integrated program for parents of preterm infants with a clearly defined global set of parental and infant outcomes

Longitudinal Determinants of Consistent Condom Use by Partner Type Among Young Injection Drug Users: The Role of Personal and Partner Characteristics

We investigated the longitudinal influence of individual-, relationship- and social-level factors on condom use by partner type among young injections drug users (IDUs) enrolled in the Collaborative Injection Drug Users Study-III/Drug Users Intervention Trial (CIDUS-III/DUIT) from 2002 to 2004. Based on longitudinal analysis using generalized estimating equations (GEE), consistent condom use with main partners was more commonly reported among males and those with greater self-efficacy for condom use; main partner’s desire for pregnancy and needle sharing were negatively associated with consistent condom use. Among those with casual partners, having fewer sex partners was associated with consistent condom use. Positive attitudes toward condom use and partner norms supporting condom use were associated with greater consistent condom use with both partner types. These findings suggest that intervention strategies targeting individual- and partner-level factors may provide avenues for intervening upon sexual risks among young IDUs

Adaptive Gain Modulation in V1 Explains Contextual Modifications during Bisection Learning

The neuronal processing of visual stimuli in primary visual cortex (V1) can be modified by perceptual training. Training in bisection discrimination, for instance, changes the contextual interactions in V1 elicited by parallel lines. Before training, two parallel lines inhibit their individual V1-responses. After bisection training, inhibition turns into non-symmetric excitation while performing the bisection task. Yet, the receptive field of the V1 neurons evaluated by a single line does not change during task performance. We present a model of recurrent processing in V1 where the neuronal gain can be modulated by a global attentional signal. Perceptual learning mainly consists in strengthening this attentional signal, leading to a more effective gain modulation. The model reproduces both the psychophysical results on bisection learning and the modified contextual interactions observed in V1 during task performance. It makes several predictions, for instance that imagery training should improve the performance, or that a slight stimulus wiggling can strongly affect the representation in V1 while performing the task. We conclude that strengthening a top-down induced gain increase can explain perceptual learning, and that this top-down signal can modify lateral interactions within V1, without significantly changing the classical receptive field of V1 neurons

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

A comparative study of navigation meshes

International audienceA navigation mesh is a representation of a 2D or 3D virtual environment that enables path planning and crowd simulation for walking characters. Various state-of-the-art navigation meshes exist, but there is no standardized way of evaluating or comparing them. Each implementation is in a different state of maturity, has been tested on different hardware, uses different example environments, and may have been designed with a different application in mind. In this paper, we conduct the first comparative study of navigation meshes. First, we give general definitions of 2D and 3D environments and navigation meshes. Second, we propose theoretical properties by which navigation meshes can be classified. Third, we introduce metrics by which the quality of a navigation mesh implementation can be measured objectively. Finally, we use these metrics to compare various state-of-the-art navigation meshes in a range of 2D and 3D environments. We expect that this work will set a new standard for the evaluation of navigation meshes, that it will help developers choose an appropriate navigation mesh for their application, and that it will steer future research on navigation meshes in interesting directions