Incidence and Sequelae of Prosthesis-Patient Mismatch in Transcatheter Versus Surgical Valve Replacement in High-Risk Patients With Severe Aortic Stenosis A PARTNER Trial Cohort-A Analysis

AbstractBackgroundLittle is known about the incidence of prosthesis-patient mismatch (PPM) and its impact on outcomes after transcatheter aortic valve replacement (TAVR).ObjectivesThe objectives of this study were: 1) to compare the incidence of PPM in the TAVR and surgical aortic valve replacement (SAVR) randomized control trial (RCT) arms of the PARTNER (Placement of AoRTic TraNscathetER Valves) I Trial cohort A; and 2) to assess the impact of PPM on regression of left ventricular (LV) hypertrophy and mortality in these 2 arms and in the TAVR nonrandomized continued access (NRCA) registry cohort.MethodsThe PARTNER Trial cohort A randomized patients 1:1 to TAVR or bioprosthetic SAVR. Postoperative PPM was defined as absent if the indexed effective orifice area (EOA) was >0.85 cm2/m2, moderate if the indexed EOA was ≥0.65 but ≤0.85 cm2/m2, or severe if the indexed EOA was <0.65 cm2/m2. LV mass regression and mortality were analyzed using the SAVR-RCT (n = 270), TAVR-RCT (n = 304), and TAVR-NRCA (n = 1,637) cohorts.ResultsThe incidence of PPM was 60.0% (severe: 28.1%) in the SAVR-RCT cohort versus 46.4% (severe: 19.7%) in the TAVR-RCT cohort (p < 0.001) and 43.8% (severe: 13.6%) in the TAVR-NRCA cohort. In patients with an aortic annulus diameter <20 mm, severe PPM developed in 33.7% undergoing SAVR compared with 19.0% undergoing TAVR (p = 0.002). PPM was an independent predictor of less LV mass regression at 1 year in the SAVR-RCT (p = 0.017) and TAVR-NRCA (p = 0.012) cohorts but not in the TAVR-RCT cohort (p = 0.35). Severe PPM was an independent predictor of 2-year mortality in the SAVR-RCT cohort (hazard ratio [HR]: 1.78; p = 0.041) but not in the TAVR-RCT cohort (HR: 0.58; p = 0.11). In the TAVR-NRCA cohort, severe PPM was not a predictor of 1-year mortality in all patients (HR: 1.05; p = 0.60) but did independently predict mortality in the subset of patients with no post-procedural aortic regurgitation (HR: 1.88; p = 0.02).ConclusionsIn patients with severe aortic stenosis and high surgical risk, PPM is more frequent and more often severe after SAVR than TAVR. Patients with PPM after SAVR have worse survival and less LV mass regression than those without PPM. Severe PPM also has a significant impact on survival after TAVR in the subset of patients with no post-procedural aortic regurgitation. TAVR may be preferable to SAVR in patients with a small aortic annulus who are susceptible to PPM to avoid its adverse impact on LV mass regression and survival. (The PARTNER Trial: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894

Particle Dark Matter Constraints from the Draco Dwarf Galaxy

It is widely thought that neutralinos, the lightest supersymmetric particles, could comprise most of the dark matter. If so, then dark halos will emit radio and gamma ray signals initiated by neutralino annihilation. A particularly promising place to look for these indicators is at the center of the local group dwarf spheroidal galaxy Draco, and recent measurements of the motion of its stars have revealed it to be an even better target for dark matter detection than previously thought. We compute limits on WIMP properties for various models of Draco's dark matter halo. We find that if the halo is nearly isothermal, as the new measurements indicate, then current gamma ray flux limits prohibit much of the neutralino parameter space. If Draco has a moderate magnetic field, then current radio limits can rule out more of it. These results are appreciably stronger than other current constraints, and so acquiring more detailed data on Draco's density profile becomes one of the most promising avenues for identifying dark matter.Comment: 13 pages, 6 figure

The emerging structure of the Extended Evolutionary Synthesis: where does Evo-Devo fit in?

The Extended Evolutionary Synthesis (EES) debate is gaining ground in contemporary evolutionary biology. In parallel, a number of philosophical standpoints have emerged in an attempt to clarify what exactly is represented by the EES. For Massimo Pigliucci, we are in the wake of the newest instantiation of a persisting Kuhnian paradigm; in contrast, Telmo Pievani has contended that the transition to an EES could be best represented as a progressive reformation of a prior Lakatosian scientific research program, with the extension of its Neo-Darwinian core and the addition of a brand-new protective belt of assumptions and auxiliary hypotheses. Here, we argue that those philosophical vantage points are not the only ways to interpret what current proposals to ‘extend’ the Modern Synthesis-derived ‘standard evolutionary theory’ (SET) entail in terms of theoretical change in evolutionary biology. We specifically propose the image of the emergent EES as a vast network of models and interweaved representations that, instantiated in diverse practices, are connected and related in multiple ways. Under that assumption, the EES could be articulated around a paraconsistent network of evolutionary theories (including some elements of the SET), as well as models, practices and representation systems of contemporary evolutionary biology, with edges and nodes that change their position and centrality as a consequence of the co-construction and stabilization of facts and historical discussions revolving around the epistemic goals of this area of the life sciences. We then critically examine the purported structure of the EES—published by Laland and collaborators in 2015—in light of our own network-based proposal. Finally, we consider which epistemic units of Evo-Devo are present or still missing from the EES, in preparation for further analyses of the topic of explanatory integration in this conceptual framework

Transcatheter or surgical aortic-valve replacement in intermediate-risk patients

BACKGROUND: Previous trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aorticvalve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients. METHODS: We randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort. RESULTS: The rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan–Meier event rates were 19.3% in the TAVR group and 21.1% in the surgery group (hazard ratio in the TAVR group, 0.89; 95% confidence interval [CI], 0.73 to 1.09; P=0.25). In the transfemoralaccess cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P=0.05), whereas in the transthoracic-access cohort, outcomes were similar in the two groups. TAVR resulted in larger aortic-valve areas than did surgery and also resulted in lower rates of acute kidney injury, severe bleeding, and new-onset atrial fibrillation; surgery resulted in fewer major vascular complications and less paravalvular aortic regurgitation. CONCLUSIONS: In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313

Two-year outcomes after transcatheter or surgical aortic-valve replacement.

BACKGROUND: The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that among high-risk patients with aortic stenosis, the 1-year survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical replacement. However, longer-term follow-up is necessary to determine whether TAVR has prolonged benefits. METHODS: At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either surgical aortic-valve replacement or TAVR. All patients were followed for at least 2 years, with assessment of clinical outcomes and echocardiographic evaluation. RESULTS: The rates of death from any cause were similar in the TAVR and surgery groups (hazard ratio with TAVR, 0.90; 95% confidence interval [CI], 0.71 to 1.15; P=0.41) and at 2 years (Kaplan-Meier analysis) were 33.9% in the TAVR group and 35.0% in the surgery group (P=0.78). The frequency of all strokes during follow-up did not differ significantly between the two groups (hazard ratio, 1.22; 95% CI, 0.67 to 2.23; P=0.52). At 30 days, strokes were more frequent with TAVR than with surgical replacement (4.6% vs. 2.4%, P=0.12); subsequently, there were 8 additional strokes in the TAVR group and 12 in the surgery group. Improvement in valve areas was similar with TAVR and surgical replacement and was maintained for 2 years. Paravalvular regurgitation was more frequent after TAVR (P<0.001), and even mild paravalvular regurgitation was associated with increased late mortality (P<0.001). CONCLUSIONS: A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative to surgery in high-risk patients. The two treatments were similar with respect to mortality, reduction in symptoms, and improved valve hemodynamics, but paravalvular regurgitation was more frequent after TAVR and was associated with increased late mortality. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.)

An epigenetic clock for gestational age at birth based on blood methylation data

Background: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. Results: We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. Conclusions: DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances

HAMLET Binding to α-Actinin Facilitates Tumor Cell Detachment

Cell adhesion is tightly regulated by specific molecular interactions and detachment from the extracellular matrix modifies proliferation and survival. HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a protein-lipid complex with tumoricidal activity that also triggers tumor cell detachment in vitro and in vivo, suggesting that molecular interactions defining detachment are perturbed in cancer cells. To identify such interactions, cell membrane extracts were used in Far-western blots and HAMLET was shown to bind α-actinins; major F-actin cross-linking proteins and focal adhesion constituents. Synthetic peptide mapping revealed that HAMLET binds to the N-terminal actin-binding domain as well as the integrin-binding domain of α-actinin-4. By co-immunoprecipitation of extracts from HAMLET-treated cancer cells, an interaction with α-actinin-1 and -4 was observed. Inhibition of α-actinin-1 and α-actinin-4 expression by siRNA transfection increased detachment, while α-actinin-4-GFP over-expression significantly delayed rounding up and detachment of tumor cells in response to HAMLET. In response to HAMLET, adherent tumor cells rounded up and detached, suggesting a loss of the actin cytoskeletal organization. These changes were accompanied by a reduction in β1 integrin staining and a decrease in FAK and ERK1/2 phosphorylation, consistent with a disruption of integrin-dependent cell adhesion signaling. Detachment per se did not increase cell death during the 22 hour experimental period, regardless of α-actinin-4 and α-actinin-1 expression levels but adherent cells with low α-actinin levels showed increased death in response to HAMLET. The results suggest that the interaction between HAMLET and α-actinins promotes tumor cell detachment. As α-actinins also associate with signaling molecules, cytoplasmic domains of transmembrane receptors and ion channels, additional α-actinin-dependent mechanisms are discussed

Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass, yet unlike white or brown adipose tissues (WAT or BAT) its metabolic functions remain unclear. Herein, we address this critical gap in knowledge. Our transcriptomic analyses revealed that BMAT is distinct from WAT and BAT, with altered glucose metabolism and decreased insulin responsiveness. We therefore tested these functions in mice and humans using positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose. This revealed that BMAT resists insulin- and cold-stimulated glucose uptake, while further in vivo studies showed that, compared to WAT, BMAT resists insulin-stimulated Akt phosphorylation. Thus, BMAT is functionally distinct from WAT and BAT. However, in humans basal glucose uptake in BMAT is greater than in axial bones or subcutaneous WAT and can be greater than that in skeletal muscle, underscoring the potential of BMAT to influence systemic glucose homeostasis. These PET/CT studies characterise BMAT function in vivo, establish new methods for BMAT analysis, and identify BMAT as a distinct, major adipose tissue subtype