Rationale and design of a randomized clinical trial comparing safety and efficacy of myval transcatheter heart valve versus contemporary transcatheter heart valves in patients with severe symptomatic aortic valve stenosis: The LANDMARK trial

BACKGROUND: The recent approval of transcatheter aortic valve replacement (TAVR) in patients with low operative risk has paved the way for the introduction of novel and potentially improved technologies. The safety and efficacy of these novel technologies should be investigated in randomized control trials against the contemporary TAVR devices. The objective of the LANDMARK trial is to compare the balloon-expandable Myval transcatheter heart valve (THV) series with contemporary THV (SAPIEN THV and Evolut THV series) series in patients with severe symptomatic native aortic stenosis. METHODS/DESIGN: The LANDMARK trial (ClinicalTrials.govNCT04275726, EudraCT number 2020-000,137-40) is a prospective, randomized, multinational, multicenter, open-label, and noninferiority trial of approximately 768 patients treated with TAVR via the transfemoral approach. Patients will be allocated in a 1:1 randomization to Myval THV series (n = 384) or to contemporary THV (n = 384) (either of SAPIEN THV or Evolut THV series). The primary combined safety and efficacy endpoint is a composite of all-cause mortality, all stroke (disabling and nondisabling), bleeding (life-threatening or disabling), acute kidney injury (stage 2 or 3), major vascular complications, prosthetic valve regurgitation (moderate or severe), and conduction system disturbances (requiring new permanent pacemaker implantation), according to the Valve Academic Research Consortium-2 criteria at 30-day follow-up. All patients will have follow-up to 10 years following TAVR. SUMMARY: The LANDMARK trial is the first randomized head-to-head trial comparing Myval THV series to commercially available THVs in patients indicated for TAVR. We review prior data on head-to-head comparisons of TAVR devices and describe the rationale and design of the LANDMARK trial

Architecture of the yeast elongator complex

The highly conserved eukaryotic Elongator complex performs specific chemical modifications on wobble base uridines of tRNAs, which are essential for proteome stability and homeostasis. The complex is formed by six individual subunits (Elp1-6) that are all equally important for its tRNA modification activity. However, its overall architecture and the detailed reaction mechanism remain elusive. Here, we report the structures of the fully assembled yeast Elongator and the Elp123 sub-complex solved by an integrative structure determination approach showing that two copies of the Elp1, Elp2, and Elp3 subunits form a two-lobed scaffold, which binds Elp456 asymmetrically. Our topological models are consistent with previous studies on individual subunits and further validated by complementary biochemical analyses. Our study provides a structural framework on how the tRNA modification activity is carried out by Elongator

Fish under exercise

Improved knowledge on the swimming physiology of fish and its application to fisheries science and aquaculture (i.e., farming a fitter fish) is currently needed in the face of global environmental changes, high fishing pressures, increased aquaculture production as well as increased concern on fish well-being. Here, we review existing data on teleost fish that indicate that sustained exercise at optimal speeds enhances muscle growth and has consequences for flesh quality. Potential added benefits of sustained exercise may be delay of ovarian development and stimulation of immune status. Exercise could represent a natural, noninvasive, and economical approach to improve growth, flesh quality as well as welfare of aquacultured fish: a FitFish for a healthy consumer. All these issues are important for setting directions for policy decisions and future studies in this area. For this purpose, the FitFish workshop on the Swimming Physiology of Fish (http://www.ub.edu/fitfish2010) was organized to bring together a multidisciplinary group of scientists using exercise models, industrial partners, and policy makers. Sixteen international experts from Europe, North America, and Japan were invited to present their work and view on migration of fishes in their natural environment, beneficial effects of exercise, and applications for sustainable aquaculture. Eighty-eight participants from 19 different countries contributed through a poster session and round table discussion. Eight papers from invited speakers at the workshop have been contributed to this special issue on The Swimming Physiology of Fish

Coronary plaque composition as assessed by greyscale intravascular ultrasound and radiofrequency spectral data analysis

Objectives: (i) To explore the relation between greyscale intravascular ultrasound (IVUS) plaque qualitative classification and IVUS radiofrequency data (RFD) analysis tissue types; (ii) to evaluate if plaque composition as assessed by RFD analysis can be predicted by visual assessment of greyscale IVUS images. Methods: In 120 IVUS-RFD cross-sections, a sector of the plaque with homogenous tissue composition (e.g., fibrous, fibrofatty, necrotic core, and dense calcium) was selected. Two experienced observers analyzed twice the corresponding greyscale IVUS images to: (1) classify the selected sectors according to greyscale IVUS plaque type classification and (2) predict the tissue type expected in the sector by RFD analysis. Results: In the greyscale IVUS plaque type classification, the observers agreed in 90/120 sectors (κ = 0.64). Calcified, soft and mixed plaques by greyscale IVUS classification were mainly composed of dense calcium, fibrofatty, and necrotic core, respectively, in the RFD analysis. The plaques classified in greyscale IVUS as fibrous were actually fibrous tissue by IVUS RFD in only 30% of the cases. Overall, high interobserver variability in the prediction of RFD results by visual assessment of greyscale IVUS images (κ = 0.23 for observer 1 and 0.55 for observer 2) was found. Sens

Unrequested Findings on Cardiac Computed Tomography: Looking Beyond the Heart

Objectives: To determine the prevalence of clinically relevant unrequested extra-cardiac imaging findings on cardiac Computed Tomography (CT) and explanatory factors thereof. Methods: A systematic review of studies drawn from online electronic databases followed by meta-analysis with metaregression was performed. The prevalence of clinically relevant unrequested findings and potentially explanatory variables were extracted (proportion of smokers, mean age of patients, use of full FOV, proportion of men, years since publication). Results: Nineteen radiological studies comprising 12922 patients met the inclusion criteria. The pooled prevalence of clinically relevant unrequested findings was 13 % (95 % confidence interval 9–18, range: 3–39%). The large differences in prevalence observed were not explained by the predefined (potentially explanatory) variables. Conclusions: Clinically relevant extra-cardiac findings are common in patients undergoing routine cardiac CT, and their prevalence differs substantially between studies. These differences may be due to unreported factors such as different definitions of clinical relevance and differences between populations. We present suggestions for basic reporting whic

Comparing the transcriptomes of embryos from domesticated and wild Atlantic salmon (Salmo salar L.) stocks and examining factors that influence heritability of gene expression

Background  Due to selective breeding, domesticated and wild Atlantic salmon are genetically diverged, which raises concerns about farmed escapees having the potential to alter the genetic composition of wild populations and thereby disrupting local adaptation. Documenting transcriptional differences between wild and domesticated stocks under controlled conditions is one way to explore the consequences of domestication and selection. We compared the transcriptomes of wild and domesticated Atlantic salmon embryos, by using a custom 44k oligonucleotide microarray to identify perturbed gene pathways between the two stocks, and to document the inheritance patterns of differentially-expressed genes by examining gene expression in their reciprocal hybrids.  Results  Data from 24 array interrogations were analysed: four reciprocal cross types (W♀×W♂, D♀×W♂; W♀×D♂, D♀×D♂)×six biological replicates. A common set of 31,491 features on the microarrays passed quality control, of which about 62% were assigned a KEGG Orthology number. A total of 6037 distinct genes were identified for gene-set enrichment/pathway analysis. The most highly enriched functional groups that were perturbed between the two stocks were cellular signalling and immune system, ribosome and RNA transport, and focal adhesion and gap junction pathways, relating to cell communication and cell adhesion molecules. Most transcripts that were differentially expressed between the stocks were governed by additive gene interaction (33 to 42%). Maternal dominance and over-dominance were also prevalent modes of inheritance, with no convincing evidence for a stock effect.  Conclusions  Our data indicate that even at this relatively early developmental stage, transcriptional differences exist between the two stocks and affect pathways that are relevant to wild versus domesticated environments. Many of the identified differentially perturbed pathways are involved in organogenesis, which is expected to be an active process at the eyed egg stage. The dominant effects are more largely due to the maternal line than to the origin of the stock. This finding is particularly relevant in the context of potential introgression between farmed and wild fish, since female escapees tend to have a higher spawning success rate compared to males

The Geomechanics of CO2 Storage in Deep Sedimentary Formations

This paper provides a review of the geomechanics and modeling of geomechanics associated with geologic carbon storage (GCS), focusing on storage in deep sedimentary formations, in particular saline aquifers. The paper first introduces the concept of storage in deep sedimentary formations, the geomechanical processes and issues related with such an operation, and the relevant geomechanical modeling tools. This is followed by a more detailed review of geomechanical aspects, including reservoir stress-strain and microseismicity, well integrity, caprock sealing performance, and the potential for fault reactivation and notable (felt) seismic events. Geomechanical observations at current GCS field deployments, mainly at the In Salah CO2 storage project in Algeria, are also integrated into the review. The In Salah project, with its injection into a relatively thin, low-permeability sandstone is an excellent analogue to the saline aquifers that might be used for large scale GCS in parts of Northwest Europe, the U.S. Midwest, and China. Some of the lessons learned at In Salah related to geomechanics are discussed, including how monitoring of geomechanical responses is used for detecting subsurface geomechanical changes and tracking fluid movements, and how such monitoring and geomechanical analyses have led to preventative changes in the injection parameters. Recently, the importance of geomechanics has become more widely recognized among GCS stakeholders, especially with respect to the potential for triggering notable (felt) seismic events and how such events could impact the long-term integrity of a CO{sub 2} repository (as well as how it could impact the public perception of GCS). As described in the paper, to date, no notable seismic event has been reported from any of the current CO{sub 2} storage projects, although some unfelt microseismic activities have been detected by geophones. However, potential future commercial GCS operations from large power plants will require injection at a much larger scale. For such largescale injections, a staged, learn-as-you-go approach is recommended, involving a gradual increase of injection rates combined with continuous monitoring of geomechanical changes, as well as siting beneath a multiple layered overburden for multiple flow barrier protection, should an unexpected deep fault reactivation occur

Joint consensus on the use of OCT in coronary bifurcation lesions by the European and Japanese bifurcation clubs

Coronary artery bifurcation lesions comprise approximately 15-20% of all percutaneous coronary interventions (PCI) and constitute a complex lesion subgroup. Intravascular optical coherence tomography (OCT) is a promising adjunctive tool for guiding coronary bifurcation with its unrivalled high resolution. Compared to angiography, intravascular OCT has a clear advantage in that it depicts ostial lesion(s) in bifurcation without the misleading two-dimensional appearance of conventional angiography such as overlap and foreshortening. In addition, OCT has the ability to reconstruct a bifurcation in three dimensions and to assess the side branch ostium from 3D reconstruction of the main vessel pullback, which can be applied to ensure the optimal recrossing position of the wire after main vessel stenting. Recently, online co-registration of OCT and angiography became widely available, helping the operator to position a stent in precise landing zones, reducing the risk of geographic miss. Despite these technological advances, the currently available clinical data are based mainly on observational studies with a small number of patients; there is little evidence from randomised trials. The joint working group of the European Bifurcation Club and the Japanese Bifurcation Club reviewed all the available literature regarding OCT use in bifurcation lesions and here provides recommendations on OCT guiding of coronary interventions in bifurcation lesions