Treatment of mitral regurgitation (MR) in the setting of severe mitral annular calcification (MAC) is challenging due to the high risk for fatal atrioventricular groove disruption and significant ...paravalvular leak.
The objective of this study was to evaluate the potential for transcatheter mitral valve replacement in patients with severe MAC using an anatomically designed mitral prosthesis.
Nine patients (77 ± 6 years of age; 5 men) were treated with the valve, using transapical delivery performed under general anesthesia and with guidance from transesophageal echocardiography and fluoroscopy.
Device implantation was successful with relief of MR in all 9 patients. There were no procedural deaths. In 1 patient, left ventricular outflow tract obstruction occurred due to malrotation of the prosthesis, and successful alcohol septal ablation was performed. During a median follow-up of 12 months (range 1 to 28 months), there was 1 cardiac death, 1 noncardiac death, no other mortality, and no prosthetic dysfunction, and MR remained absent in all treated patients. Rehospitalization for heart failure occurred in 2 patients who did not die subsequently. Clinical improvement with mild or no symptoms occurred in all patients alive at the end of follow-up.
Transcatheter mitral valve replacement in severe mitral annular calcification with a dedicated prosthesis is feasible and can result in MR relief with symptom improvement. Further evaluation of this approach for these high-risk patients is warranted.
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To elucidate the genetic bases of mycorrhizal lifestyle evolution, we sequenced new fungal genomes, including 13 ectomycorrhizal (ECM), orchid (ORM) and ericoid (ERM) species, and five saprotrophs, ...which we analyzed along with other fungal genomes. Ectomycorrhizal fungi have a reduced complement of genes encoding plant cell wall-degrading enzymes (PCWDEs), as compared to their ancestral wood decayers. Nevertheless, they have retained a unique array of PCWDEs, thus suggesting that they possess diverse abilities to decompose lignocellulose. Similar functional categories of nonorthologous genes are induced in symbiosis. Of induced genes, 7-38% are orphan genes, including genes that encode secreted effector-like proteins. Convergent evolution of the mycorrhizal habit in fungi occurred via the repeated evolution of a 'symbiosis toolkit', with reduced numbers of PCWDEs and lineage-specific suites of mycorrhiza-induced genes.
Transporters are significant in dictating drug pharmacokinetics, thus inhibition of transporter function can alter drug concentrations resulting in drug-drug interactions (DDIs). Because they can ...impact drug toxicity, transporter DDIs are a regulatory concern for which prediction of clinical effect from in vitro data is critical to understanding risk.
The authors propose in vitro strategies to assist mitigating/removing transporter DDI risk during development by frontloading specific studies, or managing patient risk in the clinic. An overview of clinically relevant drug transporters and observed DDIs is provided, alongside presentation of key considerations/recommendations for in vitro study design evaluating drugs as inhibitors or substrates. Guidance on identifying critical co-medications, clinically relevant disposition pathways, and using mechanistic static equations for quantitative prediction of DDI is compiled.
The strategies provided will facilitate project teams to study the right transporter at the right time to minimize development risks associated with DDIs. To truly alleviate or manage clinical risk, the industry will benefit from moving away from current qualitative basic static equation approaches to transporter DDI hazard assessment towards adopting the use of mechanistic models to enable quantitative DDI prediction, thereby contextualizing risk to ascertain whether a transporter DDI is simply pharmacokinetic or clinically significant requiring intervention.
The HEART Pathway is a validated risk stratification protocol for Emergency Department patients with chest pain that has yet to be tested in the prehospital setting. This study seeks to test the ...performance of a prehospital modified HEART Pathway (PMHP). A prospective cohort study of adults with chest pain without ST-segment elevation myocardial infarction was conducted at three EMS agencies between 12/2016-1/2018. To complete a PMHP assessment, paramedics drew blood, measured point-of-care (POC) troponin (i-STAT; Abbott Point of Care) and calculated a HEAR score. Patients were stratified into three groups: high-risk based on an elevated troponin, low-risk based on a HEAR score <4 with a negative troponin, or moderate risk for a HEAR score greater than or equal to4 with a negative troponin. Sensitivity, specificity, negative and positive predictive values of the PMHP for detection of major adverse cardiac events (MACE: cardiac death, MI, or coronary revascularization) at 30-days were calculated. A total of 506 patients were accrued, with PMHP completed in 78.1% (395/506). MACE at 30-days occurred in 18.7% (74/395). Among these patients, 7.1% (28/395) were high risk yielding a specificity and PPV for 30-day MACE of 96.6% (95%CI: 94.0-98.3%) and 60.7% (95%CI: 40.6-78.6%) respectively. Low-risk assessments occurred in 31.4% (124/395), which were 90.5% (95%CI: 81.5-96.1%) sensitive for 30-day MACE with a NPV of 94.4% (95%CI: 88.7-97.7%). Moderate-risk assessments occurred in 61.5% (243/395), of which 20.6% had 30-day MACE. The PMHP is able to identify high-risk and low-risk groups with high specificity and negative predictive value for 30-day MACE.
The aim of this pooled analysis was to assess the cumulative safety and effectiveness of coronary intravascular lithotripsy (IVL).
The clinical outcomes of IVL to optimize target lesion preparation ...in severely calcified de novo coronary stenoses have been examined in 4 prospective studies (Disrupt CAD I NCT02650128, Disrupt CAD II NCT03328949, Disrupt CAD III NCT03595176, and Disrupt CAD IV NCT04151628).
Patient data were pooled from the Disrupt CAD studies, which shared uniform study criteria, endpoint definitions and adjudication, and procedural follow-up. The primary safety endpoint was freedom from major adverse cardiovascular events (composite of cardiac death, all myocardial infarction, or target vessel revascularization) at 30 days. The primary effectiveness endpoint was procedural success, defined as stent delivery with a residual stenosis ≤30% by quantitative coronary angiography without in-hospital major adverse cardiovascular events. Secondary outcomes included serious angiographic complications, target lesion failure, cardiac death, and stent thrombosis at 30 days.
Between December 2015 and April 2020, 628 patients were enrolled at 72 sites from 12 countries. Presence of severe calcification was confirmed in 97.0% of target lesions with an average calcified segment length of 41.5 ± 20.0 mm. The primary safety and effectiveness endpoints were achieved in 92.7% and 92.4% of patients, respectively. At 30 days, the rates of target lesion failure, cardiac death, and stent thrombosis were 7.2%, 0.5%, and 0.8%. Rates of post-IVL and final serious angiographic complications were 2.1% and 0.3%, with no IVL-associated perforations, abrupt closure, or episodes of no reflow.
In the largest cohort of patients treated with coronary IVL assessed to date, coronary IVL safely facilitated successful stent implantation in severely calcified coronary lesions with a high rate of procedural success.
A coherent change detection (CCD) image, computed from a geometrically matched, temporally separated pair of complex-valued synthetic aperture radar (SAR) image sets, conveys the pixel-level ...equivalence between the two observations. Low-coherence values in a CCD image are typically due to either some physical change in the corresponding pixels or a low signal-to-noise observation. A CCD image does not directly convey the nature of the change that occurred to cause low coherence. In this paper, we introduce a mathematical framework for discriminating between different types of change within a CCD image. We utilize the extra degrees of freedom and information from polarimetric interferometric SAR (PolInSAR) data and PolInSAR processing techniques to define a 29-dimensional feature vector that contains information capable of discriminating between different types of change in a scene. We also propose two change-type discrimination functions that can be trained with feature vector training data and demonstrate change-type discrimination on an example image set for three different types of change. Furthermore, we also describe and characterize the performance of the two proposed change-type discrimination functions by way of receiver operating characteristic curves, confusion matrices, and pass matrices.
Ascomycete yeasts are metabolically diverse, with great potential for biotechnology. Here, we report the comparative genome analysis of 29 taxonomically and biotechnologically important yeasts, ...including 16 newly sequenced. We identify a genetic code change, CUG-Ala, in Pachysolen tannophilus in the clade sister to the known CUG-Ser clade. Our well-resolved yeast phylogeny shows that some traits, such as methylotrophy, are restricted to single clades, whereas others, such as L-rhamnose utilization, have patchy phylogenetic distributions. Gene clusters, with variable organization and distribution, encode many pathways of interest. Genomics can predict some biochemical traits precisely, but the genomic basis of others, such as xylose utilization, remains unresolved. Our data also provide insight into early evolution of ascomycetes. We document the loss of H3K9me2/3 heterochromatin, the origin of ascomycete mating-type switching, and panascomycete synteny at the MAT locus. These data and analyses will facilitate the engineering of efficient biosynthetic and degradative pathways and gateways for genomic manipulation.
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