This study examines use of an expandable bovine pericardial prosthetic valve inserted with a catheter system for valvular aortic stenosis. Outcomes were noninferior to those of surgical aortic-valve ...replacement, but the risk of stroke, aortic regurgitation, and vascular complications was substantial.
After the appearance of symptoms, aortic stenosis is associated with a high rate of death if left untreated.
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Although surgical aortic-valve replacement improves symptoms and survival,
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observational studies have identified various subgroups of patients (i.e., those with an advanced age and those with poor left ventricular function or other coexisting disorders) who are at increased risk for operative complications or death.
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In such patients, a less invasive treatment may be a desirable alternative.
Transcatheter aortic-valve replacement treats aortic stenosis by displacing and functionally replacing the native valve with a bioprosthetic valve delivered on a catheter through the . . .
The Nuclear Spectroscopic Telescope Array (NuSTAR) mission, launched on 2012 June 13, is the first focusing high-energy X-ray telescope in orbit. NuSTAR operates in the band from 3 to 79 keV, ...extending the sensitivity of focusing far beyond the ~10 keV high-energy cutoff achieved by all previous X-ray satellites. The inherently low background associated with concentrating the X-ray light enables NuSTAR to probe the hard X-ray sky with a more than 100-fold improvement in sensitivity over the collimated or coded mask instruments that have operated in this bandpass. Using its unprecedented combination of sensitivity and spatial and spectral resolution, NuSTAR will pursue five primary scientific objectives: (1) probe obscured active galactic nucleus (AGN) activity out to the peak epoch of galaxy assembly in the universe (at z <, ~ 2) by surveying selected regions of the sky; (2) study the population of hard X-ray-emitting compact objects in the Galaxy by mapping the central regions of the Milky Way; (3) study the non-thermal radiation in young supernova remnants, both the hard X-ray continuum and the emission from the radioactive element super(44)Ti; (4) observe blazars contemporaneously with ground-based radio, optical, and TeV telescopes, as well as with Fermi and Swift, to constrain the structure of AGN jets; and (5) observe line and continuum emission from core-collapse supernovae in the Local Group, and from nearby Type Ia events, to constrain explosion models. During its baseline two-year mission, NuSTAR will also undertake a broad program of targeted observations. The observatory consists of two co-aligned grazing-incidence X-ray telescopes pointed at celestial targets by a three-axis stabilized spacecraft. Deployed into a 600 km, near-circular, 6degrees inclination orbit, the observatory has now completed commissioning, and is performing consistent with pre-launch expectations. NuSTAR is now executing its primary science mission, and with an expected orbit lifetime of 10 yr, we anticipate proposing a guest investigator program, to begin in late 2014.
Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable ...targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.
Activation of the immune system is implicated in the Post-Acute Sequelae after SARS-CoV-2 infection (PASC) but the mechanisms remain unknown. Angiotensin-converting enzyme 2 (ACE2) cleaves ...angiotensin II (Ang II) resulting in decreased activation of the AT1 receptor and decreased immune system activation. We hypothesized that autoantibodies against ACE2 may develop after SARS-CoV-2 infection, as anti-idiotypic antibodies to anti-spike protein antibodies.
We tested plasma or serum for ACE2 antibodies in 67 patients with known SARS-CoV-2 infection and 13 with no history of infection. None of the 13 patients without history of SARS-CoV-2 infection and 1 of the 20 outpatients that had a positive PCR test for SARS-CoV-2 had levels of ACE2 antibodies above the cutoff threshold. In contrast, 26/32 (81%) in the convalescent group and 14/15 (93%) of patients acutely hospitalized had detectable ACE2 antibodies. Plasma from patients with antibodies against ACE2 had less soluble ACE2 activity in plasma but similar amounts of ACE2 protein compared to patients without ACE2 antibodies. We measured the capacity of the samples to inhibit ACE2 enzyme activity. Addition of plasma from patients with ACE2 antibodies led to decreased activity of an exogenous preparation of ACE2 compared to patients that did not have antibodies.
Many patients with a history of SARS-CoV-2 infection have antibodies specific for ACE2. Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma. Plasma from these patients also inhibits exogenous ACE2 activity. These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS-CoV-2 infection and decrease ACE2 activity. This could lead to an increase in the abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC.
We present results from the coordinated broadband X-ray observations of the extreme ultraluminous X-ray source Holmberg IX X-1 performed by NuSTAR, XMM-Newton, and Suzaku in late 2012. These ...observations provide the first high-quality spectra of Holmberg IX X-1 above 10 keV to date, extending the X-ray coverage of this remarkable source up to 30 keV. Broadband observations were undertaken at two epochs, between which Holmberg IX X-1 exhibited both flux and strong spectral variability, increasing in luminosity from L(sub x) = (1.90 +/- 0.03) x 10(exp 40) erg s(exp -1) to L(sub x) = (3.35 +/- 0.03) x 10(exp 40) erg s(exp -1) . Neither epoch exhibits a spectrum consistent with emission from the standard lowhard accretion state seen in Galactic black hole binaries, which would have been expected if Holmberg IX X-1 harbors a truly massive black hole accreting at substantially sub-Eddington accretion rates. The NuSTAR data confirm that the curvature observed previously in the 3-10 keV bandpass does represent a true spectral cutoff. During each epoch, the spectrum appears to be dominated by two optically thick thermal components, likely associated with an accretion disk. The spectrum also shows some evidence for a nonthermal tail at the highest energies, which may further support this scenario. The available data allow for either of the two thermal components to dominate the spectral evolution, although both scenarios require highly nonstandard behavior for thermal accretion disk emission.
Low-passage, serum-free cell lines cultured from patient tumour tissue are the gold-standard for preclinical studies and cellular investigations of glioblastoma (GBM) biology, yet entrenched, ...poorly-representative cell line models are still widely used, compromising the significance of much GBM research. We submit that greater adoption of these critical resources will be promoted by the provision of a suitably-sized, meaningfully-described reference collection along with appropriate tools for working with them. Consequently, we present a curated panel of 12 readily-usable, genetically-diverse, tumourigenic, patient-derived, low-passage, serum-free cell lines representing the spectrum of molecular subtypes of IDH-wildtype GBM along with their detailed phenotypic characterisation plus a bespoke set of lentiviral plasmids for bioluminescent/fluorescent labelling, gene expression and CRISPR/Cas9-mediated gene inactivation. The cell lines and all accompanying data are readily-accessible via a single website, Q-Cell (qimrberghofer.edu.au/q-cell/) and all plasmids are available from Addgene. These resources should prove valuable to investigators seeking readily-usable, well-characterised, clinically-relevant, gold-standard models of GBM.
Psoriasis is a chronic, inflammatory multisystem disease that affects up to 3.2% of the US population. This guideline addresses important clinical questions that arise in psoriasis management and ...care, providing recommendations based on the available evidence. The treatment of psoriasis with biologic agents will be reviewed, emphasizing treatment recommendations and the role of the dermatologist in monitoring and educating patients regarding benefits as well as associated risks.
In this randomized trial involving 13,885 patients with symptomatic peripheral artery disease (PAD), ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. ...Major bleeding occurred at similar rates with ticagrelor and clopidogrel.
Peripheral artery disease is considered to be a clinical manifestation of systemic atherosclerosis affecting the vascular territories supplying the lower limbs. Most patients presenting with peripheral artery disease do not have a clinical history of cardiac or cerebral ischemic events, yet these patients are at high risk for myocardial infarction, ischemic stroke, and cardiovascular death.
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Concomitant clinical evidence of coronary or cerebrovascular disease only magnifies this risk.
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Therapies to reduce the ischemic risk associated with atherosclerosis have focused on patients with acute coronary syndromes and stable coronary artery disease. Antithrombotic drugs, mainly antiplatelet therapies and statins, are the cornerstone of . . .
The comprehensive characterization of cardiac structure and function is critical to better understanding various murine models of cardiac disease. We demonstrate here a multimodal analysis approach ...using high-frequency four-dimensional ultrasound (4DUS) imaging and proteomics to explore the relationship between regional function and tissue composition in a murine model of metabolic cardiomyopathy (
). The presented 4DUS analysis outlines a novel approach to mapping both circumferential and longitudinal strain profiles through a standardized framework. We then demonstrate how this approach allows for spatiotemporal comparisons of cardiac function and improved localization of regional left ventricular dysfunction. Guided by observed trends in regional dysfunction, our targeted Ingenuity Pathway Analysis (IPA) results highlight metabolic dysregulation in the
model, including altered mitochondrial function and energy metabolism (i.e., oxidative phosphorylation and fatty acid/lipid handling). Finally, we present a combined 4DUS-proteomics
-score-based analysis that highlights IPA canonical pathways showing strong linear relationships with 4DUS biomarkers of regional cardiac dysfunction. The presented multimodal analysis methods aim to help future studies more comprehensively assess regional structure-function relationships in other preclinical models of cardiomyopathy.
A multimodal approach using both four-dimensional ultrasound (4DUS) and regional proteomics can help enhance our investigations of murine cardiomyopathy models. We present unique 4DUS-derived strain maps that provide a framework for both cross-sectional and longitudinal analysis of spatiotemporal cardiac function. We further detail and demonstrate an innovative 4DUS-proteomics
-score-based linear regression method, aimed at characterizing relationships between regional cardiac dysfunction and underlying mechanisms of disease.
When data are collected via anonymous Internet surveys, particularly under conditions of obligatory participation (such as with student samples), data quality can be a concern. However, little ...guidance exists in the published literature regarding techniques for detecting careless responses. Previously several potential approaches have been suggested for identifying careless respondents via indices computed from the data, yet almost no prior work has examined the relationships among these indicators or the types of data patterns identified by each. In 2 studies, we examined several methods for identifying careless responses, including (a) special items designed to detect careless response, (b) response consistency indices formed from responses to typical survey items, (c) multivariate outlier analysis, (d) response time, and (e) self-reported diligence. Results indicated that there are two distinct patterns of careless response (random and nonrandom) and that different indices are needed to identify these different response patterns. We also found that approximately 10%-12% of undergraduates completing a lengthy survey for course credit were identified as careless responders. In Study 2, we simulated data with known random response patterns to determine the efficacy of several indicators of careless response. We found that the nature of the data strongly influenced the efficacy of the indices to identify careless responses. Recommendations include using identified rather than anonymous responses, incorporating instructed response items before data collection, as well as computing consistency indices and multivariate outlier analysis to ensure high-quality data.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ
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