18F-FDG PET/CT and radiolabeled leukocyte SPECT/CT imaging for the evaluation of cardiovascular infection in the multimodality context: ASNC Imaging Indications (ASNC I2) Series Expert Consensus Recommendations from ASNC, AATS, ACC, AHA, ASE, EANM, HRS, IDSA, SCCT, SNMMI, and STS.

This document on cardiovascular infection, including infective endocarditis, is the first in the American Society of Nuclear Cardiology Imaging Indications (ASNC I2) series to assess the role of radionuclide imaging in the multimodality context for the evaluation of complex systemic diseases with multi-societal involvement including pertinent disciplines. A rigorous modified Delphi approach was used to determine consensus clinical indications, diagnostic criteria, and an algorithmic approach to diagnosis of cardiovascular infection including infective endocarditis. Cardiovascular infection incidence is increasing and is associated with high morbidity and mortality. Current strategies based on clinical criteria and an initial echocardiographic imaging approach are effective but often insufficient in complicated cardiovascular infection. Radionuclide imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and single photon emission computed tomography/CT leukocyte scintigraphy can enhance the evaluation of suspected cardiovascular infection by increasing diagnostic accuracy, identifying extracardiac involvement, and assessing cardiac implanted device pockets, leads, and all portions of ventricular assist devices. This advanced imaging can aid in key medical and surgical considerations. Consensus diagnostic features include focal/multi-focal or diffuse heterogenous intense 18F-FDG uptake on valvular and prosthetic material, perivalvular areas, device pockets and leads, and ventricular assist device hardware persisting on non-attenuation corrected images. There are numerous clinical indications with a larger role in prosthetic valves, and cardiac devices particularly with possible infective endocarditis or in the setting of prior equivocal or non-diagnostic imaging. Illustrative cases incorporating these consensus recommendations provide additional clarification. Future research is necessary to refine application of these advanced imaging tools for surgical planning, to identify treatment response, and more.

18F-FDG PET/CT and radiolabeled leukocyte SPECT/CT imaging for the evaluation of cardiovascular infection in the multimodality context: ASNC Imaging Indications (ASNC I2) Series Expert Consensus Recommendations from ASNC, AATS, ACC, AHA, ASE, EANM, HRS, IDSA, SCCT, SNMMI, and STS.

This document on cardiovascular infection, including infective endocarditis, is the first in the American Society of Nuclear Cardiology Imaging Indications (ASNC I2) series to assess the role of radionuclide imaging in the multimodality context for the evaluation of complex systemic diseases with multi-societal involvement including pertinent disciplines. A rigorous modified Delphi approach was used to determine consensus clinical indications, diagnostic criteria, and an algorithmic approach to diagnosis of cardiovascular infection including infective endocarditis. Cardiovascular infection incidence is increasing and is associated with high morbidity and mortality. Current strategies based on clinical criteria and an initial echocardiographic imaging approach are effective but often insufficient in complicated cardiovascular infection. Radionuclide imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (CT) and single photon emission computed tomography/CT leukocyte scintigraphy can enhance the evaluation of suspected cardiovascular infection by increasing diagnostic accuracy, identifying extracardiac involvement, and assessing cardiac implanted device pockets, leads, and all portions of ventricular assist devices. This advanced imaging can aid in key medical and surgical considerations. Consensus diagnostic features include focal/multi-focal or diffuse heterogenous intense 18F-FDG uptake on valvular and prosthetic material, perivalvular areas, device pockets and leads, and ventricular assist device hardware persisting on non-attenuation corrected images. There are numerous clinical indications with a larger role in prosthetic valves, and cardiac devices particularly with possible infective endocarditis or in the setting of prior equivocal or non-diagnostic imaging. Illustrative cases incorporating these consensus recommendations provide additional clarification. Future research is necessary to refine application of these advanced imaging tools for surgical planning, to identify treatment response, and more.

18F-FDG PET/CT and Radiolabeled Leukocyte SPECT/CT Imaging for the Evaluation of Cardiovascular Infection in the Multimodality Context: ASNC Imaging Indications (ASNC I2) Series Expert Consensus Recommendations From ASNC, AATS, ACC, AHA, ASE, EANM, HRS, IDSA, SCCT, SNMMI, and STS.

This document on cardiovascular infection, including infective endocarditis, is the first in the American Society of Nuclear Cardiology Imaging Indications (ASNC I2) series to assess the role of radionuclide imaging in the multimodality context for the evaluation of complex systemic diseases with multi-societal involvement including pertinent disciplines. A rigorous modified Delphi approach was used to determine consensus clinical indications, diagnostic criteria, and an algorithmic approach to diagnosis of cardiovascular infection including infective endocarditis. Cardiovascular infection incidence is increasing and is associated with high morbidity and mortality. Current strategies based on clinical criteria and an initial echocardiographic imaging approach are effective but often insufficient in complicated cardiovascular infection. Radionuclide imaging with fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (CT) and single photon emission computed tomography/CT leukocyte scintigraphy can enhance the evaluation of suspected cardiovascular infection by increasing diagnostic accuracy, identifying extracardiac involvement, and assessing cardiac implanted device pockets, leads, and all portions of ventricular assist devices. This advanced imaging can aid in key medical and surgical considerations. Consensus diagnostic features include focal/multi-focal or diffuse heterogenous intense 18F-FDG uptake on valvular and prosthetic material, perivalvular areas, device pockets and leads, and ventricular assist device hardware persisting on non-attenuation corrected images. There are numerous clinical indications with a larger role in prosthetic valves, and cardiac devices particularly with possible infective endocarditis or in the setting of prior equivocal or non-diagnostic imaging. Illustrative cases incorporating these consensus recommendations provide additional clarification. Future research is necessary to refine application of these advanced imaging tools for surgical planning, to identify treatment response, and more.

18F-FDG PET/CT and radiolabeled leukocyte SPECT/CT imaging for the evaluation of cardiovascular infection in the multimodality context: ASNC Imaging Indications (ASNC I2) Series Expert Consensus Recommendations from ASNC, AATS, ACC, AHA, ASE, EANM, HRS, IDSA, SCCT, SNMMI, and STS.

This document on cardiovascular infection, including infective endocarditis, is the first in the American Society of Nuclear Cardiology Imaging Indications (ASNC I2) series to assess the role of radionuclide imaging in the multimodality context for the evaluation of complex systemic diseases with multi-societal involvement including pertinent disciplines. A rigorous modified Delphi approach was used to determine consensus clinical indications, diagnostic criteria, and an algorithmic approach to diagnosis of cardiovascular infection including infective endocarditis. Cardiovascular infection incidence is increasing and is associated with high morbidity and mortality. Current strategies based on clinical criteria and an initial echocardiographic imaging approach are effective but often insufficient in complicated cardiovascular infection. Radionuclide imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (CT) and single photon emission computed tomography/CT leukocyte scintigraphy can enhance the evaluation of suspected cardiovascular infection by increasing diagnostic accuracy, identifying extracardiac involvement, and assessing cardiac implanted device pockets, leads, and all portions of ventricular assist devices. This advanced imaging can aid in key medical and surgical considerations. Consensus diagnostic features include focal/multi-focal or diffuse heterogenous intense 18F-FDG uptake on valvular and prosthetic material, perivalvular areas, device pockets and leads, and ventricular assist device hardware persisting on non-attenuation corrected images. There are numerous clinical indications with a larger role in prosthetic valves, and cardiac devices particularly with possible infective endocarditis or in the setting of prior equivocal or non-diagnostic imaging. Illustrative cases incorporating these consensus recommendations provide additional clarification. Future research is necessary to refine application of these advanced imaging tools for surgical planning, to identify treatment response, and more.

The origin recognition complex requires chromatin tethering by a hypervariable intrinsically disordered region that is functionally conserved from sponge to man.

The first step toward eukaryotic genome duplication is loading of the replicative helicase onto chromatin. This 'licensing' step initiates with the recruitment of the origin recognition complex (ORC) to chromatin, which is thought to occur via ORC's ATP-dependent DNA binding and encirclement activity. However, we have previously shown that ATP binding is dispensable for the chromatin recruitment of fly ORC, raising the question of how metazoan ORC binds chromosomes. We show here that the intrinsically disordered region (IDR) of fly Orc1 is both necessary and sufficient for recruitment of ORC to chromosomes in vivo and demonstrate that this is regulated by IDR phosphorylation. Consistently, we find that the IDR confers the ORC holocomplex with ATP-independent DNA binding activity in vitro. Using phylogenetic analysis, we make the surprising observation that metazoan Orc1 IDRs have diverged so markedly that they are unrecognizable as orthologs and yet we find that these compositionally homologous sequences are functionally conserved. Altogether, these data suggest that chromatin is recalcitrant to ORC's ATP-dependent DNA binding activity, necessitating IDR-dependent chromatin tethering, which we propose poises ORC to opportunistically encircle nucleosome-free regions as they become available.

Protein intrinsically disordered regions have a non-random, modular architecture.

MOTIVATION: Protein sequences can be broadly categorized into two classes: those which adopt stable secondary structure and fold into a domain (i.e. globular proteins), and those that do not. The sequences belonging to this latter class are conformationally heterogeneous and are described as being intrinsically disordered. Decades of investigation into the structure and function of globular proteins has resulted in a suite of computational tools that enable their sub-classification by domain type, an approach that has revolutionized how we understand and predict protein functionality. Conversely, it is unknown if sequences of disordered protein regions are subject to broadly generalizable organizational principles that would enable their sub-classification. RESULTS: Here, we report the development of a statistical approach that quantifies linear variance in amino acid composition across a sequence. With multiple examples, we provide evidence that intrinsically disordered regions are organized into statistically non-random modules of unique compositional bias. Modularity is observed for both low and high-complexity sequences and, in some cases, we find that modules are organized in repetitive patterns. These data demonstrate that disordered sequences are non-randomly organized into modular architectures and motivate future experiments to comprehensively classify module types and to determine the degree to which modules constitute functionally separable units analogous to the domains of globular proteins. AVAILABILITY AND IMPLEMENTATION: The source code, documentation, and data to reproduce all figures are freely available at https://github.com/MWPlabUTSW/Chi-Score-Analysis.git. The analysis is also available as a Google Colab Notebook (https://colab.research.google.com/github/MWPlabUTSW/Chi-Score-Analysis/blob/main/ChiScore_Analysis.ipynb).

Perspectives on Secondary Mitral Regurgitation in Heart Failure.

PURPOSE OF THE REVIEW: This review focuses on broader perspectives of mitral regurgitation (MR) in patients with heart failure. RECENT FINDINGS: The ratio of regurgitant volume to end-diastolic volume appears to help identify patients who may benefit from valve interventions. Secondary MR is not only attributed to geometric changes of the LV but also related to the structural changes in the mitral valve that include fibrosis of the mitral leaflets and changes in the extracellular matrix. The transition from mild to severe secondary MR can occur at different rates, from a slow LV remodeling process to a more abrupt process precipitated by an inciting event such as atrial fibrillation. Septal flash and apical rocking, two new visual markers of LV mechanical dyssynchrony, appear to be predictive of MR reduction following cardiac resynchronization therapy. Optimal guideline-directed medical therapy has been shown to decrease the severity of secondary MR effectively. A theoretical framework to characterize secondary MR as it relates to the onset of MR is proposed. Type A: Early onset of MR contemporaneous with myocardial injury. The maladaptive LV remodeling occurs in parallel with MR. Type B: LV remodeling proceeds without significant MR until the LV is moderately dilated, which coincides with or without inciting factors such as atrial fibrillation. Type C: LV remodeling proceeds after myocardial injury without significant MR until the LV is severely dilated. MR is a late manifestation of LV remodeling.

Insights Into the Standard Echocardiographic Views From Multimodality Imaging: Ventricles, Pericardium, Valves, and Atria.

The widespread use of cardiac computed tomography and cardiac magnetic resonance imaging in patients undergoing echocardiography presents an opportunity to correlate the images side by side. Accordingly, the aim of this report is to review aspects of the standard echocardiographic examination alongside similarly oriented images from the two tomographic imaging modalities. It is hoped that this exercise will enhance understanding of the structures depicted by echocardiography as they relate to other structures in the thorax. In addition to reviewing basic cardiac anatomy, the authors take advantage of these correlations with computed tomography and cardiac magnetic resonance imaging to better understand the issue of foreshortening, a common pitfall in transthoracic echocardiography. The authors also highlight an important role that three-dimensional echocardiography can potentially play in the future, especially as advances in image processing permit higher fidelity multiplanar reconstruction images.

Observer studies of image quality of denoising reduced-count cardiac single photon emission computed tomography myocardial perfusion imaging by three-dimensional Gaussian post-reconstruction filtering and deep learning.

BACKGROUND: The aim of this research was to asses perfusion-defect detection-accuracy by human observers as a function of reduced-counts for 3D Gaussian post-reconstruction filtering vs deep learning (DL) denoising to determine if there was improved performance with DL. METHODS: SPECT projection data of 156 normally interpreted patients were used for these studies. Half were altered to include hybrid perfusion defects with defect presence and location known. Ordered-subset expectation-maximization (OSEM) reconstruction was employed with the optional correction of attenuation (AC) and scatter (SC) in addition to distance-dependent resolution (RC). Count levels varied from full-counts (100%) to 6.25% of full-counts. The denoising strategies were previously optimized for defect detection using total perfusion deficit (TPD). Four medical physicist (PhD) and six physician (MD) observers rated the slices using a graphical user interface. Observer ratings were analyzed using the LABMRMC multi-reader, multi-case receiver-operating-characteristic (ROC) software to calculate and compare statistically the area-under-the-ROC-curves (AUCs). RESULTS: For the same count-level no statistically significant increase in AUCs for DL over Gaussian denoising was determined when counts were reduced to either the 25% or 12.5% of full-counts. The average AUC for full-count OSEM with solely RC and Gaussian filtering was lower than for the strategies with AC and SC, except for a reduction to 6.25% of full-counts, thus verifying the utility of employing AC and SC with RC. CONCLUSION: We did not find any indication that at the dose levels investigated and with the DL network employed, that DL denoising was superior in AUC to optimized 3D post-reconstruction Gaussian filtering.

DNA-Stimulated Liquid-Liquid phase separation by eukaryotic topoisomerase ii modulates catalytic function.

Type II topoisomerases modulate chromosome supercoiling, condensation, and catenation by moving one double-stranded DNA segment through a transient break in a second duplex. How DNA strands are chosen and selectively passed to yield appropriate topological outcomes - for example, decatenation vs. catenation - is poorly understood. Here, we show that at physiological enzyme concentrations, eukaryotic type IIA topoisomerases (topo IIs) readily coalesce into condensed bodies. DNA stimulates condensation and fluidizes these assemblies to impart liquid-like behavior. Condensation induces both budding yeast and human topo IIs to switch from DNA unlinking to active DNA catenation, and depends on an unstructured C-terminal region, the loss of which leads to high levels of knotting and reduced catenation. Our findings establish that local protein concentration and phase separation can regulate how topo II creates or dissolves DNA links, behaviors that can account for the varied roles of the enzyme in supporting transcription, replication, and chromosome compaction.

Molecular determinants of phase separation for Drosophila DNA replication licensing factors.

Liquid-liquid phase separation (LLPS) of intrinsically disordered regions (IDRs) in proteins can drive the formation of membraneless compartments in cells. Phase-separated structures enrich for specific partner proteins and exclude others. Previously, we showed that the IDRs of metazoan DNA replication initiators drive DNA-dependent phase separation in vitro and chromosome binding in vivo, and that initiator condensates selectively recruit replication-specific partner proteins (Parker et al., 2019). How initiator IDRs facilitate LLPS and maintain compositional specificity is unknown. Here, using Drosophila melanogaster (Dm) Cdt1 as a model initiation factor, we show that phase separation results from a synergy between electrostatic DNA-bridging interactions and hydrophobic inter-IDR contacts. Both sets of interactions depend on sequence composition (but not sequence order), are resistant to 1,6-hexanediol, and do not depend on aromaticity. These findings demonstrate that distinct sets of interactions drive condensate formation and specificity across different phase-separating systems and advance efforts to predict IDR LLPS propensity and partner selection a priori.

Prevalence of Left Ventricular Hypertrophy Caused by Systemic Hypertension Preceding the Development of Severe Aortic Stenosis.

It is generally assumed that left ventricular (LV) hypertrophy in aortic stenosis (AS) is a compensatory adaptation to chronic outflow obstruction. The advent of transcutaneous aortic valve replacement has stimulated more focus on AS in older patients, most of whom have antecedent hypertension. Accordingly, our aim was to investigate the interaction between hypertension and AS on LV remodeling in contemporary practice. We studied consecutive patients referred for echocardiograms with initial aortic valve (AV) peak velocity <3.0 m/s and a peak velocity of >3.5 m/s on a subsequent study performed at least 5 years later. LV size and geometry were measured echocardiographically. Midwall fractional shortening (FSmw) and peak systolic stress were calculated from 2-dimensional echocardiographic and Doppler data. Of 80 patients with progressive AS, 59% were women with mean age 82 ± 9 years. The average interval between the 2 echocardiograms was 5.9 ± 1.8 years. During the study period, peak velocity increased from 2.5 ± 0.4 to 4.2 ± 0.6 m/s (p < 0.01) and LV mass indexed to body surface area increased from 80 ± 28 to 122 ± 51 g/m2 (p < 0.01) with a corresponding shift from normal or concentric LV remodeling geometry to concentric hypertrophy. There was no correlation between change in LV mass index and AV mean gradient or valvulo-arterial impedance. However, change in LV mass index did correlate positively with initial peak velocity and inversely with initial LV mass. Plots of FSmw against circumferential stress at baseline and follow-up suggest that systolic function more than compensates for increasing load in many patients. In conclusion, most patients seen in our practice with severe AS have antecedent hypertension and LV remodeling at a time when outflow obstruction is mild. LV remodeling worsens in parallel with worsening severity of AS. Remodeling in these patients features increasing concentric remodeling of the LV, rather than LV dilation. Systolic function, as assessed by FSmw, remains compensated, or even improves relative to afterload, during progression of AS. Given these findings, we speculate that regression of LV hypertrophy to normal will not be affected by transcutaneous aortic valve replacement because LV hypertrophy preceded hemodynamically severe AS.

Differentiating Pseudo Versus True Aortic Stenosis in Patients Without Contractile Reserve: A Diagnostic Dilemma.

Low-flow, low-gradient (LF-LG) aortic stenosis with depressed left ventricular (LV) ejection fraction is a diagnostic challenge that is frequently encountered in the management of valvular heart disease. True-severe LF-LG aortic stenosis is amenable to valve replacement, whereas pseudo-severe aortic stenosis requires management of the underlying cardiomyopathy. This distinction is important as it serves as a critical branch point in guiding therapeutic decisions. We present the case of a 71-year-old male with LF-LG aortic stenosis who had a reduced and biphasic augmentation of LV flow during dobutamine stress echocardiography (DSE). Further evaluation revealed a stenotic left subclavian artery proximal to the left internal mammary artery graft to the left anterior descending (LAD) artery. Bypass of the subclavian stenosis reversed the LAD territory ischemia and confirmed pseudo-severe aortic stenosis on repeat DSE. Traditional DSE parameters are inconclusive in patients with LF-LG aortic stenosis with poor flow reserve. Calculation of the projected orifice area or measurement of aortic valve calcium via multidetector computed tomography (MDCT) may be required in this scenario. Most importantly, reversible causes of LV dysfunction identified during DSE for LF-LG aortic stenosis require a different treatment approach than that of true aortic stenosis.

Serial echocardiography for valve dysfunction and aortic dilation in bicuspid aortic valves.

BACKGROUND AND AIMS: Complications of bicuspid aortic valve commonly include aortic stenosis, aortic regurgitation, and ascending aortic dilation. The progression of these lesions is not well described. MATERIALS AND METHODS: We reviewed 249 bicuspid aortic valve patients with at least two echocardiograms from 2006 to 2016. Valve morphology (right-left or right-noncoronary cusp fusion) was confirmed by visual inspection, and aortic stenosis and regurgitation were quantified according to current guidelines; the ascending aorta was measured at end-systole 2-3 cm above the sinotubular junction. Annualized progression of stenosis, regurgitation, and aortic dilation from first to most recent echocardiogram were compared between right-left and right-nonfused valves using multivariable logistic regression to adjust for baseline differences in groups. RESULTS: Among 249 bicuspid aortic valve patients (mean age 47.6 ± 13.5 years, 66.3% male), 75.9% had right-left cusp fusion. At baseline, aortic stenosis was absent or mild in 80.3%; aortic regurgitation was absent or mild in 80.7%; and aortic diameters were 35.0 ± 5.7 mm (sinuses of Valsalva) and 37.4 ± 6.2 mm (ascending). Mean annualized decrease in aortic valve area was 0.07 cm2 /year, with 30% of bicuspid aortic valve patients progressing ≥0.1 cm2 /year. Aortic regurgitation progressed ≥1 grade in 37 patients. Mean annualized increase in ascending aorta diameter was 0.36 mm/year in right-left and 0.65 mm/year in right-nonbicuspid valves. CONCLUSIONS: In this serial echocardiographic study of bicuspid aortic valve patients, cusp orientation was not associated with progression of valve dysfunction. Right-noncoronary cusp fusion was associated with ascending aortic diameter progression.

Comparative infinite lottery logic.

As an application of his Material Theory of Induction, Norton (2018; manuscript) argues that the correct inductive logic for a fair infinite lottery, and also for evaluating eternal inflation multiverse models, is radically different from standard probability theory. This is due to a requirement of label independence. It follows, Norton argues, that finite additivity fails, and any two sets of outcomes with the same cardinality and co-cardinality have the same chance. This makes the logic useless for evaluating multiverse models based on self-locating chances, so Norton claims that we should despair of such attempts. However, his negative results depend on a certain reification of chance, consisting in the treatment of inductive support as the value of a function, a value not itself affected by relabeling. Here we define a purely comparative infinite lottery logic, where there are no primitive chances but only a relation of 'at most as likely' and its derivatives. This logic satisfies both label independence and a comparative version of additivity as well as several other desirable properties, and it draws finer distinctions between events than Norton's. Consequently, it yields better advice about choosing between sets of lottery tickets than Norton's, but it does not appear to be any more helpful for evaluating multiverse models. Hence, the limitations of Norton's logic are not entirely due to the failure of additivity, nor to the fact that all infinite, co-infinite sets of outcomes have the same chance, but to a more fundamental problem: We have no well-motivated way of comparing disjoint countably infinite sets.