John Mongan

Accelerated molecular dynamics: A promising and efficient simulation method for biomolecules

Many interesting dynamic properties of biological molecules cannot be simulated directly using molecular dynamics because of nanosecond time scale limitations. These systems are trapped in potential energy minima with high free energy barriers for large numbers of computational steps. The dynamic evolution of many molecular systems occurs through a series of rare events as the system moves from one potential energy basin to another. Therefore, we have proposed a robust bias potential function that can be used in an efficient accelerated molecular dynamics approach to simulate the transition of high energy barriers without any advance knowledge of the location of either the potential energy wells or saddle points. In this method, the potential energy landscape is altered by adding a bias potential to the true potential such that the escape rates from potential wells are enhanced, which accelerates and extends the time scale in molecular dynamics simulations. Our definition of the bias potential echoes the underlying shape of the potential energy landscape on the modified surface, thus allowing for the potential energy minima to be well defined, and hence properly sampled during the simulation. We have shown that our approach, which can be extended to biomolecules, samples the conformational space more efficiently than normal molecular dynamics simulations, and converges to the correct canonical distribution.

Constant pH molecular dynamics in generalized Born implicit solvent

A new method is proposed for constant pH molecular dynamics (MD), employing generalized Born (GB) electrostatics. Protonation states are modeled with different charge sets, and titrating residues sample a Boltzmann distribution of protonation states as the simulation progresses, using Monte Carlo sampling based on GB‐derived energies. The method is applied to four different crystal structures of hen egg‐white lysozyme (HEWL). pKa predictions derived from the simulations have root‐mean‐square (RMS) error of 0.82 relative to experimental values. Similarity of results between the four crystal structures shows the method to be independent of starting crystal structure; this is in contrast to most electrostatics‐only models. A strong correlation between conformation and protonation state is noted and quantitatively analyzed, emphasizing the importance of sampling protonation states in conjunction with dynamics.

Interactive essential dynamics

Essential dynamics(ED) is a useful method for analyzing trajectories generated by molecular dynamics (MD), but current tools are awkward to use, limiting the usefulness of the technique. This paper describes a new interactive graphical interface for visualization of ED results, including filtering a trajectory on an arbitrary set of eigenvectors and manipulation of a structures projection along any eigenvector.

Pancreatic imaging mimics: Part 1, imaging mimics of pancreatic adenocarcinoma

OBJECTIVE The purpose of this article is to describe the imaging features of diseases that may closely simulate pancreatic adenocarcinoma, either radiologically or pathologically. CONCLUSION Neoplastic and inflammatory diseases that can closely simulate pancreatic adenocarcinoma include neuroendocrine tumor, metastasis to the pancreas, lymphoma, groove pancreatitis, autoimmune pancreatitis, and focal chronic pancreatitis. Atypical imaging findings that should suggest diagnoses other than adenocarcinoma include the absence of significant duct dilatation, incidental detection, hypervascularity, large size (> 5 cm), IV tumor thrombus, and intralesional ducts or cysts.

The Radiologist's Workflow Environment: Evaluation of Disruptors and Potential Implications

Workflow interruptions in the health care delivery environment are a major contributor to medical errors and have been extensively studied within numerous hospital settings, including the nursing environment and the operating room, along with their effects on physician workflow. Less understood, though, is the role of interruptions in other highly specialized clinical domains and subspecialty services, such as diagnostic radiology. The workflow of the on-call radiologist, in particular, is especially susceptible to disruption by telephone calls and other modes of physician-to-physician communication. Herein, the authors describe their initial efforts to quantify the degree of interruption experienced by on-call radiologists and examine its potential implications in patient safety and overall clinical care.

Evaluation and binding-mode prediction of thiopyrone-based inhibitors of anthrax lethal factor.

Anthrax lethal factor (LF) is one of three proteins involved in anthrax pathogenesis and lethality. Inactivation of the LF gene in B. anthracis leads to a decrease in virulence by 1000-fold or greater, which suggests that anthrax pathology is highly dependent on LF. Herein, we report an effective inhibitor of anthrax lethal factor based on a heterocyclic chelator scaffold. We also present computational predictions of the binding mode for this inhibitor and evidence that accurate prediction of binding modes requires use of a molecular surface-like boundary between solute and solvent. Anthrax LF is a zinc(II)-dependent, hydrolytic enzyme that cleaves the N terminus of the D domain of mitogen-activated protein kinase kinases (MAPKKs). This cleavage impairs essential signal transduction pathways and results in macrophage apoptosis along with other harmful consequences for the host. The potential for bioterrorism and inadequate treatments for anthrax, especially at late stages of infection, have amplified interest in finding effective anthrax lethal factor inhibitors (LFi). Several approaches have led to the identification of a variety of LFi, including library screening and optimization, fragment-based NMR screening (BI-11B3, Figure 1), mass-spectrometry-based screening, and re-examination of inhibitors of other metalloACHTUNGTRENNUNGproteinases and related hydroxamate-based compounds. An example of the latter class is the broad-spectrum matrix metalloproteinase inhibitor (MMPi) GM6001 (Figure 1), which was found to be an effective inhibitor of LF in vitro and in cell culture. Structural characterization of GM6001 in the LF active site shows that the hydroxamate group of the inhibitor

Extravasated Contrast Material in Penetrating Abdominopelvic Trauma: Dual-Contrast Dual-Energy CT for Improved Diagnosis—Preliminary Results in an Animal Model

PURPOSE To compare the diagnostic performance of dual-energy (DE) computed tomography (CT) with two simultaneously administered contrast agents (hereafter, dual contrast) with that of conventional CT in the evaluation of the presence and source of extravasation in penetrating abdominopelvic trauma. MATERIALS AND METHODS Institutional animal care and use committee approval was obtained, and the study was performed in accordance with National Institutes of Health guidelines for the care and use of laboratory animals. Five rabbits with bowel trauma, vascular penetrating trauma, or both were imaged with simultaneous iodinated intravenous and bismuth subsalicylate enteric contrast material at DE CT. Four attending radiologists and six radiology residents without prior DE CT experience each evaluated 10 extraluminal collections to identify the vascular and/or enteric origin of extravasation and assess their level of diagnostic confidence, first with virtual monochromatic images simulating conventional CT and then with DE CT material decomposition attenuation maps. RESULTS Overall accuracy of identification of source of extravasation increased from 78% with conventional CT to 92% with DE CT (157 of 200 diagnoses vs 184 of 200 diagnoses, respectively; P < .001). Nine radiologists were more accurate with DE CT; one had no change. Mean confidence increased from 67% to 81% with DE CT (P < .001). CONCLUSION In a rabbit abdominopelvic trauma model, dual-contrast DE CT significantly increased accuracy and confidence in the diagnosis of vascular versus enteric extravasated contrast material.

In vivo comparison of tantalum, tungsten, and bismuth enteric contrast agents to complement intravenous iodine for double‐contrast dual‐energy CT of the bowel

To assess the ability of dual-energy CT (DECT) to separate intravenous contrast of bowel wall from intraluminal contrast, we scanned 16 rabbits on a clinical DECT scanner: n = 3 using only iodinated intravenous contrast, and n = 13 double-contrast enhanced scans using iodinated intravenous contrast and experimental enteric non-iodinated contrast agents in the bowel lumen (five bismuth, four tungsten, and four tantalum based). Representative image pairs from conventional CT images and DECT iodine density maps of small bowel (116 pairs from 232 images) were viewed by four abdominal imaging attending radiologists to independently score each comparison pair on a visual analog scale (-100 to +100%) for (1) preference in small bowel wall visualization and (2) preference in completeness of intraluminal enteric contrast subtraction. Median small bowel wall visualization was scored 39 and 42 percentage points (95% CI 30-44% and 36-45%, both p < 0.001) higher for double-contrast DECT than for conventional CT with enteric tungsten and tantalum contrast, respectively. Median small bowel wall visualization for double-contrast DECT was scored 29 and 35 percentage points (95% CI 20-35% and 33-39%, both p < 0.001) higher with enteric tungsten and tantalum, respectively, than with bismuth contrast. Median completeness of intraluminal enteric contrast subtraction in double-contrast DECT iodine density maps was scored 28 and 29 percentage points (95% CI 15-31% and 28-33%, both p < 0.001) higher with enteric tungsten and tantalum, respectively, than with bismuth contrast. Results suggest that in vivo double-contrast DECT with iodinated intravenous and either tantalum- or tungsten-based enteric contrast provides better visualization of small bowel than conventional CT. Copyright

Contrast Enhanced Ultrasound as a Radiation-Free Alternative to Fluoroscopic Nephrostogram for Evaluating Ureteral Patency

Purpose: We compared contrast enhanced ultrasound and fluoroscopic nephrostography in the evaluation of ureteral patency following percutaneous nephrolithotomy. Materials and Methods: This prospective cohort, noninferiority study was performed after obtaining institutional review board approval. We enrolled eligible patients with kidney and proximal ureteral stones who underwent percutaneous nephrolithotomy at our center. On postoperative day 1 patients received contrast enhanced ultrasound and fluoroscopic nephrostogram within 2 hours of each other to evaluate ureteral patency, which was the primary outcome of this study. Results: A total of 92 pairs of imaging studies were performed in 82 patients during the study period. Five study pairs were excluded due to technical errors that prevented imaging interpretation. Females slightly predominated over males with a mean ± SD age of 50.5 ± 15.9 years and a mean body mass index of 29.6 ± 8.6 kg/m2. Of the remaining 87 sets of studies 69 (79.3%) demonstrated concordant findings regarding ureteral patency for the 2 imaging techniques and 18 (20.7%) were discordant. The nephrostomy tube was removed on the same day in 15 of the 17 patients who demonstrated antegrade urine flow only on contrast enhanced ultrasound and they had no subsequent adverse events. No adverse events were noted related to ultrasound contrast injection. While contrast enhanced ultrasound used no ionizing radiation, fluoroscopic nephrostograms provided a mean radiation exposure dose of 2.8 ± 3.7 mGy. Conclusions: A contrast enhanced ultrasound nephrostogram can be safely performed to evaluate for ureteral patency following percutaneous nephrolithotomy. This imaging technique was mostly concordant with fluoroscopic findings. Most discordance was likely attributable to the higher sensitivity for patency of contrast enhanced ultrasound compared to fluoroscopy.

Age and sex-dependent trends in pulmonary embolism testing and derivation of a clinical decision rule for young patients

Importance Despite low prevalence of pulmonary embolism (PE) in young adults, they are frequently imaged for PE, which involves radiation exposure and substantial financial cost. Objective Determine the use and positive proportions for PE imaging by age, differences in clinical presentation of PE by age and the projected impact of an age-targeted decision rule. Design Analysis of two national population-based datasets: the 2009 Nationwide Emergency Department Sample, a 20% sample of US emergency departments (EDs) and the 2003–2006 Pulmonary Embolism Rule-out Criteria (PERC) dataset, a multisite cohort of ED patients with suspected PE from 12 US EDs. Results Prevalence of PE was 10 times lower in young patients (18–35 years) than in older patients (>65 years) (0.06% vs 0.60%, p<0.001), but young patients were imaged for PE almost as frequently as older patients (2.3% vs 3.2%). This resulted in a lower proportion of positive examinations in young adults than older adults (2.3% vs 17.4%, p<0.001 in women; 4.0% vs 21.4%, p<0.001 in men). Clinical predictors of PE varied by age. Tachycardia was a significant predictor of PE in older patients (OR: 1.2–1.9, p<0.001), but not young patients. Fever was a significant predictor only in young patients (OR: 1.4–7.2, p<0.01). A modification of the previously described PERC rule to include age-specific risk factors could reduce PE imaging by 51% in young patients, with a missed PE rate of 0.6% in those excluded from imaging. Conclusions and relevance Young patients are frequently imaged for PE and have lower positive imaging rates than older patients. After further validation, application of our proposed rule for excluding young patients from PE imaging could reduce imaging, increase the positive rate of imaging and result in a low rate of missed PE among those excluded from imaging.