Kartograf: A Geometrically Accurate Atom Mapper for Hybrid-Topology Relative Free Energy Calculations.

Relative binding free energy (RBFE) calculations have emerged as a powerful tool that supports ligand optimization in drug discovery. Despite many successes, the use of RBFEs can often be limited by automation problems, in particular, the setup of such calculations. Atom mapping algorithms are an essential component in setting up automatic large-scale hybrid-topology RBFE calculation campaigns. Traditional algorithms typically employ a 2D subgraph isomorphism solver (SIS) in order to estimate the maximum common substructure. SIS-based approaches can be limited by time-intensive operations and issues with capturing geometry-linked chemical properties, potentially leading to suboptimal solutions. To overcome these limitations, we have developed Kartograf, a geometric-graph-based algorithm that uses primarily the 3D coordinates of atoms to find a mapping between two ligands. In free energy approaches, the ligand conformations are usually derived from docking or other previous modeling approaches, giving the coordinates a certain importance. By considering the spatial relationships between atoms related to the molecule coordinates, our algorithm bypasses the computationally complex subgraph matching of SIS-based approaches and reduces the problem to a much simpler bipartite graph matching problem. Moreover, Kartograf effectively circumvents typical mapping issues induced by molecule symmetry and stereoisomerism, making it a more robust approach for atom mapping from a geometric perspective. To validate our method, we calculated mappings with our novel approach using a diverse set of small molecules and used the mappings in relative hydration and binding free energy calculations. The comparison with two SIS-based algorithms showed that Kartograf offers a fast alternative approach. The code for Kartograf is freely available on GitHub (https://github.com/OpenFreeEnergy/kartograf). While developed for the OpenFE ecosystem, Kartograf can also be utilized as a standalone Python package.

Path Sampling Simulations Reveal How the Q61L Mutation Alters the Dynamics of KRas.

Flexibility is essential for many proteins to function, but can be difficult to characterize. Experiments lack resolution in space and time, while the time scales involved are prohibitively long for straightforward molecular dynamics simulations. In this work, we present a multiple state transition path sampling simulation study of a protein that has been notoriously difficult to characterize in its active state. The GTPase enzyme KRas is a signal transduction protein in pathways for cell differentiation, growth, and division. When active, KRas tightly binds guanosine triphosphate (GTP) in a rigid state. The protein-GTP complex can also visit more flexible states, in which it is not active. KRas mutations can affect the conversion between these rigid and flexible states, thus prolonging the activation of signal transduction pathways, which may result in tumor formation. In this work, we apply path sampling simulations to investigate the dynamic behavior of KRas-4B (wild type, WT) and the oncogenic mutant Q61L (Q61L). Our results show that KRas visits several conformational states, which are the same for WT and Q61L. The multiple state transition path sampling (MSTPS) method samples transitions between the different states in a single calculation. Tracking which transitions occur shows large differences between WT and Q61L. The MSTPS results further reveal that for Q61L, a route to a more flexible state is inaccessible, thus shifting the equilibrium to more rigid states. The methodology presented here enables a detailed characterization of protein flexibility on time scales not accessible with brute-force molecular dynamics simulations.

ACR Appropriateness Criteria® Osteomyelitis or Septic Arthritis-Child (Excluding Axial Skeleton).

Imaging plays an integral role in the evaluation of suspected musculoskeletal infections in children, not only in the accurate identification of infection such as osteomyelitis or septic arthritis, but also in guiding management. Various diagnostic modalities serve different purposes in the assessment of suspected pediatric musculoskeletal infections. The purpose of this document is to provide imaging guidance in the most frequently encountered clinical scenarios in which osteomyelitis and/or septic arthritis are suspected, outside of the axial skeleton. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion.

Comparison of MRI appendix biometrics in children with and without acute appendicitis.

OBJECTIVES: The goal of this study is to improve MRI-specific diagnostic criteria for pediatric appendicitis through comparison of normal and abnormal appendix-related imaging features. METHODS: A retrospective multireader-multicase design was used, including non-contrast MRI performed for suspected pediatric appendicitis following non-diagnostic US from January 2014 to December 2017. Positive diagnosis was defined by surgical pathology or symptom resolution after antibiotics. Four pediatric radiologists independently graded study biometrics while blinded to clinical data. Balanced complete block design was used to determine performance characteristics. RESULTS: Global diagnosis of appendicitis (208 studies) had sensitivity 90.6% and specificity 97.7%. Median appendix diameter was 10.4 mm among positive cases and 5.8 mm among negative cases (p < 0.001) with an optimal diagnostic cutoff of 7.5 mm (sensitivity 89.4%, specificity 86.5%). Median appendix wall thickness was 2.6 mm among positive cases and 1.7 mm among negative cases (p < 0.001) with an optimal diagnostic cutoff of 2.3 mm (sensitivity 63.1%, specificity 82.9%). Performance characteristics for qualitative appendix features included distinguishable appendix luminal signal (sensitivity 89.6%, specificity 83.7%), intraluminal fluid-signal intensity (sensitivity 63.6%; specificity 52.3%), intraluminal signal intermediate between fluid and bowel wall (sensitivity 91.0%; specificity 37.1%), appendicolith (sensitivity 34.9%; specificity 100.0%), intraluminal layering (sensitivity 25.9%; specificity 100.0%), hyperintense appendix wall signal (sensitivity 31.7%; specificity 100.0%), periappendiceal fluid (sensitivity 66.8%; specificity 72.5%), periappendiceal fatty edema (sensitivity 91.3%; specificity 94.5%), and free pelvic fluid (sensitivity 88.5%; specificity 26.0). CONCLUSIONS: This study provides MRI-specific performance of pediatric appendicitis quantitative and qualitative biometrics with peri-appendiceal fatty edema, appendix diameter > 7.5 mm, and distinguishable appendix luminal signal demonstrating the highest overall accuracy. KEY POINTS: • This retrospective multireader-multicase study characterized magnetic resonance imaging-specific diagnostic accuracy of quantitative and qualitative biometrics for pediatric appendicitis. • The optimal quantitative diagnostic thresholds for an abnormal pediatric appendix at MRI included diameter and wall thickness of 7.5 mm and 2.3 mm, respectively. • Qualitative imaging biometrics with high specificity for pediatric appendicitis on MRI included the presence of distinguishable appendix lumen signal from wall signal, appendicolith, intraluminal fluid-fluid layer, appendix wall hyperintensity, and peri-appendiceal fatty edema.

Effects of multiphase versus single-phase CT angiography for the detection of distal cerebral vessel occlusion.

PURPOSE: The goal of this study was to determine whether the benefits of multiphase CTA (mCTA) over single-phase CTA (sCTA) for the detection of proximal cerebrovascular occlusions similarly extend to the distal cerebral vasculature. METHODS: Four attending radiologists, two neuroradiologists and two emergency radiologists, contributed as readers to this retrospective study. For each reader, two sessions were conducted, one using sCTA and one using mCTA. During each session, the reader interpreted the studies of 104 patients who underwent imaging for suspicion of acute ischemic stroke, resulting in a total of 832 interpretations. Changes in diagnostic accuracy, time to render final decision, and reported levels of reader confidence were quantitatively assessed. Further analysis comparing the effects for neuroradiologists versus emergency radiologists was additionally conducted. RESULTS: Using mCTA resulted in a significant 5.0% absolute increase in sensitivity (91.6% vs. 96.6%, p = .004) and an insignificant increase in specificity (99.5% vs. 99.7%, p = .39). A significant reduction in reading time (66.7 s vs. 59.6 s, p = .001) and an increase in diagnostic confidence (2.26 vs. 2.58, p < .001) were observed. Using sCTA, higher sensitivity was achieved by neuroradiologists than emergency radiologists (96.0% vs. 86.9%, p = .002); using mCTA resulted in an absolute increase in sensitivity of 0.9% (97.4%, p = .44) for neuroradiologists and 9.6% (96.5%, p < .001) for emergency radiologists, eliminating significant differences between the groups (p = 0.57). CONCLUSION: The use of mCTA results in increased sensitivity and negative predictive value, decreased reading time, increased diagnostic confidence, and the elimination of differences in accuracy between neuroradiologists and emergency radiologists.

Pediatric Panoramic Radiography: Techniques, Artifacts, and Interpretation.

Panoramic radiography, particularly in the pediatric population, is rarely addressed in the radiology literature. The authors provide an in-depth discussion of how these images are acquired, what artifacts can be visualized, and how to mitigate these artifacts. Dental anatomy, as well as relevant osseous and soft-tissue anatomy visible on a panoramic image, are reviewed. The appearance of the normal pediatric panoramic radiograph, with an emphasis on the dental follicle, is discussed, as well as how to differentiate this normal structure from underlying pathologic conditions. The most commonly encountered pathologic conditions of carious disease and trauma are emphasized. A systematic approach to diagnosing mass lesions and their appropriate work-up, including multimodality imaging examples of relevant pathologic conditions, is also provided. Finally, congenital anomalies, including some of the more commonly encountered dysplasias, are reviewed. The authors provide a concise review of the relevant information needed to confidently interpret a pediatric panoramic radiograph. The online slide presentation from the RSNA Annual Meeting is available for this article. ©RSNA, 2021.

Implementation and Impact of a Comprehensive Radiology Report Categorization System on Communication of Important Results.

PURPOSE: Effective communication of important imaging results is critical to patient care but difficult to accomplish efficiently. To improve communication at their institution, the authors introduced a radiology report categorization system (RADCAT) that organizes diagnostic imaging reports and uses automated communication systems. The study objectives were to (1) describe RADCAT's design, (2) evaluate its implementation for appropriate imaging, and (3) evaluate the communication of important, nonurgent results with recommended follow-up. METHODS: This retrospective study was performed in a multihospital adult and pediatric tertiary referral academic health system. The intervention, a radiology report categorization system with five levels of acuity and IT-supported communication workflows, was globally implemented in November 2017. The primary outcomes were the successful implementation of RADCAT to appropriate diagnostic imaging reports and the successful communication of important, nonurgent results with recommended follow-up to ordering providers and patients by the radiology quality assurance team. RESULTS: Over 18 months after implementation, 740,625 radiology reports were categorized under the RADCAT system, with 42%, 28%, and 30% from the emergency department, inpatient, and outpatient settings, respectively. A random selection of 100 studies from the 23,718 total reports without RADCAT categorization identified 4 diagnostic radiology reports that erroneously lacked RADCAT grading. In 2019, of the 38,701 studies with nonurgent imaging follow-up recommendations, 38,692 (nearly 100.0%) were successfully communicated to providers or patients on the basis of quality assurance data. CONCLUSIONS: A comprehensive radiology report categorization system was successfully implemented across a multihospital adult and pediatric health system, demonstrating reliable communication of imaging results with recommendations for nonacute imaging follow-up.

Survey of radiologists and emergency department providers after implementation of a global radiology report categorization system.

PURPOSE: Breakdown in communication of important imaging results threatens patient safety and risks malpractice claims. To facilitate closed-loop communication, our institution developed a unique radiology report categorization (RADCAT) system employing automated alert notification systems. This study aimed to understand users' initial experiences with the RADCAT system and obtain feedback. METHODS: Web-based surveys were distributed to radiologists and emergency department (ED) providers at our hospital system within 1 year of institution-wide RADCAT implementation. Survey designs differed based on clinical setting. Most prompts utilized declarative statements with 5-point agreement Likert scales. Closed-response data was analyzed with descriptive statistics. RESULTS: Response rates among radiologists and ED providers were 59.4% (63/106) and 38.4% (69/211), respectively. 78.0% (46/59) of radiologists and 60.9% (42/69) of ED providers agreed that RADCAT improves patient care. Of radiologists, 84.1% (53/63) agreed that RADCAT design is intuitive, and 57.6% (34/59) agreed that RADCAT improves efficiency. Of ED providers, 69.6% (48/69) agreed that RADCAT appropriately differentiates urgent and non-urgent findings, and 65.2% (45/69) agreed that auto-population of discharge documents with imaging results containing follow-up recommendations protects them from liability. Only 35.6% (21/59) of radiologists and 21.7% (15/69) of ED providers agreed that RADCAT implementation decreased reading room visits by ordering providers. Open-response feedback showed that some ED providers find RADCAT too complex while some radiologists desire improved transparency regarding imaging study communication status. CONCLUSION: Since its implementation, RADCAT has been well received among radiologists and ED providers with agreement that it improves patient care and effectively distinguishes and communicates important imaging findings.

Rethinking Greulich and Pyle: A Deep Learning Approach to Pediatric Bone Age Assessment Using Pediatric Trauma Hand Radiographs.

PURPOSE: To develop a deep learning approach to bone age assessment based on a training set of developmentally normal pediatric hand radiographs and to compare this approach with automated and manual bone age assessment methods based on Greulich and Pyle (GP). METHODS: In this retrospective study, a convolutional neural network (trauma hand radiograph-trained deep learning bone age assessment method [TDL-BAAM]) was trained on 15 129 frontal view pediatric trauma hand radiographs obtained between December 14, 2009, and May 31, 2017, from Children's Hospital of New York, to predict chronological age. A total of 214 trauma hand radiographs from Hasbro Children's Hospital were used as an independent test set. The test set was rated by the TDL-BAAM model as well as a GP-based deep learning model (GPDL-BAAM) and two pediatric radiologists (radiologists 1 and 2) using the GP method. All ratings were compared with chronological age using mean absolute error (MAE), and standard concordance analyses were performed. RESULTS: The MAE of the TDL-BAAM model was 11.1 months, compared with 12.9 months for GPDL-BAAM (P = .0005), 14.6 months for radiologist 1 (P < .0001), and 16.0 for radiologist 2 (P < .0001). For TDL-BAAM, 95.3% of predictions were within 24 months of chronological age compared with 91.6% for GPDL-BAAM (P = .096), 86.0% for radiologist 1 (P < .0001), and 84.6% for radiologist 2 (P < .0001). Concordance was high between all methods and chronological age (intraclass coefficient > 0.93). Deep learning models demonstrated a systematic bias with a tendency to overpredict age for younger children versus radiologists who showed a consistent mean bias. CONCLUSION: A deep learning model trained on pediatric trauma hand radiographs is on par with automated and manual GP-based methods for bone age assessment and provides a foundation for developing population-specific deep learning algorithms for bone age assessment in modern pediatric populations.Supplemental material is available for this article.© RSNA, 2020See also the commentary by Halabi in this issue.

Psychometric Validation of a Nonproprietary Survey of Patient Satisfaction for Use in Outpatient Radiology Centers.

OBJECTIVE: Demonstrate the psychometric evaluation process for and results from our radiology-specific patient experience measure. METHODS: We developed a survey to measure five dimensions of patient experience: (1) appointment, (2) reception, (3) registration, (4) procedure, and (5) facility. Each dimension included three to five questions. Each question was answered using a Likert scale (very dissatisfied to very satisfied). Data on procedure type, facility, radiologist interaction, health rating, survey length, and demographics were collected. The survey was implemented at 12 radiology offices. Analyses were conducted using responses from March 2018 to April 2019. Construct validation of the five dimensions was accomplished using confirmatory factor analysis (CFA). Internal consistency was examined using Cronbach and Guttman analysis. RESULTS: The sample included 20,736 subjects. There was strong evidence for construct validity of the five dimensions of patient experience. The CFA achieved the best fit with the five-factor model relative to other models (comparative fit index: 0.98, standardized root mean square error residual: 0.0307, root mean square error of approximation: 0.0371). There was high internal consistency (Cronbach's α 0.94, Guttman coefficient 0.93). Item analysis showed that no questions were consistently skipped. Eighty-two percent of participants said the survey was not too long. Patients reported high satisfaction on all dimensions of satisfaction across modalities and office sites. DISCUSSION: The CFA and internal consistency analyses provide evidence for this survey having good psychometric properties: construct validity for five dimensions of patient experience and high internal consistency among the items. This survey is intended to be used by, and to benefit, radiology practices and their patients.

Atomistic insight into the kinetic pathways for Watson-Crick to Hoogsteen transitions in DNA.

DNA predominantly contains Watson-Crick (WC) base pairs, but a non-negligible fraction of base pairs are in the Hoogsteen (HG) hydrogen bonding motif at any time. In HG, the purine is rotated ∼180° relative to the WC motif. The transitions between WC and HG may play a role in recognition and replication, but are difficult to investigate experimentally because they occur quickly, but only rarely. To gain insight into the mechanisms for this process, we performed transition path sampling simulations on a model nucleotide sequence in which an AT pair changes from WC to HG. This transition can occur in two ways, both starting with loss of hydrogen bonds in the base pair, followed by rotation around the glycosidic bond. In one route the adenine base converts from WC to HG geometry while remaining entirely within the double helix. The other route involves the adenine leaving the confines of the double helix and interacting with water. Our results indicate that this outside route is more probable. We used transition interface sampling to compute rate constants and relative free energies for the transitions between WC and HG. Our results agree with experiments, and provide highly detailed insights into the mechanisms of this important process.

Gadolinium-based contrast agents - review of recent literature on magnetic resonance imaging signal intensity changes and tissue deposits, with emphasis on pediatric patients.

Gadolinium has been used as a base for contrast agents in MRI for the last three decades. Numerous studies over the last 4 years have reported increased signal intensity in deep brain nuclei in non-contrast MRI images following gadolinium-based contrast agent (GBCA) administration. Pathology studies performed on adults and children, and rodent necropsy studies have also shown gadolinium deposition in brain and other tissues after GBCA administration. The purpose of this review was to summarize and discuss the knowledge gained from these reports and the relevance for imaging pediatric patients.

Survey of peer review programs among pediatric radiologists: report from the SPR Quality and Safety Committee.

During the last 15 years, peer review has been widely incorporated into radiology quality improvement programs. However, current implementations are variable and carry concerns, including subjectivity of numerical scores and a sense of merely satisfying regulatory requirements. The Society for Pediatric Radiology (SPR) Quality and Safety Committee sought to evaluate the state of peer review programs in pediatric radiology practices, including implementation methods, perceived functions, strengths and weaknesses, and opportunities for improvement. We distributed an online 16-question survey to SPR members. Questions pertained to the type of peer review system, the use of numerical scores and comments, how feedback on discordances is given and received, and the use of peer learning conferences. We collected 219 responses (15% of survey invitations), 80% of which were from children's hospitals. Fifty percent of respondents said they use a picture archiving and communication system (PACS)-integrated peer review system. Comment-enhanced feedback for interpretive discordances was either very important or somewhat important to performance improvement in 86% of responses, compared to 48% with a similar perception of numerical scores. Sixty-eight percent of respondents said they either rarely or never check their numerical scores, and 82% either strongly or somewhat agreed that comments are more effective feedback than numerical scores. Ninety-three percent either strongly or somewhat agreed that peer learning conferences would be beneficial to their practice. Forty-eight percent thought that their current peer review system should be modified. Survey results demonstrate that peer review systems in pediatric radiology practices are implemented variably, and nearly half of respondents believe their systems should be modified. Most respondents prefer feedback in the form of comments and peer learning conferences, which are thought to be more beneficial for performance improvement than numerical scores.

Practical considerations when implementing peer learning conferences.

Peer learning represents a shift away from traditional peer review. Peer learning focuses on improvement of diagnostic performance rather than on suboptimal performance. The shift in focus away from random selection and toward identification of cases with valuable teaching points can encourage more active radiologist engagement in the learning process. An effective peer learning program relies on a trusting environment that lessens the fear of embarrassment or punitive action. Here we describe the shortcomings of traditional peer review, and the benefits of peer learning. We also provide tips for a successful peer learning program and examples of implementation.

Information availability on emergency radiology fellowship websites: current state and paths to improvement.

PURPOSE: The purpose of this study is to detail the current state of the websites of each of the currently established emergency radiology fellowship programs within the USA, in terms of publicly available information. The goal of the project is to present data for emergency radiology fellowship programs to tailor that information to attract those most interested in the pursuit of an emergency radiology fellowship position. METHODS: Emergency radiology fellowship programs were identified using the American Society of Emergency Radiology website and recent published literature. The website for each program was evaluated for the presence or absence of 23 discrete areas of information. Additionally, information from a prior study evaluating radiology resident's opinions on desired information for interventional radiology fellowship websites was utilized and compared to the information currently available on emergency radiology fellowship websites. RESULTS: Eighteen emergency radiology fellowship programs were initially identified. One program website was inaccessible at the time of data collection. Of the remaining 17 program websites, contact information, application requirements, program description, stand-alone website, length of fellowship, research opportunities, salary, and other benefits were available for greater than 75% of programs, while listing of current fellows, moonlighting opportunities, social information, and alumni information were available at fewer than 25% of program websites. CONCLUSION: There is broad variability in the type and amount of data available to potential emergency radiology fellows across the surveyed program websites. Several key areas-specifically, listings of current fellows, rotation schedules, facility descriptions, and didactic information-present high-yield opportunities for improvement of desired accessible data.

OpenPathSampling: A Python Framework for Path Sampling Simulations. 1. Basics.

Transition path sampling techniques allow molecular dynamics simulations of complex systems to focus on rare dynamical events, providing insight into mechanisms and the ability to calculate rates inaccessible by ordinary dynamics simulations. While path sampling algorithms are conceptually as simple as importance sampling Monte Carlo, the technical complexity of their implementation has kept these techniques out of reach of the broad community. Here, we introduce an easy-to-use Python framework called OpenPathSampling (OPS) that facilitates path sampling for (bio)molecular systems with minimal effort and yet is still extensible. Interfaces to OpenMM and an internal dynamics engine for simple models are provided in the initial release, but new molecular simulation packages can easily be added. Multiple ready-to-use transition path sampling methodologies are implemented, including standard transition path sampling (TPS) between reactant and product states and transition interface sampling (TIS) and its replica exchange variant (RETIS), as well as recent multistate and multiset extensions of transition interface sampling (MSTIS, MISTIS). In addition, tools are provided to facilitate the implementation of new path sampling schemes built on basic path sampling components. In this paper, we give an overview of the design of this framework and illustrate the simplicity of applying the available path sampling algorithms to a variety of benchmark problems.

OpenPathSampling: A Python Framework for Path Sampling Simulations. 2. Building and Customizing Path Ensembles and Sample Schemes.

The OpenPathSampling (OPS) package provides an easy-to-use framework to apply transition path sampling methodologies to complex molecular systems with a minimum of effort. Yet, the extensibility of OPS allows for the exploration of new path sampling algorithms by building on a variety of basic operations. In a companion paper [ Swenson et al. J. Chem. Theory Comput. 2018 , 10.1021/acs.jctc.8b00626 ] we introduced the basic concepts and the structure of the OPS package, and how it can be employed to perform standard transition path sampling and (replica exchange) transition interface sampling. In this paper, we elaborate on two theoretical developments that went into the design of OPS. The first development relates to the construction of path ensembles, the what is being sampled. We introduce a novel set-based notation for the path ensemble, which provides an alternative paradigm for constructing path ensembles and allows building arbitrarily complex path ensembles from fundamental ones. The second fundamental development is the structure for the customization of Monte Carlo procedures; how path ensembles are being sampled. We describe in detail the OPS objects that implement this approach to customization, the MoveScheme and the PathMover, and provide tools to create and manipulate these objects. We illustrate both the path ensemble building and sampling scheme customization with several examples. OPS thus facilitates both standard path sampling application in complex systems as well as the development of new path sampling methodology, beyond the default.

Falling through the worm hole: an exploration of the imaging workup of the vermiform appendix in the pediatric population.

Despite the thousands of articles discussing appendicitis in the literature, the dilemma of how to best diagnosis and manage pediatric appendicitis remains unsettled. Over the past decade, evidence has been mounting about the use of antibiotics as the sole therapy in uncomplicated appendicitis in the adult population. This debate has even recently bled over into the lay press. While this change in practice pattern is still in its infancy for the pediatric population, radiologists should be aware of this change in therapy and how it can impact the imaging work-up and relevant findings. This article concisely summarizes the imaging findings and various imaging pathways to arrive at the diagnose of appendicitis with an emphasis of how to best be of use to our surgical colleagues in this evolving paradigm. It also highlights venues for further research, namely increasing accuracy of differentiating complicated from uncomplicated appendicitis.