3D printed phantom with 12 000 submillimeter lesions to improve efficiency in CT detectability assessment.

BACKGROUND: The detectability performance of a CT scanner is difficult to precisely quantify when nonlinearities are present in reconstruction. An efficient detectability assessment method that is sensitive to small effects of dose and scanner settings is desirable. We previously proposed a method using a search challenge instrument: a phantom is embedded with hundreds of lesions at random locations, and a model observer is used to detect lesions. Preliminary tests in simulation and a prototype showed promising results. PURPOSE: In this work, we fabricated a full-size search challenge phantom with design updates, including changes to lesion size, contrast, and number, and studied our implementation by comparing the lesion detectability from a nonprewhitening (NPW) model observer between different reconstructions at different exposure levels, and by estimating the instrument sensitivity to detect changes in dose. METHODS: Designed to fit into QRM anthropomorphic phantoms, our search challenge phantom is a cylindrical insert 10 cm wide and 4 cm thick, embedded with 12 000 lesions (nominal width of 0.6 mm, height of 0.8 mm, and contrast of -350 HU), and was fabricated using PixelPrint, a 3D printing technique. The insert was scanned alone at a high dose to assess printing accuracy. To evaluate lesion detectability, the insert was placed in a QRM thorax phantom and scanned from 50 to 625 mAs with increments of 25 mAs, once per exposure level, and the average of all exposure levels was used as high-dose reference. Scans were reconstructed with three different settings: filtered-backprojection (FBP) with Br40 and Br59, and Sinogram Affirmed Iterative Reconstruction (SAFIRE) with strength level 5 and Br59 kernel. An NPW model observer was used to search for lesions, and detection performance of different settings were compared using area under the exponential transform of free response ROC curve (AUC). Using propagation of uncertainty, the sensitivity to changes in dose was estimated by the percent change in exposure due to one standard deviation of AUC, measured from 5 repeat scans at 100, 200, 300, and 400 mAs. RESULTS: The printed insert lesions had an average position error of 0.20 mm compared to printing reference. As the exposure level increases from 50 mAs to 625 mAs, the lesion detectability AUCs increase from 0.38 to 0.92, 0.42 to 0.98, and 0.41 to 0.97 for FBP Br40, FBP Br59, and SAFIRE Br59, respectively, with a lower rate of increase at higher exposure level. FBP Br59 performed best with AUC 0.01 higher than SAFIRE Br59 on average and 0.07 higher than FBP Br40 (all P < 0.001). The standard deviation of AUC was less than 0.006, and the sensitivity to detect changes in mAs was within 2% for FBP Br59. CONCLUSIONS: Our 3D-printed search challenge phantom with 12 000 submillimeter lesions, together with an NPW model observer, provide an efficient CT detectability assessment method that is sensitive to subtle effects in reconstruction and is sensitive to small changes in dose.

Feasibility of precision smoking treatment in a low-income community setting: results of a pilot randomized controlled trial in The Southern Community Cohort Study.

BACKGROUND: The feasibility of precision smoking treatment in socioeconomically disadvantaged communities has not been studied. METHODS: Participants in the Southern Community Cohort Study who smoked daily were invited to join a pilot randomized controlled trial of three smoking cessation interventions: guideline-based care (GBC), GBC plus nicotine metabolism-informed care (MIC), and GBC plus counseling guided by a polygenic risk score (PRS) for lung cancer. Feasibility was assessed by rates of study enrollment, engagement, and retention, targeting > 70% for each. Using logistic regression, we also assessed whether feasibility varied by age, sex, race, income, education, and attitudes toward precision smoking treatment. RESULTS: Of 92 eligible individuals (79.3% Black; 68.2% with household income < $15,000), 67 (72.8%; 95% CI 63.0-80.9%) enrolled and were randomized. Of these, 58 (86.6%; 95% CI 76.4-92.8%) engaged with the intervention, and of these engaged participants, 43 (74.1%; 95% CI 61.6-83.7%) were retained at 6-month follow-up. Conditional on enrollment, older age was associated with lower engagement (OR 0.83, 95% CI 0.73-0.95, p = 0.008). Conditional on engagement, retention was significantly lower in the PRS arm than in the GBC arm (OR 0.18, 95% CI 0.03-1.00, p = 0.050). No other selection effects were observed. CONCLUSIONS: Genetically informed precision smoking cessation interventions are feasible in socioeconomically disadvantaged communities, exhibiting high enrollment, engagement, and retention irrespective of race, sex, income, education, or attitudes toward precision smoking treatment. Future smoking cessation interventions in this population should take steps to engage older people and to sustain participation in interventions that include genetic risk counseling. TRIAL REGISTRATION: ClinicalTrials.gov No. NCT03521141, Registered 27 April 2018, https://www. CLINICALTRIALS: gov/study/NCT03521141.

Possible improvements in effective fill factor using X-ray fluorescent interpixel reflectors.

BACKGROUND: The spatial resolution of energy-integrating diagnostic CT scanners is limited by interpixel reflectors on the detector, which optically isolate pixels but create dead space. Because the width of the reflector cannot easily be decreased, fill factor diminishes as resolution increases. PURPOSE: We propose loading (or mixing) a high-Z element into the reflectors, causing the reflectors to be X-ray fluorescent. Re-emitted characteristic X-rays could be detected in adjacent pixels, increasing the effective fill factor and compensating for fill factor loss with higher-resolution detectors. The purpose of this work is to understand the physical principles of this approach and to analyze its effectiveness using Monte Carlo simulations. METHODS: Detector pixels were modeled using the GEANT4 Monte Carlo package. The width of the reflector was kept constant at 0.1 mm throughout, and we considered pixel pitches between 0.5 and 1 mm. The pixelated scintillator material was gadolinium oxysulfide, 3 mm thick. The baseline reflector material was chosen to be acrylic, and varying concentrations of a high-Z element were loaded into the material. We assumed that the optical characteristics of pixels were ideal (no absorption within pixels, perfect reflection at boundaries). The detector was irradiated uniformly with 10,000 X-ray photons to estimate its spectral response. The figure of merit was the variance of the detector signal at zero frequency normalized to that of an ideal single-bin photon-counting detector with 100% fill factor. Sensitivity analyses were conducted to understand the effect of varying the high-Z element concentration and the spectrum. RESULTS: Initial simulations suggested that a k-edge near 50 keV would be ideal. Gd was therefore selected as the high-Z material. The relative variances for a conventional energy integrating detector without Gd at 1 mm pixel pitch (81% fill factor) and 0.5 mm pixel pitch (64% fill factor) were 1.38 and 1.74, compared to 1.00 for an ideal photon counting detector, implying a 26% variance penalty for 0.5 mm pitch. When 1 g/cm3 Gd was loaded into the interpixel reflector, the relative variance improved to 1.27 and 1.43, respectively, implying that the variance penalty for including Gd together with 0.5 mm pitch is only 4%. Performance was nearly maximized at 1.0 g/cm3 of Gd, but a concentration of 0.5 g/cm3 of Gd showed most of the benefit. Improvements depend weakly on kV, with lower kV associated with higher improvements. An external anti-scatter grid was not modeled in our simulations and would reduce the expected benefit, depending greatly on the pitch and dimensionality of the anti-scatter grid. CONCLUSIONS: The losses in fill factor associated with smaller pixel pitch can be reduced if Gd or a similar element could be loaded into the interpixel reflector. These improvements in noise efficiency are yet to be verified experimentally.

Direct energy binning for photon counting detectors: Simulation study.

BACKGROUND: Photon counting detectors (PCDs) for x-ray computed tomography (CT) face spectral distortion from pulse pileup and charge sharing. The photon counting scheme used by many PCDs is threshold-subtract (TS) with pulse height analysis (PHA), where each counter counts up-crossing events when pulses exceed an energy threshold. PCD data are not Poisson-distributed due to charge sharing and pulse pileup, but the counting statistics have never been studied yet. PURPOSE: The objectives of this study were (1) to propose a modified photon counting scheme, direct energy binning (DB), that is expected to be robust against pulse pileup; (2) to assess the performance of DB compared to TS; and (3) to evaluate its counting statistics. METHODS: With DB scheme, counter k starts a timer upon an up-crossing event of energy threshold k, and adds a count only if the next higher energy threshold (k+1) was not crossed within a short time window (hence, the pulse peak belongs to the energy bin k). We used Monte Carlo (MC) simulation and assessed count-rate curves and count-rate-dependent spectral imaging task performance for conventional CT imaging as well as water thickness estimation, water-bone material decomposition, and K-edge imaging with tungsten as the K-edge material. We also assessed count-rate-dependent measurement statistics such as expectation, variance, and covariance of total counts as well as energy bin outputs. The agreement with counting statistics models was also evaluated. RESULTS: The DB scheme improved the count-rate curve, that is, mean measured counts as a function of input count-rate, and peaked with 59% higher count-rate capability than the TS scheme (3.5 × 108 counts per second (cps)/mm2 versus 2.3 × 108  cps/mm2 ). The Cramér-Rao lower bounds (CRLB) of the variance of basis line integrals estimation for DB was better than those for TS by 2% for the conventional CT imaging, 30% for water-bone material decomposition, and 32% for K-edge imaging at 1000 mA (at 7.3 × 107  cps/sub-pixel after charge sharing). When count-rates were lower, PCD data statistics were dominated by charge sharing: the variance of total counts and lower energy bins was larger than the mean counts; the covariance of bin data was positive and non-zero. When count-rates were higher, PCD data statistics were dominated by pulse pileup: the variance of data was lower than the mean; the covariance of bin data was negative. The transition between the two regimes occurred smoothly, and pulse pileup dominated the statistics ≥400 mA (when the count-rate after charge sharing was 2.9 × 107  cps/sub-pixel and the probability of count-loss for DB was 37%). Both DB and TS had good agreement with Yu-Fessler's models of total counts; however, DB had a better agreement with Wang's variance and covariance models for energy bin data than TS did. CONCLUSIONS: The proposed DB scheme had several advantages over TS. At low to moderate flux, DB could improve the resilience of PCDs to pulse pileup. Counting statistics deviated from the Poisson distribution due to charge sharing for lower count-rate conditions and pulse pileup for higher count-rate conditions.

Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: A randomized controlled trial.

AIM: The aim was to determine whether specialist-led habit training using Habit Training with Biofeedback (HTBF) is more effective than specialist-led habit training alone (HT) for chronic constipation and whether outcomes of interventions are improved by stratification to HTBF or HT based on diagnosis (functional defaecation disorder vs. no functional defaecation disorder) by radio-physiological investigations (INVEST). METHOD: This was a parallel three-arm randomized single-blinded controlled trial, permitting two randomized comparisons: HTBF versus HT alone; INVEST- versus no-INVEST-guided intervention. The inclusion criteria were age 18-70 years; attending specialist hospitals in England; self-reported constipation for >6 months; refractory to basic treatment. The main exclusions were secondary constipation and previous experience of the trial interventions. The primary outcome was the mean change in Patient Assessment of Constipation Quality of Life score at 6 months on intention to treat. The secondary outcomes were validated disease-specific and psychological questionnaires and cost-effectiveness (based on EQ-5D-5L). RESULTS: In all, 182 patients were randomized 3:3:2 (target 384): HT n = 68; HTBF n = 68; INVEST-guided treatment n = 46. All interventions had similar reductions (improvement) in the primary outcome at 6 months (approximately -0.8 points of a 4-point scale) with no statistically significant difference between HT and HTBF (-0.03 points; 95% CI -0.33 to 0.27; P = 0.85) or INVEST versus no-INVEST (0.22; -0.11 to 0.55; P = 0.19). Secondary outcomes showed a benefit for all interventions with no evidence of greater cost-effectiveness of HTBF or INVEST compared with HT. CONCLUSION: The results of the study at 6 months were inconclusive. However, with the caveat of under-recruitment and further attrition at 6 months, a simple, cheaper approach to intervention may be as clinically effective and more cost-effective than more complex and invasive approaches.

The community engagement course and action network: strengthening community and academic research partnerships to advance health equity.

Background: Historically Black Colleges and Universities and Minority Serving Institutions are uniquely positioned to implement community-campus research partnerships based on a history of service, the pursuit of community trustworthiness and student demographics often similar to surrounding marginalized communities. The Morehouse School of Medicine Prevention Research Center collaborates with members of Historically Black Colleges and Universities, Minority Serving Institutes, and community organizations on the Community Engaged Course and Action Network. This network is the first of its kind and aims to strengthen members' ability to implement Community-Based Participatory Research (CBPR) principles and partnerships. Projects address public health priorities including mental health among communities of color, zoonotic disease prevention, and urban food deserts. Materials and methods: To assess the effectiveness of the network, a Participatory Evaluation framework was implemented to conduct process evaluation which included review of partnership structures, operations, project implementation processes, and preliminary outcomes of the research collaborations. A focus group of Community Engagement Course and Action Network members (community and academic) was also conducted to identify benefits and challenges of the network with emphasis on key areas for improvement to further enhance the relationships between partners and to facilitate their subsequent community-campus research. Results: Network improvements were tied to themes strengthening community-academic partnerships including sharing and fellowship, coalition building and collaboration, and greater connections and awareness of community needs through their current community-academic partnerships. The need to conduct ongoing evaluation during and after implementation, for determining the early adoption of CBPR approaches was also identified. Conclusion: Evaluation of the network's processes, infrastructure, and operation provides early lessons learned to strengthen the network. Ongoing assessment is also essential for ensuring continuous quality improvement across partnerships such as determining CBPR fidelity, assessing partnership synergy, and dynamics, and for quality improvement of research protocol. The implications and potential for advancing implementation science through this and similar networks are great towards advancing leadership in modeling how foundations in community service can advance to CBPR partnership formation and ultimately, health equity approaches, that are local defined and assessed.

Can Treatment Support Mitigate Nicotine Metabolism-Based Disparities in Smoking Abstinence? Secondary Analysis of the Helping HAND 4 Trial.

INTRODUCTION: The nicotine metabolite ratio (NMR), a biomarker of CYP2A6-mediated nicotine metabolism, predicts the efficacy of nicotine replacement therapy (NRT), with fast metabolizers benefiting less than slow metabolizers. Whether treatment support to optimize NRT use (henceforth "treatment support") modifies this pharmacogenetic relationship is unknown. METHODS: Hospitalized adult daily smokers were assigned to one of two post-discharge smoking cessation interventions offering NRT and counseling: (1) Transitional Tobacco Care Management, which delivered enhanced treatment support via free combination NRT at discharge and automated counseling, and (2) a quitline-based approach representing usual care (UC). The primary outcome was biochemically verified 7-day point prevalence abstinence 6 months after discharge. Secondary outcomes were the use of NRT and counseling during the 3-month intervention period. Logistic regression models tested for interactions between NMR and intervention, controlling for sex, race, alcohol use, and BMI. RESULTS: Participants (N = 321) were classified as slow (n = 80) or fast (n = 241) metabolizers relative to the first quartile of NMR (0.012-0.219 vs. 0.221-3.455, respectively). Under UC, fast (vs. slow) metabolizers had lower odds of abstinence at 6 months (aOR 0.35, 95% CI 0.13-0.95) and similar odds of NRT and counseling use. Compared to UC, enhanced treatment support increased abstinence (aOR 2.13, 95% CI 0.98-4.64) and use of combination NRT (aOR 4.62, 95% CI 2.57-8.31) in fast metabolizers, while reducing abstinence in slow metabolizers (aOR 0.21, 95% CI 0.05-0.87; NMR-by-intervention interaction p = .004). CONCLUSIONS: Treatment support increased abstinence and optimal use of NRT among fast nicotine metabolizers, thereby mitigating the gap in abstinence between fast and slow metabolizers. IMPLICATIONS: In this secondary analysis of two smoking cessation interventions for recently hospitalized smokers, fast nicotine metabolizers quit at lower rates than slow metabolizers, but providing fast metabolizers with enhanced treatment support doubled the odds of quitting in this group and mitigated the disparity in abstinence between fast and slow metabolizers. If validated, these findings could lead to personalized approaches to smoking cessation treatment that improve outcomes by targeting treatment support to those who need it most.

Racial, Ethnic, and Socioeconomic Disparities in Out-of-Hospital Pain Management for Patients With Long Bone Fractures.

STUDY OBJECTIVE: To evaluate racial and ethnic disparities in out-of-hospital analgesic administration, accounting for the influence of clinical characteristics and community socioeconomic vulnerability, among a national cohort of patients with long bone fractures. METHODS: Using the 2019-2020 ESO Data Collaborative, we retrospectively analyzed emergency medical services (EMS) records for 9-1-1 advanced life support transport of adult patients diagnosed with long bone fractures at the emergency department. We calculated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for out-of-hospital analgesic administration by race and ethnicity, accounting for age, sex, insurance, fracture location, transport time, pain severity, and scene Social Vulnerability Index. We reviewed a random sample of EMS narratives without analgesic administration to identify whether other clinical factors or patient preferences could explain differences in analgesic administration by race and ethnicity. RESULTS: Among 35,711 patients transported by 400 EMS agencies, 81% were White, non-Hispanic, 10% were Black, non-Hispanic, and 7% were Hispanic. In crude analyses, Black, non-Hispanic patients with severe pain were less likely to receive analgesics compared with White, non-Hispanic patients (59% versus 72%; Risk Difference: -12.5%, 95% CI: -15.8% to -9.9%). After adjustment, Black, non-Hispanic patients remained less likely to receive analgesics compared with White, non-Hispanic patients (aOR:0.65, 95% CI:0.53 to 0.79). Narrative review identified similar rates of patients declining analgesics offered by EMS and analgesic contraindications across racial and ethnic groups. CONCLUSIONS: Among EMS patients with long bone fractures, Black, non-Hispanic patients were substantially less likely to receive out-of-hospital analgesics compared with White, non-Hispanic patients. These disparities were not explained by differences in clinical presentations, patient preferences, or community socioeconomic conditions.

Rectal Prolapse Following Repair of Anorectal Malformation: Incidence, Risk Factors, and Management.

BACKGROUND: The incidence and optimal management of rectal prolapse following repair of an anorectal malformation (ARM) has not been well-defined. METHODS: A retrospective cohort study was performed utilizing data from the Pediatric Colorectal and Pelvic Learning Consortium registry. All children with a history of ARM repair were included. Our primary outcome was rectal prolapse. Secondary outcomes included operative management of prolapse and anoplasty stricture following operative management of prolapse. Univariate analyses were performed to identify patient factors associated with our primary and secondary outcomes. A multivariable logistic regression was developed to assess the association between laparoscopic ARM repair and rectal prolapse. RESULTS: A total of 1140 patients met inclusion criteria; 163 (14.3%) developed rectal prolapse. On univariate analysis, prolapse was significantly associated with male sex, sacral abnormalities, ARM type, ARM complexity, and laparoscopic ARM repairs (p < 0.001). ARM types with the highest rates of prolapse included rectourethral-prostatic fistula (29.2%), rectovesical/bladder neck fistula (28.8%), and cloaca (25.0%). Of those who developed prolapse, 110 (67.5%) underwent operative management. Anoplasty strictures developed in 27 (24.5%) patients after prolapse repair. After controlling for ARM type and hospital, laparoscopic ARM repair was not significantly associated with prolapse (adjusted odds ratio (95% CI): 1.50 (0.84, 2.66), p = 0.17). CONCLUSION: Rectal prolapse develops in a significant subset of patients following ARM repair. Risk factors for prolapse include male sex, complex ARM type, and sacral abnormalities. Further research investigating the indications for operative management of prolapse and operative techniques for prolapse repair are needed to define optimal treatment. TYPE OF STUDY: Retrospective cohort study. LEVEL OF EVIDENCE: II.

Dollars and Sense: The Business of Pediatric Surgery.

INTRODUCTION: This study evaluated North American pediatric surgeons' opinions and knowledge of business and economics in medicine and their perceptions of trends in their healthcare delivery environment. METHODS: We conducted an elective online survey of 1119 American Pediatric Surgical Association members. Over 8 mo, we iteratively developed the survey focused on four areas: opinion, knowledge, current practice environment, and trends in practice environment over the past 5 y. RESULTS: We received 227 (20.3%) complete surveys from pediatric surgeons. One hundred ninety four (85.5%) perceive healthcare as a business and most (85.9%) believe healthcare decisions may affect patients' out-of-pocket expenses. More than half (51.1%) of surgeons believe it has become more challenging to perform emergent cases and most believe staff quality has decreased for elective (56.4%) and emergent (63.0%) cases over the past 5 y. CONCLUSIONS: Pediatric surgeons recognize that medicine is a business and have concerns regarding the decreasing quality of operating room staff and the increasing difficulty providing surgical care over the last 5 y.

Characterizing hospitalization trajectories in the high-need, high-cost population using electronic health record data.

High utilization by a minority of patients accounts for a large share of health care costs, but the dynamics of this utilization remain poorly understood. We sought to characterize longitudinal trajectories of hospitalization among adult patients at an academic medical center from 2017 to 2023. Among 3404 patients meeting eligibility criteria, following an initial "rising-risk" period of 3 hospitalizations in 6 months, growth mixture modeling discerned 4 clusters of subsequent hospitalization trajectories: no further utilization, low chronic utilization, persistently high utilization with a slow rate of increase, and persistently high utilization with a fast rate of increase. Baseline factors associated with higher-order hospitalization trajectories included admission to a nonsurgical service, full code status, intensive care unit-level care, opioid administration, discharge home, and comorbid cardiovascular disease, end-stage kidney or liver disease, or cancer. Characterizing hospitalization trajectories and their correlates in this manner lays groundwork for early identification of those most likely to become high-need, high-cost patients.

Incidence and management of pleural effusions in patients with Wilms tumor: A Pediatric Surgical Oncology Research Collaborative study.

Wilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi-institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P = .004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event-free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage-specific treatment regimens.

A minimum SNR criterion for computed tomography object detection in the projection domain.

BACKGROUND: A common rule of thumb for object detection is the Rose criterion, which states that a signal must be five standard deviations above background to be detectable to a human observer. The validity of the Rose criterion in CT imaging is limited due to the presence of correlated noise. Recent reconstruction and denoising methodologies are also able to restore apparent image quality in very noisy conditions, and the ultimate limits of these methodologies are not yet known. PURPOSE: To establish a lower bound on the minimum achievable signal-to-noise ratio (SNR) for object detection, below which detection performance is poor regardless of reconstruction or denoising methodology. METHODS: We consider a numerical observer that operates on projection data and has perfect knowledge of the background and the objects to be detected, and determine the minimum projection SNR that is necessary to achieve predetermined lesion-level sensitivity and case-level specificity targets. We define a set of discrete signal objects O $\mathcal{O}$ that encompasses any lesion of interest and could include lesions of different sizes, shapes, and locations. The task is to determine which object of O $\mathcal{O}$ is present, or to state the null hypothesis that no object is present. We constrain each object in O $\mathcal{O}$ to have equivalent projection SNR and use Monte Carlo methods to calculate the required projection SNR necessary. Because our calculations are performed in projection space, they impose an upper limit on the performance possible from reconstructed images. We chose O $\mathcal{O}$ to be a collection of elliptical or circular low contrast metastases and simulated detection of these objects in a parallel beam system with Gaussian statistics. Unless otherwise stated, we assume a target of 80% lesion-level sensitivity and 80% case-level specificity and a search field of view that is 6 cm by 6 cm by 10 slices. RESULTS: When O $\mathcal{O}$ contains only a single object, our problem is equivalent to two-alternative forced choice (2AFC) and the required projection SNR is 1.7. When O $\mathcal{O}$ consists of circular 6-mm lesions at different locations in space, the required projection SNR is 5.1. When O $\mathcal{O}$ is extended to include ellipses and circles of different sizes, the required projection SNR increases to 5.3. The required SNR increases if the sensitivity target, specificity target, or search field of view increases. CONCLUSIONS: Even with perfect knowledge of the background and target objects, the ideal observer still requires an SNR of approximately 5. This is a lower bound on the SNR that would be required in real conditions, where the background and target objects are not known perfectly. Algorithms that denoise lesions with less than 5 projection SNR, regardless of the denoising methodology, are expected to show vanishing effects or false positive lesions.

Progress towards an OECD reporting framework for transcriptomics and metabolomics in regulatory toxicology.

Omics methodologies are widely used in toxicological research to understand modes and mechanisms of toxicity. Increasingly, these methodologies are being applied to questions of regulatory interest such as molecular point-of-departure derivation and chemical grouping/read-across. Despite its value, widespread regulatory acceptance of omics data has not yet occurred. Barriers to the routine application of omics data in regulatory decision making have been: 1) lack of transparency for data processing methods used to convert raw data into an interpretable list of observations; and 2) lack of standardization in reporting to ensure that omics data, associated metadata and the methodologies used to generate results are available for review by stakeholders, including regulators. Thus, in 2017, the Organisation for Economic Co-operation and Development (OECD) Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST) launched a project to develop guidance for the reporting of omics data aimed at fostering further regulatory use. Here, we report on the ongoing development of the first formal reporting framework describing the processing and analysis of both transcriptomic and metabolomic data for regulatory toxicology. We introduce the modular structure, content, harmonization and strategy for trialling this reporting framework prior to its publication by the OECD.

A thermodynamic scaling law for electrically perturbed lipid membranes: Validation with steepest entropy ascent framework.

Experimental evidence has demonstrated the ability of transient pulses of electric fields to alter mammalian cell behavior. Strategies with these pulsed electric fields (PEFs) have been developed for clinical applications in cancer therapeutics, in-vivo decellularization, and tissue regeneration. Successful implementation of these strategies involve understanding how PEFs impact the cellular structures and, hence, cell behavior. The caveat, however, is that the PEF parameter space (i.e., comprising different pulse widths, amplitudes, number of pulses) is large, and design of experiments to explore all possible combinations of pulse parameters is prohibitive from a cost and time standpoint. In this study, a scaling law based on the Ising model is introduced to understand the impact of PEFs on the outer cell lipid membrane so that an understanding developed in one PEF pulse regime may be extended to another. Combining non-Markovian Monte Carlo techniques to determine density-of-states with a novel non-equilibrium thermodynamic framework based on the principle of steepest entropy ascent, the applicability of this scaling model to predict the behavior of both thermally quenched and electrically perturbed lipid membranes is demonstrated. A comparison of the predictions made by the steepest-entropy-ascent quantum thermodynamic (SEAQT) framework to experimental data is performed to validate the robustness of this computational methodology and the resulting scaling law.

Improving Paralysis Compensation in Photon Counting Detectors.

Photon counting detectors (PCDs) are classically described as being either paralyzable or nonparalyzable. When the PCD is paralyzed, it is no longer sensitive to the detection of additional flux. A recent strategy in PCD design has been to compensate for detector paralysis by embedding specialized paralysis compensation electronics into the application-specific integrated circuit (ASIC). One such compensation mechanism is the pileup trigger, which places an additional energy bin at very high energy that is triggered only during pileup. Another compensation mechanism is the retrigger architecture, which converts a paralyzable PCD into a nonparalyzable PCD. We propose a third mechanism that modifies the retrigger architecture using dedicated secondary counters. We studied the incremental benefit of these three paralysis compensation mechanisms in simulation. We modeled the spectral response using Monte Carlo simulations and then estimated the variance in basis material decomposition of a single pixel using the Cramér-Rao lower bound (CRLB). In the absence of paralysis compensation, noise in basis material images shows sharp increases at moderate flux (near the characteristic count rate) due to contrast inversion and again at high flux. The pileup trigger reduces noise at high flux but does not eliminate contrast inversion. The retrigger architecture eliminates contrast inversion but does not reduce noise at high flux. Our proposed retrigger architecture with dedicated secondary counters reduce noise at both moderate and high flux.

Electro-chemo-mechanical model to investigate multi-pulse electric-field-driven integrin clustering.

The effect of pulsed electric fields (PEFs) on transmembrane proteins is not fully understood; how do chemo-mechanical cues in the microenvironment mediate the electric field sensing by these proteins? To answer this key gap in knowledge, we have developed a kinetic Monte Carlo statistical model of the integrin proteins that integrates three components of the morphogenetic field (i.e., chemical, mechanical, and electrical cues). Specifically, the model incorporates the mechanical stiffness of the cell membrane, the ligand density of the extracellular environment, the glycocalyx stiffness, thermal Brownian motion, and electric field induced diffusion. The effects of both steady-state electric fields and transient PEF pulse trains on integrin clustering are studied. Our results reveal that electric-field-driven integrin clustering is mediated by membrane stiffness and ligand density. In addition, we explore the effects of PEF pulse-train parameters (amplitude, polarity, and pulse-width) on integrin clustering. In summary, we demonstrate a computational methodology to incorporate experimental data and simulate integrin clustering when exposed to PEFs for time-scales comparable to experiments (seconds-minutes). Thus, we propose a blueprint for understanding PEF/electric field effects on protein induced signaling and highlight key impediments to incorporating experimental values into computational models such as the kinetic Monte Carlo method.

Coexistent faecal incontinence and constipation: A cross-sectional study of 4027 adults undergoing specialist assessment.

BACKGROUND: In contrast to paediatric and geriatric populations, faecal incontinence and constipation in adults are generally considered separate entities. This may be incorrect. METHODS: Cross-sectional study of consecutive patients (18-80 years) referred to a tertiary unit (2004-2016) for investigation of refractory faecal incontinence and/or constipation and meeting Rome IV core criteria (applied post-hoc) for self-reported symptoms. We sought to determine how frequently both diagnoses coexisted, how frequently coexistent diagnoses were recognised by the referring clinician and to evaluate differences in clinical characteristics between patients with single or both diagnoses. FINDINGS: Study sample consisted of 4,027 patients (3,370 females [83·7%]). According to Rome IV criteria, 807 (20·0%) patients self-reported faecal incontinence in isolation, 1,569 (39·0%) patients had functional constipation in isolation, and 1,651 (41·0%) met criteria for both diagnoses (coexistent symptoms). In contrast, only 331 (8·2%) patients were referred for coexistent symptoms. Of the 1,651 patients with self-reported coexistent symptoms, only 225 (13·6%) were recognised by the referrer i.e. 86·4% were missed. Coexistent symptoms were most often missed in patients referred for faecal incontinence in isolation. In this group of 1,640 patients, 765 (46·7%) had concomitant symptoms of functional constipation. Opioid usage, comorbidities, childhood bowel problems, mixed incontinence symptoms, prolapse symptoms and structural abnormalities on defaecography were associated with reclassification. INTERPRETATION: Over 40% of adults referred for anorectal physiological investigation had coexistent diagnoses of faecal incontinence and functional constipation, based on validated criteria. This overlap is overlooked by referrers, poorly documented in current literature, and may impact management.

Health care providers' weight management practices for adolescent obesity and alignment with clinical practice guidelines: a multi-centre, qualitative study.

BACKGROUND: Clinical practice guidelines (CPGs) include evidence-based recommendations for managing obesity in adolescents. However, information on how health care providers (HCPs) implement these recommendations in day-to-day practice is limited. Our objectives were to explore how HCPs deliver weight management health services to adolescents with obesity and describe the extent to which their reported practices align with recent CPGs for managing pediatric obesity. METHODS: From July 2017 to January 2018, we conducted a qualitative study that used purposeful sampling to recruit HCPs with experience in adolescent weight management from multidisciplinary, pediatric weight management clinics in Edmonton and Ottawa, Canada. Data were collected using audio-recorded focus groups (4-6 participants/group; 60-90 min in length). We applied inductive, semantic thematic analysis and the congruent methodological approach to analyze our data, which included transcripts, field notes, and memos. Qualitative data were compared to recent CPGs for pediatric obesity that were published by the Endocrine Society in 2017. Of the 12 obesity 'treatment-related' recommendations, four were directly relevant to the current study. RESULTS: Data were collected through three focus groups with 16 HCPs (n = 10 Edmonton; n = 6 Ottawa; 94% female; 100% Caucasian), including dietitians, exercise specialists, nurses, pediatricians, psychologists, and social workers. We identified three main themes that we later compared with CPG recommendations, including: (i) discuss realistic expectations regarding weight management (e.g., shift focus from weight to health; explore family cohesiveness; foster delayed vs instant gratification), (ii) personalize weight management (e.g., address personal barriers to change; consider developmental readiness), and (iii) exhibit non-biased attitudes and practices (e.g., de-emphasize individual causes of obesity; avoid making assumptions about lifestyle behaviors based on weight). Based on these qualitative findings, HCPs applied all four CPG recommendations in their practices. CONCLUSIONS: HCPs provided practical insights into what and how they delivered weight management for adolescents, which included operationalizing relevant CPG recommendations in their practices.