Design and Implementation of an Opt-Out, End-to-End, Preemptive DPYD Testing Program for Patients Planned for a Systemic Fluoropyrimidine.

PURPOSE: Several allelic variants of the gene DPYD encoding dihydropyrimidine dehydrogenase (DPD) are associated with impaired metabolism of the systemic fluoropyrimidine fluorouracil (5FU) and its oral prodrug, capecitabine, which elevates the risk for severe toxicity. Following a patient death related to capecitabine toxicity in which DPD deficiency was suspected, a multidisciplinary advisory panel was convened to develop an institution-wide approach to future patients planned for a systemic fluoropyrimidine. METHODS: The panel selected an opt-out testing strategy which focused on developing reliable processes to collect and report test results and targeted education. An electronic health record-based automated reminder was designed to activate when a 5FU- or capecitabine-containing chemotherapy regimen was ordered for a patient without prior exposure to either agent and without a prior DPYD sequencing test result. DPYD testing was standardized across all sites of care, and a closed loop reporting system for abnormal test results was created. Before implementation, targeted education was provided to providers, pharmacists, and nurses, and a failure mode and effects analysis was performed. Program rollout was staged over a 6-month period. RESULTS: At 10 months, the rate of preemptive testing increased from a baseline of 26% to a sustained rate of >90%. In the six network sites, the testing rate increased from 9% to 96%. A total of 1,043 patients have been tested preemptively; allelic variants have been identified in 43 (4.1%). Among 25 evaluable patients, dose reduction or change to a non-fluoropyrimidine-based regimen was accomplished in 96%. CONCLUSION: Preemptive DPYD testing is feasible, and high rates of testing can be achieved using an opt-out, reminder-based program. We provide the details of the implementation and encourage others to emulate it.

Comparing Methods for Detection and Quantification of Plasmodesmal Callose in Nicotiana benthamiana Leaves During Defense Responses.

Callose, a ß-(1,3)-d-glucan polymer, is essential for regulating intercellular trafficking via plasmodesmata (PD). Pathogens manipulate PD-localized proteins to enable intercellular trafficking by removing callose at PD or, conversely, by increasing callose accumulation at PD to limit intercellular trafficking during infection. Plant defense hormones like salicylic acid regulate PD-localized proteins to control PD and intercellular trafficking during immune defense responses such as systemic acquired resistance. Measuring callose deposition at PD in plants has therefore emerged as a popular parameter for assessing likely intercellular trafficking activity during plant immunity. Despite the popularity of this metric, there is no standard for how these measurements should be made. In this study, three commonly used methods for identifying and quantifying plasmodesmal callose by aniline blue staining were evaluated to determine the most effective in the Nicotiana benthamiana leaf model. The results reveal that the most reliable method used aniline blue staining and fluorescence microscopy to measure callose deposition in fixed tissue. Manual or semiautomated workflows for image analysis were also compared and found to produce similar results, although the semiautomated workflow produced a wider distribution of data points. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Defining the Educational Needs for a Community-Based Hematology/Oncology Career: A National Needs Assessment.

PURPOSE: Little is known about the specific needs during training for hematology/oncology providers practicing in community-based settings. We conducted a national survey of hematologists/oncologists employed in community or academic-community hybrid settings to delineate their educational needs. METHODS: An electronic questionnaire was developed and distributed nationally through professional organizations. We primarily assessed whether survey participants received any specific training during fellowship for community-based practice. Participants were also surveyed regarding training experiences that might have affected their preparation. Relative risk (RR) and 95% CI were calculated using modified Poisson regression to identify factors associated with receiving training specifically for community-based settings. RESULTS: Of 125 participants from across 25 states, 63% were male and 58% identified as White. Less than half (41.6%, binomial 95% CI, 32.8 to 50.7) received any training in a community-based setting. Participants identified rotations in community settings (47%), direct mentorship from community-based physicians (40%), and longitudinal clinic in a community setting (36%) as experiences that would have been valuable. Specific curricula of interest included medical operations and administration (63%), health policy (35%), and quality improvement (27%). Respondents in clinical practice for <10 years were more likely to have received any training specifically for a community-based career (RR, 2.13 [95% CI, 1.18 to 3.86]). CONCLUSION: Our study demonstrates substantial unmet needs as they relate to deliberately training fellows destined for community-based careers. Prospective design of clinical training and curricula emphasizing longitudinal exposures to and key aspects of health care delivery in the community setting are paramount to achieving optimal goal-concordant hematology/oncology training during fellowship.

Even-number measurement bias with Goldmann applanation tonometry in patients with glaucoma and glaucoma suspects.

CLINICAL RELEVANCE: Goldmann applanation tonometry is widely used for the diagnosis and management of glaucoma and its use is considered standard of care. However, the precision of this method may be reduced by a clinician tendency to round to even numbers. BACKGROUND: Studies have previously demonstrated an even-number measurement bias with Goldmann applanation tonometry during examination of a general patient population. Since it has not been determined whether this bias persists among glaucoma suspects and patients with glaucoma, further investigation was conducted. METHODS: A retrospective analysis was conducted on a random sample from a large dataset of >69,000 patients seen during a six-year period at an urban, academic primary eye care service. Patients without suspicion of glaucoma, patients with a suspicion of glaucoma, and patients with glaucoma were selected who had Goldmann tonometry performed. Chart reviews were performed to confirm status, and even/odd-numbered Goldmann tonometry measurement frequencies were compared. RESULTS: The analysis included 961 controls, 506 glaucoma suspects, 159 ocular hypertensives not taking medication, and 314 patients taking medications who carried a diagnosis of glaucoma or ocular hypertension. Among controls the Goldmann tonometry even/odd digit proportions were 62.8%/37.2% (N = 961, p < 0.0001), and the even-number bias persisted among the other groups with specific even/odd distributions being 61.9%/38.1% (N = 506, p < 0.0001) for glaucoma suspects not taking medications, 66.0%/34.0% (N = 159, p < 0.0001) for ocular hypertensives not taking medications, and 64.3%/35.7% (N = 314, p < 0.0001) for glaucoma/ocular hypertension patients taking medications. CONCLUSION: An even-number measurement bias with Goldmann tonometry may be prevalent even when the examiner is aware of there being greater importance for intraocular pressure measurement accuracy.

Combining a deep learning model with clinical data better predicts hepatocellular carcinoma behavior following surgery.

Hepatocellular carcinoma (HCC) is among the most common cancers worldwide, and tumor recurrence following liver resection or transplantation is one of the highest contributors to mortality in HCC patients after surgery. Using artificial intelligence (AI), we developed an interdisciplinary model to predict HCC recurrence and patient survival following surgery. We collected whole-slide H&E images, clinical variables, and follow-up data from 300 patients with HCC who underwent transplant and 169 patients who underwent resection at the Cleveland Clinic. A deep learning model was trained to predict recurrence-free survival (RFS) and disease-specific survival (DSS) from the H&E-stained slides. Repeated cross-validation splits were used to compute robust C-index estimates, and the results were compared to those obtained by fitting a Cox proportional hazard model using only clinical variables. While the deep learning model alone was predictive of recurrence and survival among patients in both cohorts, integrating the clinical and histologic models significantly increased the C-index in each cohort. In every subgroup analyzed, we found that a combined clinical and deep learning model better predicted post-surgical outcome in HCC patients compared to either approach independently.

In vivo genotoxicity testing strategies: Report from the 8th International Workshop on Genotoxicity Testing (IWGT).

The in vivo working group (WG) considered three topics: acceptable maximum doses for negative erythrocyte micronucleus (MN) tests, validation status of MN assays in non-hematopoietic tissues, and nuisance factors in the comet assay. The WG reached agreement on many issues, including: negative erythrocyte MN studies should be acceptable if dosing is conducted to Organisation for Economic Co-operation and Development (OECD) test guideline (TG) 474 recommendations and if sufficient bone marrow exposure is demonstrated; consensus on the evidence required to demonstrate "sufficient" exposure was not reached. The liver MN test using six-week-old rats is sufficiently validated to develop an OECD TG, but the impact of animal age warrants additional study. Ki-67 is a reliable marker for cellular proliferation in hepatocytes. The gastrointestinal tract MN test is useful for detecting poorly absorbed or rapidly degraded aneugens, and for genotoxic metabolites formed in the colon. Although current validation data are insufficient to support the development of an OECD TG, the methodologies are sufficient to consider as an appendix to OECD TG474. Comparison of comet assay results to laboratory historical control data (HCD) should not be used in data evaluation, unless the HCD distribution is demonstrated to be stable and the predominant source of HCD variation is due to animal, not study, factors. No universally acceptable negative control limit for any tissue was identified. Methodological differences in comet studies can result in variable data interpretations; more data are required before best practice recommendations can be made. Hedgehogs alone are unreliable indicators of cytotoxicity and additional investigations into cytotoxicity markers are required.

Reliable detection and quantification of plasmodesmal callose in Nicotiana benthamiana leaves during defense responses.

Callose, a beta-(1,3)-D-glucan polymer, is essential for regulating intercellular trafficking via plasmodesmata (PD). Pathogens manipulate PD-localized proteins to enable intercellular trafficking by removing callose at PD, or conversely by increasing callose accumulation at PD to limit intercellular trafficking during infection. Plant defense hormones like salicylic acid regulate PD-localized proteins to control PD and intercellular trafficking during innate immune defense responses such as systemic acquired resistance. Measuring callose deposition at PD in plants has therefore emerged as a popular parameter for assessing the intercellular trafficking activity during plant immunity. Despite the popularity of this metric there is no standard for how these measurements should be made. In this study, three commonly used methods for identifying and quantifying PD callose by aniline blue staining were evaluated to determine the most effective in the Nicotiana benthamiana leaf model. The results reveal that the most reliable method used aniline blue staining and fluorescent microscopy to measure callose deposition in fixed tissue. Manual or semi-automated workflows for image analysis were also compared and found to produce similar results although the semi-automated workflow produced a wider distribution of data points.

Performance of an open machine learning model to classify sleep/wake from actigraphy across ∼24-hour intervals without knowledge of rest timing.

GOAL AND AIMS: Commonly used actigraphy algorithms are designed to operate within a known in-bed interval. However, in free-living scenarios this interval is often unknown. We trained and evaluated a sleep/wake classifier that operates on actigraphy over ∼24-hour intervals, without knowledge of in-bed timing. FOCUS TECHNOLOGY: Actigraphy counts from ActiWatch Spectrum devices. REFERENCE TECHNOLOGY: Sleep staging derived from polysomnography, supplemented by observation of wakefulness outside of the staged interval. Classifications from the Oakley actigraphy algorithm were additionally used as performance reference. SAMPLE: Adults, sleeping in either a home or laboratory environment. DESIGN: Machine learning was used to train and evaluate a sleep/wake classifier in a supervised learning paradigm. The classifier is a temporal convolutional network, a form of deep neural network. CORE ANALYTICS: Performance was evaluated across ∼24 hours, and additionally restricted to only in-bed intervals, both in terms of epoch-by-epoch performance, and the discrepancy of summary statistics within the intervals. ADDITIONAL ANALYTICS AND EXPLORATORY ANALYSES: Performance of the trained model applied to the Multi-Ethnic Study of Atherosclerosis dataset. CORE OUTCOMES: Over ∼24 hours, the temporal convolutional network classifier produced the same or better performance as the Oakley classifier on all measures tested. When restricting analysis to the in-bed interval, the temporal convolutional network remained favorable on several metrics. IMPORTANT SUPPLEMENTAL OUTCOMES: Performance decreased on the Multi-Ethnic Study of Atherosclerosis dataset, especially when restricting analysis to the in-bed interval. CORE CONCLUSION: A classifier using data labeled over ∼24-hour intervals allows for the continuous classification of sleep/wake without knowledge of in-bed intervals. Further development should focus on improving generalization performance.

Co-use of MDMA with psilocybin/LSD may buffer against challenging experiences and enhance positive experiences.

Psilocybin and lysergic acid diethylamide (LSD) experiences can range from very positive to highly challenging (e.g., fear, grief, and paranoia). These challenging experiences contribute to hesitancy toward psychedelic-assisted psychotherapy among health care providers and patients. Co-use of 3,4-Methylenedioxy methamphetamine (MDMA) with psilocybin/LSD anecdotally reduces challenging experiences and enhances positive experiences associated with psilocybin/LSD. However, limited research has investigated the acute effects of co-use of MDMA and psilocybin/LSD. In a prospective convenience sample (N = 698) of individuals with plans to use psilocybin/LSD, we examined whether co-use of MDMA with psilocybin/LSD (n = 27) is associated with differences in challenging or positive experiences. Challenging experiences were measured using the Challenging Experiences Questionnaire and positive experiences were measured using the Mystical Experience Questionnaire and single-item measures of self-compassion, compassion, love, and gratitude. Potentially confounding variables were identified and included as covariates. Relative to psilocybin/LSD alone, co-use of psilocybin/LSD with a self-reported low (but not medium-high) dose of MDMA was associated with significantly less intense total challenging experiences, grief, and fear, as well as increased self-compassion, love and gratitude. Co-use of psilocybin/LSD and MDMA was not associated with differences in mystical-type experiences or compassion. Findings suggest co-use of MDMA with psilocybin/LSD may buffer against some aspects of challenging experiences and enhance certain positive experiences. Limitations include use of a convenience sample, small sample size, and non-experimental design. Additional studies (including controlled dose-response studies) that examine the effects and safety of co-administering MDMA with psilocybin/LSD (in healthy controls and clinical samples) are warranted and may assist the development of personalized treatments.

Ethylene-mediated metabolic priming increases photosynthesis and metabolism to enhance plant growth and stress tolerance.

Enhancing crop yields is a major challenge because of an increasing human population, climate change, and reduction in arable land. Here, we demonstrate that long-lasting growth enhancement and increased stress tolerance occur by pretreatment of dark grown Arabidopsis seedlings with ethylene before transitioning into light. Plants treated this way had longer primary roots, more and longer lateral roots, and larger aerial tissue and were more tolerant to high temperature, salt, and recovery from hypoxia stress. We attributed the increase in plant growth and stress tolerance to ethylene-induced photosynthetic-derived sugars because ethylene pretreatment caused a 23% increase in carbon assimilation and increased the levels of glucose (266%), sucrose/trehalose (446%), and starch (87%). Metabolomic and transcriptomic analyses several days posttreatment showed a significant increase in metabolic processes and gene transcripts implicated in cell division, photosynthesis, and carbohydrate metabolism. Because of this large effect on metabolism, we term this "ethylene-mediated metabolic priming." Reducing photosynthesis with inhibitors or mutants prevented the growth enhancement, but this was partially rescued by exogenous sucrose, implicating sugars in this growth phenomenon. Additionally, ethylene pretreatment increased the levels of CINV1 and CINV2 encoding invertases that hydrolyze sucrose, and cinv1;cinv2 mutants did not respond to ethylene pretreatment with increased growth indicating increased sucrose breakdown is critical for this trait. A model is proposed where ethylene-mediated metabolic priming causes long-term increases in photosynthesis and carbohydrate utilization to increase growth. These responses may be part of the natural development of seedlings as they navigate through the soil to emerge into light.

A non-pharmacological multi-modal therapy to improve sleep and cognition and reduce mild cognitive impairment risk: Design and methodology of a randomized clinical trial.

Aging populations are at increased risk of sleep deficiencies (e.g., insomnia) that are associated with a variety of chronic health risks, including Alzheimer's disease and related dementias (ADRD). Insomnia medications carry additional risk, including increased drowsiness and falls, as well as polypharmacy risks. The recommended first-line treatment for insomnia is cognitive behavioral therapy for insomnia (CBTi), but access is limited. Telehealth is one way to increase access, particularly for older adults, but to date telehealth has been typically limited to simple videoconferencing portals. While these portals have been shown to be non-inferior to in-person treatment, it is plausible that telehealth could be significantly improved. This work describes a protocol designed to evaluate whether a clinician-patient dashboard inclusive of several user-friendly features (e.g., patterns of sleep data from ambulatory devices, guided relaxation resources, and reminders to complete in-home CBTi practice) could improve CBTi outcomes for middle- to older-aged adults (N = 100). Participants were randomly assigned to one of three telehealth interventions delivered through 6-weekly sessions: (1) CBTi augmented with a clinician-patient dashboard, smartphone application, and integrated smart devices; (2) standard CBTi (i.e., active comparator); or (3) sleep hygiene education (i.e., active control). All participants were assessed at screening, pre-study evaluation, baseline, throughout treatment, and at 1-week post-treatment. The primary outcome is the Insomnia Severity Index. Secondary and exploratory outcomes span sleep diary, actiwatch and Apple watch assessed sleep parameters (e.g., efficiency, duration, timing, variability), psychosocial correlates (e.g., fatigue, depression, stress), cognitive performance, treatment adherence, and neurodegenerative and systemic inflammatory biomarkers.

Quantifying the impact of individual and collective compliance with infection control measures for ethical public health policy.

Infectious disease control measures often require collective compliance of large numbers of individuals to benefit public health. This raises ethical questions regarding the value of the public health benefit created by individual and collective compliance. Answering these requires estimating the extent to which individual actions prevent infection of others. We develop mathematical techniques enabling quantification of the impacts of individuals or groups complying with three public health measures: border quarantine, isolation of infected individuals, and prevention via vaccination/prophylaxis. The results suggest that (i) these interventions exhibit synergy: They become more effective on a per-individual basis as compliance increases, and (ii) there is often substantial "overdetermination" of transmission. If a susceptible person contacts multiple infectious individuals, an intervention preventing one transmission may not change the ultimate outcome (thus, risk imposed by some individuals may erode the benefits of others' compliance). These results have implications for public health policy during epidemics.

Assessing the quality and making appropriate use of historical negative control data: A report of the International Workshop on Genotoxicity Testing (IWGT).

Historical negative control data (HCD) have played an increasingly important role in interpreting the results of genotoxicity tests. In particular, Organisation for Economic Co-operation and Development (OECD) genetic toxicology test guidelines recommend comparing responses produced by exposure to test substances with the distribution of HCD as one of three criteria for evaluating and interpreting study results (referred to herein as "Criterion C"). Because of the potential for inconsistency in how HCD are acquired, maintained, described, and used to interpret genotoxicity testing results, a workgroup of the International Workshops for Genotoxicity Testing was convened to provide recommendations on this crucial topic. The workgroup used example data sets from four in vivo tests, the Pig-a gene mutation assay, the erythrocyte-based micronucleus test, the transgenic rodent gene mutation assay, and the in vivo alkaline comet assay to illustrate how the quality of HCD can be evaluated. In addition, recommendations are offered on appropriate methods for evaluating HCD distributions. Recommendations of the workgroup are: When concurrent negative control data fulfill study acceptability criteria, they represent the most important comparator for judging whether a particular test substance induced a genotoxic effect. HCD can provide useful context for interpreting study results, but this requires supporting evidence that (i) HCD were generated appropriately, and (ii) their quality has been assessed and deemed sufficiently high for this purpose. HCD should be visualized before any study comparisons take place; graph(s) that show the degree to which HCD are stable over time are particularly useful. Qualitative and semi-quantitative assessments of HCD should also be supplemented with quantitative evaluations. Key factors in the assessment of HCD include: (i) the stability of HCD over time, and (ii) the degree to which inter-study variation explains the total variability observed. When animal-to-animal variation is the predominant source of variability, the relationship between responses in the study and an HCD-derived interval or upper bounds value (i.e., OECD Criterion C) can be used with a strong degree of confidence in contextualizing a particular study's results. When inter-study variation is the major source of variability, comparisons between study data and the HCD bounds are less useful, and consequentially, less emphasis should be placed on using HCD to contextualize a particular study's results. The workgroup findings add additional support for the use of HCD for data interpretation; but relative to most current OECD test guidelines, we recommend a more flexible application that takes into consideration HCD quality. The workgroup considered only commonly used in vivo tests, but it anticipates that the same principles will apply to other genotoxicity tests, including many in vitro tests.

Perioperative water and electrolyte balance and water homeostasis regulation in children with acute surgery.

BACKGROUND: Hospital-acquired hyponatremia remains a feared event in patients receiving hypotonic fluid therapy. Our objectives were to assess post-operative plasma-sodium concentration and to provide a physiological explanation for plasma-sodium levels over time in children with acute appendicitis. METHODS: Thirteen normonatremic (plasma-sodium ≥135 mmol/L) children (8 males), median age 12.3 (IQR 11.5-13.5) years participated in this prospective observational study (ACTRN12621000587808). Urine was collected and analyzed. Blood tests, including renin, aldosterone, arginine-vasopressin, and circulating nitric oxide substrates were determined on admission, at induction of anesthesia, and at the end of surgery. RESULTS: On admission, participants were assumed to be mildly dehydrated and were prescribed 50 mL/kg of Ringer's acetate intravenously followed by half-isotonic saline as maintenance fluid therapy. Blood tests, urinary indices, plasma levels of aldosterone, arginine-vasopressin, and net water-electrolyte balance indicated that participants were dehydrated on admission. Although nearly 50% of participants still had arginine-vasopressin levels that would have been expected to produce maximum antidiuresis at the end of surgery, electrolyte-free water clearance indicated that almost all participants were able to excrete net free water. No participant became hyponatremic. CONCLUSIONS: The use of moderately hypotonic fluid therapy after correction of extracellular fluid deficit is not necessarily associated with post-operative hyponatremia. IMPACT: Our observations show that in acutely ill normonatremic children not only the composition but also the amount of volume infused influence on the risk of hyponatremia. Our observations also suggest that perioperative administration of hypotonic fluid therapy is followed by a tendency towards hyponatremia if extracellular fluid depletion is left untreated. After correcting extracellular deficit almost all patients were able to excrete net free water. This occurred despite nearly 50% of the cohort having high circulating plasma levels of arginine-vasopressin at the end of surgery, suggesting a phenomenon of renal escape from arginine-vasopressin-induced antidiuresis.

Training Hematologists/Oncologists for the Academic-Community Hybrid: Creating a Fellowship Framework for the Future.

PURPOSE: Conventional hematology/oncology fellowship training is designed to foster careers in academic practice through intensive exposure to clinical and laboratory research. Even so, a notable proportion of graduating fellows opt to pursue a clinically focused career outside the realm of academic medicine. Given the corresponding shortage of oncologists in nonurban and rural settings, improving the representation of hematologists/oncologists in the community setting is a national priority. METHODS: We reviewed current national challenges and changing models of cancer care delivery in the context of the traditional academic training model along with trends in practice patterns for recent hematology/oncology graduates. We defined the Academic-Community hybrid (ACH) and how it supports the evolution in contemporary models of cancer care. We then drew on the authors' experiences to formulate an innovative goal-concordant training paradigm for fellows seeking careers in the ACH model. RESULTS: The ACH hematology/oncology fellowship training pathway emphasizes and optimizes professional development domains including clinical care, patient safety and quality improvement, business and operations, cancer care equity and community access, healthy policy and alignment with professional organizations, and medical education. CONCLUSION: This novel hematology/oncology training model provides a paradigm for optimizing preparedness for practice in an increasingly complex cancer care delivery environment while addressing workforce shortages and health disparities.

Pain, pain management and related outcomes following pelvic exenteration surgery: a systematic review.

AIM: Pelvic exenteration surgery can improve survival in people with advanced colorectal cancer. This systematic review aimed to review pain intensity and other outcomes, for example the management of pain, the relationship between pain and the extent of surgery and the impact of pain on short-term outcomes. METHOD: Electronic databases were searched from inception to 1 May 2021. We included interventional studies of adults with any indication for pelvic exenteration surgery that also reported pain outcomes. Risk of bias was assessed using ROBINS-1. RESULTS: The search found 21 studies that reported pain following pelvic exenteration [n = 1317 patients, mean age 58.4 years (SD 4.8)]. Ten studies were judged to be at moderate risk of bias. Before pelvic exenteration, pain was reported by 19%-100% of patients. Five studies used validated measures of pain intensity. No study measured pain at all three time points in the surgical journey. The presence of pain before surgery predicted postoperative adverse pain outcomes, and pain is more likely to be experienced in those who require wider resections, including bone resection. CONCLUSION: Considering that pain following pelvic exenteration is commonly described by patients, the literature suggests that this symptom is not being measured and therefore addressed.

Establishing a quantitative framework for regulatory interpretation of genetic toxicity dose-response data: Margin of exposure case study of 48 compounds with both in vivo mutagenicity and carcinogenicity dose-response data.

Quantitative relationships between carcinogenic potency and mutagenic potency have been previously examined using a benchmark dose (BMD)-based approach. We extended those analyses by using human exposure data for 48 compounds to calculate carcinogenicity-derived and genotoxicity-derived margin of exposure values (MOEs) that can be used to prioritize substances for risk management. MOEs for 16 of the 48 compounds were below 10,000, and consequently highlighted for regulatory concern. Of these, 15 were highlighted using genotoxicity-derived (micronucleus [MN] dose-response data) MOEs. A total of 13 compounds were highlighted using carcinogenicity-derived MOEs; 12 compounds were overlapping. MOEs were also calculated using transgenic rodent (TGR) mutagenicity data. For 10 of the 12 compounds examined using TGR data, the results similarly revealed that mutagenicity-derived MOEs yield regulatory decisions that correspond with those based on carcinogenicity-derived MOEs. The effect of benchmark response (BMR) on MOE determination was also examined. Reinterpretation of the analyses using a BMR of 50% indicated that four out of 15 compounds prioritized using MN-derived MOEs based on a default BMR of 5% would have been missed. The results indicate that regulatory decisions based on in vivo genotoxicity dose-response data would be consistent with those based on carcinogenicity dose-response data; in some cases, genotoxicity-based decisions would be more conservative. Going forward, and in the absence of carcinogenicity data, in vivo genotoxicity assays (MN and TGR) can be used to effectively prioritize substances for regulatory action. Routine use of the MOE approach necessitates the availability of reliable human exposure estimates, and consensus regarding appropriate BMRs for genotoxicity endpoints.