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Leachables in pharmaceutical products may react with biomolecule active pharmaceutical ingredients (APIs), for example, monoclonal antibodies (mAb), peptides, and ribonucleic acids (RNA), potentially compromising product safety and efficacy or impacting quality attributes. This investigation explored a series of in silico models to screen extractables and leachables to assess their possible reactivity with biomolecules. These in silico models were applied to collections of known leachables to identify functional and structural chemical classes likely to be flagged by these in silico approaches. Flagged leachable functional classes included antimicrobials, colorants, and film-forming agents, whereas specific chemical classes included epoxides, acrylates, and quinones. In addition, a dataset of 22 leachables with experimental data indicating their interaction with insulin glargine was used to evaluate whether one or more in silico methods are fit-for-purpose as a preliminary screen for assessing this biomolecule reactivity. Analysis of the data showed that the sensitivity of an in silico screen using multiple methodologies was 80%-90% and the specificity was 58%-92%. A workflow supporting the use of in silico methods in this field is proposed based on both the results from this assessment and best practices in the field of computational modeling and quality risk management., (© PDA, Inc. 2024.)

An important aspect of motor function is our ability to rapidly generate goal-directed corrections for disturbances to the limb or behavioral goal. The primary motor cortex (M1) is a key region involved in processing feedback for rapid motor corrections, yet we know little about how M1 circuits are recruited by different sources of sensory feedback to make rapid corrections. We trained two male monkeys ( Macaca mulatta ) to make goal-directed reaches and on random trials introduced different sensory errors by either jumping the visual location of the goal (goal jump), jumping the visual location of the hand (cursor jump), or applying a mechanical load to displace the hand (proprioceptive feedback). Sensory perturbations evoked a broad response in M1 with ∼73% of neurons ( n  = 257) responding to at least one of the sensory perturbations. Feedback responses were also similar as response ranges between the goal and cursor jumps were highly correlated (range of r  = [0.91, 0.97]) as were the response ranges between the mechanical loads and the visual perturbations (range of r  = [0.68, 0.86]). Lastly, we identified the neural subspace each perturbation response resided in and found a strong overlap between the two visual perturbations (range of overlap index, 0.73-0.89) and between the mechanical loads and visual perturbations (range of overlap index, 0.36-0.47) indicating each perturbation evoked similar structure of activity at the population level. Collectively, our results indicate rapid responses to errors from different sensory sources target similar overlapping circuits in M1., (Copyright © 2024 Cross et al.)

As part of an analysis performed under the auspices of the International Workshop on Genotoxicity Testing (IWGT) in 2017, we and others showed that Salmonella frameshift strain TA98 and base-substitution strain TA100 together + /- S9 detected 93% of the mutagens detected by all the bacterial strains recommended by OECD TG471 (Williams et al., Mutation Res. 848:503081, 2019). We have extended this analysis by identifying the numbers and chemical classes of chemicals detected by these two strains either alone or in combination, including the role of S9. Using the Leadscope 2021 SAR Genetox database containing > 21,900 compounds, our dataset containing 7170 compounds tested in both TA98 and TA100. Together, TA98 and TA100 detected 94% (3733/3981) of the mutagens detected using all the TG471-recommended bacterial strains; 39% were mutagenic in one or both strains. TA100 detected 77% of all of these mutagens and TA98 70%. Considering the overlap of detection by both strains, 12% of these mutagens were detected only by TA98 and 19% only by TA100. In the absence of S9, sensitivity dropped by 31% for TA98 and 29% for TA100. Overall, 32% of the mutagens required S9 for detection by either strain; 9% were detected only without S9. Using the 2021 Leadscope Genetox Expert Alerts, TA100 detected 18 mutagenic alerting chemical classes with better sensitivity than TA98, whereas TA98 detected 10 classes better than TA100. TA100 detected more chemical classes than did TA98, especially hydrazines, azides, various di- and tri-halides, various nitrosamines, epoxides, aziridines, difurans, and half-mustards; TA98 especially detected polycyclic primary amines, various aromatic amines, polycyclic aromatic hydrocarbons, triazines, and dibenzo-furans. Model compounds with these structures induce primarily G to T mutations in TA100 and/or a hotspot GC deletion in TA98. Both TA98 and TA100 + /- S9 are needed for adequate mutagenicity screening with the Salmonella (Ames) assay., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David DeMarini has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Kevin P. Cross is employed by Instem and the databases used in this analysis were developed by and are the commercial property of Instem. The views expressed in this paper are those of the authors and do not reflect U.S. EPA policy., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A common problem in motor control concerns how to generate patterns of muscle activity when there are redundant solutions to attain a behavioral goal. Optimal feedback control is a theory that has guided many behavioral studies exploring how the motor system incorporates task redundancy. This theory predicts that kinematic errors that deviate the limb should not be corrected if one can still attain the behavioral goal. Studies in humans demonstrate that the motor system can flexibly integrate visual and proprioceptive feedback of the limb with goal redundancy within 90 ms and 70 ms, respectively. Here, we show monkeys ( Macaca mulatta ) demonstrate similar abilities to exploit goal redundancy. We trained four male monkeys to reach for a goal that was either a narrow square or a wide, spatially redundant rectangle. Monkeys exhibited greater trial-by-trial variability when reaching to the wide goal consistent with exploiting goal redundancy. On random trials we jumped the visual feedback of the hand and found monkeys corrected for the jump when reaching to the narrow goal and largely ignored the jump when reaching for the wide goal. In a separate set of experiments, we applied mechanical loads to the arm of the monkey and found similar corrective responses based on goal shape. Muscle activity reflecting these different corrective responses were detected for the visual and mechanical perturbations starting at ∼90 and ∼70 ms, respectively. Thus, rapid motor responses in macaques can exploit goal redundancy similar to humans, creating a paradigm to study the neural basis of goal-directed motor action and motor redundancy. SIGNIFICANCE STATEMENT Moving in the world requires selecting from an infinite set of possible motor commands. Theories predict that motor commands are selected that exploit redundancies. Corrective responses in humans to either visual or proprioceptive disturbances of the limb can rapidly exploit redundant trajectories to a goal in <100 ms after a disturbance. However, uncovering the neural correlates generating these rapid motor corrections has been hampered by the absence of an animal model. We developed a behavioral paradigm in monkeys that incorporates redundancy in the form of the shape of the goal. Critically, monkeys exhibit corrective responses and timings similar to humans performing the same task. Our paradigm provides a model for investigating the neural correlates of sophisticated rapid motor corrections., (Copyright © 2023 the authors.)

Assessing drug permeability across the blood-brain barrier (BBB) is important when evaluating the abuse potential of new pharmaceuticals as well as developing novel therapeutics that target central nervous system disorders. One of the gold-standard in vivo methods for determining BBB permeability is rodent log BB; however, like most in vivo methods, it is time-consuming and expensive. In the present study, two statistical-based quantitative structure-activity relationship (QSAR) models were developed to predict BBB permeability of drugs based on their chemical structure. The in vivo BBB permeability data were harvested for 921 compounds from publicly available literature, non-proprietary drug approval packages, and University of Washington's Drug Interaction Database. The cross-validation performance statistics for the BBB models ranged from 82 to 85% in sensitivity and 80-83% in negative predictivity. Additionally, the performance of newly developed models was assessed using an external validation set comprised of 83 chemicals. Overall, performance of individual models ranged from 70 to 75% in sensitivity, 70-72% in negative predictivity, and 78-86% in coverage. The predictive performance was further improved to 93% in coverage by combining predictions across the two software programs. These new models can be rapidly deployed to predict blood brain barrier permeability of pharmaceutical candidates and reduce the use of experimental animals., Competing Interests: Author KC was employed by the Leadscope Inc; Author SC was employed by the MultiCASE Inc. LS reports that she is the co-Principal Investigator on two Research Collaboration Agreements (RCAs) between the US Food and Drug Administration’s Center for Drug Evaluation and Research, and Leadscope Inc., and MultiCASE Inc., respectively. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Faramarzi, Kim, Volpe, Cross, Chakravarti and Stavitskaya.)

Visual and proprioceptive feedback both contribute to perceptual decisions, but it remains unknown how these feedback signals are integrated together or consider factors such as delays and variance during online control. We investigated this question by having participants reach to a target with randomly applied mechanical and/or visual disturbances. We observed that the presence of visual feedback during a mechanical disturbance did not increase the size of the muscle response significantly but did decrease variance, consistent with a dynamic Bayesian integration model. In a control experiment, we verified that vision had a potent influence when mechanical and visual disturbances were both present but opposite in sign. These results highlight a complex process for multisensory integration, where visual feedback has a relatively modest influence when the limb is mechanically disturbed, but a substantial influence when visual feedback becomes misaligned with the limb. NEW & NOTEWORTHY Visual feedback is more accurate, but proprioceptive feedback is faster. How should you integrate these sources of feedback to guide limb movement? As predicted by dynamic Bayesian models, the size of the muscle response to a mechanical disturbance was essentially the same whether visual feedback was present or not. Only under artificial conditions, such as when shifting the position of a cursor representing hand position, can one observe a muscle response from visual feedback.

Mechanistically-driven alternative approaches to hazard assessment invariably require a battery of tests, including both in silico models and experimental data. The decision-making process, from selection of the methods to combining the information based on the weight-of-evidence, is ideally described in published guidelines or protocols. This ensures that the application of such approaches is defendable to reviewers within regulatory agencies and across the industry. Examples include the ICH M7 pharmaceutical impurities guideline and the published in silico toxicology protocols. To support an efficient, transparent, consistent and fully documented implementation of these protocols, a new and novel interactive software solution is described to perform such an integrated hazard assessment based on public and proprietary information., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Understanding the reliability and relevance of a toxicological assessment is important for gauging the overall confidence and communicating the degree of uncertainty related to it. The process involved in assessing reliability and relevance is well defined for experimental data. Similar criteria need to be established for in silico predictions, as they become increasingly more important to fill data gaps and need to be reasonably integrated as additional lines of evidence. Thus, in silico assessments could be communicated with greater confidence and in a more harmonized manner. The current work expands on previous definitions of reliability, relevance, and confidence and establishes a conceptional framework to apply those to in silico data. The approach is used in two case studies: 1) phthalic anhydride, where experimental data are readily available and 2) 4-hydroxy-3-propoxybenzaldehyde, a data poor case which relies predominantly on in silico methods, showing that reliability, relevance, and confidence of in silico assessments can be effectively communicated within Integrated approaches to testing and assessment (IATA)., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Recent studies have identified rotational dynamics in motor cortex (MC), which many assume arise from intrinsic connections in MC. However, behavioral and neurophysiological studies suggest that MC behaves like a feedback controller where continuous sensory feedback and interactions with other brain areas contribute substantially to MC processing. We investigated these apparently conflicting theories by building recurrent neural networks that controlled a model arm and received sensory feedback from the limb. Networks were trained to counteract perturbations to the limb and to reach toward spatial targets. Network activities and sensory feedback signals to the network exhibited rotational structure even when the recurrent connections were removed. Furthermore, neural recordings in monkeys performing similar tasks also exhibited rotational structure not only in MC but also in somatosensory cortex. Our results argue that rotational structure may also reflect dynamics throughout the voluntary motor system involved in online control of motor actions., Competing Interests: HK, KC, TL, MO, EF, PS No competing interests declared, SS Co-founder and CSO of Kinarm which commercializes the robotic technology used in the present study, (© 2021, Kalidindi et al.)

Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic. For example, in pharmaceutical research and development it is one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. The development of faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative is critically needed. The biological mechanisms and processes underpinning hepatotoxicity are summarized and experimental approaches to support the prediction of hepatotoxicity are described, including toxicokinetic considerations. The paper describes the increasingly important role of in silico approaches and highlights challenges to the adoption of these methods including the lack of a commonly agreed upon protocol for performing such an assessment and the need for in silico solutions that take dose into consideration. A proposed framework for the integration of in silico and experimental information is provided along with a case study describing how computational methods have been used to successfully respond to a regulatory question concerning non-genotoxic impurities in chemically synthesized pharmaceuticals.

The detection of N -nitrosodimethylamine (NDMA) in several marketed drugs led regulatory agencies to require that N -nitrosamine risk assessments be performed on all marketed medical products [EMA/351053/2019 rev 1 (2019)]. Regulation of N -nitrosamine impurity levels in pharmaceutical drug substances and products is described in the ICH M7(R1) guideline where they are referred to as "cohort-of-concern" compounds as several are potent rodent carcinogens [Kroes et. al . 2004]. EMA, U.S. FDA and other regulatory agencies have set provisional acceptable daily intake limits for N- nitrosamines calculated from rodent carcinogenicity TD 50 values for experimentally measured N- nitrosamines or the measured TD 50 values of close analogs. The class-specific limit can be adjusted based upon a structure activity relationship analysis (SAR) and comparison with analogs having established carcinogenicity data [EMA/369136/2020, (2020)]. To investigate whether improvements in SARs can more accurately predict N -nitrosamine carcinogenic potency, an ad hoc workgroup of 23 companies and universities was established with the goals of addressing several scientific and regulatory issues including: reporting and review of N -nitrosamine mutagenicity and carcinogenicity reaction mechanisms, collection and review of available, public relevant experimental data, development of structure-activity relationships consistent with mechanisms for prediction of N- nitrosamine carcinogenic potency categories, and improved methods for calculating acceptable intake limits for N -nitrosamines based upon mechanistic analogs. Here we describe this collaboration and review our progress to date towards development of mechanistically based structure-activity relationships. We propose improving risk assessment of N -nitrosamines by first establishing the dominant reaction mechanism prior to retrieving an appropriate set of close analogs for use in read-across exercises., Competing Interests: Conflict of Interest The authors are employed full-time by their respective companies which develop software for the prediction of chemical toxicity as listed as their affiliations and have performed this work as part of their research tasks in collaboration with each other and the informal working group discussed; no product, commercial, market or strategic information has been shared in discussion, nor has it influenced this work. Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kevin P. Cross reports financial support was provided by National Institute of Environmental Health Sciences of the National Institutes of Health. Kevin P. Cross reports a relationship with Instem that includes: employment, equity or stocks, and travel reimbursement.

Introduction: It remains unclear which mass-casualty incident (MCI) triage tool best predicts outcomes for child disaster victims., Study Objectives: The primary objective of this study was to compare triage outcomes of Simple Triage and Rapid Treatment (START), modified START, and CareFlight in pediatric patients to an outcomes-based gold standard using the Criteria Outcomes Tool (COT). The secondary outcomes were sensitivity, specificity, under-triage, over-triage, and overall accuracy at each level for each MCI triage algorithm., Methods: Singleton trauma patients under 16 years of age with complete prehospital, emergency department (ED), and in-patient data were identified in the 2007-2009 National Trauma Data Bank (NTDB). The COT outcomes and procedures were translated into ICD-9 procedure codes with added timing criteria. Gold standard triage levels were assigned using the COT based on outcomes, including mortality, injury type, admission to the hospital, and surgical procedures. Comparison triage levels were determined based on algorithmic depictions of the three MCI triage tools., Results: A total of 31,093 patients with complete data were identified from the NTDB. The COT was applied to these patients, and the breakdown of gold standard triage levels, based on their actual clinical outcomes, was: 17,333 (55.7%) GREEN; 11,587 (37.3%) YELLOW; 1,572 (5.1%) RED; and 601 (1.9%) BLACK. CareFlight had the best sensitivity for predicting COT outcomes for BLACK (83% [95% confidence interval, 80%-86%]) and GREEN patients (79% [95% CI, 79%-80%]) and the best specificity for RED patients (89% [95% CI, 89%-90%])., Conclusion: Among three prehospital MCI triage tools, CareFlight had the best performance for correlating with outcomes in the COT. Overall, none of three tools had good test characteristics for predicting pediatric patient needs for surgical procedures or hospital admission.

The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducting a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Primary motor cortex (M1) almost exclusively controls the contralateral side of the body. However, M1 activity is also modulated during ipsilateral body movements. Previous work has shown that M1 activity related to the ipsilateral arm is independent of the M1 activity related to the contralateral arm. How do these patterns of activity interact when both arms move simultaneously? We explored this problem by training 2 monkeys (male, Macaca mulatta ) in a postural perturbation task while recording from M1. Loads were applied to one arm at a time (unimanual) or both arms simultaneously (bimanual). We found 83% of neurons ( n = 236) were responsive to both the unimanual and bimanual loads. We also observed a small reduction in activity magnitude during the bimanual loads for both limbs (25%). Across the unimanual and bimanual loads, neurons largely maintained their preferred load directions. However, there was a larger change in the preferred loads for the ipsilateral limb (∼25%) than the contralateral limb (∼9%). Lastly, we identified the contralateral and ipsilateral subspaces during the unimanual loads and found they captured a significant amount of the variance during the bimanual loads. However, the subspace captured more of the bimanual variance related to the contralateral limb (97%) than the ipsilateral limb (66%). Our results highlight that, even during bimanual motor actions, M1 largely retains its representations of the contralateral and ipsilateral limbs. SIGNIFICANCE STATEMENT Previous work has shown that primary motor cortex (M1) represents information related to the contralateral limb, its downstream target, but also reflects information related to the ipsilateral limb. Can M1 still represent both sources of information when performing simultaneous movements of the limbs? Here we record from M1 during a postural perturbation task. We show that activity related to the contralateral limb is maintained between unimanual and bimanual motor actions, whereas the activity related to the ipsilateral limb undergoes a small change between unimanual and bimanual motor actions. Our results indicate that two independent representations can be maintained and expressed simultaneously in M1., (Copyright © 2020 the authors.)

All drugs entering clinical trials are expected to undergo a series of in vitro and in vivo genotoxicity tests as outlined in the International Council on Harmonization (ICH) S2 (R1) guidance. Among the standard battery of genotoxicity tests used for pharmaceuticals, the in vivo micronucleus assay, which measures the frequency of micronucleated cells mostly from blood or bone marrow, is recommended for detecting clastogens and aneugens. (Quantitative) structure-activity relationship [(Q)SAR] models may be used as early screening tools by pharmaceutical companies to assess genetic toxicity risk during drug candidate selection. Models can also provide decision support information during regulatory review as part of the weight-of-evidence when experimental data are insufficient. In the present study, two commercial (Q)SAR platforms were used to construct in vivo micronucleus models from a recently enhanced in-house database of non-proprietary study findings in mice. Cross-validated performance statistics for the new models showed sensitivity of up to 74% and negative predictivity of up to 86%. In addition, the models demonstrated cross-validated specificity of up to 77% and coverage of up to 94%. These new models will provide more reliable predictions and offer an investigational approach for drug safety assessment with regards to identifying potentially genotoxic compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

The International Workshop on Genotoxicity Testing (IWGT) meets every four years to obtain consensus on unresolved issues associated with genotoxicity testing. At the 2017 IWGT meeting in Tokyo, four sub-groups addressed issues associated with the Organization for Economic Cooperation and Development (OECD) Test Guideline TG471, which describes the use of bacterial reverse-mutation tests. The strains sub-group analyzed test data from >10,000 chemicals, tested additional chemicals, and concluded that some strains listed in TG471 are unnecessary because they detected fewer mutagens than other strains that the guideline describes as equivalent. Thus, they concluded that a smaller panel of strains would suffice to detect most mutagens. The laboratory proficiency sub-group recommended (a) establishing strain cell banks, (b) developing bacterial growth protocols that optimize assay sensitivity, and (c) testing "proficiency compounds" to gain assay experience and establish historical positive and control databases. The sub-group on criteria for assay evaluation recommended that laboratories (a) track positive and negative control data; (b) develop acceptability criteria for positive and negative controls; (c) optimize dose-spacing and the number of analyzable doses when there is evidence of toxicity; (d) use a combination of three criteria to evaluate results: a dose-related increase in revertants, a clear increase in revertants in at least one dose relative to the concurrent negative control, and at least one dose that produced an increase in revertants above control limits established by the laboratory from historical negative controls; and (e) establish experimental designs to resolve unclear results. The in silico sub-group summarized in silico utility as a tool in genotoxicity assessment but made no specific recommendations for TG471. Thus, the workgroup identified issues that could be addressed if TG471 is revised. The companion papers (a) provide evidence-based approaches, (b) recommend priorities, and (c) give examples of clearly defined terms to support revision of TG471., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

The International Workshop on Genotoxicity Testing (IWGT) meets every four years to seek consensus on difficult or conflicting approaches to genotoxicity testing based upon experience, available data, and analysis techniques. At the 2017 IWGT meeting in Tokyo, one working group addressed the sensitivity and selectivity of the bacterial strains specified in the Organization for Economic Cooperation and Development (OECD) Test Guideline TG471 to recommend possible modification of the test guideline. Three questions were posed: (1) Although TA100 is derived from TA1535, does TA1535 detect any mutagens that are not detected by TA100? (2) Among the options of Salmonella TA1537, TA97 or TA97a, are these strains truly equivalent? (3) Because there is a choice to use one of either E. coli WP2 uvrA, E. coli WP2 uvrA pKM101, or Salmonella TA102, are these strains truly equivalent? To answer these questions, we analyzed published bacterial mutation data in multiple strains from large (>10,000 compound) databases from Leadscope and Lhasa Limited and anonymized data for 53 compounds tested in TA1535 and TA100 provided by a pharmaceutical company. Our analysis involved (1) defining criteria for determining selective responses when using different strains; (2) identifying compounds producing selective responses based upon author calls; (3) confirming selective responses by visually examining dose-response data and considering experimental conditions; (4) using statistical methods to quantify the responses; (5) performing limited additional direct-comparison testing; and (6) determining the chemical classes producing selective responses. We found that few mutagens would fail to be detected if the test battery did not include Salmonella strains TA1535 (8/1167), TA1537 (2/247), TA102 (4/46), and E. coli WP2 uvrA (2/21). Of the mutagens detected by the full TG471 strain battery, 93% were detected using only strains TA98 and TA100; consideration of results from in vitro genotoxicity assays that detect clastogenicity increased this to 99%., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The International Council on Harmonisation (ICH) M7(R1) guideline describes the use of complementary (quantitative) structure-activity relationship ((Q)SAR) models to assess the mutagenic potential of drug impurities in new and generic drugs. Historically, the CASE Ultra and Leadscope software platforms used two different statistical-based models to predict mutations at G-C (guanine-cytosine) and A-T (adenine-thymine) sites, to comprehensively assess bacterial mutagenesis. In the present study, composite bacterial mutagenicity models covering multiple mutation types were developed. These new models contain more than double the number of chemicals (n = 9,254 and n = 13,514) than the corresponding non-composite models and show better toxicophore coverage. Additionally, the use of a single composite bacterial mutagenicity model simplifies impurity analysis in an ICH M7 (Q)SAR workflow by reducing the number of model outputs requiring review. An external validation set of 388 drug impurities representing proprietary pharmaceutical chemical space showed performance statistics ranging from of 66-82% in sensitivity, 91-95% in negative predictivity and 96% in coverage. This effort represents a major enhancement to these (Q)SAR models and their use under ICH M7(R1), leading to improved patient safety through greater predictive accuracy, applicability, and efficiency when assessing the bacterial mutagenic potential of drug impurities., (Published by Elsevier Inc.)

Several lines of research demonstrate that primary motor cortex (M1) is principally involved in controlling the contralateral side of the body. However, M1 activity has been correlated with both contralateral and ipsilateral limb movements. Why does ipsilaterally-related activity not cause contralateral motor output? To address this question, we trained monkeys to counter mechanical loads applied to their right and left limbs. We found >50% of M1 neurons had load-related activity for both limbs. Contralateral loads evoked changes in activity ~10ms sooner than ipsilateral loads. We also found corresponding population activities were distinct, with contralateral activity residing in a subspace that was orthogonal to the ipsilateral activity. Thus, neural responses for the contralateral limb can be extracted without interference from the activity for the ipsilateral limb, and vice versa. Our results show that M1 activity unrelated to downstream motor targets can be segregated from activity related to the downstream motor output., Competing Interests: EH, KC, TT, DC No competing interests declared, SS Co-founder and chief scientific officer of Kinarm which commercializes the robot used in the study, (© 2019, Heming et al.)

In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol. The protocol outlines a hazard assessment framework including key effects/mechanisms and their relationships to endpoints such as gene mutation and clastogenicity. IST models and data are reviewed that support the assessment of these effects/mechanisms along with defined approaches for combining the information and evaluating the confidence in the assessment. This protocol has been developed through a consortium of toxicologists, computational scientists, and regulatory scientists across several industries to support the implementation and acceptance of in silico approaches., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Muscle responses to mechanical disturbances exhibit two distinct phases: a response starting at ~20 ms that is fairly stereotyped, and a response starting at ~60 ms modulated by many behavioral contexts including goal-redundancy and environmental obstacles. Muscle responses to disturbances of visual feedback of the hand arise within ~90 ms. However, little is known whether these muscle responses are sensitive to behavioral contexts. We had 49 human participants (27 male) execute goal-directed reaches with visual feedback of their hand presented as a cursor. On random trials, the cursor jumped laterally to the reach direction, and thus, required a correction to attain the goal. The first experiment demonstrated that the response amplitude starting at 90 ms scaled with jump magnitude, but only for jumps <2 cm. For larger jumps, the duration of the muscle response scaled with the jump size starting after 120 ms. The second experiment demonstrated that the early response was sensitive to goal redundancy as wider targets evoked a smaller corrective response. The third experiment demonstrated that the early response did not consider the presence of obstacles, as this response routinely drove participants directly to the goal even though this path was blocked by an obstacle. Instead, the appropriate muscle response to navigate around the obstacle started after 120 ms. Our findings highlight that visual feedback of the limb involves two distinct phases: a response starting at 90 ms with limited sensitivity to jump magnitude and sensitive to goal-redundancy, and a response starting at 120 ms with increased sensitivity to jump magnitude and environmental factors. SIGNIFICANCE STATEMENT The motor system can integrate proprioceptive feedback to guide an ongoing action in ~60 ms and is flexible to a broad range of behavioral contexts. In contrast, the present study identified that the motor response to a visual disturbance exhibits two distinct phases: an early response starting at 90 ms with limited scaling with disturbance size and sensitivity to goal-redundancy, and a slower response starting after 120 ms with increased sensitivity to disturbance size and sensitive to environmental obstacles. These data suggest visual feedback of the hand is processed through two distinct feedback processes., (Copyright © 2019 the authors.)

(Quantitative) structure-activity relationship or (Q)SAR predictions of DNA-reactive mutagenicity are important to support both the design of new chemicals and the assessment of impurities, degradants, metabolites, extractables and leachables, as well as existing chemicals. Aromatic N-oxides represent a class of compounds that are often considered alerting for mutagenicity yet the scientific rationale of this structural alert is not clear and has been questioned. Because aromatic N-oxide-containing compounds may be encountered as impurities, degradants and metabolites, it is important to accurately predict mutagenicity of this chemical class. This article analysed a series of publicly available aromatic N-oxide data in search of supporting information. The article also used a previously developed structure-activity relationship (SAR) fingerprint methodology where a series of aromatic N-oxide substructures was generated and matched against public and proprietary databases, including pharmaceutical data. An assessment of the number of mutagenic and non-mutagenic compounds matching each substructure across all sources was used to understand whether the general class or any specific subclasses appear to lead to mutagenicity. This analysis resulted in a downgrade of the general aromatic N-oxide alert. However, it was determined there were enough public and proprietary data to assign the quindioxin and related chemicals as well as benzo[c][1,2,5]oxadiazole 1-oxide subclasses as alerts. The overall results of this analysis were incorporated into Leadscope's expert-rule-based model to enhance its predictive accuracy., (© The Author(s) 2018. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The International Conference on Harmonization (ICH) M7 guideline allows the use of in silico approaches for predicting Ames mutagenicity for the initial assessment of impurities in pharmaceuticals. This is the first international guideline that addresses the use of quantitative structure-activity relationship (QSAR) models in lieu of actual toxicological studies for human health assessment. Therefore, QSAR models for Ames mutagenicity now require higher predictive power for identifying mutagenic chemicals. To increase the predictive power of QSAR models, larger experimental datasets from reliable sources are required. The Division of Genetics and Mutagenesis, National Institute of Health Sciences (DGM/NIHS) of Japan recently established a unique proprietary Ames mutagenicity database containing 12140 new chemicals that have not been previously used for developing QSAR models. The DGM/NIHS provided this Ames database to QSAR vendors to validate and improve their QSAR tools. The Ames/QSAR International Challenge Project was initiated in 2014 with 12 QSAR vendors testing 17 QSAR tools against these compounds in three phases. We now present the final results. All tools were considerably improved by participation in this project. Most tools achieved >50% sensitivity (positive prediction among all Ames positives) and predictive power (accuracy) was as high as 80%, almost equivalent to the inter-laboratory reproducibility of Ames tests. To further increase the predictive power of QSAR tools, accumulation of additional Ames test data is required as well as re-evaluation of some previous Ames test results. Indeed, some Ames-positive or Ames-negative chemicals may have previously been incorrectly classified because of methodological weakness, resulting in false-positive or false-negative predictions by QSAR tools. These incorrect data hamper prediction and are a source of noise in the development of QSAR models. It is thus essential to establish a large benchmark database consisting only of well-validated Ames test results to build more accurate QSAR models., (© The Author(s) 2018. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society.)

The International Council for Harmonization (ICH) M7 guideline describes a hazard assessment process for impurities that have the potential to be present in a drug substance or drug product. In the absence of adequate experimental bacterial mutagenicity data, (Q)SAR analysis may be used as a test to predict impurities' DNA reactive (mutagenic) potential. However, in certain situations, (Q)SAR software is unable to generate a positive or negative prediction either because of conflicting information or because the impurity is outside the applicability domain of the model. Such results present challenges in generating an overall mutagenicity prediction and highlight the importance of performing a thorough expert review. The following paper reviews pharmaceutical and regulatory experiences handling such situations. The paper also presents an analysis of proprietary data to help understand the likelihood of misclassifying a mutagenic impurity as non-mutagenic based on different combinations of (Q)SAR results. This information may be taken into consideration when supporting the (Q)SAR results with an expert review, especially when out-of-domain results are generated during a (Q)SAR evaluation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Many studies highlight that human movements are highly successful yet display a surprising amount of variability from trial to trial. There is a consistent pattern of variability throughout movement: initial motor errors are corrected by the end of movement, suggesting the presence of a powerful online control process. Here, we analyze the trial-by-trial variability of goal-directed reaching in nonhuman primates (five male Rhesus monkeys) and demonstrate that they display a similar pattern of variability during reaching, including a strong negative correlation between initial and late hand motion. We then demonstrate that trial-to-trial neural variability of primary motor cortex (M1) is positively correlated with variability of future hand motion (τ = ∼160 ms) during reaching. Furthermore, the variability of M1 activity is also correlated with variability of past hand motion (τ = ∼90 ms), but in the opposite polarity (i.e., negative correlation). Partial correlation analysis demonstrated that M1 activity independently reflects the variability of both past and future hand motions. These findings provide support for the hypothesis that M1 activity is involved in online feedback control of motor actions. SIGNIFICANCE STATEMENT Previous studies highlight that primary motor cortex (M1) rapidly responds to either visual or mechanical disturbances, suggesting its involvement in online feedback control. However, these studies required external disturbances to the motor system and it is not clear whether a similar feedback process addresses internal noise/errors generated by the motor system itself. Here, we introduce a novel analysis that evaluates how variations in the activity of M1 neurons covary with variations in hand motion on a trial-to-trial basis. The analyses demonstrate that M1 activity is correlated with hand motion in both the near future and the recent past, but with opposite polarity. These results suggest that M1 is involved in online feedback motor control to address errors/noise within the motor system., (Copyright © 2018 the authors 0270-6474/18/387787-13$15.00/0.)

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

We compared how different metabolic stressors, anoxic coma and food deprivation, affected signaling in neural tissue. We used the locust's Descending Contralateral Movement Detector (DCMD) interneuron because its large axon, high firing frequencies, and rapid conduction velocity make it energetically expensive. We exposed locusts to a 30min anoxic coma or 1day of food deprivation and found contrasting effects on signaling within the axon. After a prior anoxic coma, the DCMD fired fewer high-frequency (>200Hz) action potentials (APs) (Control: 12.4±1.6; Coma: 6.3±0.9) with a reduction in axonal conduction velocity (CV) at all frequencies (∼4-8%) when presented with a standard looming visual stimulus. Prior anoxic coma was also associated with a loss of supernormal conduction by reducing both the number of supernormal APs and the firing frequency with the highest CV. Initially, food deprivation caused a significant increase in the number of low- and high-frequency APs with no differences observed in CV. After controlling for isolation, food deprivation resulted in an increase in high-frequency APs (>200Hz: Control: 17.1±1.7; Food-deprived: 19.9±1.3) and an increase in relative conduction velocity for frequencies >150Hz (∼2%). Action potentials of food-deprived animals had a smaller half-width (Control: 0.45±0.02ms; Food-deprived: 0.40±0.01ms) and decay time (Control: 0.62±0.03ms; Food-deprived: 0.54±0.02ms). Our data indicate that the effects of metabolic stress on neural signaling can be stressor-dependent., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Mechanisms that could mitigate the effects of hypoxia on neuronal signaling are incompletely understood. We show that axonal performance of a locust visual interneuron varied depending on oxygen availability. To induce hypoxia, tracheae supplying the thoracic nervous system were surgically lesioned and action potentials in the axon of the descending contralateral movement detector (DCMD) neuron passing through this region were monitored extracellularly. The conduction velocity and fidelity of action potentials decreased throughout a 45-min experiment in hypoxic preparations, whereas conduction reliability remained constant when the tracheae were left intact. The reduction in conduction velocity was exacerbated for action potentials firing at high instantaneous frequencies. Bath application of octopamine mitigated the loss of conduction velocity and fidelity. Action potential conduction was more vulnerable in portions of the axon passing through the mesothoracic ganglion than in the connectives between ganglia, indicating that hypoxic modulation of the extracellular environment of the neuropil has an important role to play. In intact locusts, octopamine and its antagonist, epinastine, had effects on the entry to, and recovery from, anoxic coma consistent with octopamine increasing overall neural performance during hypoxia. These effects could have functional relevance for the animal during periods of environmental or activity-induced hypoxia., (Copyright © 2016 the American Physiological Society.)

The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive, mutagenic, impurities in pharmaceutical products to limit the potential carcinogenic risk related to such impurities. This paper outlines a series of principles and procedures to consider when generating (Q)SAR assessments aligned with the ICH M7 guideline to be included in a regulatory submission. In the absence of adequate experimental data, the results from two complementary (Q)SAR methodologies may be combined to support an initial hazard classification. This may be followed by an assessment of additional information that serves as the basis for an expert review to support or refute the predictions. This paper elucidates scenarios where additional expert knowledge may be beneficial, what such an expert review may contain, and how the results and accompanying considerations may be documented. Furthermore, the use of these principles and procedures to yield a consistent and robust (Q)SAR-based argument to support impurity qualification for regulatory purposes is described in this manuscript., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Statistical-based and expert rule-based models built using public domain mutagenicity knowledge and data are routinely used for computational (Q)SAR assessments of pharmaceutical impurities in line with the approach recommended in the ICH M7 guideline. Knowledge from proprietary corporate mutagenicity databases could be used to increase the predictive performance for selected chemical classes as well as expand the applicability domain of these (Q)SAR models. This paper outlines a mechanism for sharing knowledge without the release of proprietary data. Primary aromatic amine mutagenicity was selected as a case study because this chemical class is often encountered in pharmaceutical impurity analysis and mutagenicity of aromatic amines is currently difficult to predict. As part of this analysis, a series of aromatic amine substructures were defined and the number of mutagenic and non-mutagenic examples for each chemical substructure calculated across a series of public and proprietary mutagenicity databases. This information was pooled across all sources to identify structural classes that activate or deactivate aromatic amine mutagenicity. This structure activity knowledge, in combination with newly released primary aromatic amine data, was incorporated into Leadscope's expert rule-based and statistical-based (Q)SAR models where increased predictive performance was demonstrated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The descending contralateral movement detector (DCMD) is a high-performance interneuron in locusts with an axon capable of transmitting action potentials (AP) at more than 500 Hz. We investigated biophysical mechanisms for fidelity of high-frequency transmission in this axon. We measured conduction velocities (CVs) at room temperature during exposure to 10 mmol/L cadmium, a calcium current antagonist, and found significant reduction in CV with reduction at frequencies >200 Hz of ~10%. Higher temperatures induced greater CV reductions during exposure to cadmium across all frequencies of ~20-30%. Intracellular recordings during 15 min of exposure to cadmium or nickel, also a calcium current antagonist, revealed an increase in the magnitude of the afterhyperpolarization potential (AHP) and the time to recover to baseline after the AHP (Medians for Control: -19.8%; Nickel: 167.2%; Cadmium: 387.2%), that could be due to a T-type calcium current. However, the removal of extracellular calcium did not mimic divalent cation exposure suggesting calcium currents are not the cause of the AHP increase. Computational modeling showed that the effects of the divalent cations could be modeled with a persistent sodium current which could be blocked by high concentrations of divalent cations. Persistent sodium current shortened the AHP duration in our models and increased CV for high-frequency APs. We suggest that faithful, high-frequency axonal conduction in the DCMD is enabled by a mechanism that shortens the AHP duration like a persistent or resurgent sodium current., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Objective: Methods currently used to triage patients from mass casualty events have a sparse evidence basis. The objective of this project was to assess gaps of the widely used Simple Triage and Rapid Transport (START) algorithm using a large database when it is used to triage low-acuity patients. Subsequently, we developed and tested evidenced-based improvements to START., Methods: Using the National Trauma Database (NTDB), a large set of trauma victims were assigned START triage levels, which were then compared to recorded patient mortality outcomes using area under the receiver-operator curve (AUC). Subjects assigned to the "Minor/Green" level who nevertheless died prior to hospital discharge were considered mistriaged. Recursive partitioning identified factors associated with of these mistriaged patients. These factors were then used to develop candidate START models of improved triage, whose overall performance was then re-evaluated using data from the NTDB. This process of evaluating performance, identifying errors, and further adjusting candidate models was repeated iteratively., Results: The study included 322,162 subjects assigned to "Minor/Green" of which 2,046 died before hospital discharge. Age was the primary predictor of under-triage by START. Candidate models which re-assigned patients from the "Minor/Green" triage level to the "Delayed/Yellow" triage level based on age (either for patients >60 or >75), reduced mortality in the "Minor/Green" group from 0.6% to 0.1% and 0.3%, respectively. These candidate START models also showed net improvement in the AUC for predicting mortality overall and in select subgroups., Conclusion: In this research model using trauma registry data, most START under-triage errors occurred in elderly patients. Overall START accuracy was improved by placing elderly but otherwise minimally injured-mass casualty victims into a higher risk triage level. Alternatively, such patients would be candidates for closer monitoring at the scene or expedited transport ahead of other, younger "Minor/Green" victims.

Exertional heat stroke incidence is on the rise and has become the third leading cause of death in high school athletes. It is entirely preventable, yet this is a case of a 15-year-old, 97-kg male football player who presented unresponsive and hyperthermic after an August football practice. His blood pressure was 80/30, and his pulse was 180. He had a rectal temperature of 107.3°F, and upon entering the emergency department, he was rapidly cooled in 40 minutes. As he progressed, he developed metabolic acidosis, elevated liver enzymes, a prolapsed mitral valve with elevated troponin levels, and worsening hypotension even with extracorporeal membrane oxygenation support. After 3 days in the hospital, this young man was pronounced dead as a result of complications from exertional heat stroke. We address not only the complications of his hospital course relative to his positive blood cultures but also the complications that can result from attention-deficit/hyperactivity disorder medication our patient was taking. As the population of young adults becomes more obese and more highly medicated for attention-deficit/hyperactivity disorder, we sought out these growing trends in correlation with the increase in incidence of heat-related illness. We also address the predisposing factors that make young high school athletes more likely to experience heat illness and propose further steps to educate this susceptible population.

Objective: The objective of this study was to compare the duration of analgesia, need for analgesic medications, and pain-related nursing interventions in patients who did and did not receive ultrasound-guided femoral nerve blocks for femur fracture pain., Methods: This is a retrospective, preimplementation and postimplementation cohort study. An emergency department log of patients receiving femoral nerve blocks for femur fracture pain was compared with a similar cohort of patients with femur fractures who did not receive nerve blocks. The primary outcome is time from initial pain treatment until the next dose of analgesic. Data were analyzed using Kaplan-Meier methods. Secondary outcomes include number of doses of pain medication, total amount of morphine given, and number of pain-related nursing interventions. Data were analyzed with the Mann-Whitney U test., Results: Eighty-one patients met inclusion/exclusion criteria: 50 in the preimplementation cohort and 31 in the postimplementation group. The median times until next dose of analgesic medication were 2.2 hours (interquartile range [IQR], 1.2-3.4 hours) in the preimplementation group and 6.1 hours (IQR, 3.8-9.5 hours) in the postimplementation group (P < 0.001). The median numbers of doses of pain medication were 0.3 per hour (IQR, 0.25-0.5 per hour) in the preimplementation group and 0.15 per hour (IQR, 0.07-0.3 per hour) in the postimplementation group. The median total doses of morphine were 14.8 µg/kg per hour (IQR, 9.4-19.2 µg/kg per hour) in the preimplementation group and 6.5 µg/kg per hour (IQR, 0-12.2 µg/kg per hour) in the postimplementation group (P = 0.01). The median numbers of nursing interventions were 0.4 per hour (IQR, 0.25-0.5 per hour) in the preimplementation group and 0.15 per hour (IQR, 0.1-0.2 per hour) in the postimplementation group (P < 0.001)., Conclusions: Patients who received ultrasound-guided femoral nerve block for femur fracture pain had longer duration of analgesia, required fewer doses of analgesic medications, and needed fewer nursing interventions than those receiving systemic analgesic medication alone.

Background: Recent studies reviewing immune mechanisms of immune thrombocytopenia (ITP) have suggested acute and chronic forms may represent distinct immunopathological disorders. This study evaluated absolute lymphocyte counts (ALCs) as predictors for ITP outcomes., Procedure: CBCs with differential counts were ascertained at presentation, 3, 6, and 12 months for 204 patients. Receiver operating characteristic (ROC) curves were used to determine cutoff values. Logistic regression models and recursive partitioning were used to evaluate which variables were significantly associated with outcomes., Results: ALC values at presentation were not independently predictive of disease duration. However, ALC values at 3 months were significant predictors. Sixty-eight percent (40/59) of patients >8 years of age and 43% (20/46) of patients ≤ 8 years who had an ALC ≤ 3,000/μl at 3 months developed chronic ITP. This compares to chronic rates of only 25% (3/12) and 2% (2/87) of patients >8 and ≤ 8 years, respectively, with an ALC > 3,000/μl at 3 months. Further, 92% (60/65) of patients who developed chronic ITP had a 3-month ALC ≤ 3,000/μl. An ALC > 3,000/μl at 3 months is a strong predictor for platelet recovery as only 5% (5/99) of these patients developed chronic ITP., Conclusion: This study suggests progression to lower lymphocyte counts over the first few months of disease is a strong predictor for chronic ITP, allowing for risk stratification of patients, particularly when used in conjunction with other known predictors. Further research is needed to confirm these findings and to fully investigate the pathophysiological mechanisms responsible for this association., (© 2013 Wiley Periodicals, Inc.)

Objective: To investigate the demographic and clinical factors of children who present to the pediatric emergency department (ED) with abdominal pain and their outcomes., Methods: A review of the electronic medical record of patients 1 to 18 years old, who presented to the Children's Hospital of Pittsburgh ED with a complaint of abdominal pain over the course of 2 years, was conducted. Demographic and clinical characteristics, as well as visit outcomes, were reviewed. Subjects were grouped by age, race, and gender. Results of evaluation, treatment, and clinical outcomes were compared between groups by using multivariate analysis and recursive partitioning., Results: There were 9424 patient visits during the study period that met inclusion and exclusion criteria. Female gender comprised 61% of African American children compared with 52% of white children. Insurance was characterized as private for 75% of white and 37% of African American children. A diagnosis of appendicitis was present in 1.9% of African American children and 5.1% of white children. Older children were more likely to be admitted and have an operation associated with their ED visit. Appendicitis was uncommon in younger children. Constipation was commonly diagnosed. Multivariate analysis by diagnosis as well as recursive partitioning analysis did not reflect any racial differences in evaluation, treatment, or outcome., Conclusions: Constipation is the most common diagnosis in children presenting with abdominal pain. Our data demonstrate that no racial differences exist in the evaluation, treatment, and disposition of children with abdominal pain.

Study Objective: A variety of methods have been proposed and used in disaster triage situations, but there is little more than expert opinion to support most of them. Anecdotal disaster experiences often report mediocre real-world triage accuracy. The study objective was to determine the accuracy of several disaster triage methods when predicting clinically important outcomes in a large cohort of trauma victims., Methods: Pediatric, adult, and geriatric trauma victims from the National Trauma Data Bank were assigned triage levels, using each of 6 disaster triage methods: simple triage and rapid treatment (START), Fire Department of New York (FDNY), CareFlight, Glasgow Coma Scale (GCS), Sacco Score, and Unadjusted Sacco Score. Methods for approximating triage systems were vetted by subject matter experts. Triage assignments were compared against patient mortality at hospital discharge with area under the receiver operator curve. Secondary outcomes included death in the emergency department, use of a ventilator, and lengths of stay. Subgroup analysis assessed triage accuracy in patients by age, trauma type, and sex., Results: In this study, 530,695 records were included. The Sacco Score predicted mortality most accurately, with area under the receiver operator curve of 0.883 (95% confidence interval 0.880 to 0.885), and performed well in most subgroups. FDNY was more accurate than START for adults but less accurate for children. CareFlight was best for burn victims, with area under the receiver operator curve of 0.87 (95% confidence interval 0.85 to 0.89) but mistriaged more salvageable trauma patients to "dead/black" (41% survived) than did other disaster triage methods (≈10% survived)., Conclusion: Among 6 disaster triage methods compared against actual outcomes in trauma registry patients, the Sacco Score predicted mortality most accurately. This analysis highlighted comparative strengths and weakness of START, FDNY, CareFlight, and Sacco, suggesting areas in which each might be improved. The GCS predicted outcomes similarly to dedicated disaster triage strategies., (Copyright © 2013 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.)

Introduction: Though many mass-casualty triage methods have been proposed, few have been validated in an evidence-based manner. The Sacco Triage Method (STM) has been shown to accurately stratify adult victims of blunt and penetrating trauma into groups of increasing mortality risk. However, it has not been validated for pediatric trauma victims., Purpose: Evaluate the STM's performance in pediatric trauma victims., Methods: Records from the United States' National Trauma Data Base, a registry of trauma victims developed by the American College of Surgeons, were extracted for the 2007-2009 reporting years. Patients ≤ 18 years of age transported from a trauma scene with complete initial scene data were included in the analysis. Sacco triage scores were assigned to each registry patient, and receiver-operator curves were developed for predicting mortality, along with several secondary outcomes. Area under the receiver-operator curve (AUC) was the main outcome statistic. Sensitivity analysis was performed using a Sacco score without age adjustment, using blunt versus penetrating trauma, and using patients <12 years of age., Results: There were 210,175 pediatric records, of which 90,037 had complete data for analysis. The STM with age adjustment predicted pediatric trauma mortality with an AUC of 0.933 (95% CI: 0.925-0.940). Without the age adjustment term, it predicted mortality with an AUC of 0.924 (95% CI: 0.916-0.933). The STM with age adjustment predicted blunt trauma mortality in 72,467 patients with an AUC of 0.938 (95% CI: 0.929-0.947) and penetrating trauma mortality in 10,099 patients with an AUC of 0.927 (95% CI: 0.911-0.943). These findings did not change significantly when analysis was limited to patients <12 years of age. The Sacco Triage Method was also predictive of some secondary outcomes, such as major injury and death on arrival to the emergency department., Conclusion: The Sacco Triage Method, with or without its age adjustment term, was a highly accurate predictor of mortality in pediatric trauma patients in this registry database. This triage method appears to be a valid strategy for the prioritization of injured children.

Control and minimization of human exposure to potential genotoxic impurities found in drug substances and products is an important part of preclinical safety assessments of new drug products. The FDA's 2008 draft guidance on genotoxic and carcinogenic impurities in drug substances and products allows use of computational quantitative structure-activity relationships (QSAR) to identify structural alerts for known and expected impurities present at levels below qualified thresholds. This study provides the information necessary to establish the practical use of a new in silico toxicology model for predicting Salmonella t. mutagenicity (Ames assay outcome) of drug impurities and other chemicals. We describe the model's chemical content and toxicity fingerprint in terms of compound space, molecular and structural toxicophores, and have rigorously tested its predictive power using both cross-validation and external validation experiments, as well as case studies. Consistent with desired regulatory use, the model performs with high sensitivity (81%) and high negative predictivity (81%) based on external validation with 2368 compounds foreign to the model and having known mutagenicity. A database of drug impurities was created from proprietary FDA submissions and the public literature which found significant overlap between the structural features of drug impurities and training set chemicals in the QSAR model. Overall, the model's predictive performance was found to be acceptable for screening drug impurities for Salmonella mutagenicity., (Published by Elsevier Inc.)

Objective: Asthma is one of the most common childhood illnesses and accounts for a substantial amount of pediatric emergency department visits. Historically, acute exacerbations are treated with a beta agonist via nebulizer therapy (NEB). However, with the advent of the spacer, the medication can be delivered via a metered dose inhaler (MDI+S) with the same efficacy for mild-to-moderate asthma exacerbations. To date, no study has been done to evaluate emergency department (ED) length of stay (LOS) and opportunity cost between nebulized vs MDI+S. The objective of this study was to compare ED LOS and associated opportunity cost among children who present with a mild asthma exacerbation according to the delivery mode of albuterol: MDI+S vs NEB., Methods: A structured, retrospective cross-sectional study was conducted. Medical records were reviewed from children aged 1-18 years treated at an urban pediatric ED from July 2007 to June 2008 with a discharge diagnosis International Classification of Disease-9 of asthma. Length of stay was defined: time from initial triage until the time of the guardian signature on the discharge instructions. An operational definition was used to define a mild asthma exacerbation; those patients requiring only one standard weight based albuterol treatment. Emergency department throughput time points, demographic data, treatment course, and delivery method of albuterol were recorded., Results: Three hundred and four patients were analyzed: 94 in the MDI+S group and 209 in the NEB group. Mean age in years for the MDI+S group was 9.57 vs 5.07 for the NEB group (p<0.001). The percentage of patients that received oral corticosteroids was 39.4% in the MDI+S group vs 61.7% in the NEB group (p<0.001). There was no difference between groups in: race, insurance status, gender, or chest radiographs. The mean ED LOS for patients in the MDI+S group was 170 minutes compared to 205 minutes in the NEB group. On average, there was a 25.1 minute time savings per patient in ED treatment time (p<0.001; 95% CI=3.8-31.7). Significant predictors of outcome for treatment time were chest radiograph, steroids, and treatment mode. Opportunity cost analysis estimated a potential cost savings of $213,532 annually using MDI+S vs NEB., Conclusion: In mild asthma exacerbations, administering albuterol via MDI+S decreases ED treatment time when compared to administering nebulized albuterol. A metered dose inhaler with spacer utilization may enhance opportunity cost savings and decrease the left without being seen population with improved throughput., Limitations: The key limitations of this study include its retrospective design, the proxy non-standard definition of mild asthma exacerbation, and the opportunity cost calculation, which may over-estimate the value of ED time saved based on ED volume.

Question: I prescribe oral steroids for children in my community when they suffer asthma exacerbation. How many doses of steroids are recommended? Do all children need to take steroids for 5 days?, Answer: Traditionally, mild-to-moderate pediatric asthma exacerbations have been treated with a short course of oral steroids-often 5 days of prednisone or prednisolone. However, recent evidence suggests a similar outcome can be acheived with a single dose of dexamethasone, which has a longer half-life and powerful anti-inflammatory effects, along with easier administration and compliance. Single-dose dexamethasone offers a simple and reliable treatment for these patients in office, urgent care, and emergency department settings.

Black cohosh, red clover, hops, and chasteberry are botanicals commonly used to alleviate menopausal symptoms in the US, and are examined in this study as part of a FDA Office of Women's Health research collaboration to expand knowledge on the safety of these botanical products. Computational approaches using classic (quantitative) structure-activity relationships ((Q)SAR), probabilistic reasoning, machine learning methods, and human expert rule-based systems were employed to deliver human hepatobiliary adverse effect predictions. The objective is to profile and analyze constituents that are alerting for the human hepatobiliary adverse effects. Computational analysis of positively predicted constituents showed that common structural features contributing to the hepatobiliary adverse effect predictions contain phenolic, flavone, isoflavone, glucoside conjugated flavone and isoflavone, and 4-hydroxyacetophenone structures. Specifically, protocatechuic acid from black cohosh, benzofuran and 4-vinylphenol from chasteberry, and xanthohumol I from hops were botanical constituents predicted positive for liver toxicity endpoints and were also confirmed with literature findings. However, comparison between the estimated human exposure to these botanical constituents and the LOAEL and NOAEL in published animal liver toxicology studies for these constituents demonstrated varying margins of safety. This study will serve as regulatory decision support information for regulators at the FDA to help with the process of prioritizing chemicals for testing., (Published by Elsevier Inc.)

Objectives: Clavicle fractures are among the most common orthopedic injuries in children. Diagnosis typically involves radiographs, which expose children to radiation and may consume significant time and resources. Our objective was to determine if bedside emergency department (ED) ultrasound (US) is an accurate alternative to radiography., Methods: This was a prospective study of bedside US for diagnosing clavicle fractures. A convenience sample of children ages 1-18 years with shoulder injuries requiring radiographs was enrolled. Bedside US imaging and an unblinded interpretation were completed by a pediatric emergency physician (EP) prior to radiographs. A second interpreter, a pediatric EP attending physician with extensive US experience, determined a final interpretation of the US images at a later date. This final interpretation was blinded to both clinical and radiography outcomes. The reference standard was an attending radiologist's interpretation of radiographs. The primary outcome was the accuracy of the blinded US interpretation for detecting clavicle fractures compared to the reference standard. Secondary outcome measures included the interrater reliability of the unblinded bedside and the blinded physicians' interpretations and the FACES pain scores (range, 0-5) for US and radiograph imaging., Results: One-hundred patients were included in the study, of whom 43 had clavicle fractures by radiography. The final US interpretation had 95% sensitivity (95% confidence interval [CI] = 83% to 99%) and 96% specificity (95% CI = 87% to 99%), and overall accuracy was 96%, with 96 congruent readings. Positive and negative predictive values (PPVs and NPVs, respectively) were 95% (95% CI = 83% to 99%) and 96% (95% CI = 87% to 99%), respectively. Interrater reliability (kappa) was 0.74 (95% CI = 0.60 to 0.88). FACES pain scores were available for the 86 subjects who were at least 5 years old. Pain scores were similar during US and radiography., Conclusions: Compared to radiographs, bedside US can accurately diagnose pediatric clavicle fractures. US causes no more discomfort than radiography when detecting clavicle fractures. Given US's advantage of no radiation, pediatric EPs should consider this application., (2010 by the Society for Academic Emergency Medicine)