30 results on '"Macmillan DS"'
Search Results
2. GENETIC PREDISPOSITION TO MELANOMA AND OTHER SKIN CANCERS IN AUSTRALIANS
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Sharpe Ca, Brown Mm, Macmillan Ds, and McGovern Vj
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Oncology ,medicine.medical_specialty ,Skin Neoplasms ,business.industry ,Melanoma ,Australia ,General Medicine ,medicine.disease ,White People ,Internal medicine ,Ethnicity ,medicine ,Genetic predisposition ,Humans ,business ,Ireland - Published
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3. Addressing the challenges of acute toxicity hazard classification using a non-animal defined approach.
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Macmillan DS, Ambure P, Aranda V, Bayona Y, Bonderovic V, Dawick J, Fabre N, Fischer S, Hodges G, Llobet-Mut Á, Loisel-Joubert S, Rivetti C, Roberts J, Schirmer K, Serrano-Candelas E, Serrano Ramón B, and Stackhouse RA
- Abstract
Acute fish toxicity is an ecotoxicological endpoint which provides important information about a chemical's potential to elicit adverse effect(s) on fish. These effects are typically studied using in vivo tests but for animal welfare reasons as well as the quest for increased species relevance, biological coverage, mechanistic understanding of effects and throughput, there have been significant efforts in recent years to reduce or replace the use of animals in (eco)toxicological hazard assessment, by developing defined approaches (DA) or integrated approaches to testing and assessment (IATA). To this end, a novel score-based DA has been developed, which integrates three in silico predictions from freely available (Q)SARs: the VEGA Fish (KNN-Read-Across) and Fathead Minnow (KNN-IRFMN) models and the United States Environmental Protection Agency (USEPA) ECOSAR Fish 96-h LC50 model, along with in vitro RTgill-W1 data. The DA provides a categorical output aligned with the United Nations Globally Harmonized System of Classification and Labelling (GHS) framework (Acute Category 1, Acute Category 2, Acute Category 3 or Not Classified) with an overall accuracy of 80%, offering a reliable alternative to traditional in vivo testing methods for acute fish toxicity., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Society of Environmental Toxicology and Chemistry.)
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- 2025
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4. A systematic scoping review of the neurological effects of COVID-19.
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Hogberg HT, Tsaioun K, Breidenbach JD, Elmore B, Filipovska J, Garcia-Reyero N, Hargreaves AJ, Joshi O, Omeragic E, Plant S, Ram R, Virmani I, Waspe J, and Macmillan DS
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- Humans, SARS-CoV-2 pathogenicity, COVID-19 epidemiology, Nervous System Diseases epidemiology, Nervous System Diseases virology
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Background: The global coronavirus 2019 (COVID-19) pandemic began in early 2020, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In mid-2020 the CIAO (Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway Framework) project was established, bringing together over 75 interdisciplinary scientists worldwide to collaboratively investigate the underlying biological mechanisms of COVID-19 and consolidate the data using the Adverse Outcome Pathway (AOP) Framework. Neurological symptoms such as anosmia and encephalitis have been frequently reported to be associated with infection with SARS-CoV-2., Objective: Within CIAO, a working group was formed to conduct a systematic scoping review of COVID-19 and its related neurological symptoms to determine which key events and modulating factors are most commonly reported and to identify knowledge gaps., Design: LitCOVID was used to retrieve 86,075 papers of which 10,244 contained relevant keywords. After title and abstract screening, 2,328 remained and their full texts were reviewed based on predefined inclusion and exclusion criteria. 991 studies fulfilled the inclusion criteria and were retrieved to conduct knowledge synthesis., Results: The majority of publications reported human observational studies. Early key events were less likely to be reported compared to middle and late key events/adverse outcomes. The majority of modulating factors described related to age or sex. Less recognised COVID-19 associated AO or neurological effects of COVID-19 were also identified including multiple sclerosis/demyelination, neurodegeneration/cognitive effects and peripheral neuronal effects., Conclusion: There were many methodological and reporting issues noted in the reviewed studies. In particular, publication abstracts would benefit from clearer reporting of the methods and endpoints used and the key findings, to ensure relevant papers are included when systematic reviews are conducted. The information extracted from the scoping review may be useful in understanding the mechanisms of neurological effects of COVID-19 and to further develop or support existing AOPs linking COVID-19 and its neurological key events and adverse outcomes. Further evaluation of the less recognised COVID-19 effects is needed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ishita Virmani reports financial support was provided by a. RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic., (Copyright © 2024. Published by Elsevier B.V.)
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- 2024
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5. The last resort requirement under REACH: From principle to practice.
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Macmillan DS, Bergqvist A, Burgess-Allen E, Callan I, Dawick J, Carrick B, Ellis G, Ferro R, Goyak K, Smulders C, Stackhouse RA, Troyano E, Westmoreland C, Ramón BS, Rocha V, and Zhang X
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- Animals, Humans, European Union, Animal Testing Alternatives, Risk Assessment, Animal Welfare, Animals, Laboratory
- Abstract
REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) is a European Union regulation that aims to protect human health and the environment from the risks posed by chemicals. Article 25 clearly states that: "[i]n order to avoid animal testing, testing on vertebrate animals for the purposes of this Regulation shall be undertaken only as a last resort." In practice, however, the standard information requirements under REACH are still primarily filled using animal studies. This paper presents examples illustrating that animal testing is not always undertaken only as a last resort. Six over-arching issues have been identified which contribute to this: (1) non-acceptance of existing animal or non-animal data, (2) non-acceptance of read-across, (3) inflexible administrative processes, (4) redundancy of testing, (5) testing despite animal welfare concerns and (6) testing for cosmetic-only ingredients. We, members of the Animal-Free Safety Assessment (AFSA) Collaboration, who work together to accelerate the global adoption of non-animal approaches for chemical safety assessment, herein propose several recommendations intended to aid the European Commission, the European Chemicals Agency and registrants to protect human health and the environment while avoiding unnecessary animal tests - truly upholding the last resort requirement in REACH., 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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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6. Improvements to in silico skin sensitisation predictions through privacy-preserving data sharing.
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Macmillan DS, Chilton ML, and Hillegass J
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- Computer Simulation, Information Dissemination, Privacy, Skin
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In silico models are often built solely on publicly available data which may mean that they are less predictive for proprietary chemical space. Data sharing initiatives can improve the performance of such models, but organisations are often unable to share their data due to the need to protect their business interests and maintain the confidentiality of the chemicals in their research and development programmes. In silico models like Derek Nexus, which use expert knowledge to develop structural alerts based on chemical toxicity, can use proprietary data to identify new areas of chemical space and/or refine existing alerts whilst still preserving the privacy of the confidential data. Five hundred and thirty seven proprietary chemicals with skin sensitisation data were shared which led to the implementation of 7 new alerts and 5 modified alerts, with a concomitant 19% increase in sensitivity and 3% increase in specificity of the model., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martyn Chilton reports a relationship with Lhasa Limited that includes: employment. Corresponding author (Donna Macmillan) was previously employed by, and co-author Martyn Chilton is currently employed by, Lhasa Limited. Lhasa Limited produce Derek Nexus, the in silico tool used in the data sharing project and described within the manuscript., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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7. REACHing for solutions: Essential revisions to the EU chemicals regulation to modernise safety assessment.
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Pereira M, Macmillan DS, Willett C, and Seidle T
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- Animals, Humans, Risk Assessment methods, Animal Welfare, Animal Testing Alternatives
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The Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation was created to protect human health and the environment through the better and earlier identification of harmful intrinsic properties of chemical substances on the European market. One of its central aims was the promotion of alternatives to animal testing, yet it has instead become a long tick-box list of in vivo experiments questionable relevance to human health outcomes despite a global trend towards new approach methods (NAMs) in chemical safety assessment. The Chemicals Strategy for Sustainability (CSS), proposed by the European Commission in 2020, is a golden opportunity to revise REACH in a significant and impactful way, yet proposals presented so far have significant negative animal welfare consequences. There is still time to correct the course of the ongoing REACH revision - proposals made herein offer a path towards the promising future intended by the CSS. These proposals are anchored in three vectors of action, varying in level of complexity - from changes that ECHA can implement to improve existing processes, through technical changes aimed at minimizing animal testing and increasing NAM acceptance, to deeper structural changes to establish non-animal testing strategies as the basis for risk assessment., 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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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8. How to resolve inconclusive predictions from defined approaches for skin sensitisation in OECD Guideline No. 497.
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Macmillan DS, Chilton ML, Gao Y, Kern PS, and Schneider SN
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- Animals, Computer Simulation, Organisation for Economic Co-Operation and Development, Skin, Animal Testing Alternatives methods, Dermatitis, Allergic Contact etiology
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In June 2021 the Organisation for Economic Co-operation and Development published Guideline No. 497 on Defined Approaches for Skin Sensitisation (DASS GL). There are two DAs published, known as the 2o3 and the ITS. The 2o3 uses two concordant results from either the DPRA, KeratinoSens™, or the h-CLAT assays to predict hazard (sensitiser/non-sensitiser). The ITS applies a score to results from the DPRA, the h-CLAT and an in silico model to predict United Nations Globally Harmonized System (GHS) sub-categories (1A/1B/Not Classified). The ITS can use Derek Nexus as the in silico model (known as ITSv1) or use OECD QSAR Toolbox (known as ITSv2). As limitations of the individual in chemico/in vitro assays and in silico predictions are carried through to the DAs, inconclusive predictions are possible for chemicals with results in the borderline range, and chemicals with out of domain results. However, these inconclusive predictions can be resolved by applying a weight of evidence approach. Herein, four case studies are presented, each 'inconclusive' for skin sensitisation potential according to both DAs. A weight of evidence approach was applied to each using a robust scientific approach to provide a conclusive prediction, where possible, based on several additional, non-animal lines of evidence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martyn Chilton reports a relationship with Lhasa Limited that includes: employment. Corresponding author (Donna Macmillan) was previously employed by, and co-author Martyn Chilton is currently employed by, Lhasa Limited. Lhasa Limited produce Derek Nexus, an in silico tool used in one of the defined approaches published by the OECD and described within the manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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9. Selective Anti-Leishmanial Strathclyde Minor Groove Binders Using an N-Oxide Tail-Group Modification.
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Perieteanu MC, McGee LMC, Shaw CD, MacMillan DS, Khalaf AI, Gillingwater K, Beveridge R, Carter KC, Suckling CJ, and Scott FJ
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- Amines, DNA metabolism, Leishmania metabolism, Oxides
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The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have been shown to have potent activity against various bacteria, viruses, fungi and parasites. Herein, it is shown that S-MGBs have potent activity against L. donovani , and that an N-oxide derivation of the tertiary amine tail of typical S-MGBs leads to selective anti-leishmanial activity. Additionally, using S-MGB-219, the N-oxide derivation is shown to retain strong binding to DNA as a 2:1 dimer. These findings support the further study of anti-leishmanial S-MGBs as novel therapeutics., Competing Interests: C.J.S. and F.J.S. are part of revenue-sharing agreements with their university relating to the Strathclyde Minor Groove Binder project. Additionally, C.J.S. and F.J.S. have financial interests through shares in the company Rostra Therapeutics.
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- 2022
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10. Updating the Dermal Sensitisation Thresholds using an expanded dataset and an in silico expert system.
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Chilton ML, Api AM, Foster RS, Gerberick GF, Lavelle M, Macmillan DS, Na M, O'Brien D, O'Leary-Steele C, Patel M, Ponting DJ, Roberts DW, Safford RJ, and Tennant RE
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- Computer Simulation, Expert Systems, Humans, Local Lymph Node Assay, Risk Assessment, Skin, Dermatitis, Allergic Contact etiology, Skin Tests standards
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The Dermal Sensitisation Thresholds (DST) are Thresholds of Toxicological Concern, which can be used to justify exposure-based waiving when conducting a skin sensitisation risk assessment. This study aimed to update the published DST values by expanding the size of the Local Lymph Node Assay dataset upon which they are based, whilst assigning chemical reactivity using an in silico expert system (Derek Nexus). The potency values within the expanded dataset fitted a similar gamma distribution to that observed for the original dataset. Derek Nexus was used to classify the sensitisation activity of the 1152 chemicals in the expanded dataset and to predict which chemicals belonged to a High Potency Category (HPC). This two-step classification led to three updated thresholds: a non-reactive DST of 710 μg/cm
2 (based on 79 sensitisers), a reactive (non-HPC) DST of 73 μg/cm2 (based on 331 sensitisers) and an HPC DST of 1.0 μg/cm2 (based on 146 sensitisers). Despite the dataset containing twice as many sensitisers, these values are similar to the previously published thresholds, highlighting their robustness and increasing confidence in their use. By classifying reactivity in silico the updated DSTs can be applied within a skin sensitisation risk assessment in a reproducible, scalable and accessible manner., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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11. COVID-19 through Adverse Outcome Pathways: Building networks to better understand the disease - 3rd CIAO AOP Design Workshop.
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Clerbaux LA, Amigó N, Amorim MJ, Bal-Price A, Batista Leite S, Beronius A, Bezemer GFG, Bostroem AC, Carusi A, Coecke S, Concha R, Daskalopoulos EP, De Bernardi F, Edrosa E, Edwards SW, Filipovska J, Garcia-Reyero N, Gavins FNE, Halappanavar S, Hargreaves AJ, Hogberg HT, Huynh MT, Jacobson D, Josephs-Spaulding J, Kim YJ, Kong HJ, Krebs CE, Lam A, Landesmann B, Layton A, Lee YO, Macmillan DS, Mantovani A, Margiotta-Casaluci L, Martens M, Masereeuw R, Mayasich SA, Mei LM, Mortensen H, Munoz Pineiro A, Nymark P, Ohayon E, Ojasi J, Paini A, Parissis N, Parvatam S, Pistollato F, Sachana M, Sørli JB, Sullivan KM, Sund J, Tanabe S, Tsaioun K, Vinken M, Viviani L, Waspe J, Willett C, and Wittwehr C
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- Humans, SARS-CoV-2, Post-Acute COVID-19 Syndrome, Adverse Outcome Pathways, COVID-19 complications
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On April 28-29, 2021, 50 scientists from different fields of expertise met for the 3rd online CIAO workshop. The CIAO project “Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway (AOP) framework” aims at building a holistic assembly of the available scientific knowledge on COVID-19 using the AOP framework. An individual AOP depicts the disease progression from the initial contact with the SARS-CoV-2 virus through biological key events (KE) toward an adverse outcome such as respiratory distress, anosmia or multiorgan failure. Assembling the individual AOPs into a network highlights shared KEs as central biological nodes involved in multiple outcomes observed in COVID-19 patients. During the workshop, the KEs and AOPs established so far by the CIAO members were presented and positioned on a timeline of the disease course. Modulating factors influencing the progression and severity of the disease were also addressed as well as factors beyond purely biological phenomena. CIAO relies on an interdisciplinary crowdsourcing effort, therefore, approaches to expand the CIAO network by widening the crowd and reaching stakeholders were also discussed. To conclude the workshop, it was decided that the AOPs/KEs will be further consolidated, integrating virus variants and long COVID when relevant, while an outreach campaign will be launched to broaden the CIAO scientific crowd.
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- 2022
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12. Use of Lhasa Limited Products for the In Silico Prediction of Drug Toxicity.
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Ponting DJ, Burns MJ, Foster RS, Hemingway R, Kocks G, MacMillan DS, Shannon-Little AL, Tennant RE, Tidmarsh JR, and Yeo DJ
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- Animals, Computer Simulation, Drug-Related Side Effects and Adverse Reactions, Software
- Abstract
Lhasa Limited have had a role in the in silico prediction of drug and other chemical toxicity for over 30 years. This role has always been multifaceted, both as a provider of predictive software such as Derek Nexus, and as an honest broker for the sharing of proprietary chemical and toxicity data. A changing regulatory environment and the drive for the Replacement, Reduction and Refinement (the 3Rs) of animal testing have led both to increased acceptance of in silico predictions and a desire for the sharing of data to reduce duplicate testing. The combination of these factors has led to Lhasa Limited providing a suite of products and coordinating numerous data-sharing consortia that do indeed facilitate a significant reduction in the testing burden that companies would otherwise be laboring under. Many of these products and consortia can be organized into workflows for specific regulatory use cases, and it is these that will be used to frame the narrative in this chapter., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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13. Beyond adverse outcome pathways: making toxicity predictions from event networks, SAR models, data and knowledge.
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Ball T, Barber CG, Cayley A, Chilton ML, Foster R, Fowkes A, Heghes C, Hill E, Hill N, Kane S, Macmillan DS, Myden A, Newman D, Polit A, Stalford SA, and Vessey JD
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Adverse outcome pathways have shown themselves to be useful ways of understanding and expressing knowledge about sequences of events that lead to adverse outcomes (AOs) such as toxicity. In this paper we use the building blocks of adverse outcome pathways-namely key events (KEs) and key event relationships-to construct networks which can be used to make predictions of the likelihood of AOs. The networks of KEs are augmented by data from and knowledge about assays as well as by structure activity relationship predictions linking chemical classes to the observation of KEs. These inputs are combined within a reasoning framework to produce an information-rich display of the relevant knowledge and data and predictions of AOs both in the abstract case and for individual chemicals. Illustrative examples are given for skin sensitization, reprotoxicity and non-genotoxic carcinogenicity., (© The Author(s) 2021. Published by Oxford University Press.)
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- 2021
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14. Understanding COVID-19 through adverse outcome pathways - 2nd CIAO AOP Design Workshop.
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Wittwehr C, Amorim MJ, Clerbaux LA, Krebs C, Landesmann B, Macmillan DS, Nymark P, Ram R, Garcia-Reyero N, Sachana M, Sullivan K, Sund J, and Willett C
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- COVID-19 mortality, COVID-19 virology, Global Health, Humans, Interdisciplinary Research, Risk Assessment, Adverse Outcome Pathways, COVID-19 pathology, SARS-CoV-2
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The CIAO project (Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway framework) aims at a holistic assembly of knowledge to deliver a truly transdisciplinary description of the entire COVID-19 physiopathology starting with the initial contact with the SARS-CoV-2 virus and ending with one or several adverse outcomes, e.g., respiratory failure. On 27-28 January 2021, a group of 50+ scientists from numerous organizations around the world met in the 2nd CIAO AOP Design Workshop to discuss the depiction of the COVID-19 disease process as a series of key events (KEs) in a network of AOPs. During the workshop, 74 such KEs forming 13 AOPs were identified, covering COVID-19 manifestations that affect the respiratory, neurological, liver, cardiovascular, kidney and gastrointestinal systems. Modulating factors influencing the course and severity of the disease were also addressed, as was a possible extension of the investigations beyond purely biological phenomena. The workshop ended with the creation of seven working groups, which will further elaborate on the AOPs to be presented and discussed in the 3rd CIAO workshop on 28-29 April 2021.
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- 2021
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15. Evaluation of the global performance of eight in silico skin sensitization models using human data.
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Golden E, Macmillan DS, Dameron G, Kern P, Hartung T, and Maertens A
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- Animals, Dermatitis, Contact, Humans, Animal Testing Alternatives methods, Computer Simulation, Models, Biological
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Allergic contact dermatitis, or the clinical manifestation of skin sensitization, is a leading occupational hazard. Several testing approaches exist to assess skin sensitization, but in silico models are perhaps the most advantageous due to their high speed and low-cost results. Many in silico skin sensitization models exist, though many have only been tested against results from animal studies (e.g., LLNA); this creates uncertainty in human skin sensitization assessments in both a screening and regulatory context. This project’s aim was to evaluate the accuracy of eight in silico skin sensitization models against two human data sets: one highly curated (Basketter et al., 2014) and one screening level (HSDB). The binary skin sensitization status of each chemical in each of the two data sets was compared to the prediction from eight in silico skin sensitization tools (Toxtree, PredSkin, OECD’s QSAR Toolbox, UL’s REACHAcross™, Danish QSAR Database, TIMES-SS, and Lhasa Limited’s Derek Nexus). Models were assessed for coverage, accuracy, sensitivity, and specificity, as well as optimization features (e.g., probability of accuracy, applicability domain, etc.), if available. While there was a wide range of sensitivity and specificity, the models generally performed comparably to the LLNA in predicting human skin sensitization status (i.e., approximately 70-80% accuracy). Additionally, the models did not mispredict the same compounds, suggesting there might be an advantage in combining models. In silico skin sensitization models offer accurate and useful insights in a screening context; however, further improvements are necessary so these models may be considered fully reliable for regulatory applications.
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- 2021
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16. Modernizing and Expanding the NASA Space Geodesy Network to Meet Future Geodetic Requirements.
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Merkowitz SM, Bolotin S, Elosegui P, Esper J, Gipson J, Hilliard L, Himwich E, Hoffman ED, Lakins DD, Lamb RC, Lemoine FG, Long JL, McGarry JF, MacMillan DS, Michael BP, Noll C, Pavlis EC, Pearlman MR, Ruszczyk C, Shappirio MD, and Stowers DA
- Abstract
NASA maintains and operates a global network of Very Long Baseline Interferometry (VLBI), Satellite Laser Ranging (SLR), and Global Navigation Satellite System (GNSS) ground stations as part of the NASA Space Geodesy Program. The NASA Space Geodesy Network (NSGN) provides the geodetic products that support Earth observations and the related science requirements as outlined by the US National Research Council (NRC 2010, 2018). The Global Geodetic Observing System (GGOS) and the NRC have set an ambitious goal of improving the Terrestrial Reference Frame (TRF) to have an accuracy of 1 millimeter and stability of 0.1 millimeters per year, an order of magnitude beyond current capabilities. NASA and its partners within GGOS are addressing this challenge by planning and implementing modern geodetic stations co-located at existing and new sites around the world. In 2013, NASA demonstrated the performance of its next-generation systems at the prototype next-generation core site at NASA's Goddard Geophysical and Astronomical Observatory in Greenbelt, Maryland. Implementation of a new broadband VLBI station in Hawaii was completed in 2016. NASA is currently implementing new VLBI and SLR stations in Texas and is planning the replacement of its other aging domestic and international legacy stations. In this article, we describe critical gaps in the current global network and discuss how the new NSGN will expand the global geodetic coverage and ultimately improve the geodetic products. We also describe the characteristics of a modern NSGN site and the capabilities of the next-generation NASA SLR and VLBI systems. Finally, we outline the plans for efficiently operating the NSGN by centralizing and automating the operations of the new geodetic stations.
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- 2019
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17. A defined approach for predicting skin sensitisation hazard and potency based on the guided integration of in silico, in chemico and in vitro data using exclusion criteria.
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Macmillan DS and Chilton ML
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- Animal Testing Alternatives, Animals, Computer Simulation, Decision Trees, Dermatitis, Allergic Contact, Haptens classification, Humans, Knowledge Bases, Local Lymph Node Assay, Mice, Risk Assessment, Haptens toxicity
- Abstract
A decision tree-based defined approach (DA) has been designed using exclusion criteria based on applicability domain knowledge of in chemico/in vitro information sources covering key events 1-3 in the skin sensitisation adverse outcome pathway and an in silico tool predicting the adverse outcome (Derek Nexus). The hypothesis is that using exclusion criteria to de-prioritise less applicable assays and/or in silico outcomes produces a rational, transparent, and reliable DA for the prediction of skin sensitisation potential. Five exclusion criteria have been established: Derek Nexus reasoning level, Derek Nexus negative prediction, metabolism, lipophilicity, and lysine-reactivity. These are used to prioritise the most suitable information sources for a given chemical and results from which are used in a '2 out of 3' approach to provide a prediction of hazard. A potency category (and corresponding GHS classification) is then assigned using a k-Nearest Neighbours model containing human and LLNA data. The DA correctly identified the hazard (sensitiser/non-sensitiser) for 85% and 86% of a dataset with reference LLNA and human data. The correct potency category was identified for 59% and 68% of chemicals, and the GHS classification accurately predicted for 73% and 76% with reference LLNA and human data, respectively., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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18. Making reliable negative predictions of human skin sensitisation using an in silico fragmentation approach.
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Chilton ML, Macmillan DS, Steger-Hartmann T, Hillegass J, Bellion P, Vuorinen A, Etter S, Smith BPC, White A, Sterchele P, De Smedt A, Glogovac M, Glowienke S, O'Brien D, and Parakhia R
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- Animals, Computer Simulation, Databases, Factual, Guinea Pigs, Humans, Mice, Dermatitis, Allergic Contact, Haptens, Risk Assessment methods
- Abstract
A previously published fragmentation method for making reliable negative in silico predictions has been applied to the problem of predicting skin sensitisation in humans, making use of a dataset of over 2750 chemicals with publicly available skin sensitisation data from 18 in vivo assays. An assay hierarchy was designed to enable the classification of chemicals within this dataset as either sensitisers or non-sensitisers where data from more than one in vivo test was available. The negative prediction approach was validated internally, using a 5-fold cross-validation, and externally, against a proprietary dataset of approximately 1000 chemicals with in vivo reference data shared by members of the pharmaceutical, nutritional, and personal care industries. The negative predictivity for this proprietary dataset was high in all cases (>75%), and the model was also able to identify structural features that resulted in a lower accuracy or a higher uncertainty in the negative prediction, termed misclassified and unclassified features respectively. These features could serve as an aid for further expert assessment of the negative in silico prediction., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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19. Intracerebral Hemorrhage with Herniation in a Second-Trimester Pregnant Female.
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MacMillan DS
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- Adult, Cerebral Hemorrhage surgery, Cerebral Hemorrhage therapy, Decompressive Craniectomy, Emergency Service, Hospital, Encephalocele surgery, Encephalocele therapy, Female, Headache complications, Headache etiology, Humans, Pregnancy, Pregnancy Complications surgery, Pregnancy Trimester, Second, Tertiary Care Centers, Air Ambulances, Cerebral Hemorrhage complications, Encephalocele complications, Pregnancy Complications therapy
- Abstract
A 30-year-old woman, gravida 1, para 2, in her second trimester presented to the local emergency department complaining of an atraumatic headache described as the worst headache of her life. While undergoing evaluation, she became unresponsive with signs of herniation, including a blown pupil and bradycardia. Emergent imaging identified an intracerebral hemorrhage requiring immediate surgical decompression. The patient was transferred by helicopter to tertiary care. Upon arrival, the patient was taken directly to the operating room and underwent a decompressive craniotomy. This article reviews the considerations for transporting pregnant patients with intracerebral hemorrhage., (Copyright © 2018 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)
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- 2018
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20. A quantitative in silico model for predicting skin sensitization using a nearest neighbours approach within expert-derived structure-activity alert spaces.
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Canipa SJ, Chilton ML, Hemingway R, Macmillan DS, Myden A, Plante JP, Tennant RE, Vessey JD, Steger-Hartmann T, Gould J, Hillegass J, Etter S, Smith BPC, White A, Sterchele P, De Smedt A, O'Brien D, and Parakhia R
- Subjects
- Animal Use Alternatives, Animals, Computer Simulation, Datasets as Topic, Local Lymph Node Assay, Mice, Predictive Value of Tests, Reproducibility of Results, Structure-Activity Relationship, Dermatitis, Allergic Contact etiology, Drug-Related Side Effects and Adverse Reactions etiology, Models, Biological, Pharmaceutical Preparations chemistry
- Abstract
Dermal contact with chemicals may lead to an inflammatory reaction known as allergic contact dermatitis. Consequently, it is important to assess new and existing chemicals for their skin sensitizing potential and to mitigate exposure accordingly. There is an urgent need to develop quantitative non-animal methods to better predict the potency of potential sensitizers, driven largely by European Union (EU) Regulation 1223/2009, which forbids the use of animal tests for cosmetic ingredients sold in the EU. A Nearest Neighbours in silico model was developed using an in-house dataset of 1096 murine local lymph node (LLNA) studies. The EC3 value (the effective concentration of the test substance producing a threefold increase in the stimulation index compared to controls) of a given chemical was predicted using the weighted average of EC3 values of up to 10 most similar compounds within the same mechanistic space (as defined by activating the same Derek skin sensitization alert). The model was validated using previously unseen internal (n = 45) and external (n = 103) data and accuracy of predictions assessed using a threefold error, fivefold error, European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) and Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classifications. In particular, the model predicts the GHS skin sensitization category of compounds well, predicting 64% of chemicals in an external test set within the correct category. Of the remaining chemicals in the previously unseen dataset, 25% were over-predicted (GHS 1A predicted: GHS 1B experimentally) and 11% were under-predicted (GHS 1B predicted: GHS 1A experimentally). Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)
- Published
- 2017
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21. Predicting skin sensitisation using a decision tree integrated testing strategy with an in silico model and in chemico/in vitro assays.
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Macmillan DS, Canipa SJ, Chilton ML, Williams RV, and Barber CG
- Subjects
- Animals, Databases, Factual, Humans, Irritants chemistry, Knowledge Bases, Reproducibility of Results, Software, Structure-Activity Relationship, Workflow, Animal Testing Alternatives, Computer Simulation, Decision Trees, Dermatitis, Allergic Contact etiology, Dermatitis, Irritant etiology, Irritants toxicity, Skin drug effects, Skin Irritancy Tests methods
- Abstract
There is a pressing need for non-animal methods to predict skin sensitisation potential and a number of in chemico and in vitro assays have been designed with this in mind. However, some compounds can fall outside the applicability domain of these in chemico/in vitro assays and may not be predicted accurately. Rule-based in silico models such as Derek Nexus are expert-derived from animal and/or human data and the mechanism-based alert domain can take a number of factors into account (e.g. abiotic/biotic activation). Therefore, Derek Nexus may be able to predict for compounds outside the applicability domain of in chemico/in vitro assays. To this end, an integrated testing strategy (ITS) decision tree using Derek Nexus and a maximum of two assays (from DPRA, KeratinoSens, LuSens, h-CLAT and U-SENS) was developed. Generally, the decision tree improved upon other ITS evaluated in this study with positive and negative predictivity calculated as 86% and 81%, respectively. Our results demonstrate that an ITS using an in silico model such as Derek Nexus with a maximum of two in chemico/in vitro assays can predict the sensitising potential of a number of chemicals, including those outside the applicability domain of existing non-animal assays., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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22. Pilot test of the SALT mass casualty triage system.
- Author
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Cone DC, Serra J, Burns K, MacMillan DS, Kurland L, and Van Gelder C
- Subjects
- Disaster Planning, Efficiency, Organizational, Emergency Medical Services, Emergency Medical Technicians, Humans, Pilot Projects, Task Performance and Analysis, Mass Casualty Incidents, Triage organization & administration
- Abstract
Introduction: No existing mass casualty triage system has been scientifically scrutinized or validated. A recent work group sponsored by the Centers for Disease Control and Prevention, using a combination of expert opinion and the extremely limited research data available, created the SALT (sort-assess-lifesaving interventions-treat/transport) triage system to serve as a national model. An airport crash drill was used to pilot test the SALT system., Objective: To assess the accuracy and speed with which trained paramedics can triage victims using this new system., Methods: Investigators created 50 patient scenarios with a wide range of injuries and severities, and two additional uninjured victims were added at the time of the drill. Students wearing moulage and coached on how to portray their injuries served as "victims." Assuming proper application of the SALT system, the patient scenarios were designed such that 16 patients would be triaged as T1/red/immediate, 12 as T2/yellow/delayed, 14 as T3/green/minimal, and 10 as T4/black/dead. Paramedics were trained to proficiency in the SALT system one week prior to the drill using a 90-minute didactic/practical session, and were given "flash cards" showing the triage algorithm to be used if needed during the drill. Observers blinded to the study purpose timed and recorded the triage process for each patient during the drill. Simple descriptive statistics were used to analyze the data., Results: The two paramedics assigned to the role of triage officers applied the SALT algorithm correctly to 41 of the 52 patients (78.8% accuracy). Seven patients intended to be T2 were triaged as T1, and two patients intended to be T3 were triaged as T2, for an overtriage rate of 13.5%. Two patients intended to be T2 were triaged as T3, for an undertriage rate of 3.8%. Triage times were recorded by the observers for 42 of the 52 patients, with a mean of 15 seconds per patient (range 5-57 seconds)., Conclusions: The SALT mass casualty triage system can be applied quickly in the field and appears to be safe, as measured by a low undertriage rate. There was, however, significant overtriage. Further refinement is needed, and effect on patient outcomes needs to be evaluated.
- Published
- 2009
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23. Can emergency medical dispatch systems safely reduce first-responder call volume?
- Author
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Cone DC, Galante N, and MacMillan DS
- Subjects
- Prospective Studies, Triage, Efficiency, Organizational, Emergency Medical Service Communication Systems organization & administration, Emergency Medical Technicians statistics & numerical data, Emergency Service, Hospital statistics & numerical data, Safety Management methods
- Abstract
Objectives: Emergency medical dispatch (EMD) protocols are intended to match response resources with patient needs. In a small city that previously sent a first-responder basic life support (BLS) engine company lights-and-siren response to every emergency medical services (EMS) call, regardless of nature or severity, an EMD system was implemented in order to reduce the number of such responses. The study objectives were to determine the effects of the EMD system on first-responder call volume and to assess the safety of the system., Methods: This was a prospective, before-after trial. Using computer-assisted dispatch (CAD) records, all EMS calls in the 120 days before implementation of the EMD protocol and the 120 days after implementation were identified (excluding a one-month wash-in period). In the "after" phase, patient care reports of a random sample of cases in which an ambulance was dispatched with no first responders was manually reviewed to assess whether there might have been any benefit to first-responder dispatch. Given the lack of accepted clinical criteria for need for first responders, the investigators' clinical judgment was used. Paired t-tests were used to compare groups., Results: There were 9,820 EMS calls in the "before" phase, with 8,278 first-responder engine runs (84.3%), and 9,943 EMS calls in the "after" phase, with 3,804 first-responder engine runs (39.1%). The first-responder companies were dispatched to a median of 5.65 runs/day (range 1.1-12.7) in the "before" phase, and 3.17 runs/day (range 0.6-5.0) in the "after" phase (p = 0.0008 by paired t-test). Review of 1,816 "after" phase ambulance-only patient care reports (PCRs) found ten (0.55%) in which first-responder dispatch might have been beneficial, but review of EMS and emergency department (ED) records found no adverse outcomes in these ten patients., Conclusions: This study suggests that a formal EMD system can reduce first-responder call volume by roughly one-half. The system appears to be safe for patients, with an undertriage rate of about one-half of one percent.
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- 2008
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24. Pilot test of a proposed chemical/biological/radiation/ nuclear-capable mass casualty triage system.
- Author
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Cone DC, MacMillan DS, Parwani V, and Van Gelder C
- Subjects
- Humans, Organophosphates isolation & purification, Pilot Projects, Triage organization & administration, Hazardous Substances isolation & purification, Mass Casualty Incidents, Triage standards, Weapons of Mass Destruction
- Abstract
Introduction: Existing mass casualty triage systems do not consider the possibility of chemical, biological, or radiologic/nuclear (CBRN) contamination of the injured patients. A system that can triage injured patients who are or may be contaminated by CBRN material, developed through expert opinion, was pilot-tested at an airport disaster drill. The study objective was to determine the system's speed and accuracy., Methods: For a drill involving a plane crash with release of organophosphate material from the cargo hold, 56 patient scenarios were generated, with some involving signs and symptoms of organophosphate toxicity in addition to physical trauma. Prior to the drill, the investigators examined each scenario to determine the "correct" triage categorization, assuming proper application of the proposed system, and trained the paramedics who were expected to serve as triage officers at the drill. During the drill, the medics used the CBRN triage system to triage the 56 patients, with two observers timing and recording the events of the triage process. The IRB deemed the study exempt from full review., Results: The two triage officers applied the CBRN system correctly to 49 of the 56 patients (87.5% accuracy). One patient intended to be T2 (yellow) was triaged as T1 (red), for an over-triage rate of 1.8%. Five patients intended to be T1 were triaged as T2, and one patient intended to be T2 was triaged as T3 (green), for an under-triage rate of 10.7%. All six under-triage cases were due to failure to recognize or account for signs of organophosphate toxidrome in applying the triage system. For the 27 patients for whom times were recorded, triage was accomplished in a mean of 19 seconds (range 4-37, median 17)., Conclusions: The chemical algorithm of the proposed CBRN-capable mass casualty triage system can be applied rapidly by trained paramedics, but a significant under-triage rate (10.7%) was seen in this pilot test. Further refinement and testing are needed, and effect on outcome must be studied.
- Published
- 2008
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25. Is there a role for first responders in EMS responses to medical facilities?
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Cone DC, Galante N, MacMillan DS, Perez MM, and Parwani V
- Subjects
- Advanced Cardiac Life Support, Connecticut, Humans, Retrospective Studies, Emergency Medical Services, Emergency Medical Technicians statistics & numerical data, Health Facilities, Professional Role
- Abstract
Objective: Emergency medical dispatch (EMD) protocols should match response resources with patient needs. We tested a protocol sending only a commercial ambulance, without fire department first responders (FR), to all non-cardiac-arrest EMS calls at a physician-staffed HMO facility. Study objectives were to determine how often FR provided patient care at such facilities and whether EMD implementation could conserve FR resources without compromising patient care., Methods: All EMS dispatches to this facility in the 4 months before implementation of the EMD protocol and 4 months after implementation were identified through dispatch records, and all FR and ambulance patient care reports were reviewed. In the "after" phase, all cases needing ALS transport were reviewed to examine whether there would have been benefit to FR dispatch., Results: Of 242 dispatches in the "before" phase, BLS FR responded to 156 (64%), and ALS FR to 117 (48%). BLS FR provided patient care in 2 cases, and ALS FR in 17. Of 227 dispatches in the "after" phase, BLS FR responded to 10 (4%), and ALS FR to 10 (4%); all but one were protocol violations. BLS FR provided care in one case, and ALS FR in three. Review of the 93 "after" cases requiring ALS transport found none where FR presence would have been beneficial., Conclusions: First responders rarely provided patient care when responding to EMS calls at a physician-staffed medical facility. Implementation of an EMD protocol can safely reduce the number of FR responses to unscheduled ambulance calls at such a facility.
- Published
- 2007
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26. Can a simple reminder letter improve numbering of single-family residences?
- Author
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MacMillan DS and Cone DC
- Subjects
- Connecticut, Information Systems, Correspondence as Topic, Efficiency, Organizational, Emergency Medical Services, Housing, Reminder Systems
- Abstract
Objective: To determine if a single mailing from the local volunteer fire department can increase the number of homes with proper, visible address numbering. Proper numbering is essential in rapidly locating a house during an emergency response., Methods: The study was conducted at a suburban/rural fire department providing EMS and fire suppression services to a 22 square mile area with residential mailboxes located at the street. During a hazard identification pre-plan tour, each house was examined and assigned a classification: (A) No number visible on the house or mailbox (improper); (B) Number on only one side of the mailbox (improper); (C) Number on both sides or the end of the mailbox, or visible on the house (proper). The homeowners of all residences with improper numbering (A or B) were sent a one-page letter, discussing the need for proper numbering. The tour was repeated six weeks later to determine whether deficiencies had been corrected. It was prospectively determined that a 25% improvement was sought., Results: During the pre-plan tour, 73 houses were classified as type A, 454 as type B, and 1706 as type C. At the re-visit, 135 (26%) of the type A and B homes had been properly numbered. Correction of deficiencies was better at type A homes (37, or 51%) than at type B homes (98, or 22%) (p < 0.001 by Chi-square)., Conclusion: For houses with improper numbering, a single mailing from the fire department can be effective in encouraging residents to post proper numbers.
- Published
- 2006
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27. Mass-casualty triage systems: a hint of science.
- Author
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Cone DC and MacMillan DS
- Subjects
- Adult, Algorithms, Child, Delphi Technique, Humans, Sensitivity and Specificity, United States, Disasters prevention & control, Triage methods, Wounds and Injuries classification
- Published
- 2005
- Full Text
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28. Noninvasive fireground assessment of carboxyhemoglobin levels in firefighters.
- Author
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Cone DC, MacMillan DS, Van Gelder C, Brown DJ, Weir SD, and Bogucki S
- Subjects
- Adult, Breath Tests, Carbon Monoxide analysis, Carbon Monoxide Poisoning etiology, Chi-Square Distribution, Equipment Design, Equipment Safety, Female, Humans, Male, Middle Aged, Probability, Sampling Studies, Sensitivity and Specificity, Air Pollutants, Occupational analysis, Carbon Monoxide Poisoning diagnosis, Carboxyhemoglobin analysis, Fires
- Abstract
Objectives: Carboxyhemoglobin (COHb) levels can be estimated by chemical analysis of exhaled alveolar breath. Such noninvasive measurement could be used on the fireground to screen both firefighters (FFs) and victims. The purpose of this study was to assess the feasibility of using a hand-held carbon monoxide (CO) monitoring device to screen for CO toxicity in FFs under field conditions., Methods: Informed consent was obtained from all participants. Using a hand-held breath CO detection device, COHb readings were collected at baseline, and then as FFs exited burning buildings after performing interior fire attack and overhaul with self-contained breathing apparatus (SCBA) during live-fire training. Ambient CO levels were occasionally measured in interior areas where the FFs were working to assess the degree of CO exposure., Results: Baseline COHb readings of 64 FFs ranged from 0% to 3% (mean 1%, median 1%). One hundred eighty-four COHb readings were collected during training exercises. The mean and median COHb levels were 1%. The maximum value in a FF wearing SCBA was 3%; values of 14%, 5%, and 4% were measured in instructors who were not properly wearing SCBA. Ambient CO readings during fire attack ranged from 75 to 1,290 ppm, and the ambient CO reading for overhaul ranged from 0 to 130 ppm. When the device was used for interior CO monitoring, washout time limited its utility for COHb monitoring in FFs., Conclusions: A hand-held CO monitoring device adapted for estimation of COHb levels by exhaled breath analysis can feasibly be deployed on the fireground to assess CO exposure in FFs.
- Published
- 2005
- Full Text
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29. Officer down.
- Author
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Macmillan DS and Cone DC
- Subjects
- Adult, Cardiopulmonary Resuscitation, Crowding, Emergency Treatment psychology, Humans, Immobilization, Intubation, Intratracheal, Male, Security Measures, Spine physiology, Emergency Medical Technicians, Emergency Treatment standards, Interprofessional Relations, Police standards, Wounds, Gunshot therapy
- Published
- 2003
- Full Text
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30. Convergence of distorted wave methods: Theory and a simple example.
- Author
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MacMillan DS and Redish EF
- Published
- 1986
- Full Text
- View/download PDF
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