Publications by authors named "Matthew J Thomas"

70 Publications

The Value of Triage during Periods of Intense COVID-19 Demand: Simulation Modeling Study.

Med Decis Making 2021 Feb 9:272989X21994035. Epub 2021 Feb 9.

Centre for Healthcare Innovation and Improvement (CHI), School of Management; University of Bath, Bath, UK.

Background: During the COVID-19 pandemic, many intensive care units have been overwhelmed by unprecedented levels of demand. Notwithstanding ethical considerations, the prioritization of patients with better prognoses may support a more effective use of available capacity in maximizing aggregate outcomes. This has prompted various proposed triage criteria, although in none of these has an objective assessment been made in terms of impact on number of lives and life-years saved.

Design: An open-source computer simulation model was constructed for approximating the intensive care admission and discharge dynamics under triage. The model was calibrated from observational data for 9505 patient admissions to UK intensive care units. To explore triage efficacy under various conditions, scenario analysis was performed using a range of demand trajectories corresponding to differing nonpharmaceutical interventions.

Results: Triaging patients at the point of expressed demand had negligible effect on deaths but reduces life-years lost by up to 8.4% (95% confidence interval: 2.6% to 18.7%). Greater value may be possible through "reverse triage", that is, promptly discharging any patient not meeting the criteria if admission cannot otherwise be guaranteed for one who does. Under such policy, life-years lost can be reduced by 11.7% (2.8% to 25.8%), which represents 23.0% (5.4% to 50.1%) of what is operationally feasible with no limit on capacity and in the absence of improved clinical treatments.

Conclusions: The effect of simple triage is limited by a tradeoff between reduced deaths within intensive care (due to improved outcomes) and increased deaths resulting from declined admission (due to lower throughput given the longer lengths of stay of survivors). Improvements can be found through reverse triage, at the expense of potentially complex ethical considerations.
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http://dx.doi.org/10.1177/0272989X21994035DOI Listing
February 2021

Macrophage-stroma interactions in fibrosis: biochemical, biophysical, and cellular perspectives.

J Pathol 2021 Jan 28. Epub 2021 Jan 28.

University of Groningen, Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy, Groningen, The Netherlands.

Fibrosis results from aberrant wound healing and is characterized by an accumulation of extracellular matrix, impairing the function of an affected organ. Increased deposition of extracellular matrix proteins, disruption of matrix degradation, but also abnormal post-translational modifications alter the biochemical composition and biophysical properties of the tissue microenvironment - the stroma. Macrophages are known to play an important role in wound healing and tissue repair, but the direct influence of fibrotic stroma on macrophage behaviour is still an under-investigated element in the pathogenesis of fibrosis. In this review, the current knowledge on interactions between macrophages and (fibrotic) stroma will be discussed from biochemical, biophysical, and cellular perspectives. Furthermore, we provide future perspectives with regard to how macrophage-stroma interactions can be examined further to ultimately facilitate more specific targeting of these interactions in the treatment of fibrosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5632DOI Listing
January 2021

Dysregulation of club cell biology in idiopathic pulmonary fibrosis.

PLoS One 2020 17;15(9):e0237529. Epub 2020 Sep 17.

Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic fibrotic lung disease with an irreversible decline of lung function. "Bronchiolization", characterized by ectopic appearance of airway epithelial cells in the alveolar regions, is one of the characteristic features in the IPF lung. Based on the knowledge that club cells are the major epithelial secretory cells in human small airways, and their major secretory product uteroglobin (SCGB1A1) is significantly increased in both serum and epithelial lining fluid of IPF lung, we hypothesize that human airway club cells contribute to the pathogenesis of IPF. By assessing the transcriptomes of the single cells from human lung of control donors and IPF patients, we identified two SCGB1A1+ club cell subpopulations, highly expressing MUC5B, a significant genetic risk factor strongly associated with IPF, and SCGB3A2, a marker heterogeneously expressed in the club cells, respectively. Interestingly, the cellular proportion of SCGB1A1+MUC5B+ club cells was significantly increased in IPF patients, and this club cell subpopulation highly expressed genes related to mucous production and immune cell chemotaxis. In contrast, though the cellular proportion did not change, the molecular phenotype of the SCGB1A1+SCGB3A2high club cell subpopulation was significantly altered in IPF lung, with increased expression of mucins, cytokine and extracellular matrix genes. The single cell transcriptomic analysis reveals the cellular and molecular heterogeneity of club cells, and provide novel insights into the biological functions of club cells in the pathogenesis of IPF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237529PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498242PMC
October 2020

Cell-specific expression of lung disease risk-related genes in the human small airway epithelium.

Respir Res 2020 Jul 29;21(1):200. Epub 2020 Jul 29.

Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 164, New York, NY, 10065, USA.

Background: The human small airway epithelium (SAE) plays a central role in the early events in the pathogenesis of most inherited and acquired lung disorders. Little is known about the molecular phenotypes of the specific cell populations comprising the SAE in humans, and the contribution of SAE specific cell populations to the risk for lung diseases.

Methods: Drop-seq single-cell RNA-sequencing was used to characterize the transcriptome of single cells from human SAE of nonsmokers and smokers by bronchoscopic brushing.

Results: Eleven distinct cell populations were identified, including major and rare epithelial cells, and immune/inflammatory cells. There was cell type-specific expression of genes relevant to the risk of the inherited pulmonary disorders, genes associated with risk of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and (non-mutated) driver genes for lung cancers. Cigarette smoking significantly altered the cell type-specific transcriptomes and disease risk-related genes.

Conclusions: This data provides new insights into the possible contribution of specific lung cells to the pathogenesis of lung disorders.
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http://dx.doi.org/10.1186/s12931-020-01442-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389881PMC
July 2020

COVID-19 scenario modelling for the mitigation of capacity-dependent deaths in intensive care.

Health Care Manag Sci 2020 Sep 8;23(3):315-324. Epub 2020 Jul 8.

Centre for Healthcare Innovation and Improvement (CHI2), School of Management, University of Bath, Bath, UK.

Managing healthcare demand and capacity is especially difficult in the context of the COVID-19 pandemic, where limited intensive care resources can be overwhelmed by a large number of cases requiring admission in a short space of time. If patients are unable to access this specialist resource, then death is a likely outcome. In appreciating these 'capacity-dependent' deaths, this paper reports on the clinically-led development of a stochastic discrete event simulation model designed to capture the key dynamics of the intensive care admissions process for COVID-19 patients. With application to a large public hospital in England during an early stage of the pandemic, the purpose of this study was to estimate the extent to which such capacity-dependent deaths can be mitigated through demand-side initiatives involving non-pharmaceutical interventions and supply-side measures to increase surge capacity. Based on information available at the time, results suggest that total capacity-dependent deaths can be reduced by 75% through a combination of increasing capacity from 45 to 100 beds, reducing length of stay by 25%, and flattening the peak demand to 26 admissions per day. Accounting for the additional 'capacity-independent' deaths, which occur even when appropriate care is available within the intensive care setting, yields an aggregate reduction in total deaths of 30%. The modelling tool, which is freely available and open source, has since been used to support COVID-19 response planning at a number of healthcare systems within the UK National Health Service.
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http://dx.doi.org/10.1007/s10729-020-09511-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341703PMC
September 2020

Systematic Profiling of Full-Length Ig and TCR Repertoire Diversity in Rhesus Macaque through Long Read Transcriptome Sequencing.

J Immunol 2020 06 6;204(12):3434-3444. Epub 2020 May 6.

Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC 27607;

The diversity of Ig and TCR repertoires is a focal point of immunological studies. Rhesus macaques () are key for modeling human immune responses, placing critical importance on the accurate annotation and quantification of their Ig and TCR repertoires. However, because of incomplete reference resources, the coverage and accuracy of the traditional targeted amplification strategies for profiling rhesus Ig and TCR repertoires are largely unknown. In this study, using long read sequencing, we sequenced four Indian-origin rhesus macaque tissues and obtained high-quality, full-length sequences for over 6000 unique Ig and TCR transcripts, without the need for sequence assembly. We constructed, to our knowledge, the first complete reference set for the constant regions of all known isotypes and chain types of rhesus Ig and TCR repertoires. We show that sequence diversity exists across the entire variable regions of rhesus Ig and TCR transcripts. Consequently, existing strategies using targeted amplification of rearranged variable regions comprised of V(D)J gene segments miss a significant fraction (27-53% and 42-49%) of rhesus Ig/TCR diversity. To overcome these limitations, we designed new rhesus-specific assays that remove the need for primers conventionally targeting variable regions and allow single cell level Ig and TCR repertoire analysis. Our improved approach will enable future studies to fully capture rhesus Ig and TCR repertoire diversity and is applicable for improving annotations in any model organism.
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http://dx.doi.org/10.4049/jimmunol.1901256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276939PMC
June 2020

Recapitulating idiopathic pulmonary fibrosis related alveolar epithelial dysfunction in a human iPSC-derived air-liquid interface model.

FASEB J 2020 06 16;34(6):7825-7846. Epub 2020 Apr 16.

Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown cause that is characterized by progressive fibrotic lung remodeling. An abnormal emergence of airway epithelial-like cells within the alveolar compartments of the lung, herein termed bronchiolization, is often observed in IPF. However, the origin of this dysfunctional distal lung epithelium remains unknown due to a lack of suitable human model systems. In this study, we established a human induced pluripotent stem cell (iPSC)-derived air-liquid interface (ALI) model of alveolar epithelial type II (ATII)-like cell differentiation that allows us to investigate alveolar epithelial progenitor cell differentiation in vitro. We treated this system with an IPF-relevant cocktail (IPF-RC) to mimic the pro-fibrotic cytokine milieu present in IPF lungs. Stimulation with IPF-RC during differentiation increases secretion of IPF biomarkers and RNA sequencing (RNA-seq) of these cultures reveals significant overlap with human IPF patient data. IPF-RC treatment further impairs ATII differentiation by driving a shift toward an airway epithelial-like expression signature, providing evidence that a pro-fibrotic cytokine environment can influence the proximo-distal differentiation pattern of human lung epithelial cells. In conclusion, we show for the first time, the establishment of a human model system that recapitulates aspects of IPF-associated bronchiolization of the lung epithelium in vitro.
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http://dx.doi.org/10.1096/fj.201902926RDOI Listing
June 2020

Intermittent exposure to whole cigarette smoke alters the differentiation of primary small airway epithelial cells in the air-liquid interface culture.

Sci Rep 2020 04 10;10(1):6257. Epub 2020 Apr 10.

Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.

Cigarette smoke (CS) is the leading risk factor to develop COPD. Therefore, the pathologic effects of whole CS on the differentiation of primary small airway epithelial cells (SAEC) were investigated, using cells from three healthy donors and three COPD patients, cultured under ALI (air-liquid interface) conditions. The analysis of the epithelial physiology demonstrated that CS impaired barrier formation and reduced cilia beat activity. Although, COPD-derived ALI cultures preserved some features known from COPD patients, CS-induced effects were similarly pronounced in ALI cultures from patients compared to healthy controls. RNA sequencing analyses revealed the deregulation of marker genes for basal and secretory cells upon CS exposure. The comparison between gene signatures obtained from the in vitro model (CS vs. air) with a published data set from human epithelial brushes (smoker vs. non-smoker) revealed a high degree of similarity between deregulated genes and pathways induced by CS. Taken together, whole cigarette smoke alters the differentiation of small airway basal cells in vitro. The established model showed a good translatability to the situation in vivo. Thus, the model can help to identify and test novel therapeutic approaches to restore the impaired epithelial repair mechanisms in COPD, which is still a high medical need.
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http://dx.doi.org/10.1038/s41598-020-63345-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148343PMC
April 2020

A qualitative content analysis of retained surgical items: learning from root cause analysis investigations.

Int J Qual Health Care 2020 May;32(3):184-189

Australian Institute of Health Innovation, Macquarie University, New South Wales, Australia.

Objective: To describe incidents of retained surgical items, including their characteristics and the circumstances in which they occur.

Design: A qualitative content analysis of root cause analysis investigation reports.

Setting: Public health services in Victoria, Australia, 2010-2015.

Participants: Incidents of retained surgical items as described by 31 root cause analysis investigation reports.

Main Outcome Measure(s): The type of retained surgical item, the length of time between the item being retained and detected and qualitative descriptors of the contributing factors and the circumstances in which the retained surgical items occurred.

Results: Surgical packs, drain tubes and vascular devices comprised 68% (21/31) of the retained surgical items. Nearly one-quarter of the retained surgical items were detected either immediately in the post-operative period or on the day of the procedure (7/31). However, about one-sixth (5/31) were only detected after 6 months, with the longest period being 18 months. Contributing factors included complex or multistage surgery; the use of packs not specific to the purpose of the surgery; and design features of the surgical items.

Conclusion: Retained drains occurred in the post-operative phase where surgical counts are not applicable and clinician situational awareness may not be as great. Root cause analysis investigation reports can be a valuable means of characterizing infrequently occurring adverse events such as retained surgical items. They may detect incidents that are not detected by other data collections and can inform the design enhancements and development of technologies to reduce the impact of retained surgical items.
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http://dx.doi.org/10.1093/intqhc/mzaa005DOI Listing
May 2020

Serine Protease Imbalance in the Small Airways and Development of Centrilobular Emphysema in Chronic Obstructive Pulmonary Disease.

Am J Respir Cell Mol Biol 2020 07;63(1):67-78

Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Epithelial dysfunction in the small airways may cause the development of emphysema in chronic obstructive pulmonary disease. C/EBPα (CCAAT/enhancer binding protein-α), a transcription factor, is required for lung maturation during development, and is also important for lung homeostasis after birth, including the maintenance of serine protease/antiprotease balance in the bronchiolar epithelium. This study aimed to show the roles of C/EBPα in the distal airway during chronic cigarette smoke exposure in mice and in the small airways in smokers. In a model of chronic smoke exposure using epithelial cell-specific C/EBPα-knockout mice, significant pathological phenotypes, such as higher protease activity, impaired ciliated cell regeneration, epithelial cell barrier dysfunction via reduced zonula occludens-1 (Zo-1), and decreased alveolar attachments, were found in C/EBPα-knockout mice compared with control mice. We found that (serine protease inhibitor kazal-type 5) gene (encoding lymphoepithelial Kazal-type-related inhibitor [LEKTI], an anti-serine protease) expression in the small airways is a key regulator of protease activity in this model. Finally, we showed that daily antiprotease treatment counteracted the phenotypes of C/EBPα-knockout mice. In human studies, (CCAAT/enhancer binding protein-α) gene expression in the lung was downregulated in patients with emphysema, and six smokers with centrilobular emphysema (CLE) showed a significant reduction in LEKTI in the small airways compared with 22 smokers without CLE. LEKTI downregulation in the small airways was associated with disease development during murine small airway injury and CLE in humans, suggesting that LEKTI might be a key factor linking small airway injury to the development of emphysema.
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http://dx.doi.org/10.1165/rcmb.2019-0377OCDOI Listing
July 2020

Macrophage-associated wound healing contributes to African green monkey SIV pathogenesis control.

Nat Commun 2019 11 8;10(1):5101. Epub 2019 Nov 8.

Department of Immunology, University of Washington, Seattle, WA, USA.

Natural hosts of simian immunodeficiency virus (SIV) avoid AIDS despite lifelong infection. Here, we examined how this outcome is achieved by comparing a natural SIV host, African green monkey (AGM) to an AIDS susceptible species, rhesus macaque (RM). To asses gene expression profiles from acutely SIV infected AGMs and RMs, we developed a systems biology approach termed Conserved Gene Signature Analysis (CGSA), which compared RNA sequencing data from rectal AGM and RM tissues to various other species. We found that AGMs rapidly activate, and then maintain, evolutionarily conserved regenerative wound healing mechanisms in mucosal tissue. The wound healing protein fibronectin shows distinct tissue distribution and abundance kinetics in AGMs. Furthermore, AGM monocytes exhibit an embryonic development and repair/regeneration signature featuring TGF-β and concomitant reduced expression of inflammatory genes compared to RMs. This regenerative wound healing process likely preserves mucosal integrity and prevents inflammatory insults that underlie immune exhaustion in RMs.
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http://dx.doi.org/10.1038/s41467-019-12987-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841668PMC
November 2019

Fatigue management in practice - It's just good teamwork.

Sleep Med Rev 2019 12 17;48:101221. Epub 2019 Oct 17.

Appleton Institute - CQUniversity, Wayville, South Australia, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.smrv.2019.101221DOI Listing
December 2019

Characterization of an immortalized human small airway basal stem/progenitor cell line with airway region-specific differentiation capacity.

Respir Res 2019 Aug 23;20(1):196. Epub 2019 Aug 23.

Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 164, New York, NY, 10065, USA.

Background: The pathology of chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and most lung cancers involves the small airway epithelium (SAE), the single continuous layer of cells lining the airways ≥ 6th generations. The basal cells (BC) are the stem/progenitor cells of the SAE, responsible for the differentiation into intermediate cells and ciliated, club and mucous cells. To facilitate the study of the biology of the human SAE in health and disease, we immortalized and characterized a normal human SAE basal cell line.

Methods: Small airway basal cells were purified from brushed SAE of a healthy nonsmoker donor with a characteristic normal SAE transcriptome. The BC were immortalized by retrovirus-mediated telomerase reverse transcriptase (TERT) transduction and single cell drug selection. The resulting cell line (hSABCi-NS1.1) was characterized by RNAseq, TaqMan PCR, protein immunofluorescence, differentiation capacity on an air-liquid interface (ALI) culture, transepithelial electrical resistance (TEER), airway region-associated features and response to genetic modification with SPDEF.

Results: The hSABCi-NS1.1 single-clone-derived cell line continued to proliferate for > 200 doubling levels and > 70 passages, continuing to maintain basal cell features (TP63, KRT5). When cultured on ALI, hSABCi-NS1.1 cells consistently formed tight junctions and differentiated into ciliated, club (SCGB1A1), mucous (MUC5AC, MUC5B), neuroendocrine (CHGA), ionocyte (FOXI1) and surfactant protein positive cells (SFTPA, SFTPB, SFTPD), observations confirmed by RNAseq and TaqMan PCR. Annotation enrichment analysis showed that "cilium" and "immunity" were enriched in functions of the top-1500 up-regulated genes. RNAseq reads alignment corroborated expression of CD4, CD74 and MHC-II. Compared to the large airway cell line BCi-NS1.1, differentiated of hSABCi-NS1.1 cells on ALI were enriched with small airway epithelial genes, including surfactant protein genes, LTF and small airway development relevant transcription factors NKX2-1, GATA6, SOX9, HOPX, ID2 and ETV5. Lentivirus-mediated expression of SPDEF in hSABCi-NS1.1 cells induced secretory cell metaplasia, accompanied with characteristic COPD-associated SAE secretory cell changes, including up-regulation of MSMB, CEACAM5 and down-regulation of LTF.

Conclusions: The immortalized hSABCi-NS1.1 cell line has diverse differentiation capacities and retains SAE features, which will be useful for understanding the biology of SAE, the pathogenesis of SAE-related diseases, and testing new pharmacologic agents.
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http://dx.doi.org/10.1186/s12931-019-1140-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708250PMC
August 2019

Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases.

J Med Chem 2019 05 24;62(10):4783-4814. Epub 2018 Dec 24.

Respiratory, Inflammation & Autoimmunity Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit , AstraZeneca , Boston , Massachusetts 02451 , United States.

Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01298DOI Listing
May 2019

More than hours of work: fatigue management during high-intensity maritime operations.

Chronobiol Int 2019 01 8;36(1):143-149. Epub 2018 Oct 8.

a Appleton Institute for Behavioural Science, School of Health, Medical and Applied Sciences , Central Queensland University , Adelaide , Australia.

Objectives: This study examines the impacts of peak summer demand on operator workload and fatigue in a maritime environment.

Methods: Participants (n = 12) were senior shipboard personnel who were working during the summer "double sailing" period for a roll-on roll-off ferry service. Wrist actigraphy was used to determine sleep opportunity and sleep duration, as well as prior sleep, total wake time, performance and alertness at the beginning and end of work periods.

Results: Contrary to expectations, sleep was significantly greater, and both subjective estimates of fatigue and objective neurobehavioral performance were not impacted negatively by periods of increased work intensity.

Conclusions: This study highlights a number of features of a fatigue-risk management system that appear to have been instrumental in ensuring adequate sleep and performance was maintained throughout periods of increased operational intensity. As a simple colloquial description of the fatigue-risk management system at play in this operation, it was fine to "work hard" if you were able to "sleep hard" as well.
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http://dx.doi.org/10.1080/07420528.2018.1519571DOI Listing
January 2019

Determining the likelihood that fatigue was present in a road accident: A theoretical review and suggested accident taxonomy.

Sleep Med Rev 2018 12 29;42:202-210. Epub 2018 Aug 29.

Appleton Institute, Central Queensland University, Adelaide Campus, 44 Greenhill Rd., South Australia 5034, Australia.

Estimates in developed countries of the extent to which fatigue contributes to road accidents range from as low as 5% to as high as 50% of all accidents. Compared with other causes of road accidents (e.g., speeding, drink-driving), the variability in these estimates is exceptionally high and may be indicative of the difficulty in determining the likelihood of fatigue as a cause of road accidents. This review compares differences in the way road accidents are classified as fatigue-related (or not) by expert panels and road safety regulators, highlighting conflicting conceptual approaches, lack of consistency, and the poor psychometric qualities of classification rules used across jurisdictions. In order to facilitate future research, the review then proposes a new theoretical approach and a potentially more logical accident 'taxonomy'. A putative accident 'taxonomy' is proposed using two dimensions: (1) estimating the likelihood that a driver was fatigued at the time of the accident, and (2) estimating the degree to which accident phenomenology is consistent with fatigue-related error. This 'taxonomy' could assist accident investigators and road safety regulators to more reliably quantify the contribution of fatigue to road accidents, and may also assist researchers and regulators in the post-hoc interrogation of existing accident databases to better determine the relative incidence of fatigue-related road accidents.
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http://dx.doi.org/10.1016/j.smrv.2018.08.006DOI Listing
December 2018

Are root cause analyses recommendations effective and sustainable? An observational study.

Int J Qual Health Care 2018 Mar;30(2):124-131

Safer Care Victoria, 50 Lonsdale Street, Melbourne, Victoria 3000, Australia.

Objective: To assess the strength of root cause analysis (RCA) recommendations and their perceived levels of effectiveness and sustainability.

Design: All RCAs related to sentinel events (SEs) undertaken between the years 2010 and 2015 in the public health system in Victoria, Australia were analysed. The type and strength of each recommendation in the RCA reports were coded by an expert patient safety classifier using the US Department of Veteran Affairs type and strength criteria.

Participants And Setting: Thirty-six public health services.

Main Outcome Measure(s): The proportion of RCA recommendations which were classified as 'strong' (more likely to be effective and sustainable), 'medium' (possibly effective and sustainable) or 'weak' (less likely to be effective and sustainable).

Results: There were 227 RCAs in the period of study. In these RCAs, 1137 recommendations were made. Of these 8% were 'strong', 44% 'medium' and 48% were 'weak'. In 31 RCAs, or nearly 15%, only weak recommendations were made. In 24 (11%) RCAs five or more weak recommendations were made. In 165 (72%) RCAs no strong recommendations were made. The most frequent recommendation types were reviewing or enhancing a policy/guideline/documentation, and training and education.

Conclusions: Only a small proportion of recommendations arising from RCAs in Victoria are 'strong'. This suggests that insights from the majority of RCAs are not likely to inform practice or process improvements. Suggested improvements include more human factors expertise and independence in investigations, more extensive application of existing tools that assist teams to prioritize recommendations that are likely to be effective, and greater use of observational and simulation techniques to understand the underlying systems factors. Time spent in repeatedly investigating similar incidents may be better spent aggregating and thematically analysing existing sources of information about patient safety.
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http://dx.doi.org/10.1093/intqhc/mzx181DOI Listing
March 2018

2013 Review and Update of the Genetic Counseling Practice Based Competencies by a Task Force of the Accreditation Council for Genetic Counseling.

J Genet Couns 2016 10 23;25(5):868-79. Epub 2016 Jun 23.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

The first practice based competencies (PBCs) for the field of genetic counseling were adopted by the American Board of Genetic Counseling (ABGC), 1996. Since that time, there has been significant growth in established and new work settings (clinical and non-clinical) and changes in service delivery models and the roles of genetic counselors. These changes prompted the ABGC to appoint a PBC Task Force in 2011 to review the PBCs with respect to their current relevance and to revise and update them as necessary. There are four domains in the revised PBCs: (I) Genetics Expertise and Analysis (II) Interpersonal, Psychosocial and Counseling Skills (III) Education and (IV) Professional Development and Practice. There are 22 competencies, each clarified with learning objectives or samples of activities and skills; a glossary is included. New competencies were added that address genomics, genetic testing and genetic counselors' roles in risk assessment, education, supervision, conducting research and presenting research options to patients. With PBCs serving as the pre-defined abilities or outcomes of training, graduating genetic counselors will be well prepared to enter the field with a minimum level of skills and abilities. A description of the Task Force's work, key changes and the 2013 PBCs are presented herein.
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http://dx.doi.org/10.1007/s10897-016-9984-3DOI Listing
October 2016

α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current.

PLoS One 2016 30;11(3):e0152355. Epub 2016 Mar 30.

Division of Cardiology, Department of Medicine, Duke University School of Medicine; and Ion Channel Research Unit, Duke University Medical Center, Durham, NC, United States of America.

Drug-induced long-QT syndrome (diLQTS) is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (α1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild type (WT) or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q); and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants). In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak INa densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current) in HEK293T cells (0.58 ± 0.10 in WT vs. 0.90 ± 0.11 in A390V, p = 0.048; vs. 0.88 ± 0.07 in E409Q, p = 0.023). In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 ± 0.14 in WT vs.0.94 ± 0.23 in A390V, p = 0.099; vs. 1.12 ± 0.24 in E409Q, p = 0.019). We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the NaV1.5-interacting α1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152355PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814026PMC
August 2016

Rates of organ donation in a UK tertiary cardiac arrest centre following out-of-hospital cardiac arrest.

Resuscitation 2016 Apr 23;101:41-3. Epub 2016 Jan 23.

University Hospitals Bristol, Bristol, UK; Great Western Air Ambulance, South West Ambulance Service Trust, Bristol, UK.

Aim: To ascertain the rate of successful organ donation (OD) within patients who sustained an out of hospital cardiac arrest (OHCA) with initial return of spontaneous circulation (ROSC) and survival to hospital admission, but whom subsequently do not survive to hospital discharge.

Methods: A retrospective audit of ambulance service and hospital databases from January 2010 to January 2015 was undertaken in a United Kingdom tertiary-referral regional cardiac arrest centre. Crude denominator data for cardiac arrests was obtained from the regional ambulance service; the ICU database was interrogated for OHCA patient admissions and outcomes. Patients who died were cross-referenced against the local Organ Donation service database.

Results: Five hundred and fourteen {514} patients were admitted to ICU following OHCA over this five year period. Two hundred and forty-one {241} patients (47%) survived to hospital discharge and 273 (53%) died of whom 106 (39%) were referred to a Specialist Nurse for Organ Donation (SNOD). The conversion rate after the family was approached was 64%. Twenty-eight {28} patients proceeded to donation and 25 patients (24%) successfully donated at least one organ. On average, a patient proceeding to donation provided 1.9 organs.

Conclusions: A proactive, systematic approach to OD in OHCA patients can provide a good conversion rate and substantial number of donors. Most donations occur after death from circulatory criteria. There is a positive socio-economic benefit with nearly £4m in savings to the health service within the next 5 years potentially being realised during this period by liberating patients from dialysis.
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http://dx.doi.org/10.1016/j.resuscitation.2016.01.003DOI Listing
April 2016

Fatigue proofing: The role of protective behaviours in mediating fatigue-related risk in a defence aviation environment.

Accid Anal Prev 2017 Feb 6;99(Pt B):465-468. Epub 2015 Nov 6.

Central Queensland University, Australia.

In the military or emergency services, operational requirements and/or community expectations often preclude formal prescriptive working time arrangements as a practical means of reducing fatigue-related risk. In these environments, workers sometimes employ adaptive or protective behaviours informally to reduce the risk (i.e. likelihood or consequence) associated with a fatigue-related error. These informal behaviours enable employees to reduce risk while continuing to work while fatigued. In this study, we documented the use of informal protective behaviours in a group of defence aviation personnel including flight crews. Semi-structured interviews were conducted to determine whether and which protective behaviours were used to mitigate fatigue-related error. The 18 participants were from aviation-specific trades and included aircrew (pilots and air-crewman) and aviation maintenance personnel (aeronautical engineers and maintenance personnel). Participants identified 147 ways in which they and/or others act to reduce the likelihood or consequence of a fatigue-related error. These formed seven categories of fatigue-reduction strategies. The two most novel categories are discussed in this paper: task-related and behaviour-based strategies. Broadly speaking, these results indicate that fatigued military flight and maintenance crews use protective 'fatigue-proofing' behaviours to reduce the likelihood and/or consequence of fatigue-related error and were aware of the potential benefits. It is also important to note that these behaviours are not typically part of the formal safety management system. Rather, they have evolved spontaneously as part of the culture around protecting team performance under adverse operating conditions. When compared with previous similar studies, aviation personnel were more readily able to understand the idea of fatigue proofing than those from a fire-fighting background. These differences were thought to reflect different cultural attitudes toward error and formal training using principles of Crew Resource Management and Threat and Error Management.
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http://dx.doi.org/10.1016/j.aap.2015.10.011DOI Listing
February 2017

Fatigue risk management by volunteer fire-fighters: Use of informal strategies to augment formal policy.

Accid Anal Prev 2015 Nov 31;84:92-8. Epub 2015 Aug 31.

Central Queensland University Appleton Institute, South Australia, Australia. Electronic address:

An increasing number and intensity of catastrophic fire events in Australia has led to increasing demands on a mainly volunteer fire-fighting workforce. Despite the increasing likelihood of fatigue in the emergency services environment, there is not yet a systematic, unified approach to fatigue management in fire agencies across Australia. Accordingly, the aim of this study was to identify informal strategies used in volunteer fire-fighting and examine how these strategies are transmitted across the workforce. Thirty experienced Australian volunteer fire-fighters were interviewed in August 2010. The study identified informal fatigue-management behaviours at the individual, team and brigade level that have evolved in fire-fighting environments and are regularly implemented. However, their purpose was not explicitly recognized as such. This apparent paradox - that fatigue proofing behaviours exist but that they are not openly understood as such - may well resolve a potential conflict between a culture of indefatigability in the emergency services sector and the frequent need to operate safely while fatigued. However, formal controls require fire-fighters and their organisations to acknowledge and accept their vulnerability. This suggests two important areas in which to improve formal fatigue risk management in the emergency services sector: (1) identifying and formalising tacit or informal fatigue coping strategies as legitimate elements of the fatigue risk management system; and (2) developing culturally appropriate techniques for systematically communicating fatigue levels to self and others.
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http://dx.doi.org/10.1016/j.aap.2015.06.008DOI Listing
November 2015

Something Old, Something New: Using Family History and Genetic Testing to Diagnose and Manage Athletes with Inherited Cardiovascular Disease.

Clin Sports Med 2015 Jul 22;34(3):517-37. Epub 2015 Apr 22.

Division of Cardiology, Department of Medicine, University of Virginia Health System, Box 800158, Charlottesville, VA 22908, USA; Division of Cardiology, Department of Pediatrics, University of Virginia Health System, Box 800386, Charlottesville, VA 22908, USA; Department of Athletics, University of Virginia, Sports Medicine, McCue Center, PO Box 400834, Charlottesville, VA 22904, USA.

A primary objective of the preparticipation physical examination is to identify athletes at increased risk for sudden cardiac arrest (SCA). Review of an athlete's family history may identify those at risk for SCA. Genetic testing for inherited cardiovascular disease has emerged as a valuable addition to the repertoire of cardiologists facing the decision of clearing athletes with concerning clinical signs and/or family histories. Genetic testing may lead to various outcomes for an athlete including: reassurance, diagnosis in those with borderline clinical features, finding disease predisposition prior to the onset of clinical signs (ie, genotype-positive/phenotype-negative), or continued uncertainty.
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http://dx.doi.org/10.1016/j.csm.2015.03.006DOI Listing
July 2015

Next-generation sequencing reveals a controlled immune response to Zaire Ebola virus challenge in cynomolgus macaques immunized with vesicular stomatitis virus expressing Zaire Ebola virus glycoprotein (VSVΔG/EBOVgp).

Clin Vaccine Immunol 2015 Mar 14;22(3):354-6. Epub 2015 Jan 14.

Department of Microbiology, University of Washington, Seattle, Washington, USA Washington National Primate Research Center, University of Washington, Seattle, Washington, USA

Vesicular stomatitis virus expressing Zaire Ebola virus (EBOV) glycoprotein (VSVΔG/EBOVgp) could be used as a vaccine to meet the 2014 Ebola virus outbreak. To characterize the host response to this vaccine, we used mRNA sequencing to analyze peripheral blood mononuclear cells (PBMCs) from cynomolgus macaques after VSVΔG/EBOVgp immunization and subsequent EBOV challenge. We found a controlled transcriptional response that transitioned to immune regulation as the EBOV was cleared. This observation supports the safety of the vaccine.
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http://dx.doi.org/10.1128/CVI.00733-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340895PMC
March 2015

The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease.

Nat Biotechnol 2014 Dec 17;32(12):1250-5. Epub 2014 Nov 17.

1] Department of Microbiology, University of Washington, Seattle, Washington, USA. [2] Washington National Primate Research Center, Seattle, Washington, USA.

The domestic ferret (Mustela putorius furo) is an important animal model for multiple human respiratory diseases. It is considered the 'gold standard' for modeling human influenza virus infection and transmission. Here we describe the 2.41 Gb draft genome assembly of the domestic ferret, constituting 2.28 Gb of sequence plus gaps. We annotated 19,910 protein-coding genes on this assembly using RNA-seq data from 21 ferret tissues. We characterized the ferret host response to two influenza virus infections by RNA-seq analysis of 42 ferret samples from influenza time-course data and showed distinct signatures in ferret trachea and lung tissues specific to 1918 or 2009 human pandemic influenza virus infections. Using microarray data from 16 ferret samples reflecting cystic fibrosis disease progression, we showed that transcriptional changes in the CFTR-knockout ferret lung reflect pathways of early disease that cannot be readily studied in human infants with cystic fibrosis disease.
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http://dx.doi.org/10.1038/nbt.3079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262547PMC
December 2014

Tissue-specific transcriptome sequencing analysis expands the non-human primate reference transcriptome resource (NHPRTR).

Nucleic Acids Res 2015 Jan 11;43(Database issue):D737-42. Epub 2014 Nov 11.

Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA Institute for Computational Biology (ICB), Weill Cornell Medical College, New York, NY 10065, USA Feil Family Brain and Mind Research Institute (BMRI), Weill Cornell Medical College, New York, NY 10065, USA

The non-human primate reference transcriptome resource (NHPRTR, available online at http://nhprtr.org/) aims to generate comprehensive RNA-seq data from a wide variety of non-human primates (NHPs), from lemurs to hominids. In the 2012 Phase I of the NHPRTR project, 19 billion fragments or 3.8 terabases of transcriptome sequences were collected from pools of ∼ 20 tissues in 15 species and subspecies. Here we describe a major expansion of NHPRTR by adding 10.1 billion fragments of tissue-specific RNA-seq data. For this effort, we selected 11 of the original 15 NHP species and subspecies and constructed total RNA libraries for the same ∼ 15 tissues in each. The sequence quality is such that 88% of the reads align to human reference sequences, allowing us to compute the full list of expression abundance across all tissues for each species, using the reads mapped to human genes. This update also includes improved transcript annotations derived from RNA-seq data for rhesus and cynomolgus macaques, two of the most commonly used NHP models and additional RNA-seq data compiled from related projects. Together, these comprehensive reference transcriptomes from multiple primates serve as a valuable community resource for genome annotation, gene dynamics and comparative functional analysis.
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http://dx.doi.org/10.1093/nar/gku1110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383927PMC
January 2015

Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance.

Science 2014 Nov 30;346(6212):987-91. Epub 2014 Oct 30.

Department of Microbiology, University of Washington, Seattle, WA, USA. Washington National Primate Research Center, Seattle, WA, USA.

Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor death from shock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.
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http://dx.doi.org/10.1126/science.1259595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241145PMC
November 2014

Infection with MERS-CoV causes lethal pneumonia in the common marmoset.

PLoS Pathog 2014 Aug 21;10(8):e1004250. Epub 2014 Aug 21.

Virus Ecology Unit, Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, United States of America.

The availability of a robust disease model is essential for the development of countermeasures for Middle East respiratory syndrome coronavirus (MERS-CoV). While a rhesus macaque model of MERS-CoV has been established, the lack of uniform, severe disease in this model complicates the analysis of countermeasure studies. Modeling of the interaction between the MERS-CoV spike glycoprotein and its receptor dipeptidyl peptidase 4 predicted comparable interaction energies in common marmosets and humans. The suitability of the marmoset as a MERS-CoV model was tested by inoculation via combined intratracheal, intranasal, oral and ocular routes. Most of the marmosets developed a progressive severe pneumonia leading to euthanasia of some animals. Extensive lesions were evident in the lungs of all animals necropsied at different time points post inoculation. Some animals were also viremic; high viral loads were detected in the lungs of all infected animals, and total RNAseq demonstrated the induction of immune and inflammatory pathways. This is the first description of a severe, partially lethal, disease model of MERS-CoV, and as such will have a major impact on the ability to assess the efficacy of vaccines and treatment strategies as well as allowing more detailed pathogenesis studies.
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http://dx.doi.org/10.1371/journal.ppat.1004250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140844PMC
August 2014