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  1. Article ; Online: Innate-Like Lymphocytes Are Immediate Participants in the Hyper-Acute Immune Response to Trauma and Hemorrhagic Shock.

    Manson, Joanna / Hoffman, Rosemary / Chen, Shuhua / Ramadan, Mostafa H / Billiar, Timothy R

    Frontiers in immunology

    2019  Volume 10, Page(s) 1501

    Abstract: Adverse outcomes following severe traumatic injury are frequently attributed to a state of immunological dysfunction acquired during treatment and recovery. Recent genomic evidence however, suggests that the trajectory toward development of multiple ... ...

    Abstract Adverse outcomes following severe traumatic injury are frequently attributed to a state of immunological dysfunction acquired during treatment and recovery. Recent genomic evidence however, suggests that the trajectory toward development of multiple organ dysfunction syndrome (MODS) is already in play at admission (<2 h following injury). Improved understanding of the molecular events during the hyper-acute immunological response to trauma, <2 h following injury, may reveal opportunities to ameliorate organ injury and expedite recovery. Lymphocytes have not previously been considered key participants in this early response; however, two observations in human trauma patients namely, raised populations of circulating NKT and NK cells during the hyper-acute phase and persistent lymphopenia beyond 48 h show association with the development of MODS during recovery. These highlight the need for greater understanding of lymphocyte function in the hyper-acute phase of inflammation. An exploratory study was therefore conducted in a well-established murine model of trauma and hemorrhagic shock (T&HS) to investigate (1) the development of lymphopenia in the murine model and (2) the phenotypic and functional changes of three innate-like lymphocyte subsets, NK1.1+ CD3-, NK1.1+ CD3+, γδTCR+ CD3+ cells, focusing on the first 6 h following injury. Rapid changes in phenotype and function were demonstrated in these cells within blood and spleen, but responses in lung tissue lagged behind. This study describes the immediacy of the innate-like lymphocyte response to trauma in different body compartments and considers new lines for further investigation to develop our understanding of MODS pathogenesis.
    MeSH term(s) Animals ; Immunity, Innate/immunology ; Killer Cells, Natural/immunology ; Lymphocyte Count ; Lymphocyte Subsets/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Models, Animal ; Multiple Organ Failure/immunology ; Multiple Organ Failure/pathology ; Natural Killer T-Cells/immunology ; Shock, Hemorrhagic/immunology ; Shock, Hemorrhagic/pathology ; Wounds and Injuries/immunology ; Wounds and Injuries/pathology
    Language English
    Publishing date 2019-07-11
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2019.01501
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The role of inflammation in secondary cardiac dysfunction following trauma.

    Wilson, Nick M / De'Ath, Henry D / Manson, Joanna

    Scandinavian journal of trauma, resuscitation and emergency medicine

    2014  Volume 22, Issue 1, Page(s) 787

    Language English
    Publishing date 2014-12
    Publishing country England
    Document type Journal Article
    ISSN 1757-7241
    ISSN (online) 1757-7241
    DOI 10.1186/1757-7241-22-S1-P12
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: What helps or hinders the transformation from a major tertiary center to a major trauma center? Identifying barriers and enablers using the Theoretical Domains Framework.

    Roberts, Neil / Lorencatto, Fabiana / Manson, Joanna / Brundage, Susan I / Jansen, Jan O

    Scandinavian journal of trauma, resuscitation and emergency medicine

    2016  Volume 24, Page(s) 30

    Abstract: Background: Major Trauma Centers (MTCs), as part of a trauma system, improve survival and functional outcomes from injury. Developing such centers from current teaching hospitals is likely to generate diverse beliefs amongst staff. These may act as ... ...

    Abstract Background: Major Trauma Centers (MTCs), as part of a trauma system, improve survival and functional outcomes from injury. Developing such centers from current teaching hospitals is likely to generate diverse beliefs amongst staff. These may act as barriers or enablers. Prior identification of these may make the service development process more efficient. The importance of applying theory to systematically identify barriers and enablers to changing clinical practice in emergency medicine has been emphasized. This study systematically explored theory-based barriers and enablers towards implementing the transformation of a tertiary hospital into a MTC. Our goal was to demonstrate the use of a replicable method to identify targets that could be addressed to achieve a successful transformation from an organization evolved to provide a particular type of clinical care into a clinical system with different demands, requirements and expectations.
    Methods: The Theoretical Domains Framework (TDF) is a tool designed to elicit and analyze beliefs affecting behavior. Semi-structured interviews based around the TDF were conducted in a major tertiary hospital in Scotland due to become a MTC with a purposive sample of major stakeholders including clinicians and nurses from specialties involved in trauma care, clinical managers and administration. Belief statements were identified through qualitative analysis, and assessed for importance according to prevalence, discordance and evidence base.
    Results and discussion: 1728 utterances were recorded and coded into 91 belief statements. 58 were classified as important barriers/enablers. There were major concerns about resource demands, with optimism conditional on these being met. Distracting priorities abound within the Emergency Department. Better communication is needed. Staff motivation is high and they should be engaged in skills development and developing performance improvement processes.
    Conclusions: This study presents a systematic and replicable method of identifying theory-based barriers and enablers towards complex service development. It identifies multiple barriers/enablers that may serve as a basis for developing an implementation intervention to enhance the development of MTCs. This method can be used to address similar challenges in developing specialist centers or implementing clinical practice change in emergency care across both developing and developed countries.
    MeSH term(s) Administrative Personnel/psychology ; Cooperative Behavior ; Female ; Humans ; Interviews as Topic ; Male ; Models, Theoretical ; Organizational Innovation ; Qualitative Research ; Scotland ; Tertiary Care Centers ; Trauma Centers
    Language English
    Publishing date 2016-03-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 2455990-8
    ISSN 1757-7241 ; 1757-7241
    ISSN (online) 1757-7241
    ISSN 1757-7241
    DOI 10.1186/s13049-016-0226-3
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  4. Article ; Online: NK1.1

    Chen, Shuhua / Hoffman, Rosemary A / Scott, Melanie / Manson, Joanna / Loughran, Patricia / Ramadan, Mostafa / Demetris, Anthony J / Billiar, Timothy R

    Journal of leukocyte biology

    2017  Volume 102, Issue 1, Page(s) 127–134

    Abstract: Various cell populations expressing NK1.1 contribute to innate host defense and systemic inflammatory responses, but their role in hemorrhagic shock and trauma remains uncertain. NK1 ... ...

    Abstract Various cell populations expressing NK1.1 contribute to innate host defense and systemic inflammatory responses, but their role in hemorrhagic shock and trauma remains uncertain. NK1.1
    MeSH term(s) Alanine Transaminase/blood ; Alanine Transaminase/immunology ; Animals ; Antigens, Ly/blood ; Antigens, Ly/immunology ; Aspartate Aminotransferases/blood ; Aspartate Aminotransferases/immunology ; Cytokines/blood ; Cytokines/immunology ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Mice ; NK Cell Lectin-Like Receptor Subfamily B/blood ; NK Cell Lectin-Like Receptor Subfamily B/immunology ; Shock, Hemorrhagic/blood ; Shock, Hemorrhagic/immunology ; Shock, Hemorrhagic/pathology ; Wounds and Injuries/blood ; Wounds and Injuries/immunology ; Wounds and Injuries/pathology
    Chemical Substances Antigens, Ly ; Cytokines ; Klrb1c protein, mouse ; NK Cell Lectin-Like Receptor Subfamily B ; Aspartate Aminotransferases (EC 2.6.1.1) ; Alanine Transaminase (EC 2.6.1.2)
    Language English
    Publishing date 2017-05-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1189/jlb.3A0716-333R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Early changes within the lymphocyte population are associated with the development of multiple organ dysfunction syndrome in trauma patients.

    Manson, Joanna / Cole, Elaine / De'Ath, Henry D / Vulliamy, Paul / Meier, Ute / Pennington, Dan / Brohi, Karim

    Critical care (London, England)

    2016  Volume 20, Issue 1, Page(s) 176

    Abstract: Background: Early survival following severe injury has been improved with refined resuscitation strategies. Multiple organ dysfunction syndrome (MODS) is common among this fragile group of patients leading to prolonged hospital stay and late mortality. ... ...

    Abstract Background: Early survival following severe injury has been improved with refined resuscitation strategies. Multiple organ dysfunction syndrome (MODS) is common among this fragile group of patients leading to prolonged hospital stay and late mortality. MODS after trauma is widely attributed to dysregulated inflammation but the precise mechanics of this response and its influence on organ injury are incompletely understood. This study was conducted to investigate the relationship between early lymphocyte responses and the development of MODS during admission.
    Methods: During a 24-month period, trauma patients were recruited from an urban major trauma centre to an ongoing, observational cohort study. Admission blood samples were obtained within 2 h of injury and before in-hospital intervention, including blood transfusion. The study population was predominantly male with a blunt mechanism of injury. Lymphocyte subset populations including T helper, cytotoxic T cells, NK cells and γδ T cells were identified using flow cytometry. Early cytokine release and lymphocyte count during the first 7 days of admission were also examined.
    Results: This study demonstrated that trauma patients who developed MODS had an increased population of NK dim cells (MODS vs no MODS: 22 % vs 13 %, p < 0.01) and reduced γδ-low T cells (MODS vs no MODS: 0.02 (0.01-0.03) vs 0.09 (0.06-0.12) × 10^9/L, p < 0.01) at admission. Critically injured patients who developed MODS (n = 27) had higher interferon gamma (IFN-γ) concentrations at admission, compared with patients of matched injury severity and shock (n = 60) who did not develop MODS (MODS vs no MODS: 4.1 (1.8-9.0) vs 1.0 (0.6-1.8) pg/ml, p = 0.01). Lymphopenia was observed within 24 h of injury and was persistent in those who developed MODS. Patients with a lymphocyte count of 0.5 × 10(9)/L or less at 48 h, had a 45 % mortality rate.
    Conclusions: This study provides evidence of lymphocyte activation within 2 h of injury, as demonstrated by increased NK dim cells, reduced γδ-low T lymphocytes and high blood IFN-γ concentration. These changes are associated with the development of MODS and lymphopenia. The study reveals new opportunities for investigation to characterise the cellular response to trauma and examine its influence on recovery.
    MeSH term(s) Adult ; Biomarkers/analysis ; Biomarkers/blood ; Cohort Studies ; Female ; Humans ; Interferons/analysis ; Interferons/blood ; Killer Cells, Natural/cytology ; Logistic Models ; London ; Lymphocyte Subsets/metabolism ; Lymphocyte Subsets/physiology ; Male ; Middle Aged ; Multiple Organ Failure/diagnosis ; Multiple Organ Failure/mortality ; Multiple Trauma/blood ; Multiple Trauma/complications ; Prospective Studies ; T-Lymphocytes/cytology
    Chemical Substances Biomarkers ; IFNE protein, human ; Interferons (9008-11-1)
    Language English
    Publishing date 2016-06-07
    Publishing country England
    Document type Journal Article ; Observational Study
    ZDB-ID 2041406-7
    ISSN 1466-609X ; 1364-8535
    ISSN (online) 1466-609X
    ISSN 1364-8535
    DOI 10.1186/s13054-016-1341-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Paediatric laparoscopic hernia repair: Ex vivo skills in the reduced training era.

    Parsons, Chris / Manson, Joanna / Nataraja, Ramesh / Jones, Niall / Curry, Joe / Ade-Ajayi, Niyi

    African journal of paediatric surgery : AJPS

    2013  Volume 10, Issue 2, Page(s) 95–99

    Abstract: Introduction: Changes to surgical working hours have resulted in shorter training times and fewer learning opportunities. Tools that develop surgical skills ex-vivo are of particular interest in this era. Laparoscopic skills are regarded as essential by ...

    Abstract Introduction: Changes to surgical working hours have resulted in shorter training times and fewer learning opportunities. Tools that develop surgical skills ex-vivo are of particular interest in this era. Laparoscopic skills are regarded as essential by many for modern paediatric surgery practice. Several generic skills models have been reported and validated. However, there is limited evidence regarding the role of procedure specific models. Here, a laparoscopic paediatric hernia repair model is trialled with surgical trainees and their competence compared with consultant colleagues.
    Patients and methods: An ex-vivo paediatric inguinal hernia repair model was devised. Surgical trainees from 5 specialist centres were recruited and performed multiple standardised repairs.
    Results: 23 trainees performed 192 repairs. Experts performed 10 repairs for comparison. Trainees were timed performing the repair and their accuracy measured. With repeated attempts trainee's timings and accuracy improved until by the 10 th repair they were no different from benchmark consultant scores.
    Conclusion: A simple, procedure specific ex-vivo training model has been evaluated for laparoscopic hernia training in paediatric surgery. The results suggest improvements in competence with repetition. Trainee and benchmark consultant scores are no different by the 10 th trainee attempt. We conclude that this model may have a valuable role in the training and assessment of future paediatric surgeons.
    MeSH term(s) Child ; Clinical Competence ; Education, Medical, Continuing/trends ; Hernia, Inguinal/surgery ; Herniorrhaphy/education ; Herniorrhaphy/methods ; Humans ; Laparoscopy/education ; Laparoscopy/methods ; London ; Models, Educational ; Pediatrics/education ; Prospective Studies
    Language English
    Publishing date 2013-04
    Publishing country India
    Document type Comparative Study ; Journal Article ; Multicenter Study
    ZDB-ID 2392865-7
    ISSN 0974-5998 ; 0189-6725
    ISSN (online) 0974-5998
    ISSN 0189-6725
    DOI 10.4103/0189-6725.115031
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Major trauma and urban cyclists: physiological status and injury profile.

    Manson, Joanna / Cooper, Sian / West, Anita / Foster, Elizabeth / Cole, Elaine / Tai, Nigel R M

    Emergency medicine journal : EMJ

    2013  Volume 30, Issue 1, Page(s) 32–37

    Abstract: Introduction: Pedal cycling in cities has the potential to deliver significant health and economic benefits for individuals and society. Safety is the main concern for potential cyclists although the statistical risk of death is low. Little is known ... ...

    Abstract Introduction: Pedal cycling in cities has the potential to deliver significant health and economic benefits for individuals and society. Safety is the main concern for potential cyclists although the statistical risk of death is low. Little is known about the severity of injuries sustained by city cyclists and their outcome.
    Aim: The aim of this study was to characterise the physiological status and injury profile of cyclists admitted to our urban major trauma centre (MTC).
    Methods: Database analysis of cyclist casualties between 2004 and 2009. The physiological parameters examined were admission systolic blood pressure (SBP), admission base deficit and prehospital Glasgow Coma Scale.
    Results: 265 cyclists required full trauma-team activation. 82% were injured during a collision with a motorised vehicle. The majority (73%) had collided with a car or a heavy goods vehicle (HGV). These casualties formed the cohort for further analysis. Cyclists who collided with an HGV were more severely injured and had a higher mortality rate. Low SBP and high base deficit indicate that haemorrhagic shock is a key feature of HGV casualties.
    Conclusion: Collision with any vehicle can result in death or serious injury to a cyclist. Injury patterns vary with the type of vehicle involved. HGVs were associated with severe injuries and death as a result of uncontrollable haemorrhage. Awareness of this injury profile may aid prehospital management and expedite transfer to MTC care. Rapid haemorrhage control may salvage some, but not all, of these casualties. The need for continued collision prevention strategies and long-term outcome data collection in trauma patients is highlighted.
    MeSH term(s) Accidents, Traffic ; Adult ; Bicycling ; Blood Pressure/physiology ; Female ; Humans ; Injury Severity Score ; London/epidemiology ; Male ; Middle Aged ; Urban Population ; Wounds and Injuries/epidemiology ; Wounds and Injuries/etiology ; Wounds and Injuries/physiopathology
    Language English
    Publishing date 2013-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2040124-3
    ISSN 1472-0213 ; 1472-0205
    ISSN (online) 1472-0213
    ISSN 1472-0205
    DOI 10.1136/emermed-2011-200966
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  8. Article: Scavenging Circulating Mitochondrial DNA as a Potential Therapeutic Option for Multiple Organ Dysfunction in Trauma Hemorrhage.

    Aswani, Andrew / Manson, Joanna / Itagaki, Kiyoshi / Chiazza, Fausto / Collino, Massimo / Wupeng, Winston Liao / Chan, Tze Khee / Wong, W S Fred / Hauser, Carl J / Thiemermann, Chris / Brohi, Karim

    Frontiers in immunology

    2018  Volume 9, Page(s) 891

    Abstract: Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining severely injured patients up to 25% develop a ... ...

    Abstract Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining severely injured patients up to 25% develop a dysregulated immune response leading to multiple organ dysfunction syndrome (MODS). Despite improvements in trauma care, the morbidity and mortality of this condition remains very high. Massive traumatic injury can overwhelm endogenous homeostatic mechanisms even with prompt treatment. The underlying mechanisms driving MODS are also not fully elucidated. As a result, successful therapies for trauma-related MODS are lacking. Trauma causes tissue damage that releases a large number of endogenous damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs released in trauma, such as mitochondrial DNA (mtDNA), could help to explain part of the immune response in trauma given the structural similarities between mitochondria and bacteria. MtDNA, like bacterial DNA, contains an abundance of highly stimulatory unmethylated CpG DNA motifs that signal through toll-like receptor-9 to produce inflammation. MtDNA has been shown to be highly damaging when injected into healthy animals causing acute organ injury to develop. Elevated circulating levels of mtDNA have been reported in trauma patients but an association with clinically meaningful outcomes has not been established in a large cohort. We aimed to determine whether mtDNA released after clinical trauma hemorrhage is sufficient for the development of MODS. Secondly, we aimed to determine the extent of mtDNA release with varying degrees of tissue injury and hemorrhagic shock in a clinically relevant rodent model. Our final aim was to determine whether neutralizing mtDNA with the nucleic acid scavenging polymer, hexadimethrine bromide (HDMBr), at a clinically relevant time point
    Conclusions: We have shown that the release of mtDNA is sufficient for the development of multiple organ injury. MtDNA concentrations likely peak at different points in the early postinjury phase dependent on the degree of isolated trauma vs combined trauma and hemorrhagic shock. HDMBr scavenging of circulating mtDNA (and nuclear DNA, nDNA) is associated with rescue from severe multiple organ injury in the animal model. This suggests that HDMBr could have utility in rescue from human trauma-induced MODS.
    MeSH term(s) Adult ; Aged ; Alarmins/immunology ; Alarmins/metabolism ; Animals ; Cohort Studies ; DNA, Bacterial/blood ; DNA, Bacterial/immunology ; DNA, Mitochondrial/blood ; DNA, Mitochondrial/immunology ; Disease Models, Animal ; Female ; Hexadimethrine Bromide/pharmacology ; Hexadimethrine Bromide/therapeutic use ; Humans ; Male ; Middle Aged ; Mitochondria/drug effects ; Mitochondria/immunology ; Mitochondria/metabolism ; Mitochondria/pathology ; Multiple Organ Failure/drug therapy ; Multiple Organ Failure/immunology ; Multiple Organ Failure/mortality ; Multiple Organ Failure/pathology ; Multiple Trauma/drug therapy ; Multiple Trauma/immunology ; Multiple Trauma/mortality ; Multiple Trauma/pathology ; Prospective Studies ; Rats, Wistar ; Shock, Hemorrhagic/drug therapy ; Shock, Hemorrhagic/immunology ; Shock, Hemorrhagic/mortality ; Shock, Hemorrhagic/pathology ; Trauma Severity Indices ; Treatment Outcome ; Young Adult
    Chemical Substances Alarmins ; DNA, Bacterial ; DNA, Mitochondrial ; Hexadimethrine Bromide (4C905MSK4W)
    Language English
    Publishing date 2018-05-08
    Publishing country Switzerland
    Document type Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2606827-8
    ISSN 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2018.00891
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Correction: Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: A prospective cohort study.

    Cabrera, Claudia P / Manson, Joanna / Shepherd, Joanna M / Torrance, Hew D / Watson, David / Longhi, M Paula / Hoti, Mimoza / Patel, Minal B / O'Dwyer, Michael / Nourshargh, Sussan / Pennington, Daniel J / Barnes, Michael R / Brohi, Karim

    PLoS medicine

    2018  Volume 15, Issue 10, Page(s) e1002694

    Abstract: This corrects the article DOI: 10.1371/journal.pmed.1002352.]. ...

    Abstract [This corrects the article DOI: 10.1371/journal.pmed.1002352.].
    Language English
    Publishing date 2018-10-31
    Publishing country United States
    Document type Journal Article ; Published Erratum
    ZDB-ID 2185925-5
    ISSN 1549-1676 ; 1549-1277
    ISSN (online) 1549-1676
    ISSN 1549-1277
    DOI 10.1371/journal.pmed.1002694
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  10. Article ; Online: Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: A prospective cohort study.

    Cabrera, Claudia P / Manson, Joanna / Shepherd, Joanna M / Torrance, Hew D / Watson, David / Longhi, M Paula / Hoti, Mimoza / Patel, Minal B / O'Dwyer, Michael / Nourshargh, Sussan / Pennington, Daniel J / Barnes, Michael R / Brohi, Karim

    PLoS medicine

    2017  Volume 14, Issue 7, Page(s) e1002352

    Abstract: Background: Severe trauma induces a widespread response of the immune system. This "genomic storm" can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects ... ...

    Abstract Background: Severe trauma induces a widespread response of the immune system. This "genomic storm" can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects long-term health outcomes. Contemporary management of MODS is entirely supportive, and no specific therapeutics have been shown to be effective in reducing incidence or severity. The pathogenesis of MODS remains unclear, and several models are proposed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflammatory pathways. We postulated that the hyperacute window after trauma may hold the key to understanding how the genomic storm is initiated and may lead to a new understanding of the pathogenesis of MODS.
    Methods and findings: We performed whole blood transcriptome and flow cytometry analyses on a total of 70 critically injured patients (Injury Severity Score [ISS] ≥ 25) at The Royal London Hospital in the hyperacute time period within 2 hours of injury. We compared transcriptome findings in 36 critically injured patients with those of 6 patients with minor injuries (ISS ≤ 4). We then performed flow cytometry analyses in 34 critically injured patients and compared findings with those of 9 healthy volunteers. Immediately after injury, only 1,239 gene transcripts (4%) were differentially expressed in critically injured patients. By 24 hours after injury, 6,294 transcripts (21%) were differentially expressed compared to the hyperacute window. Only 202 (16%) genes differentially expressed in the hyperacute window were still expressed in the same direction at 24 hours postinjury. Pathway analysis showed principally up-regulation of pattern recognition and innate inflammatory pathways, with down-regulation of adaptive responses. Immune deconvolution, flow cytometry, and modular analysis suggested a central role for neutrophils and Natural Killer (NK) cells, with underexpression of T- and B cell responses. In the transcriptome cohort, 20 critically injured patients later developed MODS. Compared with the 16 patients who did not develop MODS (NoMODS), maximal differential expression was seen within the hyperacute window. In MODS versus NoMODS, 363 genes were differentially expressed on admission, compared to only 33 at 24 hours postinjury. MODS transcripts differentially expressed in the hyperacute window showed enrichment among diseases and biological functions associated with cell survival and organismal death rather than inflammatory pathways. There was differential up-regulation of NK cell signalling pathways and markers in patients who would later develop MODS, with down-regulation of neutrophil deconvolution markers. This study is limited by its sample size, precluding more detailed analyses of drivers of the hyperacute response and different MODS phenotypes, and requires validation in other critically injured cohorts.
    Conclusions: In this study, we showed how the hyperacute postinjury time window contained a focused, specific signature of the response to critical injury that led to widespread genomic activation. A transcriptomic signature for later development of MODS was present in this hyperacute window; it showed a strong signal for cell death and survival pathways and implicated NK cells and neutrophil populations in this differential response.
    MeSH term(s) Acute Disease ; Adult ; Blood Chemical Analysis ; Female ; Flow Cytometry ; Humans ; Inflammation/blood ; Inflammation/etiology ; Inflammation/immunology ; Inflammation/therapy ; London ; Male ; Middle Aged ; Multiple Organ Failure/diagnosis ; Multiple Organ Failure/etiology ; Multiple Organ Failure/immunology ; Multiple Organ Failure/therapy ; Prospective Studies ; Time Factors ; Transcriptome ; Wounds and Injuries/blood ; Wounds and Injuries/complications ; Wounds and Injuries/immunology ; Wounds and Injuries/therapy
    Language English
    Publishing date 2017-07-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2185925-5
    ISSN 1549-1676 ; 1549-1277
    ISSN (online) 1549-1676
    ISSN 1549-1277
    DOI 10.1371/journal.pmed.1002352
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