Publications by authors named "Shawn G Rhind"

50 Publications

Ex vivo hemostatic and immuno-inflammatory profiles of freeze-dried plasma.

Transfusion 2021 07;61 Suppl 1:S119-S130

St. Michael's Hospital, Toronto, Ontario, Canada.

Background: Hemorrhage is a leading cause of preventable death in civilian and military trauma. Freeze-dried plasma is promising for hemostatic resuscitation in remote prehospital settings, given its potential benefits in reducing blood loss and mortality, long storage at ambient temperatures, high portability, and rapid reconstitution for transfusion in austere environments. Here we assess the ex vivo characteristics of a novel Terumo's freeze-dried plasma product (TFDP).

Study Design And Methods: Rotational thromboelastometry (ROTEM) tests (INTEM, EXTEM, and FIBTEM) were conducted on plasma samples at 37°C with a ROTEM delta-machine using standard reagents and procedures. The following samples were analyzed: pooled plasma to produce TFDP, TFDP reconstituted, and stored immediately at -80°C, reconstituted TFDP stored at 4°C for 24 h and room temperature (RT) for 4 h before freezing at -80°C. Analysis of plasma concentrations of selected cytokines, chemokines, and vascular molecules was performed using a multiplex immunoassay system. One-way ANOVA with post hoc tests assessed differences in hemostatic and inflammatory properties.

Results: No significant differences in ROTEM variables (coagulation time [CT], clot formation time, α-angle, maximum clot firmness, and lysis index 30) between the TFDP-producing plasma and reconstituted TFDP samples were observed. Compared to control plasma, reconstituted TFDP stored at 4°C for 24 h or RT for 4 h showed a longer INTEM CT. Levels of immuno-inflammatory mediators were similar between frozen plasma and TFDP.

Conclusions: TFDP is equivalent to frozen plasma with respect to global hemostatic and immuno-inflammatory mediator profiles. Further investigations of TFDP in trauma-induced coagulopathy models and bleeding patients are warranted.
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http://dx.doi.org/10.1111/trf.16502DOI Listing
July 2021

Evaluation of trauma-induced coagulopathy in the fibrinogen in the initial resuscitation of severe trauma trial.

Transfusion 2021 07;61 Suppl 1:S49-S57

Department of Surgery, St. Michael's Hospital, Toronto, Ontario, Canada.

Background: Coagulopathic bleeding is frequently present after major trauma. However, trauma-induced coagulopathy (TIC) remains incompletely understood. This laboratory analysis of blood samples derived from our completed trial on fibrinogen in the initial resuscitation of severe trauma (FiiRST) was conducted to evaluate TIC and associated responses to fibrinogen replacement.

Study Design And Methods: We conducted a retrospective evaluation of TIC in 45 FiiRST trial patients based on rotational thromboelastometry (ROTEM), international normalized ratio (INR), and biomarkers for hemostasis and endotheliopathy. Whole blood was analyzed by ROTEM. Plasma was analyzed for INR and biomarkers.

Results: Overall, 19.0% and 30.0% of the FiiRST trial patients were coagulopathic on admission defined by EXTEM maximum clot firmness out of the range of 40-71 mm and INR >1.2, respectively. The FiiRST patients showed lower fibrinogen, factor II and V levels, protein C and antiplasmin activities, higher activated protein C, tissue plasminogen activator, d-dimer, and thrombomodulin concentrations at admission than healthy controls. Most of the biomarkers changed their activities during 48-h hospitalization, but were at abnormal levels even 48-h after admission. The fibrinogen treatment reduced hypofibrinogenemia and increased factor XIII level, but had no significant effects on other biomarkers levels. Limited development of endotheliopathy was indicated by syndean-1, thrombomodulin, and sE-selectin.

Conclusions: About 19%-30% of the trauma patients in the FiiRST trial were coagulopathic on hospital admission depending on the definition of TIC. Analyses of the TIC biomarkers demonstrated that hemostasis would not return to normal after 48-h hospitalization, and fibrinogen replacement improved hypofibrinogenemia.
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http://dx.doi.org/10.1111/trf.16488DOI Listing
July 2021

Correction: Convalescent Plasma for the Prevention and Treatment of COVID-19: A Systematic Review and Quantitative Analysis.

JMIR Public Health Surveill 2021 Jun 30;7(6):e31554. Epub 2021 Jun 30.

St. Michael's Hospital, Toronto, ON, Canada.

[This corrects the article DOI: 10.2196/25500.].
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http://dx.doi.org/10.2196/31554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280829PMC
June 2021

Teasing apart trauma: neural oscillations differentiate individual cases of mild traumatic brain injury from post-traumatic stress disorder even when symptoms overlap.

Transl Psychiatry 2021 06 4;11(1):345. Epub 2021 Jun 4.

Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, ON, Canada.

Post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are highly prevalent and closely related disorders. Affected individuals often exhibit substantially overlapping symptomatology - a major challenge for differential diagnosis in both military and civilian contexts. According to our symptom assessment, the PTSD group exhibited comparable levels of concussion symptoms and severity to the mTBI group. An objective and reliable system to uncover the key neural signatures differentiating these disorders would be an important step towards translational and applied clinical use. Here we explore use of MEG (magnetoencephalography)-multivariate statistical learning analysis in identifying the neural features for differential PTSD/mTBI characterisation. Resting state MEG-derived regional neural activity and coherence (or functional connectivity) across seven canonical neural oscillation frequencies (delta to high gamma) were used. The selected features were consistent and largely confirmatory with previously established neurophysiological markers for the two disorders. For regional power from theta, alpha and high gamma bands, the amygdala, hippocampus and temporal areas were identified. In line with regional activity, additional connections within the occipital, parietal and temporal regions were selected across a number of frequency bands. This study is the first to employ MEG-derived neural features to reliably and differentially stratify the two disorders in a multi-group context. The features from alpha and beta bands exhibited the best classification performance, even in cases where distinction by concussion symptom profiles alone were extremely difficult. We demonstrate the potential of using 'invisible' neural indices of brain functioning to understand and differentiate these debilitating conditions.
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http://dx.doi.org/10.1038/s41398-021-01467-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178364PMC
June 2021

Convalescent Plasma for the Prevention and Treatment of COVID-19: A Systematic Review and Quantitative Analysis.

JMIR Public Health Surveill 2021 04 7;7(4):e25500. Epub 2021 Apr 7.

St. Michael's Hospital, Toronto, ON, Canada.

Background: The COVID-19 pandemic, caused by a novel coronavirus termed SARS-CoV-2, has spread quickly worldwide. Convalescent plasma (CP) obtained from patients following recovery from COVID-19 infection and development of antibodies against the virus is an attractive option for either prophylactic or therapeutic treatment, since antibodies may have direct or indirect antiviral activities and immunotherapy has proven effective in principle and in many clinical reports.

Objective: We seek to characterize the latest advances and evidence in the use of CP for COVID-19 through a systematic review and quantitative analysis, identify knowledge gaps in this setting, and offer recommendations and directives for future research.

Methods: PubMed, Web of Science, and Embase were continuously searched for studies assessing the use of CP for COVID-19, including clinical studies, commentaries, reviews, guidelines or protocols, and in vitro testing of CP antibodies. The screening process and data extraction were performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Quality appraisal of all clinical studies was conducted using a universal tool independent of study designs. A meta-analysis of case-control and randomized controlled trials (RCTs) was conducted using a random-effects model.

Results: Substantial literature has been published covering various aspects of CP therapy for COVID-19. Of the references included in this review, a total of 243 eligible studies including 64 clinical studies, 79 commentary articles, 46 reviews, 19 guidance and protocols, and 35 in vitro testing of CP antibodies matched the criteria. Positive results have been mostly observed so far when using CP for the treatment of COVID-19. There were remarkable heterogeneities in the CP therapy with respect to patient demographics, donor antibody titers, and time and dose of CP administration. The studies assessing the safety of CP treatment reported low incidence of adverse events. Most clinical studies, in particular case reports and case series, had poor quality. Only 1 RCT was of high quality. Randomized and nonrandomized data were found in 2 and 11 studies, respectively, and were included for meta-analysis, suggesting that CP could reduce mortality and increase viral clearance. Despite promising pilot studies, the benefits of CP treatment can only be clearly established through carefully designed RCTs.

Conclusions: There is developing support for CP therapy, particularly for patients who are critically ill or mechanically ventilated and resistant to antivirals and supportive care. These studies provide important lessons that should inform the planning of well-designed RCTs to generate more robust knowledge for the efficacy of CP in patients with COVID-19. Future research is necessary to fill the knowledge gap regarding prevention and treatment for patients with COVID-19 with CP while other therapeutics are being developed.
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http://dx.doi.org/10.2196/25500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245055PMC
April 2021

Repeated Occupational Exposure to Low-level Blast in the Canadian Armed Forces: Effects on Hearing, Balance, and Ataxia.

Mil Med 2021 Jan 25. Epub 2021 Jan 25.

Canadian Forces Health Services, Ottawa, ON, K1A 0K2, Canada.

Introduction: Recently, there has been increasing concern about the adverse health effects of long-term occupational exposure to low-level blast in military personnel. Occupational blast exposure occurs routinely in garrison through use of armaments and controlled blast detonations. In the current study, we focused on a population of breaching instructors and range staff. Breaching is a tactical technique that is used to gain entry into closed spaces, often through the use of explosives.

Materials And Methods: Initial measurements of blast overpressure collected during breaching courses found that up to 10% of the blasts for range staff and up to 32% of the blasts for instructors exceeded the recommended 3 psi exposure limit. Using a cross-sectional design, we used tests of balance, ataxia, and hearing to compare a sample of breachers (n = 19) to age-and sex-matched military controls (n = 19).

Results: There were no significant differences between the two groups on the balance and ataxia tests, although the average scores of both groups were lower than would be expected in a normative population. The prevalence of hearing loss was low in the breacher group (4 of 19), and hearing thresholds were not significantly different from the controls. However, the prevalence of self-reported tinnitus was significantly higher in the breacher group (12 of 19) compared with the controls (4 of 19), and all breachers who were identified as having hearing loss also reported tinnitus.

Conclusions: Our results suggest that basic tests of balance, ataxia, and hearing on their own were not sensitive to the effects of long-term occupational exposure to low-level blast. Some of the blast exposure levels exceeded limits, and there was a significant association of exposure with tinnitus. Future studies should supplement with additional information including exposure history and functional hearing assessments. These findings should be considered in the design of future acute and longitudinal studies of low-level blast exposure.
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http://dx.doi.org/10.1093/milmed/usaa439DOI Listing
January 2021

Massage Therapy Modulates Inflammatory Mediators Following Sprint Exercise in Healthy Male Athletes.

J Funct Morphol Kinesiol 2020 Jan 29;5(1). Epub 2020 Jan 29.

Translational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Massage therapy is a common postexercise muscle recovery modality; however, its mechanisms of efficacy are uncertain. We evaluated the effects of massage on systemic inflammatory responses to exercise and postexercise muscle performance and soreness. In this crossover study, nine healthy male athletes completed a high-intensity intermittent sprint protocol, followed by massage therapy or control condition. Inflammatory markers were assessed pre-exercise; postexercise; and at 1, 2, and 24 h postexercise. Muscle performance was measured by squat and drop jump, and muscle soreness on a Likert scale. Significant time effects were observed for monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor alpha (TNFα), drop jump performance, squat jump performance, and soreness. No significant effects for condition were observed. However, compared with control, inflammatory marker concentrations (IL-8, TNFα, and MCP-1) returned to baseline levels earlier following the massage therapy condition ( < 0.05 for all). IL-6 returned to baseline levels earlier following the control versus massage therapy condition ( < 0.05). No differences were observed for performance or soreness variables. MCP-1 area under the curve (AUC) was negatively associated with squat and drop jump performance, while IL-10 AUC was positively associated with drop jump performance ( < 0.05 for all). In conclusion, massage therapy promotes resolution of systemic inflammatory signaling following exercise but does not appear to improve performance or soreness measurements.
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http://dx.doi.org/10.3390/jfmk5010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739334PMC
January 2020

Blast in Context: The Neuropsychological and Neurocognitive Effects of Long-Term Occupational Exposure to Repeated Low-Level Explosives on Canadian Armed Forces' Breaching Instructors and Range Staff.

Front Neurol 2020 3;11:588531. Epub 2020 Dec 3.

Canadian Forces Health Services, Ottawa, ON, Canada.

Currently, there is strong interest within the military to better understand the effects of long-term occupational exposure to repeated low-level blast on health and performance. To gain traction on the chronic sequelae of blast, we focused on -a tactical technique for gaining entry into closed/blocked spaces by placing explosives and maintaining a calculated safe distance from the detonation. Using a cross-sectional design, we compared the neuropsychological and neurocognitive profiles of breaching instructors and range staff to sex- and age-matched Canadian Armed Forces (CAF) controls. Univariate tests demonstrated that breaching was associated with greater post-concussive symptoms () and lower levels of energy (). In addition, breaching instructors and range staff were slower on a test that requires moving and thinking simultaneously (i.e., cognitive-motor integration). Next, using a multivariate approach, we explored the impact of other possible sources of injury, including concussion and prior war-zone deployment on the same outcomes. Concussion history was associated with higher post-concussive scores and musculoskeletal problems, whereas deployment was associated with higher post-concussive scores, but lower energy and greater PTSD symptomatology (using PCL-5). Our results indicate that although breaching, concussion, and deployment were similarly correlated with greater post-concussive symptoms, concussion history appears to be uniquely associated with altered musculoskeletal function, whereas deployment history appears to be uniquely associated with lower energy and risk of PTSD. We argue that the broader injury context must, therefore, be considered when studying the impact of repetitive low-level explosives on health and performance in military members.
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http://dx.doi.org/10.3389/fneur.2020.588531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744759PMC
December 2020

Virtual Reality-Based Treatment for Military Members and Veterans With Combat-Related Posttraumatic Stress Disorder: Protocol for a Multimodular Motion-Assisted Memory Desensitization and Reconsolidation Randomized Controlled Trial.

JMIR Res Protoc 2020 Oct 29;9(10):e20620. Epub 2020 Oct 29.

Heroes in Mind, Advocacy and Research Consortium, Faculty of Rehabilitation, University of Alberta, Edmonton, AB, Canada.

Background: Military members are at elevated risk of operational stress injuries, including posttraumatic stress disorder (PTSD) and moral injury. Although psychotherapy can reduce symptoms, some military members may experience treatment-resistant PTSD. Multimodular motion-assisted memory desensitization and reconsolidation (3MDR) has been introduced as a virtual reality (VR) intervention for military members with PTSD related to military service. The 3MDR intervention incorporates exposure therapy, psychotherapy, eye movement desensitization and reconsolidation, VR, supportive counselling, and treadmill walking.

Objective: The objective of this study is to investigate whether 3MDR reduces PTSD symptoms among military members with combat-related treatment-resistant PTSD (TR-PTSD); examine the technology acceptance and usability of the Computer Assisted Rehabilitation ENvironment (CAREN) and 3MDR interventions by Canadian Armed Forces service members (CAF-SMs), veterans, 3MDR clinicians, and operators; and evaluate the impact on clinicians and operators of delivering 3MDR.

Methods: This is a mixed-methods waitlist controlled crossover design randomized controlled trial. Participants include both CAF-SMs and veterans (N=40) aged 18-60 years with combat-related TR-PTSD (unsuccessful experience of at least 2 evidence-based trauma treatments). Participants will also include clinicians and operators (N=12) who have been trained in 3MDR and subsequently utilized this intervention with patients. CAF-SMs and veterans will receive 6 weekly 90-minute 3MDR sessions. Quantitative and qualitative data will be collected at baseline and at 1, 3, and 6 months postintervention. Quantitative data collection will include multiomic biomarkers (ie, blood and salivary proteomic and genomic profiles of neuroendocrine, immune-inflammatory mediators, and microRNA), eye tracking, electroencephalography, and physiological data. Data from outcome measures will capture self-reported symptoms of PTSD, moral injury, resilience, and technology acceptance and usability. Qualitative data will be collected from audiovisual recordings of 3MDR sessions and semistructured interviews. Data analysis will include univariate and multivariate approaches, and thematic analysis of treatment sessions and interviews. Machine learning analysis will be included to develop models for the prediction of diagnosis, symptom severity, and treatment outcomes.

Results: This study commenced in April 2019 and is planned to conclude in April 2021. Study results will guide the further evolution and utilization of 3MDR for military members with TR-PTSD and will have utility in treating other trauma-affected populations.

Conclusions: The goal of this study is to utilize qualitative and quantitative primary and secondary outcomes to provide evidence for the effectiveness and feasibility of 3MDR for treating CAF-SMs and veterans with combat-related TR-PTSD. The results will inform a full-scale clinical trial and stimulate development and adaptation of the protocol to mobile VR apps in supervised clinical settings. This study will add to knowledge of the clinical effectiveness of 3MDR, and provide the first comprehensive analysis of biomarkers, technology acceptance and usability, moral injury, resilience, and the experience of clinicians and operators delivering 3MDR.

Trial Registration: ISRCTN Registry 11264368; http://www.isrctn.com/ISRCTN11264368.

International Registered Report Identifier (irrid): DERR1-10.2196/20620.
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http://dx.doi.org/10.2196/20620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661230PMC
October 2020

An Open-Label Feasibility Trial Examining the Effectiveness of a Cognitive Training Program, Goal Management Training, in Individuals With Posttraumatic Stress Disorder.

Chronic Stress (Thousand Oaks) 2019 Jan-Dec;3:2470547019841599. Epub 2019 Apr 18.

Department of Psychology, Neuroscience, and Behaviour, McMaster University, Hamilton, Ontario, Canada.

Background: Posttraumatic stress disorder (PTSD) is associated with dysfunction across multiple cognitive domains including executive functioning, attention, and verbal memory. This dysfunction is associated with negative impacts on functional outcomes (e.g., work or social functioning) and reduced response to psychotherapy for PTSD. Despite this knowledge, little work has investigated the efficacy of cognitive remediation strategies in improving cognition and functional outcomes among individuals with PTSD.

Objective: The current study investigated the efficacy of an established cognitive remediation program, Goal Management Training (GMT), in improving cognitive functioning in a pilot sample of individuals with PTSD symptoms in an inpatient treatment setting.

Method: Thirty-four inpatients with PTSD symptoms participated in either GMT in addition to treatment as usual (TAU; consisting of psychiatric management, group and individual psychotherapy) (TAU+GMT;  = 18) or TAU alone (16). The TAU+GMT group received neuropsychological assessment at baseline and posttreatment, while both the TAU+GMT and TAU groups received assessment with clinical self-report measures at baseline and posttreatment.

Results: Paired-sample t-tests revealed significant improvements on measures of executive functioning (e.g., response inhibition, cognitive flexibility), processing speed, sustained attention, and verbal memory in the TAU+GMT group. Mixed-design analyses of variance (ANOVAs) revealed a trend toward an interaction effect indicating potentially greater improvements on a measure of the ability to engage in goal-directed behaviors while highly emotional in the TAU+GMT group as compared to the TAU group.

Discussion: The results of this small feasibility investigation of GMT in PTSD point toward the potential efficacy of GMT in ameliorating cognitive difficulties in individuals with PTSD.
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http://dx.doi.org/10.1177/2470547019841599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219918PMC
April 2019

An investigation of plasma interleukin-6 in sport-related concussion.

PLoS One 2020 28;15(4):e0232053. Epub 2020 Apr 28.

Faculty of Kinesiology & Physical Education, University of Toronto, Toronto, ON, Canada.

Background: Increasing evidence suggests inflammation is an important component of concussion pathophysiology. However, its etiology, restitution, and potential clinical repercussions remain unknown. The purpose of the current study was to compare the blood concentrations of interleukin (IL) -6, a prominent inflammatory cytokine, between healthy athletes and athletes with a sport-related concussion (SRC), while addressing the potential confounds of sex, recent physical activity, and the interacting effect of concussion history.

Method: A prospective, observational cohort study was conducted on athletes at a single academic institute participating across 13 interuniversity sports. Follow-up of 96 athletes who agreed to provide a blood sample was completed: 41 athletes with a physician diagnosed SRC, and 55 healthy athletes. Ella™, the high sensitivity immunoassay system by ProteinSimple was used to measure peripheral plasma concentrations of IL-6 within the first week (median = 4 days, range = 2-7) following injury. A resampled ordinary least squares regression was used to evaluate the relationship between IL-6 concentrations and concussion status, while partial least squares regression was used to evaluate the relationship between IL-6 and both symptom burden and time to clinical recovery.

Results: Regression analysis identified a negative relationship between plasma IL-6 concentrations and the interaction between an acute SRC and a history of concussion (β = -0.29, p = 0.029). IL-6 did not differ between healthy athletes and those with an acute SRC independent of concussion history, and was not correlated with either recovery time or symptom burden in athletes with SRC.

Conclusion: Perturbations to circulating IL-6 concentrations, a key inflammatory cytokine, may be more pronounced following SRC in athletes who have a history of concussion. These results add to a growing body of evidence supporting the involvement of inflammation at all phases of recovery following SRC, and potentially support a concomitant effect of prior concussion on acute SRC pathophysiology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188239PMC
July 2020

The relationship between symptom burden and systemic inflammation differs between male and female athletes following concussion.

BMC Immunol 2020 03 12;21(1):11. Epub 2020 Mar 12.

Faculty of Kinesiology & Physical Education, University of Toronto, 55 Harbord St., Toronto, ON, M5S 2W6, Canada.

Background: Inflammation appears to be an important component of concussion pathophysiology. However, its relationship to symptom burden is unclear. Therefore, the purpose of this study was to evaluate the relationship between symptoms and inflammatory biomarkers measured in the blood of male and female athletes following a sport-related concussion (SRC).

Results: Forty athletes (n = 20 male, n = 20 female) from nine interuniversity sport teams at a single institution provided blood samples within one week of an SRC. Twenty inflammatory biomarkers were quantitated by immunoassay. The Sport Concussion Assessment Tool version 5 (SCAT-5) was used to evaluate symptoms. Partial least squares (PLS) analyses were used to evaluate the relationship(s) between biomarkers and symptoms. In males, a positive correlation between interferon (IFN)-γ and symptom severity was observed following SRC. The relationship between IFN-γ and symptoms was significant among all symptom clusters, with cognitive symptoms displaying the largest effect. In females, a significant negative relationship was observed between symptom severity and cytokines IFN-γ, tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO); a positive relationship was observed between symptom severity and MCP-4. Inflammatory mediators were significantly associated with all symptom clusters in females; the somatic symptom cluster displayed the largest effect.

Conclusion: These results provide supportive evidence of a divergent relationship between inflammation and symptom burden in male and female athletes following SRC. Future investigations should be cognizant of the potentially sex-specific pathophysiology underlying symptom presentation.
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http://dx.doi.org/10.1186/s12865-020-0339-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068899PMC
March 2020

Blunted Nocturnal Salivary Melatonin Secretion Profiles in Military-Related Posttraumatic Stress Disorder.

Front Psychiatry 2019 6;10:882. Epub 2019 Dec 6.

Defence Research & Development Canada, Toronto Research Centre, Operational Health and Performance Section, Toronto, ON, Canada.

Sleep disturbances are a hallmark of posttraumatic stress disorder (PTSD), yet few studies have evaluated the role of dysregulated endogenous melatonin secretion in this condition. This study compared the sleep quality and nocturnal salivary melatonin profiles of Canadian Armed Forces (CAF) personnel diagnosed with PTSD, using the Clinician Administered PTSD Scale (CAPS score ≥50), with two healthy CAF control groups; comprising, a "light control" (LC) group with standardized evening light exposure and "normal control" (NC) group without light restriction. Participants were monitored for 1-week using wrist actigraphy to assess sleep quality, and 24-h salivary melatonin levels were measured (every 2h) by immunoassay on the penultimate day in a dim-light (< 5 lux) laboratory environment. A repeated measures design showed that mean nocturnal melatonin concentrations for LC were higher than both NC (p = .03) and PTSD (p = .003) with no difference between PTSD and NC. Relative to PTSD, NC had significantly higher melatonin levels over a 4-h period (01 to 05 h), whereas the LC group had higher melatonin levels over an 8-h period (23 to 07 h). Actigraphic sleep quality parameters were not different between healthy controls and PTSD patients, likely due to the use of prescription sleep medications in the PTSD group. These results indicate that PTSD is associated with blunted nocturnal melatonin secretion, which is consistent with previous findings showing lower melatonin after exposure to trauma and suggestive of severe chronodisruption. Future studies targeting the melatonergic system for therapeutic intervention may be beneficial for treatment-resistant PTSD.
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http://dx.doi.org/10.3389/fpsyt.2019.00882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910089PMC
December 2019

Peripheral blood neuroendocrine hormones are associated with clinical indices of sport-related concussion.

Sci Rep 2019 12 9;9(1):18605. Epub 2019 Dec 9.

Faculty of Kinesiology & Physical Education, University of Toronto, Toronto, ON, Canada.

The purpose of this study was to evaluate the relationship between neuroendocrine hormones and clinical recovery following sport-related concussion (SRC). Ninety-five athletes (n = 56 male, n = 39 female) from a cohort of 11 interuniversity sport teams at a single institution provided blood samples; twenty six athletes with SRC were recruited 2-7 days post-injury, and 69 uninjured athletes recruited prior to the start of their competitive season. Concentrations of seven neuroendocrine hormones were quantitated in either plasma or serum by solid-phase chemiluminescent immunoassay. The Sport Concussion Assessment Tool version 5 (SCAT-5) was used to evaluate symptoms at the time of blood sampling in all athletes. Multivariate partial least squares (PLS) analyses were used to evaluate the relationship between blood hormone concentrations and both (1) time to physician medical clearance and (2) initial symptom burden. A negative relationship was observed between time to medical clearance and both dehydroepiandrosterone sulfate (DHEA-S) and progesterone; a positive relationship was found between time to medical clearance and prolactin. Cognitive, somatic, fatigue and emotion symptom clusters were associated with distinct neuroendocrine signatures. Perturbations to the neuroendocrine system in athletes following SRC may contribute to initial symptom burden and longer recovery times.
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http://dx.doi.org/10.1038/s41598-019-54923-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901546PMC
December 2019

A comparative study of viscoelastic hemostatic assays and conventional coagulation tests in trauma patients receiving fibrinogen concentrate.

Clin Chim Acta 2019 Aug 17;495:253-262. Epub 2019 Apr 17.

Royal Canadian Medical Services, Ottawa, ON, Canada; McGill University, Montreal, QC, Canada.

Background: Both thrombelastography (TEG) and rotational thromboelastometry (ROTEM) have been investigated for diagnosis of coagulopathy and guidance of resuscitation in trauma and surgery. Given similarities between the two systems, it is important to determine whether one is superior to the other and how comparable they are to conventional coagulation tests (CCTs). Therefore, we conducted a comparative study of functional fibrinogen and coagulation assays using TEG and ROTEM and CCTs to determine their capability to monitor coagulation profiles, diagnose coagulopathy and predict blood transfusion requirements in trauma patients.

Methods: Blood samples were collected from 45 patients at admission and during 48-h hospitalization as part of a randomized control trial on early fibrinogen replacement in trauma. Functional fibrinogen (FF) TEG, ROTEM FIBTEM and EXTEM, and CCTs were performed and compared.

Results: We found significant differences between the placebo and fibrinogen groups over hospitalization time in FF TEG MA, ROTEM CT, MCF and LI30. FF TEG MA and ROTEM FIBTEM MCF mirrored plasma fibrinogen profiles, reached a maximum difference between the two groups 1-3 h after fibrinogen administration. In comparison, CCTs detected minimal hemostatic changes by fibrinogen treatment. TEG and ROTEM showed various degrees of correlations with CCTs. TEG MA and ROTEM MCF provided better predictions for plasma and RBC transfusions than CCTs, but poor accuracy for cryoprecipitate transfusion. Both TEG and ROTEM well predicted hypofibrinogenemia (fibrinogen concentration < 1 g/L), but poorly detected coagulopathy (INR ≥ 1.2).

Conclusions: TEG and ROTEM detected increases in clot strength following early use of fibrinogen. ROTEM also detected changes in coagulation time and clot lysis. Both were better than CCTs for monitoring coagulation profiles and predicting transfusion requirements.
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http://dx.doi.org/10.1016/j.cca.2019.04.066DOI Listing
August 2019

The relation between adverse childhood experiences and moral injury in the Canadian Armed Forces.

Eur J Psychotraumatol 2019 17;10(1):1546084. Epub 2019 Jan 17.

Mood Disorders Program, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.

: There is increasing evidence that moral injuries (MIs) may affect the mental health of Canadian Armed Forces (CAF) members and veterans. Despite knowledge suggesting that MIs are related to multiple negative mental health outcomes, including the onset of post-traumatic stress disorder (PTSD), it is unknown whether pre-traumatic variables, including the presence of childhood abuse, are related to MIs. : This study seeks to investigate the potential relationship between adverse childhood experiences and later onset MI in military members. : Thirty-three patients newly admitted to an inpatient unit for treatment of trauma-related disorders received a standardized self-assessment package, including the PTSD Checklist for DSM-5 (PCL-5), the Moral Injury Events Scale (MIES; adapted for the Canadian context), and the Adverse Childhood Experiences Questionnaire (ACE-Q), which is a retrospective measure of childhood abuse. : Analyses revealed a significant relation between childhood emotional abuse and the presence of MI in adulthood. Specifically, emotional abuse during childhood was correlated with total score on the MIES ( = 0.006) and with its two subscales, perceived betrayals ( = 0.022) and perceived transgressions ( = 0.016). These correlations remained significant when controlling for age and gender. : Among CAF members and veterans, childhood events are related to the presence of MI during adulthood. These preliminary data are provocative in suggesting that emotional abuse during childhood may increase the likelihood of endorsing MI during adult military service. Further work is needed to identify pre-traumatic variables that may serve to increase risk or enhance resilience to the development of MI in military members.
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http://dx.doi.org/10.1080/20008198.2018.1546084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338272PMC
January 2019

Evidence of a distinct peripheral inflammatory profile in sport-related concussion.

J Neuroinflammation 2019 Jan 26;16(1):17. Epub 2019 Jan 26.

Faculty of Kinesiology & Physical Education, University of Toronto, Toronto, ON, Canada.

Background: Inflammation is considered a hallmark of concussion pathophysiology in experimental models, yet is understudied in human injury. Despite the growing use of blood biomarkers in concussion, inflammatory biomarkers have not been well characterized. Furthermore, it is unclear if the systemic inflammatory response to concussion differs from that of musculoskeletal injury. The purpose of this paper was to characterize systemic inflammation after injury in athletes with sport-related concussion or musculoskeletal injury.

Methods: A prospective, observational cohort study was conducted employing 175 interuniversity athletes (sport-related concussion, n = 43; musculoskeletal injury, n = 30; healthy, n = 102) from 12 sports at a sports medicine clinic at an academic institution. High-sensitivity immunoassay was used to evaluate 20 inflammatory biomarkers in the peripheral blood of athletes within 7 days of injury (subacute) and at medical clearance. Healthy athletes were sampled prior to the start of their competitive season. Partial least squares regression analyses were used to identify salient biomarker contributions to class separation between injured and healthy athletes, as well as to evaluate the relationship between biomarkers and days to recovery in injured athletes.

Results: In the subacute period after injury, compared to healthy athletes, athletes with sport-related concussion had higher levels of the chemokines' monocyte chemoattractant protein-4 (p < 0.001) and macrophage inflammatory protein-1β (p = 0.001); athletes with musculoskeletal injury had higher levels of thymus and activation-regulated chemokine (p = 0.001). No significant differences in biomarker profiles were observed at medical clearance. Furthermore, concentrations of monocyte chemoattractant protein-1 (p = 0.007) and monocyte chemoattractant protein-4 (p < 0.001) at the subacute time point were positively correlated with days to recovery in athletes with sport-related concussion, while thymus and activation-regulated chemokine was (p = 0.001) positively correlated with days to recovery in athletes with musculoskeletal injury.

Conclusion: Sport-related concussion is associated with perturbations to systemic inflammatory chemokines that differ from those observed in athletes with a musculoskeletal injury. These results support inflammation as an important facet of secondary injury after sport-related concussion that can be measured systemically in a human model of injury.
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http://dx.doi.org/10.1186/s12974-019-1402-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347801PMC
January 2019

High-Intensity Interval Training Is Associated With Alterations in Blood Biomarkers Related to Brain Injury.

Front Physiol 2018 28;9:1367. Epub 2018 Sep 28.

Defence Research and Development Canada, Toronto Research Centre, Toronto, ON, Canada.

Blood biomarkers are a useful tool to study concussion. However, their interpretation is complicated by a number of potential biological confounds, including exercise. This is particularly relevant in military and athletic settings where injury commonly occurs during physical exertion. The impact of high-intensity interval training (HIIT) on putative brain injury biomarkers remains under-examined. The purpose of this study was to observe the effects of HIIT on a panel of blood biomarkers associated with brain injury. Eleven healthy, recreationally active males (median age = 29.0, interquartile range = 26.0-31.5) performed HIIT on a bicycle ergometer (8-12 × 60-s intervals at 100% of peak power output, interspersed by 75-s recovery at 50 W) three times/week for 2 weeks. Peripheral blood samples were collected before and immediately after HIIT during the first and last training sessions. Plasma concentrations of s100 calcium-binding protein beta (S100B), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), neurogranin (NRGN), peroxiredoxin (PRDX)-6, creatine kinase-BB isoenzyme (CKBB), visinin-like protein (VILIP)-1, von Willebrand factor (vWF), monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase (MMP)-9, and total tau (T-tau) were quantitated by high-sensitivity MULTI-SPOT immunoassay, on the MesoScale Diagnostics electrochemiluminescence detection platform. Differences in biomarker concentrations in response to HIIT were evaluated by partial least squares discriminant analysis (PLSDA) within a repeated-measures bootstrapped framework. Ten of 12 biomarkers were increased pre-to-post HIIT; VILIP-1 remained unchanged, and GFAP was not statistically evaluated due to insufficient detectability. After 2 weeks of HIIT, T-tau was no longer significantly elevated pre-to-post HIIT, and significant attenuation was noted in the acute responses of NRGN, PRDX-6, MMP-9, and vWF. In addition, compared to session 1, session 6 pre-exercise concentrations of NSE and VILIP-1 were significantly lower and higher, respectively. Blood biomarkers commonly associated with brain injury are significantly elevated in response to a single bout of HIIT. After a 2-week, six-session training protocol, this response was attenuated for some, but not all markers. While biomarkers continue to provide promise to concussion research, future studies are necessary to disentangle the common biological sequelae to both exercise and brain injury.
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http://dx.doi.org/10.3389/fphys.2018.01367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172320PMC
September 2018

Blood biomarkers are associated with brain function and blood flow following sport concussion.

J Neuroimmunol 2018 06 18;319:1-8. Epub 2018 Mar 18.

Faculty of Kinesiology & Physical Education, University of Toronto, Toronto, ON, Canada; Neuroscience Program, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada; Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada. Electronic address:

Background: Secondary injury pathophysiology after sport-related concussion (SRC) is poorly understood. Blood biomarkers may be a useful tool for characterizing these processes, yet there are limitations in their application as a single modality. Combining blood biomarker analysis with advanced neuroimaging may help validate their continued utility in brain injury research by elucidating important secondary injury mechanisms. Hence, the purpose of this study was to evaluate co-modulation between peripheral blood biomarkers and advanced functional brain imaging after SRC.

Methods: Forty-three university level athletes from 7 sports were recruited (16 recently concussed athletes; 15 healthy athletes with no prior history of concussion; 12 healthy athletes with a history of concussion). Seven blood biomarkers were evaluated: s100B, total tau (T-tau), von Willebrand factor (vWF), brain derived neurotrophic factor (BDNF), peroxiredoxin (PRDX)-6, monocyte chemoattractant protein (MCP)-1 and -4. Resting-state functional MRI was employed to assess global neural connectivity (Gconn), and arterial spin labelling was used to evaluate cerebral blood flow (CBF). We tested for concurrent alterations in blood biomarkers and MRI measures of brain function between athlete groups using a non-parametric, bootstrapped resampling framework.

Results: Compared to healthy athletes, recently concussed athletes showed greater concurrent alterations in several peripheral blood biomarker and MRI measures: a decrease in T-Tau and Gconn, a decrease in T-Tau and CBF, a decrease in Gconn with elevated PRDX-6, a decrease in CBF with elevated PRDX-6, and a decrease in Gconn with elevated MCP-4. In addition, compared to healthy athletes with no concussion history, healthy athletes with a history of concussion displayed greater concurrent alterations in blood biomarkers and Gconn; lower GConn covaried with higher blood levels of s100B and MCP-4.

Conclusion: We identified robust relationships between peripheral blood biomarkers and MRI measures in both recently concussed athletes and healthy athletes with a history of concussion. The results from this combinatorial approach further support that human concussion is associated with inflammation, oxidative stress, and cellular damage, and that physiological perturbations may extend chronically beyond recovery. Finally, our results support the continued implementation of blood biomarkers as a tool to investigate brain injury, particularly in a multimodal framework.
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http://dx.doi.org/10.1016/j.jneuroim.2018.03.002DOI Listing
June 2018

Biological Response to Stress During Battlefield Trauma Training: Live Tissue Versus High-Fidelity Patient Simulator.

Mil Med 2018 09;183(9-10):e349-e356

McGill University, Montreal, QC, Canada.

Introduction: Tactical Combat Casualty Care (TCCC) training imposes psychophysiological stress on medics. It is unclear whether these stress levels vary with the training modalities selected. It is also unclear how stress levels could have an impact on medical performance and skill uptake.

Materials And Methods: We conducted a pilot study to compare the effects of live tissue (LT) with a high-fidelity patient simulator (SIM) on the level of stress elicited, performance, and skill uptake during battlefield trauma training course in an operating room (OR) and in a simulated battlefield scenario (field). In the report, we studied the effects of training modalities and their changes on stress levels by measuring different biomarkers (salivary amylase, plasma catecholamines, and neuropeptide Y) at various time points during the trauma training course.

Results: We found that the training resulted in significant psychophysiological stress as indicated by elevated levels of various biomarkers relative to baseline immediately after both OR and field assessment (p < 0.05). Compared with pre-OR levels, the LT training in the OR resulted in significant increases in the plasma levels of epinephrine, norepinephrine, and neuropeptide (p = 0.013, 0.023, 0.004, respectively), whereas the SIM training in the OR resulted in significant increases in the plasma levels of norepinephrine and neuropeptide (p = 0.003 and 0.008). Compared with pre-field levels, we found significant increases in plasma epinephrine concentration in the SIM group (p = 0.016), plasma norepinephrine concentration in the LT group (p = 0.015), and plasma neuropeptide Y concentration in both LT (p = 0.006) and SIM groups (p = 0.029). No differences in the changes of biomarker levels were found between LT and SIM groups in the OR and field. Compared with pre-field levels, the testing on the same modality as that in the OR in the simulated battlefield resulted in significant increases in norepinephrine and neuropeptide levels (p = 0.013 and 0.015), whereas the testing on different modalities resulted in significant increases in amylase, epinephrine, and neuropeptide levels (p = 0.016, 0.05, 0.018, respectively). There was a significantly larger increase in plasma norepinephrine concentration (p = 0.031) and a trend toward a greater increase in the salivary amylase level (p = 0.052) when the field testing involved a different modality than the OR compared with when OR and field testing involved the same modality. Although most of the biomarkers returned to baseline levels after 24 h, plasma norepinephrine levels remained significantly higher regardless of whether field testing occurred on the same or different modality compared with OR (p = 0.040 and 0.002).

Conclusion: TCCC training led to significant increase in psychophysiological stress, as indicated by elevated levels of various biomarkers. The training modalities did not result in any differences in stress levels, whereas the switch in training modalities appeared to elicit greater stress as evidenced by changes in specific biomarkers (amylase and norepinephrine). A comparative study with a larger sample size is warranted.
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http://dx.doi.org/10.1093/milmed/usx236DOI Listing
September 2018

An investigation of neuroinjury biomarkers after sport-related concussion: from the subacute phase to clinical recovery.

Brain Inj 2018 8;32(5):575-582. Epub 2018 Feb 8.

c Faculty of Kinesiology & Physical Education , University of Toronto , Toronto , ON , Canada.

Objectives: To characterise a panel of neuroinjury-related blood biomarkers after sport-related concussion (SRC). We hypothesised significant differences in biomarker profiles between athletes with SRC and healthy controls at both subacute and medical clearance time points.

Methods: Thirty-eight interuniversity athletes were recruited over two athletic seasons (n = 19 SRC; n = 19 healthy matched-control). High-sensitivity immunoassay was used to evaluate 11 blood analytes at both the subacute phase after SRC and at medical clearance.

Results: Univariate analysis identified elevated circulating peroxiredoxin-6 (PRDX-6) in athletes with SRC compared to healthy controls at the subacute time point. Multivariate analyses yielded similar results in the subacute phase, but identified both PRDX-6 and T-tau as significant contributors to class separation between athletes with SRC and controls at medical clearance.

Conclusions: Our results are consistent with the increasing recognition that physiological recovery after SRC extends beyond clinical recovery. Blood biomarkers appear to be useful in elucidating the biology of brain restitution after SRC. However, their implementation requires mindfulness of factors such as academic stress, exercise, and injury heterogeneity.
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http://dx.doi.org/10.1080/02699052.2018.1432892DOI Listing
May 2019

Systematic Review of Human and Animal Studies Examining the Efficacy and Safety of Acetylcysteine (NAC) and Acetylcysteine Amide (NACA) in Traumatic Brain Injury: Impact on Neurofunctional Outcome and Biomarkers of Oxidative Stress and Inflammation.

Front Neurol 2017 15;8:744. Epub 2018 Jan 15.

Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

Background: No new therapies for traumatic brain injury (TBI) have been officially translated into current practice. At the tissue and cellular level, both inflammatory and oxidative processes may be exacerbated post-injury and contribute to further brain damage. acetylcysteine (NAC) has the potential to downregulate both processes. This review focuses on the potential neuroprotective utility of NAC and -acetylcysteine amide (NACA) post-TBI.

Methods: Medline, Embase, Cochrane Library, and ClinicalTrials.gov were searched up to July 2017. Studies that examined clinical and laboratory effects of NAC and NACA post-TBI in human and animal studies were included. Risk of bias was assessed in human and animal studies according to the design of each study (randomized or not). The primary outcome assessed was the effect of NAC/NACA treatment on functional outcome, while secondary outcomes included the impact on biomarkers of inflammation and oxidation. Due to the clinical and methodological heterogeneity observed across studies, no meta-analyses were conducted.

Results: Our analyses revealed only three human trials, including two randomized controlled trials (RCTs) and 20 animal studies conducted using standardized animal models of brain injury. The two RCTs reported improvement in the functional outcome post-NAC/NACA administration. Overall, the evidence from animal studies is more robust and demonstrated substantial improvement of cognition and psychomotor performance following NAC/NACA use. Animal studies also reported significantly more cortical sparing, reduced apoptosis, and lower levels of biomarkers of inflammation and oxidative stress. No safety concerns were reported in any of the studies included in this analysis.

Conclusion: Evidence from the animal literature demonstrates a robust association for the prophylactic application of NAC and NACA post-TBI with improved neurofunctional outcomes and downregulation of inflammatory and oxidative stress markers at the tissue level. While a growing body of scientific literature suggests putative beneficial effects of NAC/NACA treatment for TBI, the lack of well-designed and controlled clinical investigations, evaluating therapeutic outcomes, prognostic biomarkers, and safety profiles, limits definitive interpretation and recommendations for its application in humans at this time.
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http://dx.doi.org/10.3389/fneur.2017.00744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776005PMC
January 2018

Human hair follicle transcriptome profiling: a minimally invasive tool to assess molecular adaptations upon low-volume, high-intensity interval training.

Physiol Rep 2017 Dec;5(23)

Chemistry and Chemical Engineering Department, Royal Military College of Canada, Kingston, ON, Canada.

High-intensity interval training (HIIT) has become a popular fitness training approach under both civilian and military settings. Consisting of brief and intense exercise intervals, HIIT requires less time commitment yet is able to produce the consistent targeted physical adaptations as conventional endurance training. To effectively characterize and monitor HIIT-induced cellular and molecular responses, a highly accessible yet comprehensive biomarker discovery source is desirable. Both gene differential expression (DE) and gene set (GS) analyses were conducted using hair follicle transcriptome established from pre and postexercise subjects upon a 10-day HIIT program by RNA-Seq, Comparing between pre and posttraining groups, differentially expressed protein coding genes were identified. To interpret the functional significance of the DE results, a comprehensive GS analysis approach featuring multiple algorithms was used to enrich gene ontology (GO) terms and KEGG pathways. The GS analysis revealed enriched themes such as energy metabolism, cell proliferation/growth/survival, muscle adaptations, and cytokine-cytokine interaction, all of which have been previously proposed as HIIT responses. Moreover, related cell signaling pathways were also measured. Specifically, G-protein-mediated signal transduction, phosphatidylinositide 3-kinases (PI3K) - protein kinase B (PKB) and Janus kinase (JAK) - Signal Transducer and Activator of Transcription (STAT) signaling cascades were over-represented. Additionally, the RNA-Seq analysis also identified several HIIT-responsive microRNAs (miRNAs) that were involved in regulating hair follicle-specific processes, such as For the first time, this study demonstrated that both existing and new biomarkers like miRNA can be explored for HIIT using the transcriptomic responses exhibited by the hair follicle.
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http://dx.doi.org/10.14814/phy2.13534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727284PMC
December 2017

Disturbed EEG sleep, paranoid cognition and somatic symptoms identify veterans with post-traumatic stress disorder.

BJPsych Open 2016 Nov 9;2(6):359-365. Epub 2016 Nov 9.

, MD, FRCPC, Operational Stress Injury Clinic, Parkwood Hospital, London, Ontario, Canada; Department of Psychiatry, Western University, London, Ontario, Canada; Department of Psychiatry & Behavioral Neuroscience, McMaster University, Hamilton, Ontario, Canada.

Background: Chronic post-traumatic stress disorder (PTSD) behavioural symptoms and medically unexplainable somatic symptoms are reported to occur following the stressful experience of military combatants in war zones.

Aims: To determine the contribution of disordered EEG sleep physiology in those military combatants who have unexplainable physical symptoms and PTSD behavioural difficulties following war-zone exposure.

Method: This case-controlled study compared 59 veterans with chronic sleep disturbance with 39 veterans with DSM-IV and clinician-administered PTSD Scale diagnosed PTSD who were unresponsive to pharmacological and psychological treatments. All had standardised EEG polysomnography, computerised sleep EEG cyclical alternating pattern (CAP) as a measure of sleep stability, self-ratings of combat exposure, paranoid cognition and hostility subscales of Symptom Checklist-90, Beck Depression Inventory and the Wahler Physical Symptom Inventory. Statistical group comparisons employed linear models, logistic regression and chi-square automatic interaction detection (CHAID)-like decision trees.

Results: Veterans with PTSD were more likely than those without PTSD to show disturbances in non-rapid eye movement (REM) and REM sleep including delayed sleep onset, less efficient EEG sleep, less stage 4 (deep) non-REM sleep, reduced REM and delayed onset to REM. There were no group differences in the prevalence of obstructive sleep apnoeas/hypopnoeas and periodic leg movements, but sleep-disturbed, non-PTSD military had more EEG CAP sleep instability. Rank order determinants for the diagnosis of PTSD comprise paranoid thinking, onset to REM sleep, combat history and somatic symptoms. Decision-tree analysis showed that a specific military event (combat), delayed onset to REM sleep, paranoid thinking and medically unexplainable somatic pain and fatigue characterise chronic PTSD. More PTSD veterans reported domestic and social misbehaviour.

Conclusions: Military combat, disturbed REM/non-REM EEG sleep, paranoid ideation and medically unexplained chronic musculoskeletal pain and fatigue are key factors in determining PTSD disability following war-zone exposure.

Declaration Of Interest: None.

Copyright And Usage: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.
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http://dx.doi.org/10.1192/bjpo.bp.116.003483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609777PMC
November 2016

Catecholamines as outcome markers in isolated traumatic brain injury: the COMA-TBI study.

Crit Care 2017 Feb 23;21(1):37. Epub 2017 Feb 23.

St. Michael's Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada.

Background: Elevated catecholamine levels might be associated with unfavorable outcome after traumatic brain injury (TBI). We investigated the association between catecholamine levels in the first 24 h post-trauma and functional outcome in patients with isolated moderate-to-severe TBI.

Methods: A cohort of 174 patients who sustained isolated blunt TBI was prospectively enrolled from three Level-1 Trauma Centers. Epinephrine (Epi) and norepinephrine (NE) concentrations were measured at admission (baseline), 6, 12 and 24 h post-injury. Outcome was assessed at 6 months by the extended Glasgow Outcome Scale (GOSE) score. Fractional polynomial plots and logistic regression models (fixed and random effects) were used to study the association between catecholamine levels and outcome. Effect size was reported as the odds ratio (OR) associated with one logarithmic change in catecholamine level.

Results: At 6 months, 109 patients (62.6%) had an unfavorable outcome (GOSE 5-8 vs. 1-4), including 51 deaths (29.3%). Higher admission levels of Epi were associated with a higher risk of unfavorable outcome (OR, 2.04, 95% CI: 1.31-3.18, p = 0.002) and mortality (OR, 2.86, 95% CI: 1.62-5.01, p = 0.001). Higher admission levels of NE were associated with higher risk of unfavorable outcome (OR, 1.59, 95% CI: 1.07-2.35, p = 0.022) but not mortality (OR, 1.45, 95% CI: 0.98-2.17, p = 0.07). There was no relationship between the changes in Epi levels over time and mortality or unfavorable outcome. Changes in NE levels with time were statistically associated with a higher risk of mortality, but the changes had no relation to unfavorable outcome.

Conclusions: Elevated circulating catecholamines, especially Epi levels on hospital admission, are independently associated with functional outcome and mortality after isolated moderate-to-severe TBI.
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http://dx.doi.org/10.1186/s13054-017-1620-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322658PMC
February 2017

Biomarkers of Glycocalyx Injury are Associated with Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Case Series Supporting a New Hypothesis.

Neurocrit Care 2017 Jun;26(3):339-347

Division of Critical Care Medicine, Department of Anesthesia, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.

Background: Delayed cerebral ischemia (DCI) contributes to morbidity following aneurysmal subarachnoid hemorrhage; however, its etiology remains poorly understood. DCI is not only a consequence of angiographic vasospasm, but also involves microthrombosis and neuroinflammation, two events with unexplained phenomenology. The vascular endothelial glycocalyx mediates platelet aggregation and endothelial cell-leukocyte interactions and may play an important role in DCI pathogenesis.

Methods: We present a case series in which we conducted multiplex and singlet enzyme-linked immunosorbent assays of endothelial, glycocalyx, inflammatory, and neuroinjury proteins in both CSF and plasma in three patients during active DCI following SAH. Samples were obtained at baseline following surgical repair of SAH, and again at DCI onset. CSF was sampled at the same time points from in situ external ventricular drains.

Results: DCI was associated with significant elevations of soluble markers of endotheliopathy, including vascular adhesion protein-1, soluble fractions of endothelial cell adhesion molecules (CAMs), procoagulant tissue factor, and specific markers of glycocalyx injury, including syndecan-1, and CD44. These phenomena were also associated with an elevation of both circulating and CSF matrix metalloproteinases, which are known to cleave components of the glycocalyx. Elevation of vascular CAM-1 in the CSF with DCI indicated these events were possibly associated with the breakdown of brain microvasculature integrity.

Conclusions: These preliminary data support the hypothesis that glycocalyx injury occurs in SAH, and might contribute to DCI by regulating cerebral microthrombosis and delayed neuroinflammation.
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http://dx.doi.org/10.1007/s12028-016-0357-4DOI Listing
June 2017

Altered Blood Biomarker Profiles in Athletes with a History of Repetitive Head Impacts.

PLoS One 2016 26;11(7):e0159929. Epub 2016 Jul 26.

Faculty of Kinesiology & Physical Education, University of Toronto, Toronto ON, Canada.

The long-term health effects of concussion and sub-concussive impacts in sport are unknown. Growing evidence suggests both inflammation and neurodegeneration are pivotal to secondary injury processes and the etiology of neurodegenerative diseases. In the present study we characterized circulating brain injury and inflammatory mediators in healthy male and female athletes according to concussion history and collision sport participation. Eighty-seven university level athletes (male, n = 60; female, n = 27) were recruited before the start of the competitive season. Athletes were healthy at the time of the study (no medications, illness, concussion or musculoskeletal injuries). Dependent variables included 29 inflammatory and 10 neurological injury analytes assessed in the peripheral blood by immunoassay. Biomarkers were statistically evaluated using partial least squares multivariate analysis to identify possible relationships to self-reported previous concussion history, number of previous concussions and collision sport participation in male and female athletes. Multiple concussions were associated with increases in peripheral MCP-1 in females, and MCP-4 in males. Collision sport participation was associated with increases in tau levels in males. These results are consistent with previous experimental and clinical findings that suggest ongoing inflammatory and cerebral injury processes after repetitive mild head trauma. However, further validation is needed to correlate systemic biomarkers to repetitive brain impacts, as opposed to the extracranial effects common to an athletic population such as exercise and muscle damage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159929PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961456PMC
July 2017

Sympathoadrenal Activation is Associated with Acute Traumatic Coagulopathy and Endotheliopathy in Isolated Brain Injury.

Shock 2016 09;46(3 Suppl 1):96-103

*Defence Research and Development Canada, Toronto Research Centre, Toronto, Ontario, Canada †Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada ‡Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada §Department of Critical Care, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada ¶Department of Anesthesia and Surgery, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada ||Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, Ontario, Canada **Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada ††Division of Trauma and Critical Care, University of Southern California, Los Angeles, California ‡‡LA County and USC Medical Center, Los Angeles, California §§Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada ¶¶Canadian Forces Health Services, The 1 Canadian Field Hospital, Petawawa, Ontario, and The Trauma Program, McGill University Health Centre, Montréal, Quebec, Canada.

Background: Acute coagulopathy after traumatic brain injury (TBI) involves a complex multifactorial hemostatic response that is poorly characterized.

Objectives: To examine early posttraumatic alterations in coagulofibrinolytic, endothelial, and inflammatory blood biomarkers in relation to sympathetic nervous system (SNS) activation and 6-month patient outcomes, using multivariate partial least-squares (PLS) analysis.

Patients And Methods: A multicenter observational study of 159 adult isolated TBI patients admitted to the emergency department at an urban level I trauma center, was performed. Plasma concentrations of 6 coagulofibrinolytic, 10 vascular endothelial, 19 inflammatory, and 2 catecholamine biomarkers were measured by immunoassay on admission and 24 h postinjury. Neurological outcome at 6 months was assessed using the Extended Glasgow Outcome Scale. PLS-discriminant analysis was used to identify salient biomarker contributions to unfavorable outcome, whereas PLS regression analysis was used to evaluate the covariance between SNS correlates (catecholamines) and biomarkers of coagulopathy, endotheliopathy, and inflammation.

Results: Biomarker profiles in patients with an unfavorable outcome displayed procoagulation, hyperfibrinolysis, glycocalyx and endothelial damage, vasculature activation, and inflammation. A strong covariant relationship was evident between catecholamines and biomarkers of coagulopathy, endotheliopathy, and inflammation at both admission and 24 h postinjury.

Conclusions: Biomarkers of coagulopathy and endotheliopathy are associated with poor outcome after TBI. Catecholamine levels were highly correlated with endotheliopathy and coagulopathy markers within the first 24 h after injury. Further research is warranted to characterize the pathogenic role of SNS-mediated hemostatic alterations in isolated TBI.
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http://dx.doi.org/10.1097/SHK.0000000000000642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978599PMC
September 2016

Inflammatory cytokine and chemokine profiles are associated with patient outcome and the hyperadrenergic state following acute brain injury.

J Neuroinflammation 2016 Feb 16;13:40. Epub 2016 Feb 16.

Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Background: Traumatic brain injury (TBI) elicits intense sympathetic nervous system (SNS) activation with profuse catecholamine secretion. The resultant hyperadrenergic state is linked to immunomodulation both within the brain and systemically. Dysregulated inflammation post-TBI exacerbates secondary brain injury and contributes to unfavorable patient outcomes including death. The aim of this study was to characterize the early dynamic profile of circulating inflammatory cytokines/chemokines in patients admitted for moderate-to-severe TBI, to examine interrelationships between these mediators and catecholamines, as well as clinical indices of injury severity and neurological outcome.

Methods: Blood was sampled from 166 isolated TBI patients (aged 45 ± 20.3 years; 74.7 % male) on admission, 6-, 12-, and 24-h post-injury and from healthy controls (N = 21). Plasma cytokine [interleukin (IL)-1β, -2, -4, -5, -10, -12p70, -13, tumor necrosis factor (TNF)-α, interferon (IFN)-γ] and chemokine [IL-8, eotaxin, eotaxin-3, IFN-γ-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, -4, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1β, thymus activation regulated chemokine (TARC)] concentrations were analyzed using high-sensitivity electrochemiluminescence multiplex immunoassays. Plasma catecholamines [epinephrine (Epi), norepinephrine (NE)] were measured by immunoassay. Neurological outcome at 6 months was assessed using the extended Glasgow outcome scale (GOSE) dichotomized as good (>4) or poor (≤4) outcomes.

Results: Patients showed altered levels of IL-10 and all chemokines assayed relative to controls. Significant differences in a number of markers were evident between moderate and severe TBI cohorts. Elevated IL-8, IL-10, and TNF-α, as well as alterations in 8 of 9 chemokines, were associated with poor outcome at 6 months. Notably, a positive association was found between Epi and IL-1β, IL-10, Eotaxin, IL-8, and MCP-1. NE was positively associated with IL-1β, IL-10, TNF-α, eotaxin, IL-8, IP-10, and MCP-1.

Conclusions: Our results provide further evidence that exaggerated SNS activation acutely after isolated TBI in humans may contribute to harmful peripheral inflammatory cytokine/chemokine dysregulation. These findings are consistent with a potentially beneficial role for therapies aimed at modulating the inflammatory response and hyperadrenergic state acutely post-injury.
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http://dx.doi.org/10.1186/s12974-016-0500-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754875PMC
February 2016
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