Brent Winston - Academia.edu (original) (raw)
Papers by Brent Winston
European journal of medical research, May 14, 2024
Background The Berlin definition of acute respiratory distress syndrome (ARDS) includes only clin... more Background The Berlin definition of acute respiratory distress syndrome (ARDS) includes only clinical characteristics. Understanding unique patient pathobiology may allow personalized treatment. We aimed to define and describe ARDS phenotypes/endotypes combining clinical and pathophysiologic parameters from a Canadian ARDS cohort. Methods A cohort of adult ARDS patients from multiple sites in Calgary, Canada, had plasma cytokine levels and clinical parameters measured in the first 24 h of ICU admission. We used a latent class model (LCM) to group the patients into several ARDS subgroups and identified the features differentiating those subgroups. We then discuss the subgroup effect on 30 day mortality. Results The LCM suggested three subgroups (n 1 = 64, n 2 = 86, and n 3 = 30), and 23 out of 69 features made these subgroups distinct. The top five discriminating features were IL-8, IL-6, IL-10, TNF-a, and serum lactate. Mortality distinctively varied between subgroups. Individual clinical characteristics within the subgroup associated with mortality included mean PaO 2 /FiO 2 ratio, pneumonia, platelet count, and bicarbonate negatively associated with mortality, while lactate, creatinine, shock, chronic kidney disease, vasopressor/ionotropic use, low GCS at admission, and sepsis were positively associated. IL-8 and Apache II were individual markers strongly associated with mortality (Area Under the Curve = 0.84). Perspective ARDS subgrouping using biomarkers and clinical characteristics is useful for categorizing a heterogeneous condition into several homogenous patient groups. This study found three ARDS subgroups using LCM; each subgroup has a different level of mortality. This model may also apply to developing further trial design, prognostication, and treatment selection.
Journal of Proteome Research, Dec 3, 2023
PubMed, Dec 1, 1999
Macrophages are versatile cells found in every tissue in the body. They must perform a number of ... more Macrophages are versatile cells found in every tissue in the body. They must perform a number of diverse cellular functions that allow them to kill invading micro-organisms and neoplastic cells as well as produce growth factors involved in wound healing. Macrophages that develop these diverse functions arise from a common precursor. By a process of selective adaptation, the common precursor monocyte/macrophage differentiates into a distinctive macrophage with a different and specific phenotype, characterized by the expression of a specific set of gene products. The local environment plays a critical role in shaping or directing the pattern or pathway of macrophage differentiation. The authors have focused on 2 specific macrophage differentiation pathways in a murine bone marrow-derived macrophage model. One pathway is believed to play a role in wound repair and is characterized by the induction of insulin-like growth factor-1 (IGF-I). The second pathway is involved in macrophage cytocidal activation and is characterized by the induction of the inducible form of nitric oxide synthase (iNOS). The pleotropic cytokine tumour necrosis factor-alpha (TNF-alpha) appears to mediate macrophage differentiation along both of these pathways. Interferon-gamma (IFN-gamma), however, appears to act as a molecular switch. In the presence of IFN-gamma, stimulation of macrophages with TNF-alpha results in macrophage differentiation along a pathway in which iNOS is expressed, whereas, in the absence of IFN-gamma, stimulation of macrophages with TNF-alpha results in differentiation along a pathway in which IGF-I is expressed. The authors focus on some of the molecular events involved in TNF-alpha and IFN-gamma signal transduction and the regulation of iNOS and IGF-I genes in macrophages.
International Journal of Biochemistry, 1981
ABSTRACT
Critical care, Feb 27, 2024
Rationale Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome... more Rationale Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair. Objective To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis. Methods We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms. Results Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms.
Critical Care
Background Prognostication is very important to clinicians and families during the early manageme... more Background Prognostication is very important to clinicians and families during the early management of severe traumatic brain injury (sTBI), however, there are no gold standard biomarkers to determine prognosis in sTBI. As has been demonstrated in several diseases, early measurement of serum metabolomic profiles can be used as sensitive and specific biomarkers to predict outcomes. Methods We prospectively enrolled 59 adults with sTBI (Glasgow coma scale, GCS ≤ 8) in a multicenter Canadian TBI (CanTBI) study. Serum samples were drawn for metabolomic profiling on the 1st and 4th days following injury. The Glasgow outcome scale extended (GOSE) was collected at 3- and 12-months post-injury. Targeted direct infusion liquid chromatography-tandem mass spectrometry (DI/LC–MS/MS) and untargeted proton nuclear magnetic resonance spectroscopy (1H-NMR) were used to profile serum metabolites. Multivariate analysis was used to determine the association between serum metabolomics and GOSE, dichoto...
Canadian journal of kidney health and disease, 2021
Background: Acute kidney injury (AKI) is a potentially fatal complication of Coronavirus Disease-... more Background: Acute kidney injury (AKI) is a potentially fatal complication of Coronavirus Disease-2019 (COVID-19). Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, to its viral receptor, angiotensin converting enzyme 2 (ACE2), results in viral entry and may cause AKI. Objectives: We performed a systematic review and meta-analysis of the frequencies of AKI and renal replacement therapy (RRT) in critically ill COVID-19 patients and compared those frequencies with patients who were infected by respiratory viruses that bind or downregulate ACE2 (ACE2-associated viruses) and viruses that do not bind nor downregulate ACE2 (non-ACE2-associated viruses). Design: Systematic review and meta-analysis. Setting: Observational studies on COVID-19 and other respiratory viral infections reporting AKI and RRT were included. The exclusion criteria were non-English articles, non-peer-reviewed articles, review articles, studies that included patients under the age of 18, studies including fewer than 10 patients, and studies not reporting AKI and RRT rates. Patients: Adult COVID-19, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and influenza patients. Measurements: We extracted the following data from the included studies: author, year, study location, age, sex, race, diabetes mellitus, hypertension, chronic kidney disease, shock, vasopressor use, mortality, intensive care unit (ICU) admission, ICU mortality, AKI, and RRT. Methods: We systematically searched PubMed and EMBASE for articles reporting AKI or RRT. AKI was defined by authors of included studies. Critical illness was defined by ICU admission. We performed a random effects metaanalysis to calculate pooled estimates for the AKI and RRT rate within each virus group using a random intercept logistic regression model. Results: Of 23 655 hospitalized, critically ill COVID-19 patients, AKI frequencies were not significantly different between COVID-19 patients (51%, 95% confidence interval [CI]: 44%-57%) and critically ill patients infected with ACE2-associated (56%, 95% CI: 37%-74%, P = .610) or non-ACE2-associated viruses (63%, 95% CI: 43%-79%, P = .255). Pooled RRT rates were also not significantly different between critically ill, hospitalized patients with COVID-19 (20%, 95% CI: 16%-24%) and ACE2-associated viruses (18%, 95% CI: 8%-33%, P = .747). RRT rates for both COVID-19 and ACE2-associated viruses were significantly different (P < .001 for both) from non-ACE2-associated viruses (49%, 95% CI: 44%-54%). After adjusting for shock or vasopressor use, AKI and RRT rates were not significantly different between groups. Limitations: Limitations of this study include the heterogeneity of definitions of AKI that were used across different virus studies. We could not match severity of infection or do propensity matching across studies. Most of the included studies were conducted in retrospective fashion. Last, we did not include non-English publications.
Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically... more Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-inhuman trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18-0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-inhuman clinical studies.
Critical Care Medicine, May 18, 2022
OBJECTIVES: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting e... more OBJECTIVES: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are associated with improved outcomes in hospitalized patients with COVID-19 according to sex and to report sex-related differences in renin-angiotensin system (RAS) components. DESIGN: Prospective observational cohort study comparing the effects of ARB or ACE inhibitors versus no ARBs or ACE inhibitors in males versus females. Severe acute respiratory syndrome coronavirus 2 downregulates ACE-2, potentially increasing angiotensin II (a pro-inflammatory vasoconstrictor). Sex-based differences in RAS dysregulation may explain sex-based differences in responses to ARBs because the ACE2 gene is on the X chromosome. We recorded baseline characteristics, comorbidities, prehospital ARBs or ACE inhibitor treatment, use of organ support and mortality, and measured RAS components at admission and days 2, 4, 7, and 14 in a subgroup (n = 46), recorded d-dimer (n = 967), comparing males with females. SETTING: ARBs CORONA I is a multicenter Canadian observational cohort of patients hospitalized with acute COVID-19. This analysis includes patients admitted to 10 large urban hospitals across the four most populated provinces. PATIENTS: One-thousand six-hundred eighty-six patients with polymerase chain reaction-confirmed COVID-19 (February 2020 to March 2021) for acute COVID-19 illness were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Males on ARBs before admission had decreased use of ventilation (adjusted odds ratio [aOR] = 0.52; p = 0.007) and vasopressors (aOR = 0.55; p = 0.011) compared with males not on ARBs or ACE inhibitors. No significant effects were observed in females for these outcomes. The test for interaction was significant for use of ventilation (p = 0.006) and vasopressors (p = 0.044) indicating significantly different responses to ARBs according to sex. Males had significantly higher plasma ACE-1 at baseline and angiotensin II at day 7 and 14 than females. CONCLUSIONS: ARBs use was associated with less ventilation and vasopressors in males but not females. Sex-based differences in RAS dysregulation may contribute to sex-based differences in outcomes and responses to ARBs in COVID-19.
Chest, Jul 1, 1999
Figure 2. DN-MEKK1 inhibits TNF-␣ ϩ IFN-␥ induction of iNOS.
CJC open, Jul 1, 2021
Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
EClinicalMedicine, Feb 1, 2020
Background: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as... more Background: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as this novel therapy continues to be evaluated in clinical trials for various inflammatory conditions. Due to an increase in published randomized controlled trials (RCTs) from 2012À2019, we performed an updated systematic review to further characterize the MSC safety profile. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to May 2018) were searched. RCTs that compared intravascular delivery of MSCs to controls in adult populations were included. Pre-specified adverse events were grouped according to: (1) immediate, (2) infection, (3) thrombotic/embolic, and (4) longer-term events (mortality, malignancy). Adverse events were pooled and meta-analyzed by fitting inverse-variance binary random effects models. Primary and secondary clinical efficacy endpoints were summarized descriptively. Findings: 7473 citations were reviewed and 55 studies met inclusion criteria (n = 2696 patients). MSCs as compared to controls were associated with an increased risk of fever (Relative Risk (RR) = 2¢48, 95% Confidence Interval (CI) = 1¢27À4¢86; I 2 = 0%), but not non-fever acute infusional toxicity, infection, thrombotic/ embolic events, death, or malignancy (RR = 1¢16,
PLOS ONE, Oct 25, 2012
Background: Mesenchymal stromal cells (MSCs, ''adult stem cells'') have been widely used experime... more Background: Mesenchymal stromal cells (MSCs, ''adult stem cells'') have been widely used experimentally in a variety of clinical contexts. There is interest in using these cells in critical illness, however, the safety profile of these cells is not well known. We thus conducted a systematic review of clinical trials that examined the use MSCs to evaluate their safety. Methods and Findings: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (to June 2011), were searched. Prospective clinical trials that used intravascular delivery of MSCs (intravenously or intra-arterially) in adult populations or mixed adult and pediatric populations were identified. Studies using differentiated MSCs or additional cell types were excluded. The primary outcome adverse events were grouped according to immediate events (acute infusional toxicity, fever), organ system complications, infection, and longer term adverse events (death, malignancy). 2347 citations were reviewed and 36 studies met inclusion criteria. A total of 1012 participants with clinical conditions of ischemic stroke, Crohn's disease, cardiomyopathy, myocardial infarction, graft versus host disease, and healthy volunteers were included. Eight studies were randomized control trials (RCTs) and enrolled 321 participants. Meta-analysis of the RCTs did not detect an association between acute infusional toxicity, organ system complications, infection, death or malignancy. There was a significant association between MSCs and transient fever. Conclusions: Based on the current clinical trials, MSC therapy appears safe. However, further larger scale controlled clinical trials with rigorous reporting of adverse events are required to further define the safety profile of MSCs.
Canadian Critical Care Translational Biology Group 7.) Review Objective To systematically review ... more Canadian Critical Care Translational Biology Group 7.) Review Objective To systematically review the effects of MSCs on death, organ dysfunction, inflammation, and pathogen clearance in in-vivo animal models of sepsis 8.) Searches The search strategies outlined below were developed in conjunction with an information specialist. Embase, BIOSIS, MEDLINE, and Web of Science will be searched. The strategy below was used to search in MEDLINE. In addition, a manual review of the bibliographies of eligible studies and relevant review articles will be performed. Relevant conference proceedings and abstracts will also be searched.
Journal of Immunology, Aug 1, 1995
Cross-linking of the dichotomous cell surface receptors for TNF-alpha (CD120a (p55) and CD120b (p... more Cross-linking of the dichotomous cell surface receptors for TNF-alpha (CD120a (p55) and CD120b (p75)) induces the activation of a variety of macrophage responses that mediate the role of this cell in inflammation and host defense. Although significant progress has been made in understanding the role that lipid second messengers play in mediating the action(s) of this multifunctional cytokine, less is known about the role of specific kinases in TNF-alpha-initiated signaling. We show that exposure of mouse macrophages to TNF-alpha stimulates a rapid and transient tyrosine phosphorylation and activation of p42mapk/erk2. By contrast, p44mapk/erk1 was found to be constitutively phosphorylated, with minimal further response to TNF-alpha. To investigate the use of CD120a (p55) and CD120b (p75) in the activation of p42mapk/erk2 in mouse macrophages, we determined the effects of blocking Ab on the activation of p42mapk/erk2 in response to TNF-alpha. In addition, we independently cross-linked each receptor with specific agonistic Ab, which have previously been shown to mimic the effects of TNF-alpha. Collectively, the results from these experiments indicate that cross-linking of CD120a (p55), but not that of CD120b (p75), was both necessary and sufficient for the activation of p42mapk/erk2 in mouse macrophages.
CMAJ open, Jul 1, 2023
micron, the predominant variant of concern of SARS-CoV-2, 1 is more transmissible but does not in... more micron, the predominant variant of concern of SARS-CoV-2, 1 is more transmissible but does not increase-and even decreases 2,3-risks of hospitalization 4-7 and death 8,9 compared with previous variants. From March 2020 to July 2022, COVID-19 waves in Canada 10 were driven by wild-type, Alpha, Delta and Omicron variants, and mortality decreased after wave 1 8,9,11-16 except in hospitalized patients aged 65 years or older in Ontario. 17 Mortality of patients hospitalized during previous COVID-19 waves in Canada 16 had decreased from waves 1 to 3 because of differing demographic characteristics, management (e.g., dexamethasone use, other COVID-19 therapies 18,19) and vaccines. 20 Overall, Omicron fatality rates decreased community wide. 8,9 This study focuses on patients hospitalized with COVID-19 in 3 Canadian provinces (British Columbia, Ontario and Quebec) during the Omicron and first 3 waves. Our objectives were to compare outcomes of patients in the Omicron wave by vaccination status, and also to compare outcomes between patients hospitalized during the Omicron wave and patients in previous waves.
Background: Diagnosis and prognostication of severe traumatic brain injury (sTBI) continue to be ... more Background: Diagnosis and prognostication of severe traumatic brain injury (sTBI) continue to be problematic despite research efforts for years. There is currently no clinically reliable biomarkers, though advances in protein biomarkers are being made. Utilizing Omics technology, particularly metabolomics, may provide new diagnostic biomarkers for severe traumatic brain injury. Several published studies have attempted to determine specific metabolites and metabolic pathways involved; these studies will be reviewed. Aims: This scoping review aims to summarize current literature concerning metabolomics in severe traumatic brain injury, review the comprehensive data and identify commonalities, if any, to define metabolites with potential clinical use. In addition, we will examine related metabolic pathways through pathway analysis. Methods: Scoping review methodology was used to examine the current literature published in Embase, Scopus, PubMed and Medline. An initial 1090 publications...
Background Prognostication is very important to clinicians and families during the early manageme... more Background Prognostication is very important to clinicians and families during the early management of severe traumatic brain injury (sTBI), however, there are no gold standard biomarkers to determine prognosis in sTBI. As has been demonstrated in several diseases, early measurement of serum metabolomic profiles can be used as sensitive and specific biomarkers to predict outcome. Methods We prospectively enrolled adults with sTBI (Glasgow coma scale, GCS ≤ 8) in a multicenter Canadian TBI (CanTBI) study. Serum samples were drawn on the 1st and 4th day following injury for metabolomic profiling. The Glasgow outcome scale extended (GOSE) was collected at 3- and 12-months post-injury. Targeted direct infusion liquid chromatography tandem mass spectrometry (DI/LC-MS/MS) and untargeted proton nuclear magnetic resonance spectroscopy (1H-NMR) were used to profile serum metabolites. Multivariate analysis was used to determine the association between serum metabolomics and GOSE, dichotomized...
European journal of medical research, May 14, 2024
Background The Berlin definition of acute respiratory distress syndrome (ARDS) includes only clin... more Background The Berlin definition of acute respiratory distress syndrome (ARDS) includes only clinical characteristics. Understanding unique patient pathobiology may allow personalized treatment. We aimed to define and describe ARDS phenotypes/endotypes combining clinical and pathophysiologic parameters from a Canadian ARDS cohort. Methods A cohort of adult ARDS patients from multiple sites in Calgary, Canada, had plasma cytokine levels and clinical parameters measured in the first 24 h of ICU admission. We used a latent class model (LCM) to group the patients into several ARDS subgroups and identified the features differentiating those subgroups. We then discuss the subgroup effect on 30 day mortality. Results The LCM suggested three subgroups (n 1 = 64, n 2 = 86, and n 3 = 30), and 23 out of 69 features made these subgroups distinct. The top five discriminating features were IL-8, IL-6, IL-10, TNF-a, and serum lactate. Mortality distinctively varied between subgroups. Individual clinical characteristics within the subgroup associated with mortality included mean PaO 2 /FiO 2 ratio, pneumonia, platelet count, and bicarbonate negatively associated with mortality, while lactate, creatinine, shock, chronic kidney disease, vasopressor/ionotropic use, low GCS at admission, and sepsis were positively associated. IL-8 and Apache II were individual markers strongly associated with mortality (Area Under the Curve = 0.84). Perspective ARDS subgrouping using biomarkers and clinical characteristics is useful for categorizing a heterogeneous condition into several homogenous patient groups. This study found three ARDS subgroups using LCM; each subgroup has a different level of mortality. This model may also apply to developing further trial design, prognostication, and treatment selection.
Journal of Proteome Research, Dec 3, 2023
PubMed, Dec 1, 1999
Macrophages are versatile cells found in every tissue in the body. They must perform a number of ... more Macrophages are versatile cells found in every tissue in the body. They must perform a number of diverse cellular functions that allow them to kill invading micro-organisms and neoplastic cells as well as produce growth factors involved in wound healing. Macrophages that develop these diverse functions arise from a common precursor. By a process of selective adaptation, the common precursor monocyte/macrophage differentiates into a distinctive macrophage with a different and specific phenotype, characterized by the expression of a specific set of gene products. The local environment plays a critical role in shaping or directing the pattern or pathway of macrophage differentiation. The authors have focused on 2 specific macrophage differentiation pathways in a murine bone marrow-derived macrophage model. One pathway is believed to play a role in wound repair and is characterized by the induction of insulin-like growth factor-1 (IGF-I). The second pathway is involved in macrophage cytocidal activation and is characterized by the induction of the inducible form of nitric oxide synthase (iNOS). The pleotropic cytokine tumour necrosis factor-alpha (TNF-alpha) appears to mediate macrophage differentiation along both of these pathways. Interferon-gamma (IFN-gamma), however, appears to act as a molecular switch. In the presence of IFN-gamma, stimulation of macrophages with TNF-alpha results in macrophage differentiation along a pathway in which iNOS is expressed, whereas, in the absence of IFN-gamma, stimulation of macrophages with TNF-alpha results in differentiation along a pathway in which IGF-I is expressed. The authors focus on some of the molecular events involved in TNF-alpha and IFN-gamma signal transduction and the regulation of iNOS and IGF-I genes in macrophages.
International Journal of Biochemistry, 1981
ABSTRACT
Critical care, Feb 27, 2024
Rationale Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome... more Rationale Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair. Objective To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis. Methods We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms. Results Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms.
Critical Care
Background Prognostication is very important to clinicians and families during the early manageme... more Background Prognostication is very important to clinicians and families during the early management of severe traumatic brain injury (sTBI), however, there are no gold standard biomarkers to determine prognosis in sTBI. As has been demonstrated in several diseases, early measurement of serum metabolomic profiles can be used as sensitive and specific biomarkers to predict outcomes. Methods We prospectively enrolled 59 adults with sTBI (Glasgow coma scale, GCS ≤ 8) in a multicenter Canadian TBI (CanTBI) study. Serum samples were drawn for metabolomic profiling on the 1st and 4th days following injury. The Glasgow outcome scale extended (GOSE) was collected at 3- and 12-months post-injury. Targeted direct infusion liquid chromatography-tandem mass spectrometry (DI/LC–MS/MS) and untargeted proton nuclear magnetic resonance spectroscopy (1H-NMR) were used to profile serum metabolites. Multivariate analysis was used to determine the association between serum metabolomics and GOSE, dichoto...
Canadian journal of kidney health and disease, 2021
Background: Acute kidney injury (AKI) is a potentially fatal complication of Coronavirus Disease-... more Background: Acute kidney injury (AKI) is a potentially fatal complication of Coronavirus Disease-2019 (COVID-19). Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, to its viral receptor, angiotensin converting enzyme 2 (ACE2), results in viral entry and may cause AKI. Objectives: We performed a systematic review and meta-analysis of the frequencies of AKI and renal replacement therapy (RRT) in critically ill COVID-19 patients and compared those frequencies with patients who were infected by respiratory viruses that bind or downregulate ACE2 (ACE2-associated viruses) and viruses that do not bind nor downregulate ACE2 (non-ACE2-associated viruses). Design: Systematic review and meta-analysis. Setting: Observational studies on COVID-19 and other respiratory viral infections reporting AKI and RRT were included. The exclusion criteria were non-English articles, non-peer-reviewed articles, review articles, studies that included patients under the age of 18, studies including fewer than 10 patients, and studies not reporting AKI and RRT rates. Patients: Adult COVID-19, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and influenza patients. Measurements: We extracted the following data from the included studies: author, year, study location, age, sex, race, diabetes mellitus, hypertension, chronic kidney disease, shock, vasopressor use, mortality, intensive care unit (ICU) admission, ICU mortality, AKI, and RRT. Methods: We systematically searched PubMed and EMBASE for articles reporting AKI or RRT. AKI was defined by authors of included studies. Critical illness was defined by ICU admission. We performed a random effects metaanalysis to calculate pooled estimates for the AKI and RRT rate within each virus group using a random intercept logistic regression model. Results: Of 23 655 hospitalized, critically ill COVID-19 patients, AKI frequencies were not significantly different between COVID-19 patients (51%, 95% confidence interval [CI]: 44%-57%) and critically ill patients infected with ACE2-associated (56%, 95% CI: 37%-74%, P = .610) or non-ACE2-associated viruses (63%, 95% CI: 43%-79%, P = .255). Pooled RRT rates were also not significantly different between critically ill, hospitalized patients with COVID-19 (20%, 95% CI: 16%-24%) and ACE2-associated viruses (18%, 95% CI: 8%-33%, P = .747). RRT rates for both COVID-19 and ACE2-associated viruses were significantly different (P < .001 for both) from non-ACE2-associated viruses (49%, 95% CI: 44%-54%). After adjusting for shock or vasopressor use, AKI and RRT rates were not significantly different between groups. Limitations: Limitations of this study include the heterogeneity of definitions of AKI that were used across different virus studies. We could not match severity of infection or do propensity matching across studies. Most of the included studies were conducted in retrospective fashion. Last, we did not include non-English publications.
Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically... more Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-inhuman trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18-0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-inhuman clinical studies.
Critical Care Medicine, May 18, 2022
OBJECTIVES: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting e... more OBJECTIVES: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are associated with improved outcomes in hospitalized patients with COVID-19 according to sex and to report sex-related differences in renin-angiotensin system (RAS) components. DESIGN: Prospective observational cohort study comparing the effects of ARB or ACE inhibitors versus no ARBs or ACE inhibitors in males versus females. Severe acute respiratory syndrome coronavirus 2 downregulates ACE-2, potentially increasing angiotensin II (a pro-inflammatory vasoconstrictor). Sex-based differences in RAS dysregulation may explain sex-based differences in responses to ARBs because the ACE2 gene is on the X chromosome. We recorded baseline characteristics, comorbidities, prehospital ARBs or ACE inhibitor treatment, use of organ support and mortality, and measured RAS components at admission and days 2, 4, 7, and 14 in a subgroup (n = 46), recorded d-dimer (n = 967), comparing males with females. SETTING: ARBs CORONA I is a multicenter Canadian observational cohort of patients hospitalized with acute COVID-19. This analysis includes patients admitted to 10 large urban hospitals across the four most populated provinces. PATIENTS: One-thousand six-hundred eighty-six patients with polymerase chain reaction-confirmed COVID-19 (February 2020 to March 2021) for acute COVID-19 illness were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Males on ARBs before admission had decreased use of ventilation (adjusted odds ratio [aOR] = 0.52; p = 0.007) and vasopressors (aOR = 0.55; p = 0.011) compared with males not on ARBs or ACE inhibitors. No significant effects were observed in females for these outcomes. The test for interaction was significant for use of ventilation (p = 0.006) and vasopressors (p = 0.044) indicating significantly different responses to ARBs according to sex. Males had significantly higher plasma ACE-1 at baseline and angiotensin II at day 7 and 14 than females. CONCLUSIONS: ARBs use was associated with less ventilation and vasopressors in males but not females. Sex-based differences in RAS dysregulation may contribute to sex-based differences in outcomes and responses to ARBs in COVID-19.
Chest, Jul 1, 1999
Figure 2. DN-MEKK1 inhibits TNF-␣ ϩ IFN-␥ induction of iNOS.
CJC open, Jul 1, 2021
Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
EClinicalMedicine, Feb 1, 2020
Background: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as... more Background: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as this novel therapy continues to be evaluated in clinical trials for various inflammatory conditions. Due to an increase in published randomized controlled trials (RCTs) from 2012À2019, we performed an updated systematic review to further characterize the MSC safety profile. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to May 2018) were searched. RCTs that compared intravascular delivery of MSCs to controls in adult populations were included. Pre-specified adverse events were grouped according to: (1) immediate, (2) infection, (3) thrombotic/embolic, and (4) longer-term events (mortality, malignancy). Adverse events were pooled and meta-analyzed by fitting inverse-variance binary random effects models. Primary and secondary clinical efficacy endpoints were summarized descriptively. Findings: 7473 citations were reviewed and 55 studies met inclusion criteria (n = 2696 patients). MSCs as compared to controls were associated with an increased risk of fever (Relative Risk (RR) = 2¢48, 95% Confidence Interval (CI) = 1¢27À4¢86; I 2 = 0%), but not non-fever acute infusional toxicity, infection, thrombotic/ embolic events, death, or malignancy (RR = 1¢16,
PLOS ONE, Oct 25, 2012
Background: Mesenchymal stromal cells (MSCs, ''adult stem cells'') have been widely used experime... more Background: Mesenchymal stromal cells (MSCs, ''adult stem cells'') have been widely used experimentally in a variety of clinical contexts. There is interest in using these cells in critical illness, however, the safety profile of these cells is not well known. We thus conducted a systematic review of clinical trials that examined the use MSCs to evaluate their safety. Methods and Findings: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (to June 2011), were searched. Prospective clinical trials that used intravascular delivery of MSCs (intravenously or intra-arterially) in adult populations or mixed adult and pediatric populations were identified. Studies using differentiated MSCs or additional cell types were excluded. The primary outcome adverse events were grouped according to immediate events (acute infusional toxicity, fever), organ system complications, infection, and longer term adverse events (death, malignancy). 2347 citations were reviewed and 36 studies met inclusion criteria. A total of 1012 participants with clinical conditions of ischemic stroke, Crohn's disease, cardiomyopathy, myocardial infarction, graft versus host disease, and healthy volunteers were included. Eight studies were randomized control trials (RCTs) and enrolled 321 participants. Meta-analysis of the RCTs did not detect an association between acute infusional toxicity, organ system complications, infection, death or malignancy. There was a significant association between MSCs and transient fever. Conclusions: Based on the current clinical trials, MSC therapy appears safe. However, further larger scale controlled clinical trials with rigorous reporting of adverse events are required to further define the safety profile of MSCs.
Canadian Critical Care Translational Biology Group 7.) Review Objective To systematically review ... more Canadian Critical Care Translational Biology Group 7.) Review Objective To systematically review the effects of MSCs on death, organ dysfunction, inflammation, and pathogen clearance in in-vivo animal models of sepsis 8.) Searches The search strategies outlined below were developed in conjunction with an information specialist. Embase, BIOSIS, MEDLINE, and Web of Science will be searched. The strategy below was used to search in MEDLINE. In addition, a manual review of the bibliographies of eligible studies and relevant review articles will be performed. Relevant conference proceedings and abstracts will also be searched.
Journal of Immunology, Aug 1, 1995
Cross-linking of the dichotomous cell surface receptors for TNF-alpha (CD120a (p55) and CD120b (p... more Cross-linking of the dichotomous cell surface receptors for TNF-alpha (CD120a (p55) and CD120b (p75)) induces the activation of a variety of macrophage responses that mediate the role of this cell in inflammation and host defense. Although significant progress has been made in understanding the role that lipid second messengers play in mediating the action(s) of this multifunctional cytokine, less is known about the role of specific kinases in TNF-alpha-initiated signaling. We show that exposure of mouse macrophages to TNF-alpha stimulates a rapid and transient tyrosine phosphorylation and activation of p42mapk/erk2. By contrast, p44mapk/erk1 was found to be constitutively phosphorylated, with minimal further response to TNF-alpha. To investigate the use of CD120a (p55) and CD120b (p75) in the activation of p42mapk/erk2 in mouse macrophages, we determined the effects of blocking Ab on the activation of p42mapk/erk2 in response to TNF-alpha. In addition, we independently cross-linked each receptor with specific agonistic Ab, which have previously been shown to mimic the effects of TNF-alpha. Collectively, the results from these experiments indicate that cross-linking of CD120a (p55), but not that of CD120b (p75), was both necessary and sufficient for the activation of p42mapk/erk2 in mouse macrophages.
CMAJ open, Jul 1, 2023
micron, the predominant variant of concern of SARS-CoV-2, 1 is more transmissible but does not in... more micron, the predominant variant of concern of SARS-CoV-2, 1 is more transmissible but does not increase-and even decreases 2,3-risks of hospitalization 4-7 and death 8,9 compared with previous variants. From March 2020 to July 2022, COVID-19 waves in Canada 10 were driven by wild-type, Alpha, Delta and Omicron variants, and mortality decreased after wave 1 8,9,11-16 except in hospitalized patients aged 65 years or older in Ontario. 17 Mortality of patients hospitalized during previous COVID-19 waves in Canada 16 had decreased from waves 1 to 3 because of differing demographic characteristics, management (e.g., dexamethasone use, other COVID-19 therapies 18,19) and vaccines. 20 Overall, Omicron fatality rates decreased community wide. 8,9 This study focuses on patients hospitalized with COVID-19 in 3 Canadian provinces (British Columbia, Ontario and Quebec) during the Omicron and first 3 waves. Our objectives were to compare outcomes of patients in the Omicron wave by vaccination status, and also to compare outcomes between patients hospitalized during the Omicron wave and patients in previous waves.
Background: Diagnosis and prognostication of severe traumatic brain injury (sTBI) continue to be ... more Background: Diagnosis and prognostication of severe traumatic brain injury (sTBI) continue to be problematic despite research efforts for years. There is currently no clinically reliable biomarkers, though advances in protein biomarkers are being made. Utilizing Omics technology, particularly metabolomics, may provide new diagnostic biomarkers for severe traumatic brain injury. Several published studies have attempted to determine specific metabolites and metabolic pathways involved; these studies will be reviewed. Aims: This scoping review aims to summarize current literature concerning metabolomics in severe traumatic brain injury, review the comprehensive data and identify commonalities, if any, to define metabolites with potential clinical use. In addition, we will examine related metabolic pathways through pathway analysis. Methods: Scoping review methodology was used to examine the current literature published in Embase, Scopus, PubMed and Medline. An initial 1090 publications...
Background Prognostication is very important to clinicians and families during the early manageme... more Background Prognostication is very important to clinicians and families during the early management of severe traumatic brain injury (sTBI), however, there are no gold standard biomarkers to determine prognosis in sTBI. As has been demonstrated in several diseases, early measurement of serum metabolomic profiles can be used as sensitive and specific biomarkers to predict outcome. Methods We prospectively enrolled adults with sTBI (Glasgow coma scale, GCS ≤ 8) in a multicenter Canadian TBI (CanTBI) study. Serum samples were drawn on the 1st and 4th day following injury for metabolomic profiling. The Glasgow outcome scale extended (GOSE) was collected at 3- and 12-months post-injury. Targeted direct infusion liquid chromatography tandem mass spectrometry (DI/LC-MS/MS) and untargeted proton nuclear magnetic resonance spectroscopy (1H-NMR) were used to profile serum metabolites. Multivariate analysis was used to determine the association between serum metabolomics and GOSE, dichotomized...