Browsing by Author "Winston, Brent W."

Now showing 1 - 9 of 9
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    Complement activation in a murine model of s. pneumoniae pneumonia-induced sepsis
    (2011) Goring, Kimberly-Ann Ruth; Winston, Brent W.
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    Endotyping in ARDS: one step forward in precision medicine
    (2024-05-14) Côté, Andréanne; Lee, Chel H.; Metwaly, Sayed M.; Doig, Christopher J.; Andonegui, Graciela; Yipp, Bryan G.; Parhar, Ken K. S.; Winston, Brent W.
    Abstract 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 (n1 = 64, n2 = 86, and n3 = 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 PaO2/FiO2 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.
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    Metabolomics in severe traumatic brain injury: a scoping review
    (2023-10-16) Fedoruk, Riley P.; Lee, Chel H.; Banoei, Mohammad M.; Winston, Brent W.
    Abstract Background Diagnosis and prognostication of severe traumatic brain injury (sTBI) continue to be problematic despite years of research efforts. There are currently no clinically reliable biomarkers, though advances in protein biomarkers are being made. Utilizing Omics technology, particularly metabolomics, may provide new diagnostic biomarkers for sTBI. Several published studies have attempted to determine the specific metabolites and metabolic pathways involved; these studies will be reviewed. Aims This scoping review aims to summarize the current literature concerning metabolomics in sTBI, 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 were identified and vetted with specific inclusion criteria. Of these, 20 publications were selected for further examination and summary. Metabolic data was classified using the Human Metabolome Database (HMDB) and arranged to determine the ‘recurrent’ metabolites and classes found in sTBI. To help understand potential mechanisms of injury, pathway analysis was performed using these metabolites and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database. Results Several metabolites related to sTBI and their effects on biological pathways were identified in this review. Across the literature, proline, citrulline, lactate, alanine, valine, leucine, and serine all decreased in adults post sTBI, whereas both octanoic and decanoic acid increased. Hydroxy acids and organooxygen compounds generally increased following sTBI, while most carboxylic acids decreased. Pathway analysis showed significantly affected glycine and serine metabolism, glycolysis, branched-chain amino acid (BCAA) metabolism, and other amino acid metabolisms. Interestingly, no tricarboxylic acid cycle metabolites were affected. Conclusion Aside from a select few metabolites, classification of a metabolic profile proved difficult due to significant ambiguity between study design, sample size, type of sample, metabolomic detection techniques, and other confounding variables found in sTBI literature. Given the trends found in some studies, further metabolomics investigation of sTBI may be useful to identify clinically relevant metabolites.
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    Metabolomics Study of ARDS Diagnosis, Heterogeneity, and Mortality
    (2020-08-06) Mohamed Metwaly, Sayed Ahmed Osman; Winston, Brent W.; Vogel, Hans J.; Niven, Daniel J.; Lewis, Ian A.
    Background: Acute Respiratory Distress Syndrome (ARDS) represents 10.4% of all Intensive Care Unit (ICU) admissions with an overall mortality rate of 35.3%. Early diagnosis of ARDS is an important requirement for the timely institution of proper supportive care but it is hampered by the unreliable tissue diagnosis, lack of an early diagnostic biomarker and lack of specific therapy. Metabolomics is a systems biology approach to examine changes in metabolites in response to physiological and pathological stimuli. It is more closely related to observed phenotypes and more responsive to real-time pathophysiological changes, thus constitutes an attractive platform for studying ARDS.Hypothesis: We hypothesize that the diverse inflammatory, pathobiological and adaptive processes involved in ARDS would manifest as unique metabolic fingerprint that sets ARDS apart from other ICU conditions. Biomarker identification may help early diagnosis of ARDS, explore its mechanism, differentiate ARDS subclasses and predict ARDS mortality. Methodology: Serum samples from 108 ARDS patients and 27 ICU ventilated age- and sex-matched controls were included in this study. Samples were analyzed by proton nuclear magnetic resonance spectroscopy (1H-NMR) and gas chromatography mass spectrometry (GC-MS). The proteins/cytokines IL-6, IL-8, IL-10, TNF-?, Ang-2, RAGE, vWF, TNF-RI, ICAM-1, PAI-1, SP-D and Protein-C were also measured. Multivariate statistical models that distinguish ARDS from ICU controls (diagnose ARDS), subclassify ARDS and predict ARDS non-survival were built. Results were externally validated in an independent cohort of 188 patients comprising 118 ARDS patients and 70 ICU ventilated controls.Results: Our data indicates that NMR and GC-MS metabolomics are more accurate than proteins/cytokines in differentiating ARDS from ICU controls and ARDS subgroups. Pathway analysis of ARDS versus controls identified a dominant involvement of serine-glycine metabolism. In external validation, ARDS patients were correctly identified in 93% using NMR and 96% using GC-MS. Metabolomics was not able to predict mortality in the ARDS population studied.Conclusion: ARDS subgroups are metabolically distinct. Further research is needed to explore the role of dysfunctional folate metabolism in the development of ARDS. Metabolomics provides a novel technology to not only understand but intervene on the pathophysiology of ARDS.
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    Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia
    (2024-02-27) Lee, Chel H.; Banoei, Mohammad M.; Ansari, Mariam; Cheng, Matthew P.; Lamontagne, Francois; Griesdale, Donald; Lasry, David E.; Demir, Koray; Dhingra, Vinay; Tran, Karen C.; Lee, Terry; Burns, Kevin; Sweet, David; Marshall, John; Slutsky, Arthur; Murthy, Srinivas; Singer, Joel; Patrick, David M.; Lee, Todd C.; Boyd, John H.; Walley, Keith R.; Fowler, Robert; Haljan, Greg; Vinh, Donald C.; Mcgeer, Alison; Maslove, David; Mann, Puneet; Donohoe, Kathryn; Hernandez, Geraldine; Rocheleau, Genevieve; Trahtemberg, Uriel; Kumar, Anand; Lou, Ma; dos Santos, Claudia; Baker, Andrew; Russell, James A.; Winston, Brent W.
    Abstract 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. Conclusion Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.
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    Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia
    (2024-02-27) Lee, Chel H.; Banoei, Mohammad M.; Ansari, Mariam; Cheng, Matthew P.; Lamontagne, Francois; Griesdale, Donald; Lasry, David E.; Demir, Koray; Dhingra, Vinay; Tran, Karen C.; Lee, Terry; Burns, Kevin; Sweet, David; Marshall, John; Slutsky, Arthur; Murthy, Srinivas; Singer, Joel; Patrick, David M.; Lee, Todd C.; Boyd, John H.; Walley, Keith R.; Fowler, Robert; Haljan, Greg; Vinh, Donald C.; Mcgeer, Alison; Maslove, David; Mann, Puneet; Donohoe, Kathryn; Hernandez, Geraldine; Rocheleau, Genevieve; Trahtemberg, Uriel; Kumar, Anand; Lou, Ma; dos Santos, Claudia; Baker, Andrew; Russell, James A.; Winston, Brent W.
    Abstract 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. Conclusion Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.
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    Using metabolomics to predict severe traumatic brain injury outcome (GOSE) at 3 and 12 months
    (2023-07-22) Banoei, Mohammad M.; Lee, Chel H.; Hutchison, James; Panenka, William; Wellington, Cheryl; Wishart, David S.; Winston, Brent W.
    Abstract 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, dichotomized into favorable (GOSE 5–8) and unfavorable (GOSE 1–4), outcomes. Results Serum metabolic profiles on days 1 and 4 post-injury were highly predictive (Q2 > 0.4–0.5) and highly accurate (AUC > 0.99) to predict GOSE outcome at 3- and 12-months post-injury and mortality at 3 months. The metabolic profiles on day 4 were more predictive (Q2 > 0.55) than those measured on day 1 post-injury. Unfavorable outcomes were associated with considerable metabolite changes from day 1 to day 4 compared to favorable outcomes. Increased lysophosphatidylcholines, acylcarnitines, energy-related metabolites (glucose, lactate), aromatic amino acids, and glutamate were associated with poor outcomes and mortality. Discussion Metabolomic profiles were strongly associated with the prognosis of GOSE outcome at 3 and 12 months and mortality following sTBI in adults. The metabolic phenotypes on day 4 post-injury were more predictive and significant for predicting the sTBI outcome compared to the day 1 sample. This may reflect the larger contribution of secondary brain injury (day 4) to sTBI outcome. Patients with unfavorable outcomes demonstrated more metabolite changes from day 1 to day 4 post-injury. These findings highlighted increased concentration of neurobiomarkers such as N-acetylaspartate (NAA) and tyrosine, decreased concentrations of ketone bodies, and decreased urea cycle metabolites on day 4 presenting potential metabolites to predict the outcome. The current findings strongly support the use of serum metabolomics, that are shown to be better than clinical data, in determining prognosis in adults with sTBI in the early days post-injury. Our findings, however, require validation in a larger cohort of adults with sTBI to be used for clinical practice.