Percorrer por autor "Binnie, Alexandra"
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- Association of epigenetic age and outcome in critically Ill patientsPublication . Sharma-Oates, Archana; Sullivan, Jack; Pestana, Daniel; Santos, Claudia C. dos; Binnie, Alexandra; Lord, Janet M.OBJECTIVES: DNA methylation can be used to determine an individual’s biological age, as opposed to chronological age, an indicator of underlying health status. This study aimed to assess epigenetic age in critically ill patients with and without sepsis to determine if higher epigenetic age is associated with admission diagnosis or mortality. DESIGN: Secondary analysis of whole blood DNA methylation data generated from a nested case–control study of critically ill septic and nonseptic patients. SETTING: Four tertiary care hospitals in Canada. INTERVENTIONS: None. PATIENTS: Critically ill patients with and without sepsis. MEASUREMENTS AND MAIN RESULTS: Epigenetic age was derived from DNA methylation data using the Hannum and PhenoAge algorithms and deviation from the patient’s chronological age in years was determined. Of the 66 patients with sepsis, 34 were male (51.5%), the mean age was 65.03 years and 25 patients (37.8%) died before discharge. Of the 68 nonseptic patients, 47 were male (69.1%), the mean age was 64.92 years and 25 (36.7%) died before discharge. Epigenetic age calculated using the PhenoAge algorithm showed a significant age acceleration of 4.97 years in septic patients (p = 0.045), but no significant acceleration in nonseptic patients. Epigenetic age calculated using the Hannum algorithm showed no significant acceleration in the septic or nonseptic patients. Similarly, in the combined septic and nonseptic cohorts, nonsurvivors showed an epigenetic age acceleration of 7.62 years (p = 0.004) using the PhenoAge algorithm while survivors showed no significant age acceleration. Survivor status was not associated with age acceleration using the Hannum algorithm.
- The burden of COVID-19 care in community and academic intensive care units in Ontario, Canada: a retrospective cohort studyPublication . Pestana, Daniel; Joshi, Divya; Duan, Erick; Fowler, Robert; Tsang, Jennifer; Binnie, AlexandraDuring the COVID-19 pandemic, neighbourhoods with high material deprivation and high proportions of racialized Canadians were disproportionately affected by COVID-19. Many of these neighbourhoods were served by community hospitals. We sought to compare the burden of COVID-19 care in community and academic intensive care units (ICUs) in Ontario, Canada. We included all adult patients admitted to Ontario ICUs with COVID-19 between 1 March 2020 and 31 July 2021 in a retrospective cohort study. We compared patient volumes, demographics, interventions, and outcomes between community hospital corporations (CHCs) and academic hospital corporations (AHCs). During the first three waves of the pandemic, 9,651 adult ICU admissions for COVID-19 were reported across 72 hospital corporations in Ontario: 6,902 (71.5%) in CHCs and 2,749 (28.5%) in AHCs. Days of ICU care per baseline ICU bed were highest in large CHCs ([ 10 baseline ICU beds) relative to AHCs and small CHCs (median [interquartile range], 73.7 [53.8–110.6] vs 42.2 [32.7–71.8] vs 21.4 [7.2–40.3]; Kruskal–Wallis test, P \ 0.001). Among direct ICU admissions, CHC patients had greater severity of illness whereas among transfer ICU admissions, AHC patients were more severely ill. In a multivariable logistic regression model, mortality was similar among patients with index admission to a CHC or AHC; however, patients with index admission to an AHC were more likely to receive extracorporeal membrane oxygenation (adjusted odds ratio, 6.16; 95% confidence interval, 4.72 to 8.11). During the pandemic, Ontario’s large CHCs provided significantly more days of ICU COVID-19 care per baseline ICU bed compared with AHCs and small CHCs. Equipping large CHCs to handle ICU surges during future emerging disease outbreaks should be a priority for pandemic preparedness.
- Community versus academic hospital community-acquired pneumonia patients: a nested cohort studyPublication . Tsang, Jennifer L. Y.; Rego, Kian; Binnie, Alexandra; Binnie, Alexandra; Lee, Terry; Mccarthy, Anne; Cowan, Juthaporn; Archambault, Patrick; Lellouche, Francois; Turgeon, Alexis F.; Yoon, Jennifer; Lamontagne, Francois; Mcgeer, Allison; Douglas, Josh; Daley, Peter; Fowler, Robert; Maslove, David M.; Winston, Brent W.; Lee, Todd C.; Tran, Karen C.; Cheng, Matthew P.; Vinh, Donald C.; Boyd, John H.; Walley, Keith R.; Singer, Joel; Marshall, John C.; Haljan, Gregory; Jain, Fagun; Russell, James A.Background: Most Canadians receive their care in community hospitals, yet most clinical research is conducted in academic hospitals. This study aims to compare patients with community acquired pneumonia (CAP) treated in academic and community hospitals with respect to their demographics, clinical characteristics, treatments and outcomes. Methods This nested observational cohort substudy of the Community Acquired Pneumonia: Toward InnoVAtive Treatment (CAPTIVATE) trial included 1,329 hospitalized adults with CAP recruited between March 1st, 2018 and September 31st, 2023 from 15 Canadian hospitals. Unadjusted and adjusted analyses for age, sex and co-morbidities using logistic, Cox and censored quantile regressions were conducted. Results Patients in community hospitals were older (mean [SD] 75.0 [15.7] years vs. 68.3 [16.2] years; p < 0.001), were more likely to be female (49.7% vs. 41.0%, p = 0.002), and had more comorbidities (75.9% vs. 64.8%, p < 0.001). More patients in community hospitals received corticosteroids (49.2% vs. 37.4%, p < 0.001). Community hospital patients had a higher likelihood of developing acute respiratory distress syndrome (OR 3.13, 95% CI: 1.87, 5.24, p = < 0.001), and acute cardiac injury (OR 2.53, 95% CI: 1.33, 4.83, p = 0.005). In unadjusted and adjusted analyses, 28-day mortality difference did not meet statistical significance (OR 1.43, 95% CI: 0.98, 20.7, p = 0.062 and OR 1.23, 95% CI: 0.81, 1.87, p = 0.332, respective). Conclusion Patients with CAP in Canadian community and academic hospitals differed with respect to their age, clinical characteristics, treatments and outcomes, emphasizing the importance of including more community hospitals in clinical research studies to ensure the generalizability of results.
- COVID-19 research in critical care: the good, the bad, and the uglyPublication . Salluh, Jorge I. F.; Arabi, Yaseen M.; Binnie, AlexandraThe extraordinary pace of research on coronavirus disease 2019 (COVID-19) has been one of the major success stories of the pandemic. Therapeutic trials involving thousands of patients, which usually take years to complete, have been reported in a matter of months. National and international registries and networks have reported on tens of thousands of patients in near real time. However, there have also been many challenges: hundreds of trials have been underpowered, duplicated, or of poor quality; excessive bureaucracy has complicated study initiation; and only a small percentage of eligible patients worldwide have been enrolled in studies, while many others have been treated with off-label, unproven therapies. All of this has been complicated by an “infodemic” of low-quality medical information, accelerated by social media.
- CRISPR-based strategies in infectious disease diagnosis and therapyPublication . Binnie, Alexandra; Fernandes, Emanuel; Almeida‑Lousada, Helder; De Mello, Ramon Andrade; Castelo-Branco, PedroCRISPR gene-editing technology has the potential to transform the diagnosis and treatment of infectious diseases, but most clinicians are unaware of its broad applicability. Derived from an ancient microbial defence system, these so-called "molecular scissors" enable precise gene editing with a low error rate. However, CRISPR systems can also be targeted against pathogenic DNA or RNA sequences. This potential is being combined with innovative delivery systems to develop new therapeutic approaches to infectious diseases.
- Developing a toolkit for building a community hospital clinical research programPublication . Rego, Kian; Orlando, Elaina; Archambault, Patrick; Geagea, Anna; Mitra, Anish R.; Vazquez-Grande, Gloria; Marticorena, Rosa M.; Patterson, Lisa; DiDiodato, Giulio; Rewa, Oleksa G.; Senaratne, Janek; Law, Madelyn; Binnie, Alexandra; Tsang, JenniferPurpose Although health research in Canada is primarily conducted in academic hospitals, most patients receive their care in community hospitals. The benefits of increasing research capacity in community hospitals include improved study recruitment, increased generalizability of results, broader patient access to novel therapies, better patient outcomes, enhanced staff satisfaction, and improved organizational efficiency.
- Epigenetic profiling in severe sepsis: a pilot study of DNA methylation profiles in critical illnessPublication . Binnie, Alexandra; Walsh, Christopher J.; Hu, Pingzhao; Dwivedi, Dhruva J.; Fox-Robichaud, Alison; Liaw, Patricia C.; Tsang, Jennifer L. Y.; Batt, Jane; Carrasqueiro, Gabriela; Gupta, Sahil; Marshall, John C.; Castelo-Branco, Pedro; dos Santos, Claudia C.Objectives: Epigenetic alterations are an important regulator of gene expression in health and disease; however, epigenetic data in sepsis are lacking. To demonstrate proof of concept and estimate effect size, we performed the first epigenome-wide methylation analysis of whole blood DNA samples from a cohort of septic and nonseptic critically ill patients. Design: A nested case-control study using genomic DNA isolated from whole blood from septic (n = 66) and nonseptic (n = 68) critically ill patients on "Day 1" of ICU admission. Methylation patterns were identified using Illumina 450K arrays with percent methylation expressed as beta values. After quality control, 134 participants and 414,818 autosomal cytosine-phosphate-guanine sites were used for epigenome-wide methylation analyses. Setting: Tertiary care hospitals. Subjects: Critically ill septic and nonseptic patients. Interventions: Observational study. Measurements and Main Results: A total of 668 differentially methylated regions corresponding to 443 genes were identified. Known sepsis-associated genes included complement component 3; angiopoietin 2; myeloperoxidase; lactoperoxidase; major histocompatibility complex, class I, A; major histocompatibility complex, class II, isotype DR beta I; major histocompatibility complex, class I, C; and major histocompatibility complex, class II, isotype DQ beta I. When compared with whole blood gene expression data from seven external datasets containing septic and nonseptic patients, 81% of the differentially methylated region-associated genes were differentially expressed in one or more datasets and 31% in three or more datasets. Functional analysis showed enrichment for antigen processing and presentation, methyltransferase activity, cell adhesion, and cell junctions. Analysis by weighted gene coexpression network analysis revealed DNA comethylation modules that were associated with clinical traits including severity of illness, need for vasopressors, and length of stay. Conclusions: DNA methylation marks may provide important causal and potentially biomarker information in critically ill patients with sepsis.
- Epigenetic therapy in urologic cancers: an update on clinical trialsPublication . Faleiro, Inês; Leão, Ricardo; Binnie, Alexandra; De Mello, Ramon Andrade; Maia, Ana Teresa; Castelo-Branco, PedroEpigenetic dysregulation is one of many factors that contribute to cancer development and progression. Numerous epigenetic alterations have been identified in urologic cancers including histone modifications, DNA methylation changes, and microRNA expression. Since these changes are reversible, efforts are being made to develop epigenetic drugs that restore the normal epigenetic patterns of cells, and many clinical trials are already underway to test their clinical potential. In this review we analyze multiple clinical trials (n=51) that test the efficacy of these drugs in patients with urologic cancers. The most frequently used epigenetic drugs were histone deacetylase inhibitors followed by antisense oligonucleotides, DNA methyltransferase inhibitors and histone demethylase inhibitors, the last of which are only being tested in prostate cancer. In more than 50% of the clinical trials considered, epigenetic drugs were used as part of combination therapy, which achieved the best results. The epigenetic regulation of some cancers is still matter of research but will undoubtedly open a window to new therapeutic approaches in the era of personalized medicine. The future of therapy for urological malignancies is likely to include multidrug regimens in which epigenetic modifying drugs will play an important role.
- Epigenetics of sepsisPublication . Binnie, Alexandra; Tsang, Jennifer L. Y.; Hu, Pingzhao; Carrasqueiro, Gabriela; Castelo-Branco, Pedro; dos Santos, Claudia C.Recent evidence from the fields of microbiology and immunology, as well as a small number of human sepsis studies, suggest that epigenetic regulation may play a central role in the pathogenesis of sepsis. The term "epigenetics" refers to regulatory mechanisms that control gene expression but are not related to changes in DNA sequence. These include DNA methylation, histone modifications, and regulation of transcription via non-coding RNAs. Epigenetic modifications, occurring in response to external stressors, lead to changes in gene expression, and thus lie at the intersection between genetics and the environment. In this review, we examine data from in vitro studies, animal studies, and the existing human sepsis studies in epigenetics to demonstrate that epigenetic mechanisms are likely central to the pathogenesis of sepsis and that epigenetic therapies may have potential in the treatment of sepsis and its associated organ failures.
- Factors influencing community intensive care unit research participation: a qualitative descriptive studyPublication . Gehrke, Paige; Rego, Kian; Orlando, Elaina; Jack, Susan; Law, Madelyn; Cook, Deborah; Marticorena, Rosa M.; Binnie, Alexandra; Tsang, Jennifer L. Y.Purpose Community hospitals account for 90% of hospitals in Canada, but clinical research is mainly conducted in academic hospitals. Increasing community hospital research participation can improve generalizability of study results, while also accelerating study recruitment and increasing staff engagement. We aimed to identify and describe the factors that influence community intensive care unit (ICU) research participation and the development, implementation, and sustainability of a community ICU research program.MethodsWe conducted a qualitative descriptive study using semistructured interviews. Between April 2022 and May 2023, we interviewed a purposeful sample of individuals interested or involved in community hospital research in Canadian community ICUs. We analyzed qualitative data using both conventional content analysis and rapid qualitative analysis. Findings were deductively mapped out using the Ecological Model of Health Behavior. Quantitative survey data were analyzed using descriptive statistics.ResultsParticipants included 23 health care workers, ten research staff, and five hospital administrators (n = 38) from 20 community hospitals across six provinces in Canada. The main factors associated with community ICU research participation were 1) infrastructure, 2) personnel characteristics, 3) key relationships and connections, and 4) the COVID-19 pandemic.ConclusionIn this qualitative descriptive study, participants identified the physical resources, skills, and relationships required to start and sustain a clinical research program in a Canadian community ICU. Our findings suggest that all levels of the Canadian health care system need to invest in strengthening community hospital research capacity to increase research participation.