Browsing by Author "Macala, Kimberly F."

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    Development and characterization of a fecal-induced peritonitis model of murine sepsis: results from a multi-laboratory study and iterative modification of experimental conditions
    (2023-07-17) Sharma, Neha; Chwastek, Damian; Dwivedi, Dhruva J.; Schlechte, Jared; Yu, Ian-Ling; McDonald, Braedon; Arora, Jaskirat; Cani, Erblin; Eng, Mikaela; Engelberts, Doreen; Kuhar, Eva; Medeiros, Sarah K.; Bourque, Stephane L.; Cepinskas, Gediminas; Gill, Sean E.; Jahandideh, Forough; Macala, Kimberly F.; Panahi, Sareh; Pape, Cynthia; Sontag, David; Sunohara-Neilson, Janet; Fergusson, Dean A.; Fox-Robichaud, Alison E.; Liaw, Patricia C.; Lalu, Manoj M.; Mendelson, Asher A.
    Abstract Background Preclinical sepsis models have been criticized for their inability to recapitulate human sepsis and suffer from methodological shortcomings that limit external validity and reproducibility. The National Preclinical Sepsis Platform (NPSP) is a consortium of basic science researchers, veterinarians, and stakeholders in Canada undertaking standardized multi-laboratory sepsis research to increase the efficacy and efficiency of bench-to-bedside translation. In this study, we aimed to develop and characterize a 72-h fecal-induced peritonitis (FIP) model of murine sepsis conducted in two independent laboratories. The experimental protocol was optimized by sequentially modifying dose of fecal slurry and timing of antibiotics in an iterative fashion, and then repeating the experimental series at site 1 and site 2. Results Escalating doses of fecal slurry (0.5–2.5 mg/g) resulted in increased disease severity, as assessed by the modified Murine Sepsis Score (MSS). However, the MSS was poorly associated with progression to death during the experiments, and mice were found dead without elevated MSS scores. Administration of early antibiotics within 4 h of inoculation rescued the animals from sepsis compared with late administration of antibiotics after 12 h, as evidenced by 100% survival and reduced bacterial load in peritoneum and blood in the early antibiotic group. Site 1 and site 2 had statistically significant differences in mortality (60% vs 88%; p < 0.05) for the same dose of fecal slurry (0.75 mg/g) and marked differences in body temperature between groups. Conclusions We demonstrate a systematic approach to optimizing a 72-h FIP model of murine sepsis for use in multi-laboratory studies. Alterations to experimental conditions, such as dose of fecal slurry and timing of antibiotics, have clear impact on outcomes. Differences in mortality between sites despite rigorous standardization warrants further investigations to better understand inter-laboratory variation and methodological design in preclinical studies.
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    Protocol for co-producing a framework and integrated resource platform for engaging patients in laboratory-based research
    (2024-02-12) Lalu, Manoj M.; Richards, Dawn; Foster, Madison; French, Brittany; Crawley, Angela M.; Fiest, Kirsten M.; Hendrick, Kathryn; Macala, Kimberly F.; Mendelson, Asher A.; Messner, Pat; Nicholls, Stuart G.; Presseau, Justin; Séguin, Cheryle A.; Sullivan, Patrick; Thébaud, Bernard; Fergusson, Dean A.
    Abstract Background Patient engagement in research is the meaningful and collaborative interaction between patients and researchers throughout the research process. Patient engagement can help to ensure patient-oriented values and perspectives are incorporated into the development, conduct, and dissemination of research. While patient engagement is increasingly prevalent in clinical research, it remains relatively unrealized in preclinical laboratory research. This may reflect the nature of preclinical research, in which routine interactions or engagement with patients may be less common. Our team of patient partners and researchers has previously identified few published examples of patient engagement in preclinical laboratory research, as well as a paucity of guidance on this topic. Here we propose the development of a process framework to facilitate patient engagement in preclinical laboratory research. Methods Our team, inclusive of researchers and patient partners, will develop a comprehensive, empirically-derived, and stakeholder-informed process framework for ‘patient engagement in preclinical laboratory research.’ First, our team will create a ‘deliberative knowledge space’ to conduct semi-structured discussions that will inform a draft framework for preclinical patient engagement. Over the course of several sessions, we will identify actions, activities, barriers, and enablers (e.g. considerations and motivations for patient engagement in preclinical laboratory research, define roles of key players). The resulting draft process framework will be further populated with examples and refined through an international consensus-building Delphi survey with patients, researchers, and other collaborator organizations. We will then conduct pilot field tests to evaluate the framework with preclinical laboratory research groups paired with patient partners. These results will be used to create a refined framework enriched with real-world examples and considerations. All resources developed will be made available through an online repository. Discussion Our proposed process framework will provide guidance, best practices, and standardized procedures to promote patient engagement in preclinical laboratory research. Supporting and facilitating patient engagement in this setting presents an exciting new opportunity to help realize the important impact that patients can make.
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    Sex-based analysis of treatment responses in animal models of sepsis: a preclinical systematic review protocol
    (2023-03-21) Zhang, MengQi; Fergusson, Dean A.; Sharma, Rahul; Khoo, Ciel; Mendelson, Asher A.; McDonald, Braedon; Macala, Kimberly F.; Sharma, Neha; Gill, Sean E.; Fiest, Kirsten M.; Lehmann, Christian; Shorr, Risa; Jahandideh, Forough; Bourque, Stephane L.; Liaw, Patricia C.; Fox-Robichaud, Alison; Lalu, Manoj M.
    Abstract Background The importance of investigating sex- and gender-dependent differences has been recently emphasized by major funding agencies. Notably, the influence of biological sex on clinical outcomes in sepsis is unclear, and observational studies suffer from the effect of confounding factors. The controlled experimental environment afforded by preclinical studies allows for clarification and mechanistic evaluation of sex-dependent differences. We propose a systematic review to assess the impact of biological sex on baseline responses to disease induction as well as treatment responses in animal models of sepsis. Given the lack of guidance surrounding sex-based analyses in preclinical systematic reviews, careful consideration of various factors is needed to understand how best to conduct analyses and communicate findings. Methods MEDLINE and Embase will be searched (2011-present) to identify preclinical studies of sepsis in which any intervention was administered and sex-stratified data reported. The primary outcome will be mortality. Secondary outcomes will include organ dysfunction, bacterial load, and IL-6 levels. Study selection will be conducted independently and in duplicate by two reviewers. Data extraction will be conducted by one reviewer and audited by a second independent reviewer. Data extracted from included studies will be pooled, and meta-analysis will be conducted using random effects modeling. Primary analyses will be stratified by animal age and will assess the impact of sex at the following time points: pre-intervention, in response to treatment, and post-intervention. Risk of bias will be assessed using the SYRCLE’s risk-of-bias tool. Illustrative examples of potential methods to analyze sex-based differences are provided in this protocol. Discussion Our systematic review will summarize the current state of knowledge on sex-dependent differences in sepsis. This will identify current knowledge gaps that future studies can address. Finally, this review will provide a framework for sex-based analysis in future preclinical systematic reviews. Systematic review registration PROSPERO CRD42022367726.