Dataset Information

Sex-based analysis of treatment responses in animal models of sepsis: a preclinical systematic review protocol.

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.

SUBMITTER: Zhang M

PROVIDER: S-EPMC10029211 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Sex-based analysis of treatment responses in animal models of sepsis: a preclinical systematic review protocol.

Zhang MengQi M Fergusson Dean A DA Sharma Rahul R Khoo Ciel C Mendelson Asher A AA McDonald Braedon B Macala Kimberly F KF Sharma Neha N Gill Sean E SE Fiest Kirsten M KM Lehmann Christian C Shorr Risa R Jahandideh Forough F Bourque Stephane L SL Liaw Patricia C PC Fox-Robichaud Alison A Lalu Manoj M MM

Systematic reviews 20230321 1

<h4>Background</h4>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 ...[more]

PMID: 36945012

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Project description:BACKGROUND:Animal studies reporting immune checkpoint inhibitors (CPIs) improved host defense and survival during bacterial sepsis provided one basis for phase I CPI sepsis trials. We performed a systematic review and meta-analysis examining the benefit of CPI therapy in preclinical studies, and whether variables potentially altering this clinical benefit were investigated. Studies were analyzed that compared survival following bacteria or lipopolysaccharide challenge in animals treated with inhibitors to programmed death-1 (PD-1), PD-ligand1 (PD-L1), cytotoxic T lymphocyte-associated protein-4 (CTLA-4), or B- and T-lymphocyte attenuator (BTLA) versus control. RESULTS:Nineteen experiments from 11 studies (n = 709) were included. All experiments were in mice, and 10 of the 19 were published from a single research group. Sample size calculations and randomization were not reported in any studies, and blinding procedures were reported in just 1. Across all 19 experiments, CPIs increased the odds ratio for survival (OR, 95% CI) [3.37(1. 55, 7.31)] but with heterogeneity (I2 = 59%, p < 0.01). After stratification by checkpoint molecule targeted, challenge site or type, or concurrent antibacterial treatment, CPIs had consistent effects over most experiments in the 9 that included antibacterial treatment [OR = 2.82 (1.60, 4.98), I2 = 6%, p = 0.39 with versus 4.01 (0.89, 18.05), I2 = 74%, p < 0.01 without]. All 9 antibiotic experiments employed cecal-ligation and puncture (CLP) bacterial challenge while 6 also included a Candida albicans challenge 3-4 days after CLP. In these six experiments (n = 322), CPIs were directed at the fungal challenge when CLP lethality had resolved, and were consistently beneficial [2.91 (2.41, 3.50), I2 = 0%, p = 0.99]. In the three experiments (n = 66) providing antibiotics without fungal challenge, CPIs were administered within 1 day of CLP and had variable and non-significant effects [0.05 (0.00, 1.03); 7.86 (0.28, 217.11); and 8.50 (0.90, 80.03)]. No experiment examined pneumonia. CONCLUSIONS:Preclinical studies showing that CPIs add benefit to antibiotic therapy for the common bacterial infections causing sepsis clinically are needed to support this therapeutic approach. Studies should be reproducible across multiple laboratories and include procedures to reduce the risk of bias.

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Dataset Information

Sex-based analysis of treatment responses in animal models of sepsis: a preclinical systematic review protocol.

Background

Methods

Discussion

Systematic review registration

Publications

Sex-based analysis of treatment responses in animal models of sepsis: a preclinical systematic review protocol.

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