TABLE 3.

Important Knowledge Gaps and Future Directions

Area of Sepsis Research	Knowledge Gaps and Future Directions
Immunometabolism	Characterize sex-dependent immune cell population differences for the development of cell-specific therapeutic targets.
	Study the sequence of immunometabolic changes in immune cell populations to identify shifts associated with overactive or suppressed immune responses during sepsis, to aid in the development of precise, individualized immunometabolic therapies.
	Decipher the regulation of X chromosome inheritance with respect to immunometabolic regulatory mechanisms using an integrative omics approach.
Microbiome	Determine the impact of sex-dependent differences in the microbiome and the influence on sepsis outcomes, in both human cohorts as well as preclinical models.
	Apply germ-free and gnotobiotic approaches together with genetic tools, to dissect the role of the microbiome in the pathogenesis of sepsis, including the impact of sex-dependent differences.
	Determine the impact of biological sex on the therapeutic response to microbiota-targeted therapies in sepsis and critical illness (e.g., antibiotics and digestive decontamination, probiotics, synbiotics).
Epigenetics	Establish a baseline understanding of epigenetic modifications which occur during sepsis (in animal models as well as human cohorts).
	Investigate the effects of X-linked mosaicism and the role of the X-chromosome in potentially divergent sepsis outcomes in the clinical setting.
	Clarify the influence of sex-dependent differences in noncoding RNA expression and histone/gene modifications which may affect the development and progression of sepsis.
Cardiovascular	Stratification of hemodynamic phenotypes in human sepsis according to biological sex.
	Investigate the direct and indirect effects of sex hormones and/or menopausal status on hemodynamics and cardiovascular function in human sepsis.
	Identify sex-dependent resuscitation targets in sepsis.
	Investigate the salutary effects of sex hormones as adjunct therapies in sepsis, shock and trauma.
Reverse translation	Apply clinical knowledge to develop novel models and modify existing models of preclinical sepsis to better represent the human condition.
	Use clinical knowledge of sex-dependent differences in the design of preclinical studies, which may provide mechanistic insight and guide future research.
	Apply principles espoused by the minimum quality threshold in preclinical sepsis studies expert consensus statements.