No abstract

Sexual dimorphisms exist in multiple domains, from learning and memory to neurocognitive disease, and even in the immune system. Male sex has been associated with increased susceptibility to infection, as well as increased risk of adverse outcomes. Sepsis remains a major source of morbidity and mortality globally, and over half of septic patients admitted to intensive care are believed to suffer some degree of sepsis-associated encephalopathy (SAE). In the short term, SAE is associated with an increased risk of in-hospital mortality, and in the long term, has the potential for significant impairment of cognition, memory, and acceleration of neurocognitive disease. Despite increasing information regarding sexual dimorphism in neurologic and immunologic systems, research into these dimorphisms in sepsis-associated encephalopathy remains critically understudied. In this narrative review, we discuss how sex has been associated with brain morphology, chemistry, and disease, sexual dimorphism in immunity, and existing research into the effects of sex on SAE.

M ultiple organ failure (MOF) emerged as a deadly syndrome in surgical intensive care units (ICUs) in the early 1970s. Sepsis and trauma were the primary inciting events. With tremendous the advances in care over the ensuing four decades, the epidemiology of MOF evolved from a fulminant phenotype of progressive organ failure leading to early death into a lingering phenotype of chronic critical illness (CCI) leading to indolent death. 1,2 CCI was first described in a 1985 article entitled "to save or let die." 3 This was followed by reports in the 1990s describing CCI in ventilator-dependent patients who were discharged to long-term acute care (LTAC) facilities for ventilator weaning. 4 These reports focused on long-term functional disability using descriptive terms including "polyneuropathy of critical illness," "myopathy of critical illness," and "ICU-acquired weakness." 5 It was subsequently recognized that CCI affected other systems. 6 Most recently, the CCI literature has popularized the term "postintensive care unit syndrome," adding that ICU delirium contributes to long-term cognitive impairments with depression and posttraumatic stress disorders. 7 These reports have largely come from heterogeneous medical ICU patients and implicate different risk factors depending upon the patient population, but offer no unifying underlying pathobiology for CCI.In a 2012 review article, the University of Florida Sepsis Critical Illness Research Center coined the term persistent inflammation, immunosuppression, and catabolism syndrome (PICS) to describe underlying pathobiology of the CCI phenotype that is now commonly seen in surgical ICU survivors. 8 This term was proposed to provide a mechanistic paradigm in which to study CCI in surgical ICU patients who are now surviving previously lethal inflammatory insults (e.g., trauma, sepsis, burns, and pancreatitis). The purpose of this review article is to summarize the shift from MOF into PICS-CCI in surgical patients.

Central tolerance checkpoints are critical for the elimination of autoreactive B cells and the prevention of autoimmunity. When autoreactive B cells encounter their Ag at the immature B cell stage, BCR cross-linking induces receptor editing, followed by apoptosis if edited cells remain autoreactive. Although the transcription factor Foxo1 is known to promote receptor editing, the role of the related factor Foxo3 in central B cell tolerance is poorly understood. We find that BCR-stimulated immature B cells from Foxo3-deficient mice demonstrate reduced apoptosis compared with wild type cells. Despite this, Foxo3 mice do not develop increased autoantibodies. This suggests that the increased survival of Foxo3 immature B cells allows additional rounds of receptor editing, resulting in more cells "redeeming" themselves by becoming nonautoreactive. Indeed, increased Igλ usage and increased recombining sequence recombination among Igλ-expressing cells were observed in Foxo3 mice, indicative of increased receptor editing. We also observed that deletion of high-affinity autoreactive cells was intact in the absence of Foxo3 in the anti-hen egg lysozyme (HEL)/membrane-bound HEL model. However, Foxo3 levels in B cells from systemic lupus erythematosus (SLE) patients were inversely correlated with disease activity and reduced in patients with elevated anti-dsDNA Abs. Although this is likely due in part to increased B cell activation in these SLE patients, it is also possible that low-affinity B cells that remain autoreactive after editing may survive inappropriately in the absence of Foxo3 and become activated to secrete autoantibodies in the context of other SLE-associated defects.