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In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine.

ABSTRACT: In spite of over half a century of research, sepsis still constitutes a major problem in health care delivery. Although advances in research have significantly increased our knowledge of the pathogenesis of sepsis and resulted in better prognosis and improved survival outcome, sepsis still remains a major challenge in modern medicine with an increase in occurrence predicted and a huge socioeconomic burden. It is generally accepted that sepsis is due to an initial hyperinflammatory response. However, numerous efforts aimed at targeting the proinflammatory cytokine network have been largely unsuccessful and the search for novel potential therapeutic targets continues. Recent studies provide compelling evidence that dysregulated anti-inflammatory responses may also contribute to sepsis mortality. Our previous studies on the role of regulatory T cells and phosphoinositide 3-kinases in sepsis highlight immunological approaches that could be explored for sepsis therapy. In this article, we review the current and emerging concepts in sepsis, highlight novel potential therapeutic targets and immunological approaches for sepsis treatment and propose a biphasic treatment approach for management of the condition.

SUBMITTER: Okeke EB

PROVIDER: S-EPMC6738754 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine.

Okeke Emeka B EB Uzonna Jude E JE

Journal of innate immunity 20160116 2

In spite of over half a century of research, sepsis still constitutes a major problem in health care delivery. Although advances in research have significantly increased our knowledge of the pathogenesis of sepsis and resulted in better prognosis and improved survival outcome, sepsis still remains a major challenge in modern medicine with an increase in occurrence predicted and a huge socioeconomic burden. It is generally accepted that sepsis is due to an initial hyperinflammatory response. Howe ...[more]

PMID: 26771196

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Project description:Traditional approaches to clinical risk assessment utilize age as a marker of increased vulnerability to stress. Relatively recent advancements in the study of aging have led to the concept of the frailty syndrome, which represents a multidimensional state of depleted physiologic and psychosocial reserve and clinical vulnerability that is related to but variably present with advancing age. The frailty syndrome is now a well-established clinical entity that serves as both a guide for clinical intervention and a predictor of poor outcomes in the primary and acute care settings. The biological aspects of the syndrome broadly represent a network of interrelated perturbations involving the age-related accumulation of molecular, cellular, and tissue damage that leads to multisystem dysregulation, functional decline, and disproportionately poor response to physiologic stress. Given the complexity of the underlying biologic processes, several well-validated approaches to define frailty clinically have been developed, each with distinct and reasonable considerations. Stemming from this background, the past several years have seen a number of observational studies conducted in intensive care units that have established that the determination of frailty is both feasible and prognostically useful in the critical care setting. Specifically, frailty as determined by several different frailty measurement tools appears associated with mortality, increased health care utilization, and disability, and has the potential to improve risk stratification of intensive care patients. While substantial variability in the implementation of frailty measurement likely limits the generalizability of specific findings, the overall prognostic trends may offer some assistance in guiding management decisions with patients and their families. Although no trials have assessed interventions to improve the outcomes of critically ill older people living with frailty, the particular vulnerability of this population offers a promising target for intervention in the future.

Project description:Detection of RNA structure similarities is still one of the major computational problems in the discovery of RNA functions. A case in point is the study of the new appreciated long non-coding RNAs (lncRNAs), emerging as new players involved in many cellular processes and molecular interactions. Among several mechanisms of action, some lncRNAs show specific substructures that are likely to be instrumental for their functioning. For instance, it has been reported in literature that some lncRNAs have a guiding or scaffolding role by binding chromatin-modifying protein complexes. Thus, a functionally characterized lncRNA (reference) can be used to infer the function of others that are functionally unknown (target), based on shared structural motifs.In our previous work we presented a tool, MONSTER v1.0, able to identify structural motifs shared between two full-length RNAs. Our procedure is mainly composed of two ad-hoc developed algorithms: nbRSSP_extractor for characterizing the folding of an RNA sequence by means of a sequence-structure descriptor (i.e., an array of non-overlapping substructures located on the RNA sequence and coded by dot-bracket notation); and SSD_finder, to enable an effective search engine for groups of matches (i.e., chains) common to the reference and target RNA based on a dynamic programming approach with a new score function. Here, we present an updated version of the previous one (MONSTER v1.1) accounting for the peculiar feature of lncRNAs that are not expected to have a unique fold, but appear to fluctuate among a large number of equally-stable folds. In particular, we improved our SSD_finder algorithm in order to take into account all the alternative equally-stable structures.We present an application of MONSTER v1.1 on lincRNAs, which are a specific class of lncRNAs located in genomic regions which do not overlap protein-coding genes. In particular, we provide reliable predictions of the shared chains between HOTAIR, ANRIL and COLDAIR. The latter are lincRNAs which interact with the same protein complexes of the Polycomb group and hence they are expected to share structural motifs.

Project description:IntroductionCritically ill patients and their pharmacokinetics present complexities often not considered by consensus guidelines from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Prior surveys have suggested discordance between certain guideline recommendations and reported infectious disease pharmacist practice. Vancomycin dosing practices, including institutional considerations, have not previously been well described in the critically ill patient population.ObjectivesTo evaluate critical care pharmacists' self-reported vancomycin practices in comparison to the 2009 guideline recommendations and other best practices identified by the study investigators.MethodsAn online survey developed by the Research and Scholarship Committee of the Clinical Pharmacy and Pharmacology (CPP) Section of the Society of Critical Care Medicine (SCCM) was sent to pharmacist members of the SCCM CPP Section practicing in adult intensive care units in the spring of 2017. This survey queried pharmacists' self-reported practices regarding vancomycin dosing and monitoring in critically ill adults.ResultsThree-hundred and sixty-four responses were received for an estimated response rate of 26%. Critical care pharmacists self-reported largely following the 2009 vancomycin dosing and monitoring guidelines. The largest deviations in guideline recommendation compliance involve consistent use of a loading dose, dosing weight in obese patients, and quality improvement efforts related to systematically monitoring vancomycin-associated nephrotoxicity. Variation exists regarding pharmacist protocols and other practices of vancomycin use in critically ill patients.ConclusionAmong critical care pharmacists, reported vancomycin practices are largely consistent with the 2009 guideline recommendations. Variations in vancomycin dosing and monitoring protocols are identified, and rationale for guideline non-adherence with loading doses elucidated.

Dataset Information

In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine.

Publications

In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine.

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