RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome.
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ABSTRACT:
SUBMITTER: Urak KT
PROVIDER: S-EPMC6328615 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
Publications
RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome.
Urak Kevin T KT Blanco Giselle N GN Shubham Shambhavi S Lin Li-Hsien LH Dassie Justin P JP Thiel William H WH Chen Yani Y Sonkar Vijay Kumar VK Lei Beilei B Murthy Shubha S Gutierrez Wade R WR Wilson Mary E ME Stiber Jonathan A JA Klesney-Tait Julia J Dayal Sanjana S Miller Francis J FJ Giangrande Paloma H PH
Nature communications 20190110 1
The development of multiple organ dysfunction syndrome (MODS) following infection or tissue injury is associated with increased patient morbidity and mortality. Extensive cellular injury results in the release of nuclear proteins, of which histones are the most abundant, into the circulation. Circulating histones are implicated as essential mediators of MODS. Available anti-histone therapies have failed in clinical trials due to off-target effects such as bleeding and toxicity. Here, we describe ...[more]
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Project description:Since its introduction into the medical literature in the 1970s, the term multiple organ dysfunction syndrome (or some variant) has been applied broadly to any patient with >1 concurrent organ dysfunction. However, the epidemiology, mechanisms, time course, and outcomes among children with multiple organ dysfunction vary substantially. We posit that the term pediatric multiple organ dysfunction syndrome (or MODS) should be reserved for patients with a systemic pathologic state resulting from a common mechanism (or mechanisms) that affects numerous organ systems simultaneously. In contrast, children in whom organ injuries are attributable to distinct mechanisms should be considered to have additive organ system dysfunctions but not the syndrome of MODS. Although such differentiation may not always be possible with current scientific knowledge, we make the case for how attempts to differentiate multiple organ dysfunction from other states of additive organ dysfunctions can help to evolve clinical and research priorities in diagnosis, monitoring, and therapy from largely organ-specific to more holistic strategies.
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Project description:ObjectiveTo describe the state of the science, identify knowledge gaps, and offer potential future research questions regarding promising therapies for children with multiple organ dysfunction syndrome presented during the Eunice Kennedy Shriver National Institute of Child Health and Human Development Workshop on Pediatric Multiple Organ Dysfunction Syndrome (March 26-27, 2015).Data sourcesLiterature review, research data, and expert opinion.Study selectionNot applicable.Data extractionModerated by an expert from the field, issues relevant to the association of multiple organ dysfunction syndrome with a variety of conditions were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities.Data synthesisSummary of presentations and discussion supported and supplemented by relevant literature.ConclusionsAmong critically ill children, multiple organ dysfunction syndrome is relatively common and associated with significant morbidity and mortality. For outcomes to improve, effective therapies aimed at preventing and treating this condition must be discovered and rigorously evaluated. In this article, a number of potential opportunities to enhance current care are highlighted including the need for a better understanding of the pharmacokinetics and pharmacodynamics of medications, the effect of early and optimized nutrition, and the impact of effective glucose control in the setting of multiple organ dysfunction syndrome. Additionally, a handful of the promising therapies either currently being implemented or developed are described. These include extracorporeal therapies, anticytokine therapies, antitoxin treatments, antioxidant approaches, and multiple forms of exogenous steroids. For the field to advance, promising therapies and other therapies must be assessed in rigorous manner and implemented accordingly.
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Project description:BACKGROUND AND PURPOSE: Melanocortins reverse circulatory shock and improve survival by counteracting the systemic inflammatory response, and through the activation of the vagus nerve-mediated cholinergic anti-inflammatory pathway. To gain insight into the potential therapeutic value of melanocortins against multiple organ damage following systemic inflammatory response, here we investigated the effects of the melanocortin analogue [Nle? D-Phe?]?-MSH (NDP-?-MSH) in a widely used murine model of multiple organ dysfunction syndrome (MODS). EXPERIMENTAL APPROACH: MODS was induced in mice by a single intraperitoneal injection of lipopolysaccharide followed, 6 days later (= day 0), by zymosan. After MODS or sham MODS induction, animals were randomized to receive intraperitoneally NDP-?-MSH (340 µg·kg?¹ day) or saline for up to 16 days. Additional groups of MODS mice were concomitantly treated with the melanocortin MC? receptor antagonist HS024, or the nicotinic acetylcholine receptor antagonist chlorisondamine, and NDP-?-MSH. KEY RESULTS: At day 7, in the liver and lung NDP-?-MSH, significantly reduced mRNA expression of tumour necrosis factor-? (TNF-?), increased mRNA expression of interleukin-10 and improved the histological picture, as well as reduced TNF-? plasma levels; furthermore, NDP-?-MSH dose-dependently increased survival rate, as assessed throughout the 16 day observation period. HS024 and chlorisondamine prevented all the beneficial effects of NDP-?-MSH in MODS mice. CONCLUSIONS AND IMPLICATIONS: These data indicate that NDP-?-MSH protects against experimental MODS by counteracting the systemic inflammatory response, probably through brain MC? receptor-triggered activation of the cholinergic anti-inflammatory pathway. These findings reveal previously undescribed effects of melanocortins and could have clinical relevance in the MODS setting.
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Project description:Sepsis is a devastating condition that is generally treated as a single disease. Identification of meaningfully distinct clusters may improve research, treatment and prognostication among septic patients. We therefore sought to identify clusters among patients with severe sepsis or septic shock.We retrospectively studied all patients with severe sepsis or septic shock admitted directly from the emergency department to the intensive care units (ICUs) of three hospitals, 2006-2013. Using age and Sequential Organ Failure Assessment (SOFA) subscores, we defined clusters utilizing self-organizing maps, a method for representing multidimensional data in intuitive two-dimensional grids to facilitate cluster identification.We identified 2533 patients with severe sepsis or septic shock. Overall mortality was 17 %, with a mean APACHE II score of 24, mean SOFA score of 8 and a mean ICU stay of 5.4 days. Four distinct clusters were identified; (1) shock with elevated creatinine, (2) minimal multi-organ dysfunction syndrome (MODS), (3) shock with hypoxemia and altered mental status, and (4) hepatic disease. Mortality (95 % confidence intervals) for these clusters was 11 (8-14), 12 (11-14), 28 (25-32), and 21 (16-26) %, respectively (p < 0.0001). Regression modeling demonstrated that the clusters differed in the association between clinical outcomes and predictors, including APACHE II score.We identified four distinct clusters of MODS among patients with severe sepsis or septic shock. These clusters may reflect underlying pathophysiological differences and could potentially facilitate tailored treatments or directed research.
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Project description:ObjectiveTo summarize the epidemiology and outcomes of children with multiple organ dysfunction syndrome as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development multiple organ dysfunction syndrome workshop (March 26-27, 2015).Data sourcesLiterature review, research data, and expert opinion.Study selectionNot applicable.Data extractionModerated by an experienced expert from the field, issues relevant to the epidemiology and outcomes of children with multiple organ dysfunction syndrome were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities.Data synthesisSummary of presentations and discussion supported and supplemented by the relevant literature.ConclusionsA full understanding the epidemiology and outcome of multiple organ dysfunction syndrome in children is limited by inconsistent definitions and populations studied. Nonetheless, pediatric multiple organ dysfunction syndrome is common among PICU patients, occurring in up to 57% depending on the population studied; sepsis remains its leading cause. Pediatric multiple organ dysfunction syndrome leads to considerable short-term morbidity and mortality. Long-term outcomes of multiple organ dysfunction syndrome in children have not been well studied; however, studies of adults and children with other critical illnesses suggest that the risk of long-term adverse sequelae is high. Characterization of the long-term outcomes of pediatric multiple organ dysfunction syndrome is crucial to identify opportunities for improved treatment and recovery strategies that will improve the quality of life of critically ill children and their families. The workshop identified important knowledge gaps and research priorities intended to promote the development of standard definitions and the identification of modifiable factors related to its occurrence and outcome.
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Project description:Sepsis-induced multiple organ dysfunction syndrome (MODS) is a major cause of morbidity and mortality in critically ill patients and remains impervious to most therapeutic interventions. We utilized a clinically relevant murine model of MODS induced by ventilator-associated pneumonia to systematically delineate pathways dysregulated in lung, liver, and kidney. We focused on processes commonly activated across injured organs and constructed a MODS-associated network based on connectivity among the gene members of these functionally coherent pathways. Our analyses led to the identification of several putative drivers of MODS whose expression was regulated by epidermal growth factor receptor. Our unbiased, integrative method is a promising approach to unravel mechanisms in system-wide disorders afflicting multiple compartments such as sepsis-induced MODS, and guide the discovery of novel putative therapeutic targets.
2014-12-31 | GSE60088 | GEO
Project description:OBJECTIVES:We sought to describe current outcomes of Multiple Organ Dysfunction Syndrome present on day 1 of PICU admission. DESIGN:Retrospective observational cohort study. SETTING:Virtual Pediatric Systems, LLC, database admissions, January 2014 and December 2015. PATIENTS:We analyzed 194,017 consecutive PICU admissions, (age 1 mo to 18 yr) from the 2014-2015 Virtual Pediatric Systems database. INTERVENTIONS:We identified day 1 Multiple Organ Dysfunction Syndrome by International Pediatric Sepsis Consensus Conference criteria with day 1 laboratory and vital sign values. Functional status was evaluated by Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores from PICU admission and discharge. MEASUREMENTS AND MAIN RESULTS:Overall, PICU mortality was 2.1%. We identified day 1 Multiple Organ Dysfunction Syndrome in 14.4% of admissions. Patients with Multiple Organ Dysfunction Syndrome had higher mortality than those without Multiple Organ Dysfunction Syndrome (10.3% vs 0.7%; p < 0.0001), and a higher percentage of survivors had greater than or equal to 2 category worsening in Pediatric Cerebral Performance Category score (3.6% vs 0.5%; p < 0.0001) or Pediatric Overall Performance Category score (6.0% vs 1.8%; p < 0.0001). The odds of death with day 1 Multiple Organ Dysfunction Syndrome was 14.3 (95% CI, 13-15.7), while the odds of death or discharge with Pediatric Overall Performance Category/Pediatric Cerebral Performance Category score greater than or equal to 3 (poor functional outcome) was 6.7 (95% CI, 6-7.4). In a subset of 148,188 patients from hospitals where limitation of support decisions were recorded, 5.8% patients with Multiple Organ Dysfunction Syndrome had limitation of support decisions in place, compared with 0.8% of patients without Multiple Organ Dysfunction Syndrome (p < 0.0001). Of day 1 Multiple Organ Dysfunction Syndrome patients who died, 43.1% had limitation of support decisions in place, and 41.6% had withdrawal of life-sustaining therapies (p < 0.0001). CONCLUSIONS:Multiple Organ Dysfunction Syndrome present on day 1 of admission continues to be a major source of morbidity and mortality in the PICU, but risk of poor neurologic outcome may be improved. Further research is needed to understand decisions regarding limitation of support and withdrawal of life-sustaining therapy decisions in patients admitted with day 1 Multiple Organ Dysfunction Syndrome.
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Project description:BackgroundSevere stroke patients have poor clinical outcome which may be associated with development of multiple organ dysfunction syndrome (MODS). Therefore, the aim of our study was to investigate independent risk factors for development of MODS in severe stroke patients.MethodsNinety seven severe stroke patients were prospective recruited from Jan 2011 to Jun 2015. The development of MODS was identified by Sequential Organ Failure Assessment (SOFA) score (score ? 3, at least two organs), which was assessed on day 1, 4, 7, 10 and 14 after admission. Baseline characteristics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Glasgow coma score (GCS) and cerebral imaging parameters were collected at admission. Cox regression was performed to determine predictors for the development of MODS. Medical complications after admission and in-hospital mortality were also investigated.Results33 (34%) patients were in MODS group and 64 (66%) were in non-MODS group within 14 days after admission. Patients in MODS group had more smoker (51.5% vs 28.1%, p = 0.023), higher NIHSS score (23.48 ± 6.12 vs 19.81 ± 4.83, p = 0.004), higher APACHE II score (18.70 ± 5.18 vs 15.64 ± 4.36, p = 0.003) and lower GCS score (6.33 ± 2.48 vs 8.14 ± 2.73, p = 0.002). They also had higher rate of infarction in multi vascular territories (36.4% vs 10.9%, p = 0.003). The most common complication in all patients was pulmonary infection, while complication scores were comparable between two groups. Patients with MODS had higher in-hospital mortality (69.7% vs 9.4%, p = 0.000). In Cox regression, NIHSS score (RR = 1.084, 95% CI 1.019-1.153) and infarction in multi vascular territories (RR = 2.345 95% CI 1.105-4.978) were independent risk factors for development of MODS.ConclusionsIn acute phase of stroke, NIHSS score and infarction in multi vascular territories predicted MODS in severe stroke patients. Moreover, patients with MODS had higher in-hospital mortality, suggesting that early identification of MODS is critical important.
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Project description:MotivationSepsis is a leading cause of death and disability in children globally, accounting for ∼3 million childhood deaths per year. In pediatric sepsis patients, the multiple organ dysfunction syndrome (MODS) is considered a significant risk factor for adverse clinical outcomes characterized by high mortality and morbidity in the pediatric intensive care unit. The recent rapidly growing availability of electronic health records (EHRs) has allowed researchers to vastly develop data-driven approaches like machine learning in healthcare and achieved great successes. However, effective machine learning models which could make the accurate early prediction of the recovery in pediatric sepsis patients from MODS to a mild state and thus assist the clinicians in the decision-making process is still lacking.ResultsThis study develops a machine learning-based approach to predict the recovery from MODS to zero or single organ dysfunction by 1 week in advance in the Swiss Pediatric Sepsis Study cohort of children with blood-culture confirmed bacteremia. Our model achieves internal validation performance on the SPSS cohort with an area under the receiver operating characteristic (AUROC) of 79.1% and area under the precision-recall curve (AUPRC) of 73.6%, and it was also externally validated on another pediatric sepsis patients cohort collected in the USA, yielding an AUROC of 76.4% and AUPRC of 72.4%. These results indicate that our model has the potential to be included into the EHRs system and contribute to patient assessment and triage in pediatric sepsis patient care.Availability and implementationCode available at https://github.com/BorgwardtLab/MODS-recovery. The data underlying this article is not publicly available for the privacy of individuals that participated in the study.Supplementary informationSupplementary data are available at Bioinformatics online.
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Project description:BackgroundThe relationship between hyperlactatemia and prognosis after cardiopulmonary bypass (CPB) is controversial, and some studies ignore the presence of lactic acidosis in patients with severe hyperlactacemia. This study explored the association between lactic acidosis (LA) and the occurrence of multiple organ dysfunction syndrome (MODS) after cardiopulmonary bypass.MethodsThis study was a post hoc analysis of patients who underwent cardiac surgery between February 2017 and August 2018 and participated in a prospective study at Taizhou Hospital. The data were collected at: ICU admission (H0), and 4, 8, 12, 24, and 48 h after admission. Blood lactate levels gradually increased after CPB, peaking at H8 and then gradually decreasing. The patients were grouped as LA, hyperlactatemia (HL), and normal control (NC) based on blood test results 8 h after ICU admission. Basic preoperative, perioperative, and postoperative conditions were compared between the three groups, as well as postoperative perfusion and oxygen metabolism indexes.ResultsThere were 22 (19%), 73 (64%), and 19 (17%) patients in the LA, HL, and NC groups, respectively. APACHE II (24h) and SOFA (24h) scores were the highest in the LA group (P < 0.05). ICU stay duration was the longest for the LA group (48.5 (42.5, 50) h), compared with the HL (27 (22, 48) h) and NC (27 (25, 46) h) groups (P = 0.012). The LA group had the highest incidence of MODS (36%), compared with the HL (14%) and NC (5%) groups (P = 0.015). In the LA group, the oxygen extraction ratio (O2ER) was lower (21.5 (17.05, 32.8)%) than in the HL (31.3 (24.8, 37.6)%) and the NC group (31.3 (29.0, 35.4) %) (P = 0.018). In the univariable analyses, patient age (OR = 1.054, 95% CI [1.003-1.109], P = 0.038), the LA group (vs. the NC group, (OR = 10.286, 95% CI [1.148-92.185], P = 0.037), and ΔPCO2 at H8 (OR = 1.197, 95% CI [1.022-1.401], P = 0.025) were risk factor of MODS after CPB.ConclusionsWe speculated that there was correlation between lactic acidosis and MODS after CPB. In addition, LA should be monitored intensively after CPB.
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