Rationale: Septic shock is a significant cause of morbidity and mortality in the pediatric population. Early recognition of septic shock and appropriate treatment increase survival rate; thus, developing new diagnostic tools may improve patients' outcomes. Objectives: To determine whether a metabolomics approach could be useful in the diagnosis and prognosis of septic shock in pediatric intensive care unit (PICUs). Methods: Serum samples were collected from 60 patients with septic shock, 40 PICU patients with systemic inflammatory response syndrome (not suspected of having an infection), and 40 healthy children. Proton nuclear magnetic resonance spectroscopy spectra were analyzed and quantified using targeted profiling methodology. Measurements and Main Results: Multivariate statistical analysis was applied to detect specific patterns in metabolic profiles and to highlight differences between patient samples. Supervised analysis afforded good predictive models and managed to separate patient populations. Some of the metabolite concentrations identified in serum samples changed markedly, indicating their influence on the separation between patient groups. These metabolites represent a composite biopattern of the pediatric metabolic response to septic shock and might be considered as the basis for a biomarker panel for the diagnosis of septic shock and its mortality in PICU. Conclusions: Our results indicate that nuclear magnetic resonance metabolite profiling might serve as a promising approach for the diagnosis and prediction of mortality in septic shock in a pediatric population and that quantitative metabolomics methods can be applied in the clinical evaluations of pediatric septic shock.Keywords: pediatric septic shock; biomarkers; metabolomics; proton nuclear magnetic resonance spectroscopy; mortalityIn the 1980s the death rate from septic shock in children was around 50% (1, 2), but over the past few decades with better early diagnosis and therapy it has decreased to approximately 10% (3, 4). Unfortunately, in third world countries the mortality rate is still extremely high (5, 6). Moreover, every hour of septic shock without appropriate resuscitation and restoration of blood pressure increases mortality risk by 40% (7). Septic shock is a very dynamic process, and the clinical status of a child can deteriorate quickly (8). The first hours after the diagnosis are called the "golden hours" for a patient's survival; therefore, aggressive and goal-directed treatment should be initiated as quickly as possible (9). It is reported that those children in whom septic shock is recognized early and properly treated have a much higher survival rate than children who were diagnosed later (10-12). Thus, developing diagnostic approaches that might accelerate disease recognition is extremely important to improve patient outcomes and decrease mortality.In this study we investigated whether we could use a metabolomics approach for the diagnosis and prognosis of pediatric septic shock. Metabolomics is defined as "the quantita...

Our results indicate that nuclear magnetic resonance-based metabolic profiling could be used for diagnosis and mortality prediction of septic shock in the ICU.

IntroductionPancreatic and periampullary adenocarcinomas are associated with abnormal body composition visible on CT scans, including low muscle mass (sarcopenia) and low muscle radiodensity due to fat infiltration in muscle (myosteatosis). The biological and clinical correlates to these features are poorly understood.MethodsClinical characteristics and outcomes were studied in 123 patients who underwent pancreaticoduodenectomy for pancreatic or non-pancreatic periampullary adenocarcinoma and who had available preoperative CT scans. In a subgroup of patients with pancreatic cancer (n = 29), rectus abdominus muscle mRNA expression was determined by cDNA microarray and in another subgroup (n = 29) 1H-NMR spectroscopy and gas chromatography-mass spectrometry were used to characterize the serum metabolome.ResultsMuscle mass and radiodensity were not significantly correlated. Distinct groups were identified: sarcopenia (40.7%), myosteatosis (25.2%), both (11.4%). Fat distribution differed in these groups; sarcopenia associated with lower subcutaneous adipose tissue (P<0.0001) and myosteatosis associated with greater visceral adipose tissue (P<0.0001). Sarcopenia, myosteatosis and their combined presence associated with shorter survival, Log Rank P = 0.005, P = 0.06, and P = 0.002, respectively. In muscle, transcriptomic analysis suggested increased inflammation and decreased growth in sarcopenia and disrupted oxidative phosphorylation and lipid accumulation in myosteatosis. In the circulating metabolome, metabolites consistent with muscle catabolism associated with sarcopenia. Metabolites consistent with disordered carbohydrate metabolism were identified in both sarcopenia and myosteatosis.DiscussionMuscle phenotypes differ clinically and biologically. Because these muscle phenotypes are linked to poor survival, it will be imperative to delineate their pathophysiologic mechanisms, including whether they are driven by variable tumor biology or host response.

IntroductionSeptic shock is a major life-threatening condition in critically ill patients and it is well known that early recognition of septic shock and expedient initiation of appropriate treatment improves patient outcome. Unfortunately, to date no single compound has shown sufficient sensitivity and specificity to be used as a routine biomarker for early diagnosis and prognosis of septic shock in the intensive care unit (ICU). Therefore, the identification of new diagnostic tools remains a priority for increasing the survival rate of ICU patients. In this study, we have evaluated whether a combined nuclear magnetic resonance spectroscopy-based metabolomics and a multiplex cytokine/chemokine profiling approach could be used for diagnosis and prognostic evaluation of septic shock patients in the ICU.MethodsSerum and plasma samples were collected from septic shock patients and ICU controls (ICU patients with the systemic inflammatory response syndrome but not suspected of having an infection). 1H Nuclear magnetic resonance spectra were analyzed and quantified using the targeted profiling methodology. The analysis of the inflammatory mediators was performed using human cytokine and chemokine assay kits.ResultsBy using multivariate statistical analysis we were able to distinguish patient groups and detect specific metabolic and cytokine/chemokine patterns associated with septic shock and its mortality. These metabolites and cytokines/chemokines represent candidate biomarkers of the human response to septic shock and have the potential to improve early diagnosis and prognosis of septic shock.ConclusionsOur findings show that integration of quantitative metabolic and inflammatory mediator data can be utilized for the diagnosis and prognosis of septic shock in the ICU.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0729-0) contains supplementary material, which is available to authorized users.

Osteoarthritis (OA) is a leading cause of chronic joint pain in the older human population. Diagnosis of OA at an earlier stage may enable the development of new treatments to one day effectively modify the progression and prognosis of the disease. In this work, we explore whether an integrated metabolomics approach could be utilized for the diagnosis of OA. Synovial fluid (SF) samples were collected from symptomatic chronic knee OA patients and normal human cadaveric knee joints. The samples were analyzed using 1 H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) followed by multivariate statistical analysis. Based on the metabolic profiles, we were able to distinguish OA patients from the controls and validate the statistical models. Moreover, we have integrated the 1 H NMR and GC-MS results and we found that 11 metabolites were statistically important for the separation between OA and normal SF. Additionally, statistical analysis showed an excellent predictive ability of the constructed metabolomics model (area under the receiver operating characteristic curve ¼ 1.0). Our findings indicate that metabolomics might serve as a promising approach for the diagnosis and prognosis of degenerative changes in the knee joint and should be further validated in clinical settings.

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IntroductionThe first steps in goal-directed therapy for sepsis are early diagnosis followed by appropriate triage. These steps are usually left to the physician’s judgment, as there is no accepted biomarker available. We aimed to determine biomarker phenotypes that differentiate children with sepsis who require intensive care from those who do not.MethodsWe conducted a prospective, observational nested cohort study at two pediatric intensive care units (PICUs) and one pediatric emergency department (ED). Children ages 2–17 years presenting to the PICU or ED with sepsis or presenting for procedural sedation to the ED were enrolled. We used the judgment of regional pediatric ED and PICU attending physicians as the standard to determine triage location (PICU or ED). We performed metabolic and inflammatory protein mediator profiling with serum and plasma samples, respectively, collected upon presentation, followed by multivariate statistical analysis.ResultsNinety-four PICU sepsis, 81 ED sepsis, and 63 ED control patients were included. Metabolomic profiling revealed clear separation of groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.89, area under the receiver operating characteristic curve (AUROC) of 0.96 (standard deviation [SD] 0.01), and predictive ability (Q2) of 0.60. Protein mediator profiling also showed clear separation of the groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.78 and AUROC of 0.88 (SD 0.03). Combining metabolomic and protein mediator profiling improved the model (Q2 =0.62), differentiating PICU sepsis from ED sepsis with accuracy of 0.87 and AUROC of 0.95 (SD 0.01). Separation of PICU sepsis or ED sepsis from ED controls was even more accurate. Prespecified age subgroups (2–5 years old and 6–17 years old) improved model accuracy minimally. Seventeen metabolites or protein mediators accounted for separation of PICU sepsis and ED sepsis with 95 % confidence.ConclusionsIn children ages 2–17 years, combining metabolomic and inflammatory protein mediator profiling early after presentation may differentiate children with sepsis requiring care in a PICU from children with or without sepsis safely cared for outside a PICU. This may aid in making triage decisions, particularly in an ED without pediatric expertise. This finding requires validation in an independent cohort.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1026-2) contains supplementary material, which is available to authorized users.

Joint injuries and subsequent osteoarthritis (OA) are the leading causes of chronic joint disease. In this work, we explore the possibility of applying magnetic resonance spectroscopy-based metabolomics to detect host responses to an anterior cruciate ligament (ACL) reconstruction injury in synovial fluid in an ovine model. Using multivariate statistical analysis, we were able to distinguish post-injury joint samples (ACL and sham surgery) from the uninjured control samples, and as well the ACL surgical samples from sham surgery. In all samples there were 65 metabolites quantified, of which six could be suggested as biomarkers for early post-injury degenerative changes in the knee joints: isobutyrate, glucose, hydroxyproline, asparagine, serine, and uridine. Our results raise a cautionary note indicating that surgical interventions into the knee can result in metabolic alterations that need to be distinguished from those caused by the early onset of OA. Our findings illustrate the potential application of metabolomics as a diagnostic and prognostic tool for detection of injuries to the knee joint. The ability to detect a unique pattern of metabolic changes in the synovial fluid of sheep offers the possibility of extending the approach to precision medicine protocols in patient populations in the future. ß