Abstract The plasma profile of subjects with nonalcoholic fatty liver disease (NAFLD), steatosis, and steatohepatitis (NASH) was examined using an untargeted global metabolomic analysis to identify ...specific disease-related patterns and to identify potential noninvasive biomarkers. Plasma samples were obtained after an overnight fast from histologically confirmed nondiabetic subjects with hepatic steatosis (n = 11) or NASH (n = 24) and were compared with healthy, age- and sex-matched controls (n = 25). Subjects with NAFLD were obese, were insulin resistant, and had higher plasma concentrations of homocysteine and total cysteine and lower plasma concentrations of total glutathione. Metabolomic analysis showed markedly higher levels of glycocholate, taurocholate, and glycochenodeoxycholate in subjects with NAFLD. Plasma concentrations of long-chain fatty acids were lower and concentrations of free carnitine, butyrylcarnitine, and methylbutyrylcarnitine were higher in NASH. Several glutamyl dipeptides were higher whereas cysteine-glutathione levels were lower in NASH and steatosis. Other changes included higher branched-chain amino acids, phosphocholine, carbohydrates (glucose, mannose), lactate, pyruvate, and several unknown metabolites. Random forest analysis and recursive partitioning of the metabolomic data could separate healthy subjects from NAFLD with an error rate of approximately 8% and separate NASH from healthy controls with an error rate of 4%. Hepatic steatosis and steatohepatitis could not be separated using the metabolomic profile. Plasma metabolomic analysis revealed marked changes in bile salts and in biochemicals related to glutathione in subjects with NAFLD. Statistical analysis identified a panel of biomarkers that could effectively separate healthy controls from NAFLD and healthy controls from NASH. These biomarkers can potentially be used to follow response to therapeutic interventions.
Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of ...2,204 females (115 type 2 diabetic T2D case subjects, 192 individuals with impaired fasting glucose IFG, and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio OR 1.65 95% CI 1.39-1.95, P = 8.46 × 10(-9)) and was moderately heritable (h(2) = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 1.34-2.11, P = 6.52 × 10(-6)) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 1.27-2.75, P = 1 × 10(-3)). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.
Abstract
Our objective was to identify plasma biomarkers of ALS that can aid in distinguishing patients with ALS from those with disease mimics. In this multi-center study, plasma samples were ...collected from 172 patients recently diagnosed with ALS, 50 healthy controls, and 73 neurological disease mimics. Samples were analyzed using metabolomics. Using all identified biochemicals detected in > 50% of all samples in the metabolomics analysis, samples were classified as ALS or mimic with 65% sensitivity and 81% specificity by LASSO analysis (AUC of 0.76). A subset panel of 32 candidate biomarkers classified these diagnosis groups with a specificity of 90%/sensitivity 58% (AUC of 0.81). Creatinine was lower in subjects with lower revised ALS Functional Rating Scale (ALSFRS-R) scores. In conclusion, ALS can be distinguished from neurological disease mimics by global biochemical profiling of plasma samples. Our analysis identified ALS versus mimics with relatively high sensitivity. We identified a subset of 32 metabolites that identify patients with ALS with a high specificity. Interestingly, lower creatinine correlates significantly with a lower ALSFRS-R score. Finally, molecules previously reported to be important in disease pathophysiology, such as urate, are included in our metabolite panel.
The plasma profile of subjects with non-alcoholic fatty liver disease (NAFLD), steatosis and steatohepatitis (NASH), was examined using an untargeted global metabolomic analysis in order to identify ...specific disease-related pattern/s and to identify potential non-invasive biomarkers. Plasma samples were obtained after an overnight fast from histologically confirmed non-diabetic subjects with hepatic steatosis (N=11) or NASH (N=24), and compared with healthy, age and sex-matched controls (n=25). Subjects with NAFLD were obese, were insulin resistant and had higher plasma concentration of homocysteine and total cysteine and lower plasma concentrations of total glutathione. Metabolomic analysis showed markedly higher levels of glycocholate, taurocholate and glycochenodeoxycholate in subjects with NAFLD. Plasma concentrations of long chain fatty acids were lower and concentrations of free carnitine, butyrylcarnitine and methylbutyryl carnitine were higher in NASH. Several glutamyl dipeptides were higher, while cysteine-glutathione levels were lower in NASH and steatosis. Other changes included higher branched chain amino acids, phosphocholine, carbohydrates (glucose, mannose), lactate, pyruvate, and several unknown metabolites. Random forest analysis and recursive partitioning of the metabolomic data could separate healthy subjects from NAFLD with an error rate of ~8%, and NASH from healthy controls with an error rate of 4%. Hepatic steatosis and steatohepatitis could not be separated using the metabolomic profile.
The metabolomics of aging Berger, Alvin; Milgram, Eric; Mitchell, Matthew ...
The FASEB journal,
2007, 2007-01-00, Letnik:
21, Številka:
6
Journal Article
Recenzirano
We evaluated the effects of aging on the plasma metabolome in a racially mixed cohort of 270 human subjects, aged 25–65. Using a global LC‐ and GC‐MS approach, 432 compounds (131 named) were detected ...in plasma. Age, race, and gender affected 250‐ (68% being increased), 100‐, and 100‐ compounds, respectively. Increased age was associated with increased TCA intermediates, creatine, essential/non‐essential amino acids, urea, ornithine and polyamines. Compounds related to fat metabolism, including fatty acids, carnitine, betahydroxybutyrate, cholesterol and glycocholate, were higher in persons 51–65 years. DHEA levels (a proposed anti‐aging androgen) were lower in this older age group; whereas markers of oxidative stress including oxoproline, hippurate and 3,4‐dihydroxybenzoate were higher. Xenobiotics (e.g., caffeine) were increased in older subjects, which may relate to P450 metabolism. The data suggest aging is associated with significant changes in protein, fat and energy metabolism, and provide evidence for increased oxidative stress. Increases in plasma amino acid and fatty acids with age may result from increased sarcopenia and insulin resistance. Evaluation of the plasma metabolome provides a rapid and powerful method for examining physiological perturbations in aging and other biological processes.
The purpose of the COMPLETE (International Acute Ischemic Stroke Registry With the Penumbra System Aspiration Including the 3D Revascularization Device) registry was to evaluate the generalizability ...of the safety and efficacy of the Penumbra System (Penumbra, Inc, Alameda) in a real-world setting.
COMPLETE was a global, prospective, postmarket, multicenter registry. Patients with large vessel occlusion-acute ischemic stroke who underwent mechanical thrombectomy using the Penumbra System with or without the 3D Revascularization Device as frontline approach were enrolled at 42 centers (29 United States, 13 Europe) from July 2018 to October 2019. Primary efficacy end points were successful postprocedure angiographic revascularization (modified Thrombolysis in Cerebral Infarction ≥2b) and 90-day functional outcome (modified Rankin Scale score 0-2). The primary safety end point was 90-day all-cause mortality. An imaging core lab determined modified Thrombolysis in Cerebral Infarction scores, Alberta Stroke Program Early CT Scores, clot location, and occurrence of intracranial hemorrhage at 24 hours. Independent medical reviewers adjudicated safety end points.
Six hundred fifty patients were enrolled (median age 70 years, 54.0% female, 49.2% given intravenous recombinant tissue-type plasminogen activator before thrombectomy). Rate of modified Thrombolysis in Cerebral Infarction 2b to 3 postprocedure was 87.8% (95% CI, 85.3%-90.4%). First pass and postprocedure rates of modified Thrombolysis in Cerebral Infarction 2c to 3 were 41.5% and 66.2%, respectively. At 90 days, 55.8% (95% CI, 51.9%-59.7%) had modified Rankin Scale score 0 to 2, and all-cause mortality was 15.5% (95% CI, 12.8%-18.3%).
Using Penumbra System for frontline mechanical thrombectomy treatment of patients with large vessel occlusion-acute ischemic stroke in a real-world setting was associated with angiographic, clinical, and safety outcomes that were comparable to prior randomized clinical trials with stringent site and operator selection criteria. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03464565.
Abstract
Background
Staphylococcus aureus colonization in infants in the neonatal intensive care unit (NICU) often leads to repeated infections and severe disease. Methicillin-resistant S. aureus ...(MRSA) and methicillin-sensitive S. aureus (MSSA) infections are major causes of NICU outbreaks. Current national practice in NICUs utilizes nare swab surveillance for S. aureus. We hypothesize that infants colonized in the stool with S. aureus may go unrecognized particularly when nare swab negative, allowing for a transmission reservoir. While it is unclear why some S. aureus nare carriers are also stool colonized, isolates tend to have clonality. A true prevalence of S. aureus fecal carriage is not well understood and variable.
Methods
Available stool samples were prospectively collected from 42 of 55 infants admitted in a level IV NICU on a single day, per Cincinnati Children’s institutional review board approval. Nare swab results were obtained from electronic medical records. DNA was isolated from stool and shotgun metagenomic sequencing was performed via Hiseq Illuminex 2500. The presence of S. aureus and MRSA were defined as having >100 sequencing reads and a mecA DNA read fraction ratio >40 per stool sample, respectively.
Results
Of the 42 stool samples sequenced, 33 were S. aureus (15 MSSA, 18 MRSA) positive. All infants with nare positive MSSA (n = 9) were colonized in the stool with a 93% and 100% sensitivity and specificity, respectively. While infants with nare positive MRSA (n = 10) were stool colonized with 100% and 83% sensitivity and specificity, respectively. Three nare positive infants with MRSA had S.a. in the stool but lacked the presence of mecA. When comparing clinical nare swabs to stool metagenomic surveillance, sensitivities were 60% for MSSA and 56% for MRSA.
Conclusion
Infant colonization of S. aureus in the NICU remains a major problem despite current national surveillance and isolation practices. We found that nare swab surveillance for S. aureus in infants significantly underestimated colonization rates when compared with shotgun metagenomics of stool. These results suggest that nare swabs alone may not have adequate sensitivity and the implementation of stool surveillance should be considered to augment current practices. Future study is necessary to understand how the S. aureus stool reservoir contributes to transmission
Disclosures
All authors: No reported disclosures.
The SARS-CoV-2 pandemic presented healthcare providers with an extreme challenge to provide cancer services. The impact upon the diagnostic and treatment capacity to treat pancreatic cancer is ...unclear. This study aimed to identify national variation in treatment pathways during the pandemic.
A survey was distributed to all United Kingdom pancreatic specialist centres, to assess diagnostic, therapeutic and interventional services availability, and alterations in treatment pathways. A repeating methodology enabled assessment over time as the pandemic evolved.
Responses were received from all 29 centres. Over the first six weeks of the pandemic, less than a quarter of centres had normal availability of diagnostic pathways and a fifth of centres had no capacity whatsoever to undertake surgery. As the pandemic progressed services have gradually improved though most centres remain constrained to some degree. One third of centres changed their standard resectable pathway from surgery-first to neoadjuvant chemotherapy. Elderly patients, and those with COPD were less likely to be offered treatment during the pandemic.
The COVID-19 pandemic has affected the capacity of the NHS to provide diagnostic and staging investigations for pancreatic cancer. The impact of revised treatment pathways has yet to be realised.
The book is a handbook of cultural discourse analysis, a theory developed by Donal Carbaugh, and celebration of his work. The book features an explanation of the theory and sixteen chapters using the ...theory to examine communication issues across the globe.
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