a secondary analysis of two pharmacokinetic studies in surgical ICU patients

Background In ICU patients, glomerular filtration is often impaired, but also supraphysiological values are observed (“augmented renal clearance”, >130 mL/min/1.73 m2). Renally eliminated drugs (e.g. many antibiotics) must be adjusted accordingly, which requires a quantitative measure of renal function throughout all the range of clinically encountered values. Estimation from plasma creatinine is standard, but cystatin C may be a valuable alternative. Methods This was a secondary analysis of renal function parameters in 100 ICU patients from two pharmacokinetic studies on vancomycin and betalactam antibiotics. Estimated clearance values obtained by the Cockcroft-Gault formula (eCLCG), the CKD-EPI formula (eCLCKD-EPI) or the cystatin C based Hoek formula (eCLHoek) were compared with the measured endogenous creatinine clearance (CLCR). Agreement of values was assessed by modified Bland-Altman plots and by calculating bias (median error) and precision (median absolute error). Sensitivity and specificity of estimates to identify patients with reduced (130 mL/min/1.73 m2) CLCR were calculated. Results The CLCR was well distributed from highly compromised to supraphysiological values (median 73.2, range 16.8-234 mL/min/1.73 m2), even when plasma creatinine was not elevated (≤0.8 mg/dL for women, ≤1.1 mg/dL for men). Bias and precision were +13.5 mL/min/1.73 m2 and ±18.5 mL/min/1.73 m2 for eCLCG, +7.59 and ±16.8 mL/min/1.73 m2 for eCLCKD-EPI, and -4.15 and ±12.9 mL/min/1.73 m2 for eCLHoek, respectively, with eCLHoek being more precise than the other two (p < 0.05). The central 95% of observed errors fell between -59.8 and +250 mL/min/1.73 m2 for eCLCG, -83.9 and +79.8 mL/min/1.73 m2 for eCLCKD-EPI, and -103 and +27.9 mL/min/1.73 m2 for eCLHoek. Augmented renal clearance was underestimated by eCLCKD-EPI and eCLHoek. Patients with reduced CLCR were identified with good specificity by eCLCG, eCLCKD-EPI and eCLHoek (0.95, 0.97 and 0.91, respectively), but with less sensitivity (0.55, 0.55 and 0.83). For augmented renal clearance, specificity was 0.81, 0.96 and 0.96, but sensitivity only 0.69, 0.25 and 0.38. Conclusions Normal plasma creatinine concentrations can be highly misleading in ICU patients. Agreement of the cystatin C based eCLHoek with CLCR is better than that of the creatinine based eCLCG or eCLCKD-EPI. Detection and quantification of augmented renal clearance by estimates is problematic, and should rather rely on CLCR

Petrolio e politica nella decolonizzazione Algerina: verso un network energetico Europeo?

Le relazioni tra Francia e Italia nella guerra d’Algeria sono state oggetto di diverse analisi storiche; questo lavoro si concentra sul ruolo dell’industria petrolifera nelle relazioni tra i due paesi nel periodo specifico. Le riserve d’idrocarburi algerine furono scoperte nel 1956, due anni dopo l’inizio della guerra. I ritrovamenti ebbero una notevole eco in Francia, e la possibilità di diventare un paese produttore di petrolio rese più urgente il dibattito sull’amministrazione del Sahara e sull’opportunità di aprire le porte alle compagnie straniere. Questa ricerca ha come obiettivo l’esame delle azioni intraprese dalla Francia per la messa a punto di un’industria petrolifera nel Sahara, e le parallele strategie dell’industria petrolifera internazionale per la penetrazione in un nuovo territorio e in un’area contestata. In particolare, l’analisi si concentra sulla strategia dell’Eni, la compagnia di Stato Italiana, che rifiutò apertamente di collaborare con il governo francese per mantenere un atteggiamento pro-arabo. L’articolo punta a ricostruire il dibattito sulle risorse del sottosuolo sahariano, il problema del controllo del territorio e le frizioni tra l’industria petrolifera di Stato europea e le grandi multinazionali americane, nel contesto più ampio della decolonizzazione, dei negoziati per la costruzione dell’Unione Europea e della ricerca di una maggiore indipendenza dagli Stati Uniti. Italian-French relations during the Algerian war have been the subject of thorough historical investigations; this paper concentrates on the hydrocarbon industry and its role in the Algerian decolonization process and in the Italian-French relations. Algerian hydrocarbon reserves were found in 1956, two years after the outbreak of the war. The discovery had a considerable impact in France, where the possibility of becoming an oil exporting country reinvigorated the debate over the management of the Saharan area and on whether (and to which degree) to allow the presence of foreign oil companies in its exploitation. The research aims to investigate the actions taken by the French government for the set-up of an oil industry in the Sahara and the parallel strategies of the international oil industry for the penetration of a new territory in a contented area. In particular, the paper focuses on the Italian State company ENI, which openly refused to collaborate with the French government in order to maintain a pro-Arab approach. This paper aims to reconstruct the debate over the Saharan oil resources, the control over the territory and the frictions between European SOEs and the American oil giants, in the broader contest of decolonization, the negotiations for the construction of the European Union and the research for more independence from the United States

Glycomics meets lipidomics - associations of N-glycans with classical lipids, glycerophospholipids, and sphingolipids in three European populations

Recently, high-throughput technologies have been made available which allow the measurement of a broad spectrum of glycomics and lipidomics parameters in many samples. The aim of this study was to apply these methods and investigate associations between 46 glycan and 183 lipid traits measured in blood of 2041 Europeans from three different local populations (Croatia - VIS cohort; Sweden - NSPHS cohort; Great Britain - ORCADES cohort). N-glycans have been analyzed with High Performance Liquid Chromatography (HPLC) and lipids with Electrospray Ionization Tandem Mass Spectrometry (ESI-MS/MS) covering sterol lipids, glycerolipids, glycerophospholipids and sphingolipids in eight subclasses. Overall, 8418 associations were calculated using linear mixed effect models adjusted for pedigree, sex, age and multiple testing. We found 330 significant correlations in VIS. Pearson's correlation coefficient r ranged from −0.27 to 0.34 with corresponding p-values between 1.45 × 10−19 and 4.83 × 10−6, indicating statistical significance. A total of 71 correlations in VIS could be replicated in NSPHS (r = [−0.19; 0.35], p = [4.16 × 10−18; 9.38 × 10−5]) and 31 correlations in VIS were also found in ORCADES (r = [−0.20; 0.24], p = [2.69 × 10−10; 7.55 × 10−5]). However, in total only 10 correlations between a subset of triantennary glycans and unsaturated phosphatidylcholine, saturated ceramide, and sphingomyelin lipids in VIS (r = [0.18; 0.34], p = [2.98 × 10−21; 1.69 × 10−06]) could be replicated in both NSPHS and ORCADES. In summary, the results show strong and consistent associations between certain glycans and lipids in all populations, but also population-specific correlations which may be caused by environmental and genetic differences. These associations point towards potential interactive metabolic pathways

Renal Recovery after the Implementation of an Electronic Alert and Biomarker-Guided Kidney-Protection Strategy following Major Surgery

Background: The facilitation of early recovery of acute kidney injury (AKI) is an important step to improve outcome, particularly because of the limited therapeutic interventions currently available for AKI. The combination of an electronic alert and biomarker-guided kidney-protection strategy implemented in the routine care may have an impact on the incidence of early complete reversal of AKI after major non-cardiac surgery. Methods: We studied 294 patients in two cohorts before (n = 151) and after protocol implementation (n = 143). Data collection required 6 months for each cohort. The kidney-protection protocol included an electronic alert to detect patients who were eligible for urinary biomarker [TIMP2 × IGFBP7]-guided kidney-protection intervention. Intervention was stratified according to three levels of immediate AKI risk: low, moderate, and high. After intervention, postoperative changes in the glomerular filtration rate (eGFR) were identified with a tracking software that included an alert for nephrology consultation if the eGFR had declined by >25% from the preoperative reference value. Primary outcome was early AKI recovery, i.e., the complete reversal of any AKI stage to absence of AKI within the first 7 postoperative days. Results: Protocol implementation significantly increased the recovery of AKI (36/46, 78% compared to control 27/48, 56%, (p = 0.025)) and reduced the length of the ICU stay (p < 0.001). There was no significant difference in the overall incidence of all AKI and moderate and severe AKI in the first 7 postoperative days: 46/143 (32%) and 12/151 (8%) in the protocol implementation group compared to 48/151 (32%) and 18/151 (12%) in the historical control group. Patients with AKI reversal within the first 7 postoperative days had lower in-hospital mortality than patients without AKI reversal. Conclusions: Implementing a combined electronic alert and biomarker-guided kidney-protection strategy in routine care improved early recovery of AKI after major surgery

Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

The growth hormone/insulin‐like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF‐related proteins including IGF‐I and IGF‐binding protein‐3 (IGFBP‐3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF‐I and IGFBP‐3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP‐3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF‐I and IGFBP‐3 concentrations. The IGF‐I‐decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity‐associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF‐I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF‐I‐ and IGFBP‐3‐associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF‐I and IGFBP‐3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity‐associated loci

Modeling of Environmental Effects in Genome-Wide Association Studies Identifies SLC2A2 and HP as Novel Loci Influencing Serum Cholesterol Levels

Genome-wide association studies (GWAS) have identified 38 larger genetic regions affecting classical blood lipid levels without adjusting for important environmental influences. We modeled diet and physical activity in a GWAS in order to identify novel loci affecting total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. The Swedish (SE) EUROSPAN cohort (NSE = 656) was screened for candidate genes and the non-Swedish (NS) EUROSPAN cohorts (NNS = 3,282) were used for replication. In total, 3 SNPs were associated in the Swedish sample and were replicated in the non-Swedish cohorts. While SNP rs1532624 was a replication of the previously published association between CETP and HDL cholesterol, the other two were novel findings. For the latter SNPs, the p-value for association was substantially improved by inclusion of environmental covariates: SNP rs5400 (pSE,unadjusted = 3.6×10−5, pSE,adjusted = 2.2×10−6, pNS,unadjusted = 0.047) in the SLC2A2 (Glucose transporter type 2) and rs2000999 (pSE,unadjusted = 1.1×10−3, pSE,adjusted = 3.8×10−4, pNS,unadjusted = 0.035) in the HP gene (Haptoglobin-related protein precursor). Both showed evidence of association with total cholesterol. These results demonstrate that inclusion of important environmental factors in the analysis model can reveal new genetic susceptibility loci

Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations.

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57)). After a correction for multiple comparisons (P-value<2.2×10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits

Automated workflow-based exploitation of pathway databases provides new insights into genetic associations of metabolite profiles

Background: Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) that associate with clinical phenotypes, but these SNPs usually explain just a small part of the heritability and have relatively modest effect sizes. In contrast, SNPs that associate with metabolite levels generally explain a higher percentage of the genetic variation and demonstrate larger effect sizes. Still, the discovery of SNPs associated with metabolite levels is challenging since testing all metabolites measured in typical metabolomics studies with all SNPs comes with a severe multiple testing penalty. We have developed an automated workflow approach that utilizes prior knowledge of biochemical pathways present in databases like KEGG and BioCyc to generate a smaller SNP set relevant to the metabolite. This paper explores the opportunities and challenges in the analysis of GWAS of metabolomic phenotypes and provides novel insights into the genetic basis of metabolic variation through the re-analysis of published GWAS datasets. Results: Re-analysis of the published GWAS dataset from Illig et al. (Nature Genetics, 2010) using a pathway-based workflow (http://www.myexperiment.org/packs/319.html), confirmed previously identified hits and identified a new locus of human metabolic individuality, associating Aldehyde dehydrogenase family1 L1 (ALDH1L1) with serine/glycine ratios in blood. Replication in an independent GWAS dataset of phospholipids (Demirkan et al., PLoS Genetics, 2012) identified two novel loci supported by additional literature evidence: GPAM (Glycerol-3 phosphate acyltransferase) and CBS (Cystathionine beta-synthase). In addition, the workflow approach provided novel insight into the affected pathways and relevance of some of these gene-metabolite pairs in disease development and progression. Conclusions: We demonstrate the utility of automated exploitation of background knowledge present in pathway databases for the analysis of GWAS datasets of metabolomic phenotypes. We report novel loci and potential biochemical mechanisms that contribute to our understanding of the genetic basis of metabolic variation and its relationship to disease development and progression