Effects of dexmedetomidine, propofol, sevoflurane and S-ketamine on the human metabolome A randomised trial using nuclear magnetic resonance spectroscopy

BACKGROUND Pharmacometabolomics uses large-scale data capturing methods to uncover drug-induced shifts in the metabolic profile. The specific effects of anaesthetics on the human metabolome are largely unknown. OBJECTIVE We aimed to discover whether exposure to routinely used anaesthetics have an acute effect on the human metabolic profile. DESIGN Randomised, open-label, controlled, parallel group, phase IV clinical drug trial. SETTING The study was conducted at Turku PET Centre, University of Turku, Finland, 2016 to 2017. PARTICIPANTS One hundred and sixty healthy male volunteers were recruited. The metabolomic data of 159 were evaluable. INTERVENTIONS Volunteers were randomised to receive a 1-h exposure to equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml(-1); n = 40), propofol (1.7 mu g ml(-1); n = 40), sevoflurane (0.9% end-tidal; n = 39), S-ketamine (0.75 mu g ml(-1); n = 20) or placebo (n = 20). MAIN OUTCOME MEASURES Metabolite subgroups of apolipoproteins and lipoproteins, cholesterol, glycerides and phospholipids, fatty acids, glycolysis, amino acids, ketone bodies, creatinine and albumin and the inflammatory marker GlycA, were analysed with nuclear magnetic resonance spectroscopy from arterial blood samples collected at baseline, after anaesthetic administration and 70 min post-anaesthesia. RESULTS All metabolite subgroups were affected. Statistically significant changes vs. placebo were observed in 11.0, 41.3, 0.65 and 3.9% of the 155 analytes in the dexmedetomidine, propofol, sevoflurane and S-ketamine groups, respectively. Dexmedetomidine increased glucose, decreased ketone bodies and affected lipoproteins and apolipoproteins. Propofol altered lipoproteins, fatty acids, glycerides and phospholipids and slightly increased inflammatory marker glycoprotein acetylation. Sevoflurane was relatively inert. S-ketamine increased glucose and lactate, whereasbranched chain amino acids and tyrosine decreased. CONCLUSION A 1-h exposure to moderate doses of routinely used anaesthetics led to significant and characteristic alterations in the metabolic profile. Dexmedetomidine-induced alterations mirror a2-adrenoceptor agonism. Propofol emulsion altered the lipid profile. The inertness of sevoflurane might prove useful in vulnerable patients. S-ketamine induced amino acid alterations might be linked to its suggested antidepressive properties.Peer reviewe

Legislative change enabling use of early part-time sick leave enhanced return to work and work participation in Finland

Objectives The aim of the study was to assess the effectiveness of the use of part-time sick leave at the early (first 12 weeks) stage of work disability due to mental disorder or musculoskeletal disease on sustained return to work (RTW) and overall work participation. Methods In a nation-wide register-based quasi-experimental study, we compared sustained RTW (ie, ≥28 consecutive days at work) and 2-year work participation between the part- and full-time sickness absence (SA) benefit groups (N=1878 in each group) using propensity-score matching. Persons who received partial or full SA benefit due to musculoskeletal diseases or mental disorders between January 1, 2010 and December 31, 2011 were eligible as cases or controls, respectively. Results A higher proportion showed sustained RTW after part- compared to full-time sick leave [absolute risk difference 8.0%, 95% confidence interval (95% CI) 5.3-10.9]. Moreover, the proportion of time at work was at a 10.5% higher level in the part- compared to full-time sick leave group. The prevalence of full disability retirement was almost three-fold among the full- compared to part-time sick leave group, whereas partial disability retirement was 4.5-fold more prevalent in the part- compared to full-time sick leave group. Conclusions The use of part-time sick leave during the first three months of SA enhances RTW and overall work participation during two years among persons with mental disorders and musculoskeletal diseases. The prescription of part-time sick leave can be recommended at an early stage of work disability

Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Abstract Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Abstract Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids