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New-onset diabetes mellitus after transplantation (NODAT) is a complication following solid organ transplantation (SOT) and may be related to immune or inflammatory responses. We investigated whether single nucleotide polymorphisms (SNPs) within 158 immune- or inflammation-related genes contribute to NODAT in SOT recipients. The association between 263 SNPs and NODAT was investigated in a discovery sample of SOT recipients from the Swiss Transplant Cohort Study (STCS, n 1 = 696). Positive results were tested in a first STCS replication sample (n 2 = 489) and SNPs remaining significant after multiple test corrections were tested in a second SOT replication sample (n 3 = 156). Associations with diabetic traits were further tested in several large general population-based samples (n > 480 000). Only SP110 rs2114592C>T remained associated with NODAT in the STCS replication sample. Carriers of rs2114592-TT had 9.9 times (95% confidence interval [CI]: 3.22-30.5, P = .00006) higher risk for NODAT in the combined STCS samples (n = 1184). rs2114592C>T was further associated with NODAT in the second SOT sample (odds ratio: 4.8, 95% CI: 1.55-14.6, P = .006). On the other hand, SP110 rs2114592C>T was not associated with diabetic traits in population-based samples, suggesting a specific gene-environment interaction, possibly due to the use of specific medications (ie, immunosuppressants) in transplant patients and/or to the illness that may unmask the gene effect.

Aims The biological response to clopidogrel is highly variable and a poor responsiveness is associated with major adverse cardiac events. Adherence to therapy is a major cause of poor responsiveness but its impact on long-term platelet inhibition is unknown. The objective of the present study was to evaluate the effect of different programmes monitoring adherence to clopidogrel on platelet reactivity. Methods The study took the form of a monocentric, parallel group, randomized controlled trial. Adults treated with clopidogrel 75 mg after elective coronary stenting were randomized into one of three groups: (i) a standard of care group; (ii) a standard of care + adherence electronic monitoring group, in which drug intake was recorded but kept blinded until the study end; or (iii) an integrated care group, with regular feedback on recorded adherence. Clopidogrel response was assessed with the vasodilator-stimulated phosphoprotein–platelet reactivity index (VASP-PRI) at randomization, 3 months and 6 months. Results A total of 123 adults were enrolled and randomized. Baseline VASP-PRI was highly variable, with a mean of 48 ± 18.8%. No difference between groups in VASP-PRI was found at 6 months (P = 0.761), despite better adherence to clopidogrel in the integrated care group. However, adherence (P = 0.035) and baseline VASP-PRI (P = 0.015) were associated with VASP-PRI at 3 months and 6 months. The association between adherence and VASP-PRI was lost in patients with baseline VASP-PRI > 50%. Diabetes, CYP2C19*2 carrier status and body mass index were significant predictors of VASP-PRI. Conclusions The platelet response to clopidogrel during chronic therapy remained highly variable, despite high adherence. Different adherence monitoring programmes did not affect VASP-PRI at 6 months. Poor adherence is associated with lower VASP-PRI only in initial good responders to clopidogrel.

Supplemental material, Supplementary_data for Prevalence of ECG abnormalities and risk factors for QTc interval prolongation in hospitalized psychiatric patients by Nicolas Ansermot, Meredith Bochatay, Jürg Schläpfer, Mehdi Gholam, Ariane Gonthier, Philippe Conus and Chin B Eap in Therapeutic Advances in Psychopharmacology

New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain: 1.60 [1.36-1.90], p = 3.72*10-8 and ORreplication: 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (ORw-GRS 2:1.09 [1.04-1.15], p = 0.001 and ORw-GRS 3:1.14 [1.01-1.29], p = 0.03) and a similar ORw-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.

Importance: Multiple studies conducted in the general population identified an association between self-reported coffee consumption and plasma lipid levels. To date, no study assessed whether and which plasma methylxanthines (caffeine and/or its metabolites, i.e., paraxanthine, theophylline, and theobromine) are associated with plasma lipids. In psychiatric patients, an important coffee consumption is often reported and many psychotropic drugs can induce a rapid and substantial increase of plasma lipid levels. Objective: To determine whether plasma methylxanthines are associated with metabolic parameters in psychiatric patients receiving treatments known to induce metabolic disturbances. Design, Setting, and Participants: Data were obtained from a prospective study including 630 patients with metabolic parameters [i.e., body mass index (BMI), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and fasting triglycerides (TG)] monitored routinely during psychotropic treatment. Exposures: Plasma methylxanthines levels. Main Outcomes and Measures: Metabolic variables including BMI and plasma lipid levels. Results: Multivariate analyses indicated that BMI, TC, HDL-C, and non-HDL-C increased significantly with increasing total methylxanthines (pcorrected

OBJECTIVE: To measure the in vivo variations of CYP3A activity induced by anti-HIV drugs in human immunodeficiency virus (HIV)1-positive patients. METHODS: A low oral dose of midazolam (MID) (0.075 mg) was given to the patients and the 30-min total 1-OH midazolam (1-OHMID)/MID ratio was determined. Patients were phenotyped either before the introduction of antiretroviral treatments (control group, 90 patients) or after a variable period of antiretroviral treatment (56 patients). Twenty-one subjects underwent multiple phenotyping tests (before and during the course of the treatment). RESULTS: The median MID ratio was 3.51 in the control group (range 0.20-14.6). It was 5-fold higher in the group with efavirenz (28 patients; median, range: 16.0, 3.81-367; P < 0.0001), 13-fold lower with nelfinavir (18 patients; 0.27, 0.06-36.3; P < 0.0001), 17-fold lower with efavirenz + ritonavir (three patients; 0.21, 0.05-0.47; P = 0.006), 50-fold lower with ritonavir (four patients; 0.07, 0.06-0.17; P = 0.0007), and 7-fold lower with nevirapine + (ritonavir or nelfinavir or grapefruit juice) (three patients; 0.48, 0.03-1.83; P = 0.03). CYP3A activity was lower in the efavirenz + ritonavir group (P = 0.01) and in the ritonavir group (P = 0.04) than in the nelfinavir group, although already strongly inhibited in the latter. CONCLUSION: The low-dose MID phenotyping test was successfully used to measure the in vivo variations of CYP3A activity induced by antiretroviral drugs. Efavirenz strongly induces CYP3A activity, while ritonavir almost completely inhibits it. Nelfinavir strongly decreases CYP3A activity, but to a lesser extent than ritonavir. The inhibition of CYP3A by ritonavir or nelfinavir offsets the inductive effects of efavirenz or nevirapine administered concomitantly. Finally, no induction of CYP3A activity was noticeable after long-term administration of ritonavir at low dosages (200 mg/day b.i.d.) or of nelfinavir at standard dosages (2,500 mg/day b.i.d.).

Information on floristic biodiversity and stem volume is necessary for the sustainable management of forests in Sierra Leone for the current and future generation. The aim of this paper was to investigate the flora biodiversity and stem volume of Kambui forest reserve. Random sampling quadrat methods of vegetation analysis were used to determine the flora biodiversity and stem volume. Ten sample quadrats (10m ?10m) with a distance of at least 400m away from each other were demarcated. All trees species found in the quadrats were recorded in the local and scientific name. A total of 36 species from 22 families with 122 individual?s trees were recorded. The species Importance Value Index [IVI], Shannon Weiner Index, Species Richness, Simpson Diversity Index, Species Evenness, Species Dominance, Relative Frequency and Relative Density were computed to determine the floral diversity and richness. Diameter at breast height (Dbh) and total height of trees were the parameters used to estimate the stem volume. The total Shannon Weiner index for the ten quadrats was 3.241, species evenness was 0.90 while the Simpson diversity was 0.05. The regression correlation between Dbh and height was R2 0.6344. Parinari excelsa had the highest average Dbh (80.13cm) and height of 47m. The total stem volume was (391.78m3). Paracrolobium coeruleum, Daniella thurifera and Parinari excelsa recorded the highest (IVI). The study revealed that the flora biodiversity of Kambui forest reserve is low as compared to other regions in the country. Biotic pressure among other factors contributed to the decline of the flora biodiversity but the stem volume potential was great. It is recommended that if sound management strategies are put in place, Kambui forest has the potential to increase it biodiversity and stem volume while at the same time meeting the needs of the locals.

This retrospective study aims to evaluate off-label prescriptions and administrations of psychotropic medications in adolescents in a university psychiatric hospital in Switzerland. Data were collected during the entire stays from the electronic database for 76 inpatients in 2008 and 76 inpatients in 2014. Data collected included gender, age, psychiatric diagnosis, duration of hospitalization, and psychotropic drug prescriptions and administrations. A total of 224 psychotropic drugs (mean 2.9 drugs/patient) were prescribed in 2008 and 268 (mean 3.5 drugs/patient) in 2014. Due to the prescriptions of some drugs as required, only 76% of the prescriptions were actually administered in 2008 (mean 2.3 drugs/patient) and 55% in 2014 (mean 1.9 drugs/patient). Antipsychotics were the most frequently prescribed drugs in 2008 (74% of patients) and 2014 (86% of patients). Anxiolytics were also highly prescribed in 2008 (54% of patients) and 2014 (66% of patients), as well as antidepressants in 2008 (30% of patients), but less in 2014 (13% of patients). Overall, 69% of prescriptions were found to be off label in 2008 and 68% in 2014, according to age, diagnosis, dose, or formulation as approved by Swissmedic. The medication classes with the highest rate of off-label prescriptions were antidepressants (100% for both years), antipsychotics (94% in 2008 and 92% in 2014), and hypnotics (67% in 2008 and 100% in 2014). For both study periods, at least one off-label psychotropic drug prescription and administration was recorded in 96% and 79% of the patients, respectively. The high rate of off-label psychotropic drug use strengthens the need for clinical trials to better evaluate the efficacy and safety of these treatments in adolescents.

Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC’s impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Objectifs Les traitements psychotropes peuvent entrainer une prise de poids ainsi que d’autres troubles metaboliques influencant la morbidite et la mortalite dans la population psychiatrique, qui presente une reduction de l’esperance de vie de 10 a 15 ans [1] . Cette etude a pour objectif de determiner si une approche de metabolomique ciblee, qui est l’analyse des petits metabolites endogenes produits par l’organisme apres une exposition a un xenobiotique notamment, peut contribuer a predire la prise de poids induite par les psychotropes. Methode Soixante-deux patients debutant un traitement par un psychotrope pouvant induire une prise de poids ont ete inclus. Des echantillons de plasma ont ete preleves avant l’instauration du traitement et apres un mois de traitement par psychotropes. Les 124 echantillons ont ete analyses sur deux plateformes analytiques complementaires : – par methode de metabolomique ciblee large permettant la detection de 231 metabolites appartenant a differentes classes et voies metaboliques : acides amines, peptides, lipides, acides carboxyliques, glucides, ou encore nucleosides ; – par methode quantitative ciblant le dosage de 15 metabolites de la voie des kynurenines (KP). Chacune de ces methodes a ete developpee par chromatographie liquide couplee a la spectrometrie de masse (LC-QqQ-MS) en mode d’acquisition MRM. L’analyse statistique par test de Student sur donnees appariees est utilisee pour mettre en evidence une signature metabolomique suite a un mois de traitement. Un modele lineaire a effet mixte est utilise pour souligner le potentiel predictif des variations precoces de metabolites sur la prise de poids sur trois mois d’exposition au traitement. Resultats Les analyses des profils metabolomiques obtenus ont permis de mettre en evidence une signature de 19 metabolites, specifique d’une exposition a un mois de traitement par psychotropes. En particulier, une augmentation significative de la kynurenine (pcorrige = 0,046), ainsi qu’une diminution significative de l’hexanoylcarnitine (pcorrige = 0,046) et de la biliverdine (pcorrige = 0,046), apres un mois de traitement, sont associees a une prise de poids plus importante au cours des trois premiers mois de traitement. L’analyse quantitative des metabolites de la KP a permis de confirmer un lien entre le ratio kynurenine/tryptophane (pcorrige = 0,036) et l’evolution du poids au cours des trois mois de traitement. Conclusion L’approche metabolomique utilisee dans cette etude met en evidence des deregulations apres un mois de traitement par psychotropes, qui peuvent etre specifiquement associees a une prise de poids pharmaco-induite. Ces resultats sont d’un grand interet puisqu’ils apportent des hypotheses quant aux mecanismes de la prise de poids pharmaco-induite. Les metabolites mis en evidence pourraient egalement etre utilises dans le futur en pratique clinique, associes a d’autres marqueurs dans un modele combinatoire, pour evaluer le risque de prise de poids sous psychotropes dans la population psychiatrique et ainsi contribuer a une meilleure medecine personnalisee.

Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of CRTC2 polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (n1=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2=1294 and n3=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46'186, n5=123'865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (PcorrectedA was significantly associated with several metabolic abnormalities. CRTC2 rs8450G>A appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples.The Pharmacogenomics Journal advance online publication, 8 December 2015; doi:10.1038/tpj.2015.82.

To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150–5,000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy.

Background Metabolic syndrome (MetS) associated with psychiatric disorders and psychotropic treatments represents a major health issue. 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) is an enzyme that catalyzes tissue regeneration of active cortisol from cortisone. Elevated enzymatic activity of 11 beta-HSD1 may lead to the development of MetS. Methods We investigated the association between seven HSD11B1 gene (encoding 11 beta-HSD1) polymorphisms and BMI and MetS components in a psychiatric sample treated with potential weight gain-inducing psychotropic drugs (n = 478). The polymorphisms that survived Bonferroni correction were analyzed in two independent psychiatric samples (n(R1) = 168, n(R2) = 188) and in several large population-based samples (n(1) = 5338; n(2) = 123 865; n(3) > 100 000). Results HSD11B1 rs846910-A, rs375319-A, and rs4844488-G allele carriers were found to be associated with lower BMI, waist circumference, and diastolic blood pressure compared with the reference genotype (P-corrected < 0.05). These associations were exclusively detected in women (n = 257) with more than 3.1 kg/m(2), 7.5 cm, and 4.2 mmHg lower BMI, waist circumference, and diastolic blood pressure, respectively, in rs846910-A, rs375319-A, and rs4844488-G allele carriers compared with noncarriers (P-corrected < 0.05). Conversely, carriers of the rs846906-T allele had significantly higher waist circumference and triglycerides and lower high-density lipoprotein-cholesterol exclusively in men (P-corrected = 0.028). The rs846906-T allele was also associated with a higher risk of MetS at 3 months of follow-up (odds ratio: 3.31, 95% confidence interval: 1.53-7.17, P-corrected = 0.014). No association was observed between HSD11B1 polymorphisms and BMI and MetS components in the population-based samples. Conclusions Our results indicate that HSD11B1 polymorphisms may contribute toward the development of MetS in psychiatric patients treated with potential weight gain-inducing psychotropic drugs, but do not play a significant role in the general population. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.