Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods, [and] Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes

Rapport de synthèse1. Partie de laboratoireCette première étude décrit le développement et la validation, selon les standards internationaux, de deux techniques de mesure des concentrations sanguines de voriconazole, un nouvel agent antifongique à large spectre: 1) la chromatographic en phase liquide à haute pression et 2) le bio-essai utilisant une souche mutante de Candida hypersensible au voriconazole. Ce travail a aussi permis de mettre en évidence une importante et imprévisible variabilité inter- et intra-individuelle des concentrations sanguines de voriconazole malgré l'utilisation des doses recommandées par le fabriquant. Ce travail a été publié dans un journal avec "peer-review": "Variability of voriconazole plasma levels measured by new high- performance liquid chromatography and bioassay methods" by A. Pascual, V. Nieth, T. Calandra, J. Bille, S. Bolay, L.A. Decosterd, T. Buclin, P.A. Majcherczyk, D. Sanglard, 0. Marchetti. Antimicrobial Agents Chemotherapy, 2007; 51:137-432. Partie CliniqueCette deuxième étude a évalué de façon prospective l'impact clinique des concentrations sanguines de voriconazole sur l'efficacité et sécurité thérapeutique chez des patients atteints d'infections fongiques. Des concentrations sanguines élevées étaient significativement associés à la survenue d'une toxicité neurologique (encéphalopathie avec confusion, hallucinations et myoclonies) et des concentrations sanguines basses à une réponse insuffisante au traitement antifongique (persistance ou progression des signes cliniques et radiologiques de l'infection). Dans la majorité des cas, un ajustement de la dose de voriconazole, sur la base des concentrations mesurées, a abouti à une récupération neurologique complète ou à une résolution de l'infection, respectivement. Ce travail a été publié dans un journal avec "peer-review": " Voriconazole Therapeutic Drug Monitoring in Patients with Invasive Mycoses Improves Efficacy and Safety Outcomes" by A. Pascual, T. Calandra, S. Bolay, T. Buclin, J. Bille, and O. Marchetti. Clinical Infectious Diseases, 2008 January 15; 46(2): 201-11.Ces deux études, financées de façon conjointe par un "grant" international de la Société suisse d'infectiologie et la Société internationale de maladies infectieuses et par la Fondation pour le progrès en microbiologie médicale et maladies infectieuses (FAMMID, Lausanne), ont été réalisées au sein du Service des Maladies Infectieuses, Département de Médecine, au CHUV, en étroite collaboration avec la Division de Pharmacologie Clinique, Département de Médecine, au CHUV et l'Institut de Microbiologie du CHUV et de l'Université de Lausanne.

Design and methodology of the Swiss Transplant Cohort Study (STCS): a comprehensive prospective nationwide long-term follow-up cohort.

In Switzerland, organ procurement is well organized at the national-level but transplant outcomes have not been systematically monitored so far. Therefore, a novel project, the Swiss Transplant Cohort Study (STCS), was established. The STCS is a prospective multicentre study, designed as a dynamic cohort, which enrolls all solid organ recipients at the national level. The features of the STCS are a flexible patient-case system that allows capturing all transplant scenarios and collection of patient-specific and allograft-specific data. Beyond comprehensive clinical data, specific focus is directed at psychosocial and behavioral factors, infectious disease development, and bio-banking. Between May 2008 and end of 2011, the six Swiss transplant centers recruited 1,677 patients involving 1,721 transplantations, and a total of 1,800 organs implanted in 15 different transplantation scenarios. 10 % of all patients underwent re-transplantation and 3% had a second transplantation, either in the past or during follow-up. 34% of all kidney allografts originated from living donation. Until the end of 2011 we observed 4,385 infection episodes in our patient population. The STCS showed operative capabilities to collect high-quality data and to adequately reflect the complexity of the post-transplantation process. The STCS represents a promising novel project for comparative effectiveness research in transplantation medicine.

National Survey of Noncommunicable Diseases in Seychelles, 2013-2014 (Seychelles Heart Study IV) : methods and main findings

This report provides information on selected summary results of the National Survey of Noncommunicable Diseases in Seychelles in 2013‐2014 (Seychelles Heart Study IV). The survey is also referred shortly as the "2013 Survey" in this report. Overall crude results were reported in a comprehensive report in November 2014. Further detailed analyses and recommendations on particular topics will be performed separately.

Diagnostic methods and treatment options for focal cortical dysplasia.

Our inability to adequately treat many patients with refractory epilepsy caused by focal cortical dysplasia (FCD), surgical inaccessibility and failures are significant clinical drawbacks. The targeting of physiologic features of epileptogenesis in FCD and colocalizing functionality has enhanced completeness of surgical resection, the main determinant of outcome. Electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) and magnetoencephalography are helpful in guiding electrode implantation and surgical treatment, and high-frequency oscillations help defining the extent of the epileptogenic dysplasia. Ultra high-field MRI has a role in understanding the laminar organization of the cortex, and fluorodeoxyglucose-positron emission tomography (FDG-PET) is highly sensitive for detecting FCD in MRI-negative cases. Multimodal imaging is clinically valuable, either by improving the rate of postoperative seizure freedom or by reducing postoperative deficits. However, there is no level 1 evidence that it improves outcomes. Proof for a specific effect of antiepileptic drugs (AEDs) in FCD is lacking. Pathogenic mutations recently described in mammalian target of rapamycin (mTOR) genes in FCD have yielded important insights into novel treatment options with mTOR inhibitors, which might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease. The ketogenic diet (KD) has been demonstrated to be particularly effective in children with epilepsy caused by structural abnormalities, especially FCD. It attenuates epigenetic chromatin modifications, a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression. This could imply lasting benefit of dietary manipulation. Neurostimulation techniques have produced variable clinical outcomes in FCD. In widespread dysplasias, vagus nerve stimulation (VNS) has achieved responder rates >50%; however, the efficacy of noninvasive cranial nerve stimulation modalities such as transcutaneous VNS (tVNS) and noninvasive (nVNS) requires further study. Although review of current strategies underscores the serious shortcomings of treatment-resistant cases, initial evidence from novel approaches suggests that future success is possible.

Risk of Bronchiolitis Obliterans Syndrome Is Twice as High in Cyclosporine Treated Patients in Comparison to Tacrolimus 3 Years after Lung Transplantation: Results of a Prospective Randomized International Trial of 248 Patients

Purpose: In this prospective randomized study efficacy and safety of two immunosuppressive regimens (Tac, MMF, Steroids vs. CsA, MMF, Steroids) after Lung Transplantation were compared. Primary objective was the incidence of bronchiolitis obliterans syndrome (BOS). Secondary objectives were incidence of acute rejection and infection, survival and adverse events. 248 patients with a complete 3 year follow-up were included in the analysis. Methods and Materials: Patients were randomized to treatment group A: Tac (0.01-0.03 mg/kg/d iv-0.05-0.3 mg/kg/d po) or B: CsA (1-3 mg/kg/d iv-2-8 mg/kg/d po). MMF dose was1-4 mg/d in both groups. No induction therapy was given. Patients were stratified for cystic fibrosis. Intention to treat analysis was performed in patients who were switched to a different immunosuppressive regimen. Results: 3 of 123 Tac patients and 41 of 125 CsA patients were switched to another immunosuppressive regimen and were analyzed as intention to treat. Three year follow-up data of the complete patient cohort were included in this final analysis. Groups showed no difference in demographic data. Kaplan Meier analysis revealed significantly less BOS in Tac treated patients (p=0.033, log rank test, pooled over strata). Cox regression showed a twice as high risk for BOS in the CsA group (factor 2.003). Incidence of acute rejection was 67.5% (Tac) and 75.2% (CsA) (p=0.583). One- and 3-year-survival-rates were not different (85.4% Tac vs. 88.8% CsA, and 80.5% Tac vs. 83.2% CsA, p=n.s.). Incidence of infections and renal failure was similar (p=n.s.). Conclusions: Tac significantly reduced the risk for BOS after 3 years in this intention to treat analysis. Both regimens have a good immunosuppressive potential and offer a similar safety profile with excellent one and three year survival rates. Acute rejection rates were similar in both groups. Incidence of infections and renal failure showed no difference.

Towards the utilization of EEG as a brain imaging tool.

Recent advances in signal analysis have engendered EEG with the status of a true brain mapping and brain imaging method capable of providing spatio-temporal information regarding brain (dys)function. Because of the increasing interest in the temporal dynamics of brain networks, and because of the straightforward compatibility of the EEG with other brain imaging techniques, EEG is increasingly used in the neuroimaging community. However, the full capability of EEG is highly underestimated. Many combined EEG-fMRI studies use the EEG only as a spike-counter or an oscilloscope. Many cognitive and clinical EEG studies use the EEG still in its traditional way and analyze grapho-elements at certain electrodes and latencies. We here show that this way of using the EEG is not only dangerous because it leads to misinterpretations, but it is also largely ignoring the spatial aspects of the signals. In fact, EEG primarily measures the electric potential field at the scalp surface in the same way as MEG measures the magnetic field. By properly sampling and correctly analyzing this electric field, EEG can provide reliable information about the neuronal activity in the brain and the temporal dynamics of this activity in the millisecond range. This review explains some of these analysis methods and illustrates their potential in clinical and experimental applications.

ENFIN--A European network for integrative systems biology.

Integration of biological data of various types and the development of adapted bioinformatics tools represent critical objectives to enable research at the systems level. The European Network of Excellence ENFIN is engaged in developing an adapted infrastructure to connect databases, and platforms to enable both the generation of new bioinformatics tools and the experimental validation of computational predictions. With the aim of bridging the gap existing between standard wet laboratories and bioinformatics, the ENFIN Network runs integrative research projects to bring the latest computational techniques to bear directly on questions dedicated to systems biology in the wet laboratory environment. The Network maintains internally close collaboration between experimental and computational research, enabling a permanent cycling of experimental validation and improvement of computational prediction methods. The computational work includes the development of a database infrastructure (EnCORE), bioinformatics analysis methods and a novel platform for protein function analysis FuncNet.

Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.

BACKGROUND: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). METHODS AND FINDINGS: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction)  = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio  = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio  = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. CONCLUSIONS: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.