Methodological Gaps in Left Atrial Function Assessment by 2D Speckle Tracking Echocardiography

Abstract The assessment of left atrial (LA) function is used in various cardiovascular diseases. LA plays a complementary role in cardiac performance by modulating left ventricular (LV) function. Transthoracic two-dimensional (2D) phasic volumes and Doppler echocardiography can measure LA function non‑invasively. However, evaluation of LA deformation derived from 2D speckle tracking echocardiography (STE) is a new feasible and promising approach for assessment of LA mechanics. These parameters are able to detect subclinical LA dysfunction in different pathological condition. Normal ranges for LA deformation and cut-off values to diagnose LA dysfunction with different diseases have been reported, but data are still conflicting, probably because of some methodological and technical issues. This review highlights the importance of an unique standardized technique to assess the LA phasic functions by STE, and discusses recent studies on the most important clinical applications of this technique.

Equity and CO2 emissions distribution in climate change integrated assessment

Emissions distribution is a focus variable for the design of future international agreements to tackle global warming. This paper specifically analyses the future path of emissions distribution and its determinants in different scenarios. Whereas our analysis is driven by tools which are typically applied in the income distribution literature and which have recently been applied to the analysis of CO2 emissions distribution, a new methodological approach is that our study is driven by simulations run with a popular regionalised optimal growth climate change model over the 1995-2105 period. We find that the architecture of environmental policies, the implementation of flexible mechanisms and income concentration are key determinants of emissions distribution over time. In particular we find a robust positive relationship between measures of inequalities.

Evaluation de la douleur chez les personnes cérébrolésées non-communicantes aux soins intensifs

La douleur est fréquente en milieu de soins intensifs et sa gestion est l'une des missions des infirmières. Son évaluation est une prémisse indispensable à son soulagement. Cependant lorsque le patient est incapable de signaler sa douleur, les infirmières doivent se baser sur des signes externes pour l'évaluer. Les guides de bonne pratique recommandent chez les personnes non communicantes l'usage d'un instrument validé pour la population donnée et basé sur l'observation des comportements. A l'heure actuelle, les instruments d'évaluation de la douleur disponibles ne sont que partiellement adaptés aux personnes cérébrolésées dans la mesure où ces personnes présentent des comportements qui leur sont spécifiques. C'est pourquoi, cette étude vise à identifier, décrire et valider des indicateurs, et des descripteurs, de la douleur chez les personnes cérébrolésées. Un devis d'étude mixte multiphase avec une dominante quantitative a été choisi pour cette étude. Une première phase consistait à identifier des indicateurs et des descripteurs de la douleur chez les personnes cérébrolésées non communicantes aux soins intensifs en combinant trois sources de données : une revue intégrative des écrits, une démarche consultative utilisant la technique du groupe nominal auprès de 18 cliniciens expérimentés (6 médecins et 12 infirmières) et les résultats d'une étude pilote observationnelle réalisée auprès de 10 traumatisés crâniens. Les résultats ont permis d'identifier 6 indicateurs et 47 descripteurs comportementaux, vocaux et physiologiques susceptibles d'être inclus dans un instrument d'évaluation de la douleur destiné aux personnes cérébrolésées non- communicantes aux soins intensifs. Une deuxième phase séquentielle vérifiait les propriétés psychométriques des indicateurs et des descripteurs préalablement identifiés. La validation de contenu a été testée auprès de 10 experts cliniques et 4 experts scientifiques à l'aide d'un questionnaire structuré qui cherchait à évaluer la pertinence et la clarté/compréhensibilité de chaque descripteur. Cette démarche a permis de sélectionner 33 des 47 descripteurs et valider 6 indicateurs. Dans un deuxième temps, les propriétés psychométriques de ces indicateurs et descripteurs ont été étudiés au repos, lors de stimulation non nociceptive et lors d'une stimulation nociceptive (la latéralisation du patient) auprès de 116 personnes cérébrolésées aux soins intensifs hospitalisées dans deux centres hospitaliers universitaires. Les résultats montrent d'importantes variations dans les descripteurs observés lors de stimulation nociceptive probablement dues à l'hétérogénéité des patients au niveau de leur état de conscience. Dix descripteurs ont été éliminés, car leur fréquence lors de la stimulation nociceptive était inférieure à 5% ou leur fiabilité insuffisante. Les descripteurs physiologiques ont tous été supprimés en raison de leur faible variabilité et d'une fiabilité inter juge problématique. Les résultats montrent que la validité concomitante, c'est-à-dire la corrélation entre l'auto- évaluation du patient et les mesures réalisées avec les descripteurs, est satisfaisante lors de stimulation nociceptive {rs=0,527, p=0,003, n=30). Par contre la validité convergente, qui vérifiait l'association entre l'évaluation de la douleur par l'infirmière en charge du patient et les mesures réalisés avec les descripteurs, ainsi que la validité divergente, qui vérifiait si les indicateurs discriminent entre la stimulation nociceptive et le repos, mettent en évidence des résultats variables en fonction de l'état de conscience des patients. Ces résultats soulignent la nécessité d'étudier les descripteurs de la douleur chez des patients cérébrolésés en fonction du niveau de conscience et de considérer l'hétérogénéité de cette population dans la conception d'un instrument d'évaluation de la douleur pour les personnes cérébrolésées non communicantes aux soins intensifs. - Pain is frequent in the intensive care unit (ICU) and its management is a major issue for nurses. The assessment of pain is a prerequisite for appropriate pain management. However, pain assessment is difficult when patients are unable to communicate about their experience and nurses have to base their evaluation on external signs. Clinical practice guidelines highlight the need to use behavioral scales that have been validated for nonverbal patients. Current behavioral pain tools for ICU patients unable to communicate may not be appropriate for nonverbal brain-injured ICU patients, as they demonstrate specific responses to pain. This study aimed to identify, describe and validate pain indicators and descriptors in brain-injured ICU patients. A mixed multiphase method design with a quantitative dominant was chosen for this study. The first phase aimed to identify indicators and descriptors of pain for nonverbal brain- injured ICU patients using data from three sources: an integrative literature review, a consultation using the nominal group technique with 18 experienced clinicians (12 nurses and 6 physicians) and the results of an observational pilot study with 10 traumatic brain injured patients. The results of this first phase identified 6 indicators and 47 behavioral, vocal and physiological descriptors of pain that could be included in a pain assessment tool for this population. The sequential phase two tested the psychometric properties of the list of previously identified indicators and descriptors. Content validity was tested with 10 clinical and 4 scientific experts for pertinence and comprehensibility using a structured questionnaire. This process resulted in 33 descriptors to be selected out of 47 previously identified, and six validated indicators. Then, the psychometric properties of the descriptors and indicators were tested at rest, during non nociceptive stimulation and nociceptive stimulation (turning) in a sample of 116 brain-injured ICLI patients who were hospitalized in two university centers. Results showed important variations in the descriptors observed during the nociceptive stimulation, probably due to the heterogeneity of patients' level of consciousness. Ten descriptors were excluded, as they were observed less than 5% of the time or their reliability was insufficient. All physiologic descriptors were deleted as they showed little variability and inter observer reliability was lacking. Concomitant validity, testing the association between patients' self report of pain and measures performed using the descriptors, was acceptable during nociceptive stimulation (rs=0,527, p=0,003, n=30). However, convergent validity ( testing for an association between the nurses' pain assessment and measures done with descriptors) and divergent validity (testing for the ability of the indicators to discriminate between rest and a nociceptive stimulation) varied according to the level of consciousness These results highlight the need to study pain descriptors in brain-injured patients with different level of consciousness and to take into account the heterogeneity of this population forthe conception of a pain assessment tool for nonverbal brain-injured ICU patients.

Scenario-based assessment of future land use change on butterfly species distributions

Species distribution models (SDMs) are increasingly used to predict environmentally induced range shifts of habitats of plant and animal species. Consequently SDMs are valuable tools for scientifically based conservation decisions. The aims of this paper are (1) to identify important drivers of butterfly species persistence or extinction, and (2) to analyse the responses of endangered butterfly species of dry grasslands and wetlands to likely future landscape changes in Switzerland. Future land use was represented by four scenarios describing: (1) ongoing land use changes as observed at the end of the last century; (2) a liberalisation of the agricultural markets; (3) a slightly lowered agricultural production; and (4) a strongly lowered agricultural production. Two model approaches have been applied. The first (logistic regression with principal components) explains what environmental variables have significant impact on species presence (and absence). The second (predictive SDM) is used to project species distribution under current and likely future land uses. The results of the explanatory analyses reveal that four principal components related to urbanisation, abandonment of open land and intensive agricultural practices as well as two climate parameters are primary drivers of species occurrence (decline). The scenario analyses show that lowered agricultural production is likely to favour dry grassland species due to an increase of non-intensively used land, open canopy forests, and overgrown areas. In the liberalisation scenario dry grassland species show a decrease in abundance due to a strong increase of forested patches. Wetland butterfly species would decrease under all four scenarios as their habitats become overgrown

Development of CBCT-based prostate setup correction strategies and impact of rectal distension.

BACKGROUND: Cone-beam computed tomography (CBCT) image-guided radiotherapy (IGRT) systems are widely used tools to verify and correct the target position before each fraction, allowing to maximize treatment accuracy and precision. In this study, we evaluate automatic three-dimensional intensity-based rigid registration (RR) methods for prostate setup correction using CBCT scans and study the impact of rectal distension on registration quality. METHODS: We retrospectively analyzed 115 CBCT scans of 10 prostate patients. CT-to-CBCT registration was performed using (a) global RR, (b) bony RR, or (c) bony RR refined by a local prostate RR using the CT clinical target volume (CTV) expanded with 1-to-20-mm varying margins. After propagation of the manual CT contours, automatic CBCT contours were generated. For evaluation, a radiation oncologist manually delineated the CTV on the CBCT scans. The propagated and manual CBCT contours were compared using the Dice similarity and a measure based on the bidirectional local distance (BLD). We also conducted a blind visual assessment of the quality of the propagated segmentations. Moreover, we automatically quantified rectal distension between the CT and CBCT scans without using the manual CBCT contours and we investigated its correlation with the registration failures. To improve the registration quality, the air in the rectum was replaced with soft tissue using a filter. The results with and without filtering were compared. RESULTS: The statistical analysis of the Dice coefficients and the BLD values resulted in highly significant differences (p<10(-6)) for the 5-mm and 8-mm local RRs vs the global, bony and 1-mm local RRs. The 8-mm local RR provided the best compromise between accuracy and robustness (Dice median of 0.814 and 97% of success with filtering the air in the rectum). We observed that all failures were due to high rectal distension. Moreover, the visual assessment confirmed the superiority of the 8-mm local RR over the bony RR. CONCLUSION: The most successful CT-to-CBCT RR method proved to be the 8-mm local RR. We have shown the correlation between its registration failures and rectal distension. Furthermore, we have provided a simple (easily applicable in routine) and automatic method to quantify rectal distension and to predict registration failure using only the manual CT contours.

Addressing Sea Surface Salinity retrieval at different spatial resolution. Feasibility study using OCCAM data within SEPS simulator and L2 processor tools

Projecte de recerca elaborat a partir d’una estada a la National Oceanography Centre of Southampton (NOCS), Gran Bretanya, entre maig i juliol del 2006. La possibilitat d’obtenir una estimació precissa de la salinitat marina (SSS) és important per a investigar i predir l’extensió del fenòmen del canvi climàtic. La missió Soil Moisture and Ocean Salinity (SMOS) va ser seleccionada per l’Agència Espacial Europea (ESA) per a obtenir mapes de salinitat de la superfície marina a escala global i amb un temps de revisita petit. Abans del llençament de SMOS es preveu l’anàlisi de la variabilitat horitzontal de la SSS i del potencial de les dades recuperades a partir de mesures de SMOS per a reproduir comportaments oceanogràfics coneguts. L’objectiu de tot plegat és emplenar el buit existent entre les fonts de dades d’entrada/auxiliars fiables i les eines desenvolupades per a simular i processar les dades adquirides segons la configuració de SMOS. El SMOS End-to-end Performance Simulator (SEPS) és un simulador adhoc desenvolupat per la Universitat Politècnica de Catalunya (UPC) per a generar dades segons la configuració de SMOS. Es va utilitzar dades d’entrada a SEPS procedents del projecte Ocean Circulation and Climate Advanced Modeling (OCCAM), utilitzat al NOCS, a diferents resolucions espacials. Modificant SEPS per a poder fer servir com a entrada les dades OCCAM es van obtenir dades de temperatura de brillantor simulades durant un mes amb diferents observacions ascendents que cobrien la zona seleccionada. Les tasques realitzades durant l’estada a NOCS tenien la finalitat de proporcionar una tècnica fiable per a realitzar la calibració externa i per tant cancel•lar el bias, una metodologia per a promitjar temporalment les diferents adquisicions durant les observacions ascendents, i determinar la millor configuració de la funció de cost abans d’explotar i investigar les posibiltats de les dades SEPS/OCCAM per a derivar la SSS recuperada amb patrons d’alta resolució.

Appropriateness criteria for surgery improve clinical outcomes in patients with low back pain and/or sciatica.

STUDY DESIGN: Prospective, controlled, observational outcome study using clinical, radiographic, and patient/physician-based questionnaire data, with patient outcomes at 12 months follow-up. OBJECTIVE: To validate appropriateness criteria for low back surgery. SUMMARY OF BACKGROUND DATA: Most surgical treatment failures are attributed to poor patient selection, but no widely accepted consensus exists on detailed indications for appropriate surgery. METHODS: Appropriateness criteria for low back surgery have been developed by a multispecialty panel using the RAND appropriateness method. Based on panel criteria, a prospective study compared outcomes of patients appropriately and inappropriately treated at a single institution with 12 months follow-up assessment. Included were patients with low back pain and/or sciatica referred to the neurosurgical department. Information about symptoms, neurologic signs, the health-related quality of life (SF-36), disability status (Roland-Morris), and pain intensity (VAS) was assessed at baseline, at 6 months, and at 12 months follow-up. The appropriateness criteria were administered prospectively to each clinical situation and outside of the clinical setting, with the surgeon and patients blinded to the results of the panel decision. The patients were further stratified into 2 groups: appropriate treatment group (ATG) and inappropriate treatment group (ITG). RESULTS: Overall, 398 patients completed all forms at 12 months. Treatment was considered appropriate for 365 participants and inappropriate for 33 participants. The mean improvement in the SF-36 physical component score at 12 months was significantly higher in the ATG (mean: 12.3 points) than in the ITG (mean: 6.8 points) (P = 0.01), as well as the mean improvement in the SF-36 mental component score (ATG mean: 5.0 points; ITG mean: -0.5 points) (P = 0.02). Improvement was also significantly higher in the ATG for the mean VAS back pain (ATG mean: 2.3 points; ITG mean: 0.8 points; P = 0.02) and Roland-Morris disability score (ATG mean: 7.7 points; ITG mean: 4.2 points; P = 0.004). The ATG also had a higher improvement in mean VAS for sciatica (4.0 points) than the ITG (2.8 points), but the difference was not significant (P = 0.08). The SF-36 General Health score declined in both groups after 12 months, however, the decline was worse in the ITG (mean decline: 8.2 points) than in the ATG (mean decline: 1.2 points) (P = 0.04). Overall, in comparison to ITG patients, ATG patients had significantly higher improvement at 12 months, both statistically and clinically. CONCLUSION: In comparison to previously reported literature, our study is the first to assess the utility of appropriateness criteria for low back surgery at 1-year follow-up with multiple outcome dimensions. Our results confirm the hypothesis that application of appropriateness criteria can significantly improve patient outcomes.

Optimized venous return with a self-expanding cannula: from computational fluid dynamics to clinical application.

The Smart canula concept allows for collapsed cannula insertion, and self-expansion within a vein of the body. (A) Computational fluid dynamics, and (B) bovine experiments (76+/-3.8 kg) were performed for comparative analyses, prior to (C) the first clinical application. For an 18F access, a given flow of 4 l/min (A) resulted in a pressure drop of 49 mmHg for smart cannula versus 140 mmHg for control. The corresponding Reynolds numbers are 680 versus 1170, respectively. (B) For an access of 28F, the maximal flow for smart cannula was 5.8+/-0.5 l/min versus 4.0+/-0.1 l/min for standard (P<0.0001), for 24F 5.5+/-0.6 l/min versus 3.2+/-0.4 l/min (P<0.0001), and for 20F 4.1+/-0.3 l/min versus 1.6+/-0.3 l/min (P<0.0001). The flow obtained with the smart cannula was 270+/-45% (20F), 172+/-26% (24F), and 134+/-13% (28F) of standard (one-way ANOVA, P=0.014). (C) First clinical application (1.42 m2) with a smart cannula showed 3.55 l/min (100% predicted) without additional fluids. All three assessment steps confirm the superior performance of the smart cannula design.

Benchmarking therapeutic drug monitoring software: A review of available computer tools

Therapeutic drug monitoring (TDM) aims to optimize treatments by individualizing dosage regimens based on the measurement of blood concentrations. Dosage individualization to maintain concentrations within a target range requires pharmacokinetic and clinical capabilities. Bayesian calculations currently represent the gold standard TDM approach but require computation assistance. In recent decades computer programs have been developed to assist clinicians in this assignment. The aim of this survey was to assess and compare computer tools designed to support TDM clinical activities. The literature and the Internet were searched to identify software. All programs were tested on personal computers. Each program was scored against a standardized grid covering pharmacokinetic relevance, user friendliness, computing aspects, interfacing and storage. A weighting factor was applied to each criterion of the grid to account for its relative importance. To assess the robustness of the software, six representative clinical vignettes were processed through each of them. Altogether, 12 software tools were identified, tested and ranked, representing a comprehensive review of the available software. Numbers of drugs handled by the software vary widely (from two to 180), and eight programs offer users the possibility of adding new drug models based on population pharmacokinetic analyses. Bayesian computation to predict dosage adaptation from blood concentration (a posteriori adjustment) is performed by ten tools, while nine are also able to propose a priori dosage regimens, based only on individual patient covariates such as age, sex and bodyweight. Among those applying Bayesian calculation, MM-USC*PACK© uses the non-parametric approach. The top two programs emerging from this benchmark were MwPharm© and TCIWorks. Most other programs evaluated had good potential while being less sophisticated or less user friendly. Programs vary in complexity and might not fit all healthcare settings. Each software tool must therefore be regarded with respect to the individual needs of hospitals or clinicians. Programs should be easy and fast for routine activities, including for non-experienced users. Computer-assisted TDM is gaining growing interest and should further improve, especially in terms of information system interfacing, user friendliness, data storage capability and report generation.

Clinical review: practical recommendations on the management of perioperative heart failure in cardiac surgery.

Acute cardiovascular dysfunction occurs perioperatively in more than 20% of cardiosurgical patients, yet current acute heart failure (HF) classification is not applicable to this period. Indicators of major perioperative risk include unstable coronary syndromes, decompensated HF, significant arrhythmias and valvular disease. Clinical risk factors include history of heart disease, compensated HF, cerebrovascular disease, presence of diabetes mellitus, renal insufficiency and high-risk surgery. EuroSCORE reliably predicts perioperative cardiovascular alteration in patients aged less than 80 years. Preoperative B-type natriuretic peptide level is an additional risk stratification factor. Aggressively preserving heart function during cardiosurgery is a major goal. Volatile anaesthetics and levosimendan seem to be promising cardioprotective agents, but large trials are still needed to assess the best cardioprotective agent(s) and optimal protocol(s). The aim of monitoring is early detection and assessment of mechanisms of perioperative cardiovascular dysfunction. Ideally, volume status should be assessed by 'dynamic' measurement of haemodynamic parameters. Assess heart function first by echocardiography, then using a pulmonary artery catheter (especially in right heart dysfunction). If volaemia and heart function are in the normal range, cardiovascular dysfunction is very likely related to vascular dysfunction. In treating myocardial dysfunction, consider the following options, either alone or in combination: low-to-moderate doses of dobutamine and epinephrine, milrinone or levosimendan. In vasoplegia-induced hypotension, use norepinephrine to maintain adequate perfusion pressure. Exclude hypovolaemia in patients under vasopressors, through repeated volume assessments. Optimal perioperative use of inotropes/vasopressors in cardiosurgery remains controversial, and further large multinational studies are needed. Cardiosurgical perioperative classification of cardiac impairment should be based on time of occurrence (precardiotomy, failure to wean, postcardiotomy) and haemodynamic severity of the patient's condition (crash and burn, deteriorating fast, stable but inotrope dependent). In heart dysfunction with suspected coronary hypoperfusion, an intra-aortic balloon pump is highly recommended. A ventricular assist device should be considered before end organ dysfunction becomes evident. Extra-corporeal membrane oxygenation is an elegant solution as a bridge to recovery and/or decision making. This paper offers practical recommendations for management of perioperative HF in cardiosurgery based on European experts' opinion. It also emphasizes the need for large surveys and studies to assess the optimal way to manage perioperative HF in cardiac surgery.

Prevention and treatment options for postoperative delirium in the elderly.

PURPOSE OF REVIEW: To review recent findings and developments in strategies for prevention and treatment of postoperative delirium. RECENT FINDINGS: Current advances in the field include improved knowledge about predisposing and precipitating factors, evidence for efficacy of multicomponent prevention programmes, refinement of perioperative procedures, and promising pharmacological approaches for prophylaxis and management of postoperative delirium. SUMMARY: Postoperative delirium is a common and serious complication in elderly patients. Preoperative assessment of risk profiles and tailored multimodal prevention approaches proved effective and should be integrated into clinical practice. Despite promising recent findings, at present, the routine use of pharmacological prophylaxis cannot be recommended. Validated and easy-to-use bedside diagnostic tools are available and should be regularly applied for delirium screening in the first days after surgery. In patients developing delirium, causal conditions and contributing factors need to be identified and addressed. Whereas administration of antipsychotics may represent an option for symptomatic treatment, further studies are needed to evaluate the effects of pharmacological approaches on long-term outcomes in elderly patients with delirium.

Prospective validation of the Pulmonary Embolism Severity Index. A clinical prognostic model for pulmonary embolism

Practice guidelines recommend outpatient care for selected patients with non-massive pulmonary embolism (PE), but fail to specify how these low-risk patients should be identified. Using data from U.S. patients, we previously derived the Pulmonary Embolism Severity Index (PESI), a prediction rule that risk stratifies patients with PE. We sought to validate the PESI in a European patient cohort. We prospectively validated the PESI in patients with PE diagnosed at six emergency departments in three European countries. We used baseline data for the rule's 11 prognostic variables to stratify patients into five risk classes (I-V) of increasing probability of mortality. The outcome was overall mortality at 90 days after presentation. To assess the accuracy of the PESI to predict mortality, we estimated the sensitivity, specificity, and predictive values for low- (risk classes I/II) versus higher-risk patients (risk classes III-V), and the discriminatory power using the area under the receiver operating characteristic (ROC) curve. Among 357 patients with PE, overall mortality was 5.9%, ranging from 0% in class I to 17.9% in class V. The 186 (52%) low-risk patients had an overall mortality of 1.1% (95% confidence interval [CI]: 0.1-3.8%) compared to 11.1% (95% CI: 6.8-16.8%) in the 171 (48%) higher-risk patients. The PESI had a high sensitivity (91%, 95% CI: 71-97%) and a negative predictive value (99%, 95% CI: 96-100%) for predicting mortality. The area under the ROC curve was 0.78 (95% CI: 0.70-0.86). The PESI reliably identifies patients with PE who are at low risk of death and who are potential candidates for outpatient care. The PESI may help physicians make more rational decisions about hospitalization for patients with PE.

Clinical and pharmacogenetic study on smoking and smoking cessation

Currently, smoking cessation represents one of the main strategies to reduce the incidence of tobacco-related diseases in the population. Smoking can also influence pharmacotherapy through several pharmacokinetic or pharmacodynamic interactions. Some of the most concerned drugs are those metabolized by the cytochrome P450 (CYP) 1A2 enzyme (e.g. caffeine, theophylline, clozapine, olanzapine, duloxetine), whose activity is induced by the polycyclic aromatic hydrocarbons found in tobacco smoke. This can result in a clinically significant decrease in the pharmacological effect of the drugs and the need of higher doses in smokers. Conversely, upon smoking cessation, toxic plasma levels of the drugs can be reached. The main objective of this thesis was to study the interindividual variability in CYP1A2 induction in a large cohort of smokers, by measuring CYP1A2 activity before smoking cessation and one month later in continuously abstinent subjects. For this purpose, a clinical study was conducted, including 194 smokers from the general population who wished to participate in a smoking cessation program and therefore received medical counseling and substitution therapy (nicotine or varenicline). An analytical method for the simultaneous quantification of nicotine, its metabolites and varenicline in plasma was developed and validated using ultra performance liquid chromatography coupled with tandem mass spectrometry. This method was used to confirm abstinence at different time points during the follow-up. Moreover, it was used to determine plasma levels of the smoking cessation drugs, to be used in the study of their pharmacogenetics, which was the secondary objective of this thesis. High interindividual variability in CYP1A2 induction by smoking was observed, ranging from no change to approximately 7 times decreased CYP1A2 activity after smoking cessation. Several clinical and genetic factors were investigated in an attempt to explain this variability. Firstly, a significant influence of CYP1A2*1F and *1D alleles, of contraceptive use and of the number of cigarettes smoked per day on CYP1A2 induced activity was observed, and of CYP1A2*1F and the use of contraceptives on the basal activity. But no influence of these factors was found on CYP1A2 inducibility. Given that known genetic polymorphisms in CYP1A2 gene were shown to explain only poorly the observed variations in activity, additional genetic factors were studied. SNPs in the CYP oxidoreductase (POR) gene were found to influence CYP1A2 basal activity, but not the induction. Finally, a pathway-based approach allowed to identify SNPs in genes coding for nuclear receptors (CAR, RXRa, VDR, PXR) and induction-mediating receptors (AhR), which significantly influenced CYP1A2 inducibility and basal activity (SNPs in the gene coding for CAR and RXRa). As secondary objective of the study, the pharmacogenetics of nicotine and varenicline is being investigated. Therefore, the nicotine metabolite ratio is used in the attempt to better explain nicotine dependence and the failure/success of quitting smoking. A population pharmacokinetic model is being developed for varenicline, integrating clinical and genetic factors (genes coding for its metabolizing enzymes and transporters), with the purpose of trying to predict efficacy and side effects. These findings suggest that the influence of smoking on pharmacotherapy could be better managed by including clinical and possibly in the future genetic factors, in the assessment of the adaptations needed when a person starts or stops smoking.  - L'arrêt du tabac représente une des principales stratégies pour diminuer l'incidence des maladies causées par celui-ci. Le tabagisme peut influencer la thérapie médicamenteuse par des interactions pharmacocinétiques ou pharmacodynamiques. Parmi les médicaments concernés, il y a ceux métabolisés par le cytochrome P450 (CYP) 1A2 (caféine, théophylline, clozapine, olanzapine, duloxétine, etc), dont l'activité enzymatique est induite par les hydrocarbures aromatiques polycycliques présents dans la fumée de cigarette. Ceci peut se traduire par une diminution de l'effet pharmacologique du traitement et la nécessité d'augmenter les doses d'entretien chez les fumeurs. Au contraire, à l'arrêt de la cigarette, les taux plasmatiques des médicaments peuvent devenir toxiques. L'objectif principal de cette thèse était d'étudier la variabilité interindividuelle dans l'induction du CYP1A2 dans une large cohorte de fumeurs, par la mesure de l'activité du CYP1A2 avant l'arrêt de la cigarette, ainsi qu'un mois après chez les sujets abstinents. Pour ce faire, une étude clinique a été conduite, incluant 194 fumeurs de la population générale dans un programme d'arrêt du tabac offrant des consultations spécifiques et un traitement pharmacologique (nicotine ou varénicline). Une méthode analytique pour la quantification simultanée de la nicotine, ses métabolites et la varénicline dans le plasma par chromatographie liquide couplée à la spectrométrie de masse en tandem à été développée et validée. Cette méthode a été utilisée pour confirmer l'abstinence pendant l'étude et déterminer les taux plasmatiques des médicaments, dans le but d'étudier leur pharmacogénétique. Une grande variabilité interindividuelle dans l'induction du CYP1A2 par la fumée a été observée, parfois sans changement et pouvant aller jusqu'à une diminution d'environ 7 fois l'activité du CYP1A2 après l'arrêt de la cigarette. Plusieurs facteurs cliniques et génétiques ont été étudiés pour essayer d'expliquer cette variabilité. Tout d'abord, on a observé une influence significative: des allèles CYP1A2*1F et *1D, des contraceptifs et du nombre de cigarettes fumées par jour sur l'activité induite du CYP1A2, ainsi que l'influence de l'allèle *1F et des contraceptifs sur l'activité basale. Cependant, aucune influence de ces facteurs n'a été démontrée sur l'inductibilité du CYP1A2. Étant donné que les polymorphismes génétiques du CYP1A2 apportent peu de renseignements sur la variabilité de son activité, des facteurs génétiques supplémentaires ont été étudiés. Des polymorphismes dans le gène POR (CYP oxidoreductase) ont été associés à l'activité basale du CYP1A2, mais pas à l'induction. Finalement, une approche basée sur la voie de signalisation du CYP1A2 a permis d'identifier des polymorphismes dans des gènes codant pour des récepteurs nucléaires (CAR, RXRa, VDR, PXR) et d'autres liés à l'induction (AhR) qui influencent significativement l'inductibilité et l'activité basale (les SNPs du CAR et RXRa). L'objectif secondaire de cette étude était d'investiguer la pharmacogénétique de la nicotine et de la varénicline. Le ratio métabolique de la nicotine est utilisé pour mieux expliquer la dépendance à la nicotine et le succès/échec de l'arrêt de la cigarette. Un modèle pharmacocinétique de population est en cours de développement pour la varénicline, intégrant des facteurs cliniques et génétiques (gènes codant pour ses enzymes de métabolisme et transporteurs), pour tenter de prédire son efficacité et ses effets secondaires. Les résultats de cette thèse suggèrent que l'influence du tabagisme sur la pharmacothérapie serait mieux gérée par l'inclusion des facteurs cliniques et peut-être, dans le futur, génétiques, dans l'évaluation des adaptations nécessaires lorsqu'une personne fume ou arrête de fumer.  - l'arrêt du tabac représente une des principales stratégies pour diminuer l'incidence des maladies causées par celui-ci dans la population. Le tabagisme peut influencer les traitements médicamenteux, soit en modifiant leur élimination par l'organisme, soit en agissant sur leur mode d'action. Parmi les médicaments les plus concernés, on retrouve par exemple: la caféine, la théophylline, la clozapine, l'olanzapine, la duloxétine, dont l'élimination est accélérée par la fumée de cigarette (induction enzymatique). Ceci peut se traduire par une diminution de l'effet du traitement et la nécessité d'en augmenter les doses chez les fumeurs. Au contraire, à l'arrêt de la cigarette, on observe un ralentissement de la fonction enzymatique, qui a pour conséquence une augmentation du taux de médicament dans le sang, pouvant devenir toxique. L'objectif principal de cette thèse était d'étudier comment cette induction par le tabac varie dans une population de fumeurs, par la mesure de l'activité de l'enzyme avant l'arrêt de la cigarette, ainsi qu'un mois après chez les sujets abstinents. Pour ce faire, une étude clinique a été conduite, incluant 194 fumeurs de la population générale dans un programme d'arrêt du tabac offrant des consultations spécifiques et un traitement médicamenteux (nicotine ou varénicline). Une méthode analytique a été mise au point pour mesurer la quantité de nicotine, de ses produits de dégradation et de la varénicline dans le sang des participants à l'étude. De plus, cette méthode a été utilisée pour confirmer l'abstinence pendant l'étude. Une grande variabilité interindividuelle a été observée dans l'induction de l'enzyme par la fumée; il en résulte aucun changement d'activité chez certains sujets après l'arrêt de la cigarette, alors que pour d'autres elle peut être diminuée jusqu'à 7 fois. Plusieurs facteurs cliniques et génétiques ont été étudiés pour essayer d'expliquer cette variabilité. Premièrement, une influence sur l'activité de l'enzyme a été observée pour les contraceptifs hormonaux et le nombre de cigarettes fumées par jour, ainsi que pour certaines variations génétiques dans le gène codant pour l'enzyme d'intérêt, mais il η y a pas eu d'influence sur l'induction. Par la suite, des variations génétiques dans d'autres gènes influençant le fonctionnement de l'enzyme ont été associées soit avec son activité, soit avec son induction par le tabac. Finalement, l'étude propose également d'investiguer si le métabolisme de la nicotine a une influence sur la dépendance, les symptômes de sevrage et le succès/échec de l'arrêt de la cigarette. Des variations génétiques dans les gènes du métabolisme de la varénicline sont également étudiées en lien avec les quantités de varénicline mesurées dans le sang ainsi que les effets du médicament. Ceci permettra peut-être de prédire son efficacité et ses effets secondaires. Les résultats de cette thèse suggèrent que l'influence du tabagisme sur la thérapie médicamenteuse serait mieux gérée en tenant compte des facteurs cliniques et peut-être, dans le futur, de la génétique dans l'adaptation des traitements, que la personne soit fumeuse ou en phase d'arrêt.

ESPEN endorsed recommendations: nutritional therapy in major burns.

BACKGROUND & AIMS: Nutrition therapy is a cornerstone of burn care from the early resuscitation phase until the end of rehabilitation. While several aspects of nutrition therapy are similar in major burns and other critical care conditions, the patho-physiology of burn injury with its major endocrine, inflammatory, metabolic and immune alterations requires some specific nutritional interventions. The present text developed by the French speaking societies, is updated to provide evidenced-based recommendations for clinical practice. METHODS: A group of burn specialists used the GRADE methodology (Grade of Recommendation, Assessment, Development and Evaluation) to evaluate human burn clinical trials between 1979 and 2011. The resulting recommendations, strong suggestions or suggestions were then rated by the non-burn specialized experts according to their agreement (strong, moderate or weak). RESULTS: Eight major recommendations were made. Strong recommendations were made regarding, 1) early enteral feeding, 2) the elevated protein requirements (1.5-2 g/kg in adults, 3 g/kg in children), 3) the limitation of glucose delivery to a maximum of 55% of energy and 5 mg/kg/h associated with moderate blood glucose (target ≤ 8 mmol/l) control by means of continuous infusion, 4) to associated trace element and vitamin substitution early on, and 5) to use non-nutritional strategies to attenuate hypermetabolism by pharmacological (propranolol, oxandrolone) and physical tools (early surgery and thermo-neutral room) during the first weeks after injury. Suggestion were made in absence of indirect calorimetry, to use of the Toronto equation (Schoffield in children) for energy requirement determination (risk of overfeeding), and to maintain fat administration ≤ 30% of total energy delivery. CONCLUSION: The nutritional therapy in major burns has evidence-based specificities that contribute to improve clinical outcome.