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.

Rational design of an organometallic glutathione transferase inhibitor.

Double trouble: A hybrid organic-inorganic (organometallic) inhibitor was designed to target glutathione transferases. The metal center is used to direct protein binding, while the organic moiety acts as the active-site inhibitor (see picture). The mechanism of inhibition was studied using a range of biophysical and biochemical methods.

Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral therapy: a phase I/II, randomized trial.

OBJECTIVE: Tuberculosis (TB) is highly prevalent among HIV-infected people, including those receiving combination antiretroviral therapy (cART), necessitating a well tolerated and efficacious TB vaccine for these populations. We evaluated the safety and immunogenicity of the candidate TB vaccine M72/AS01 in adults with well controlled HIV infection on cART. DESIGN: A randomized, observer-blind, controlled trial (NCT00707967). METHODS: HIV-infected adults on cART in Switzerland were randomized 3 : 1 : 1 to receive two doses, 1 month apart, of M72/AS01, AS01 or 0.9% physiological saline (N = 22, N = 8 and N = 7, respectively) and were followed up to 6 months postdose 2 (D210). Individuals with CD4⁺ cell counts below 200 cells/μl were excluded. Adverse events (AEs) including HIV-specific and laboratory safety parameters were recorded. Cell-mediated (ICS) and humoral (ELISA) responses were evaluated before vaccination, 1 month after each dose (D30, D60) and D210. RESULTS: Thirty-seven individuals [interquartile range (IQR) CD4⁺ cell counts at screening: 438-872 cells/μl; undetectable HIV-1 viremia] were enrolled; 73% of individuals reported previous BCG vaccination, 97.3% tested negative for the QuantiFERON-TB assay. For M72/AS01 recipients, no vaccine-related serious AEs or cART-regimen adjustments were recorded, and there were no clinically relevant effects on laboratory safety parameters, HIV-1 viral loads or CD4⁺ cell counts. M72/AS01 was immunogenic, inducing persistent and polyfunctional M72-specific CD4⁺ T-cell responses [medians 0.70% (IQR 0.37-1.07) at D60] and 0.42% (0.24-0.61) at D210, predominantly CD40L⁺IL-2⁺TNF-α⁺, CD40L⁺IL-2⁺ and CD40L⁺IL-2⁺TNF-α⁺IFN-γ⁺]. All M72/AS01 vaccines were seropositive for anti-M72 IgG after second vaccination until study end. CONCLUSION: M72/AS01 was clinically well tolerated and immunogenic in this population, supporting further clinical evaluation in HIV-infected individuals in TB-endemic settings.

Using active learning for monitoring networks design: The example of wind power plants sites evaluation

Locating new wind farms is of crucial importance for energy policies of the next decade. To select the new location, an accurate picture of the wind fields is necessary. However, characterizing wind fields is a difficult task, since the phenomenon is highly nonlinear and related to complex topographical features. In this paper, we propose both a nonparametric model to estimate wind speed at different time instants and a procedure to discover underrepresented topographic conditions, where new measuring stations could be added. Compared to space filling techniques, this last approach privileges optimization of the output space, thus locating new potential measuring sites through the uncertainty of the model itself.

Design and evaluation of a solid sampler for the monitoring of airborne 1,6-hexamethylene diisocyanate (HDI) and its prepolymers in 2-component spray painting

An active, solvent-free solid sampler was developed for the collection of 1,6-hexamethylene diisocyanate (HDI) aerosol and prepolymers. The sampler was made of a filter impregnated with 1-(2-methoxyphenyl)piperazine contained in a filter holder. Interferences with HDI were observed when a set of cellulose acetate filters and a polystyrene filter holder were used; a glass fiber filter and polypropylene filter cassette gave better results. The applicability of the sampling and analytical procedure was validated with a test chamber, constructed for the dynamic generation of HDI aerosol and prepolymers in commercial two-component spray paints (Desmodur(R) N75) used in car refinishing. The particle size distribution, temporal stability, and spatial uniformity of the simulated aerosol were established in order to test the sample. The monitoring of aerosol concentrations was conducted with the solid sampler paired to the reference impinger technique (impinger flasks contained 10 mL of 0.5 mg/mL 1-(2-methoxyphenyl)piperazine in toluene) under a controlled atmosphere in the test chamber. Analyses of derivatized HDI and prepolymers were carried out by using high-performance liquid chromatography and ultraviolet detection. The correlation between the solvent-free and the impinger techniques appeared fairly good (Y = 0.979X - 0.161; R = 0.978), when the tests were conducted in the range of 0.1 to 10 times the threshold limit value (TLV) for HDI monomer and up to 60-mu-g/m3 (3 U.K. TLVs) for total -N = C = O groups.

Experimental design for acquiring relevant data to address the issue of comparing consecutively manufactured tools and firearms

The comparison of consecutively manufactured tools and firearms has provided much, but not all, of the basis for the profession of firearm and toolmark examination. The authors accept the fundamental soundness of this approach but appeal to the experimental community to close two minor gaps in the experimental procedure. We suggest that "blinding" and attention to appropriateness of other experimental conditions that would consolidate the foundations of our profession. We do not suggest that previous work is unsound.

New concepts for the design of dermal substitutes

Objectives: Skin can be partially regenerated after full thickness defects by collagen matrices, In this study, we identified the main limitations of induced regeneration aiming to improve the design of dermal matrices. Methods: Single mice received a 1 cm2, full thickness skin wound on the dorsum, which were grafted with collagen-GAG matrices or left ungrafted. The healing modulation induced by the collagen-GAG matrices was compared to spontaneous healing and to custom designed, bioactive, poly-N-Acetyl- Glucosamine (NAG) matrices. Wound staging was based on macroscopic, histological and immunhistochemical analysis on days 3, 7, 10 and 21 post wounding. Results: Cell density was higher in spontaneously granulating wounds compared to grafted wounds. While grafted wounds exhibited increased levels of cell proliferation on days 7 and 10, vascularity was dramatically reduced. NAG scaffolds accelerated both angiogenesis and wound re-epithelialization. Conclusions: Since slow integration and revascularization severely limit the engraftment of clinically used dermal scaffolds, the design of dermal matrices using bioactive materials represent the next step in skin regeneration.

The impact of iron supplementation efficiency in female blood donors with a decreased ferritin level and no anaemia. Rationale and design of a randomised controlled trial: a study protocol.

ABSTRACT: BACKGROUND: There is no recommendation to screen ferritin level in blood donors, even though several studies have noted the high prevalence of iron deficiency after blood donation, particularly among menstruating females. Furthermore, some clinical trials have shown that non-anaemic women with unexplained fatigue may benefit from iron supplementation. Our objective is to determine the clinical effect of iron supplementation on fatigue in female blood donors without anaemia, but with a mean serum ferritin </= 30 ng/ml. METHODS/DESIGN: In a double blind randomised controlled trial, we will measure blood count and ferritin level of women under age 50 yr, who donate blood to the University Hospital of Lausanne Blood Transfusion Department, at the time of the donation and after 1 week. One hundred and forty donors with a ferritin level </= 30 ng/ml and haemoglobin level >/= 120 g/l (non-anaemic) a week after the donation will be included in the study and randomised. A one-month course of oral ferrous sulphate (80 mg/day of elemental iron) will be introduced vs. placebo. Self-reported fatigue will be measured using a visual analogue scale. Secondary outcomes are: score of fatigue (Fatigue Severity Scale), maximal aerobic power (Chester Step Test), quality of life (SF-12), and mood disorders (Prime-MD). Haemoglobin and ferritin concentration will be monitored before and after the intervention. DISCUSSION: Iron deficiency is a potential problem for all blood donors, especially menstruating women. To our knowledge, no other intervention study has yet evaluated the impact of iron supplementation on subjective symptoms after a blood donation. TRIAL REGISTRATION: NCT00689793.

Design and analysis of ChIP-Seq experiments for nuclear factor I DNA-binding proteins

SUMMARY : Eukaryotic DNA interacts with the nuclear proteins using non-covalent ionic interactions. Proteins can recognize specific nucleotide sequences based on the sterical interactions with the DNA and these specific protein-DNA interactions are the basis for many nuclear processes, e.g. gene transcription, chromosomal replication, and recombination. New technology termed ChIP-Seq has been recently developed for the analysis of protein-DNA interactions on a whole genome scale and it is based on immunoprecipitation of chromatin and high-throughput DNA sequencing procedure. ChIP-Seq is a novel technique with a great potential to replace older techniques for mapping of protein-DNA interactions. In this thesis, we bring some new insights into the ChIP-Seq data analysis. First, we point out to some common and so far unknown artifacts of the method. Sequence tag distribution in the genome does not follow uniform distribution and we have found extreme hot-spots of tag accumulation over specific loci in the human and mouse genomes. These artifactual sequence tags accumulations will create false peaks in every ChIP-Seq dataset and we propose different filtering methods to reduce the number of false positives. Next, we propose random sampling as a powerful analytical tool in the ChIP-Seq data analysis that could be used to infer biological knowledge from the massive ChIP-Seq datasets. We created unbiased random sampling algorithm and we used this methodology to reveal some of the important biological properties of Nuclear Factor I DNA binding proteins. Finally, by analyzing the ChIP-Seq data in detail, we revealed that Nuclear Factor I transcription factors mainly act as activators of transcription, and that they are associated with specific chromatin modifications that are markers of open chromatin. We speculate that NFI factors only interact with the DNA wrapped around the nucleosome. We also found multiple loci that indicate possible chromatin barrier activity of NFI proteins, which could suggest the use of NFI binding sequences as chromatin insulators in biotechnology applications. RESUME : L'ADN des eucaryotes interagit avec les protéines nucléaires par des interactions noncovalentes ioniques. Les protéines peuvent reconnaître les séquences nucléotidiques spécifiques basées sur l'interaction stérique avec l'ADN, et des interactions spécifiques contrôlent de nombreux processus nucléaire, p.ex. transcription du gène, la réplication chromosomique, et la recombinaison. Une nouvelle technologie appelée ChIP-Seq a été récemment développée pour l'analyse des interactions protéine-ADN à l'échelle du génome entier et cette approche est basée sur l'immuno-précipitation de la chromatine et sur la procédure de séquençage de l'ADN à haut débit. La nouvelle approche ChIP-Seq a donc un fort potentiel pour remplacer les anciennes techniques de cartographie des interactions protéine-ADN. Dans cette thèse, nous apportons de nouvelles perspectives dans l'analyse des données ChIP-Seq. Tout d'abord, nous avons identifié des artefacts très communs associés à cette méthode qui étaient jusqu'à présent insoupçonnés. La distribution des séquences dans le génome ne suit pas une distribution uniforme et nous avons constaté des positions extrêmes d'accumulation de séquence à des régions spécifiques, des génomes humains et de la souris. Ces accumulations des séquences artéfactuelles créera de faux pics dans toutes les données ChIP-Seq, et nous proposons différentes méthodes de filtrage pour réduire le nombre de faux positifs. Ensuite, nous proposons un nouvel échantillonnage aléatoire comme un outil puissant d'analyse des données ChIP-Seq, ce qui pourraient augmenter l'acquisition de connaissances biologiques à partir des données ChIP-Seq. Nous avons créé un algorithme d'échantillonnage aléatoire et nous avons utilisé cette méthode pour révéler certaines des propriétés biologiques importantes de protéines liant à l'ADN nommés Facteur Nucléaire I (NFI). Enfin, en analysant en détail les données de ChIP-Seq pour la famille de facteurs de transcription nommés Facteur Nucléaire I, nous avons révélé que ces protéines agissent principalement comme des activateurs de transcription, et qu'elles sont associées à des modifications de la chromatine spécifiques qui sont des marqueurs de la chromatine ouverte. Nous pensons que lés facteurs NFI interagir uniquement avec l'ADN enroulé autour du nucléosome. Nous avons également constaté plusieurs régions génomiques qui indiquent une éventuelle activité de barrière chromatinienne des protéines NFI, ce qui pourrait suggérer l'utilisation de séquences de liaison NFI comme séquences isolatrices dans des applications de la biotechnologie.

Study design for technology assessment: critical issues.

The epidemiological methods have become useful tools for the assessment of the effectiveness and safety of health care technologies. The experimental methods, namely the randomized controlled trials (RCT), give the best evidence of the effect of a technology. However, the ethical issues and the very nature of the intervention under study sometimes make it difficult to carry out an RCT. Therefore, quasi-experimental and non-experimental study designs are also applied. The critical issues concerning these designs are discussed. The results of evaluative studies are of importance for decision-makers in health policy. The measurements of the impact of a medical technology should go beyond a statement of its effectiveness, because the essential outcome of an intervention or programme is the health status and quality of life of the individuals and populations concerned.

Beyond splitting: observer-rated defense mechanisms in borderline personality disorder

Defense mechanism is a key concept in the psychoanalytic psychopathology of borderline personality disorder (BPD). Theoretical and empirical elaborations on this question are briefly reviewed and discussed with respect to process assessment of defense mechanisms; we put forward observer-rater methodology as an accurate means of assessing unconscious in-session processes. A sample of 25 patients presenting with BPD were interviewed, as were subjects from a matched control group without psychiatric symptoms (n = 25), using a psychodynamic interview paradigm. These interviews were transcribed and rated using the Defense Mechanisms Rating Scales. The results indicate that, compared to controls, patients with BPD used higher percentages of a action, borderline, disavowal, narcissistic, and hysteric defenses, along with lower levels of mature and obsessional defenses. Overall defensive functioning was significantly lower in the patients with BPD, compared to controls. Narcissistic defenses were related with symptom level. These results are discussed in light of previous studies on defensive functioning of BPD and the literature on psychoanalytic psychopathology. These results have several important clinical implications.

Docking, virtual high throughput screening and in silico fragment-based drug design.

ABSTRACT The drug discovery process has been profoundly changed recently by the adoption of computational methods helping the design of new drug candidates more rapidly and at lower costs. In silico drug design consists of a collection of tools helping to make rational decisions at the different steps of the drug discovery process, such as the identification of a biomolecular target of therapeutical interest, the selection or the design of new lead compounds and their modification to obtain better affinities, as well as pharmacokinetic and pharmacodynamic properties. Among the different tools available, a particular emphasis is placed in this review on molecular docking, virtual high throughput screening and fragment-based ligand design.

Using a NPWE model observer to assess suitable image quality for a digital mammography quality assurance programme.

A method of objectively determining imaging performance for a mammography quality assurance programme for digital systems was developed. The method is based on the assessment of the visibility of a spherical microcalcification of 0.2 mm using a quasi-ideal observer model. It requires the assessment of the spatial resolution (modulation transfer function) and the noise power spectra of the systems. The contrast is measured using a 0.2-mm thick Al sheet and Polymethylmethacrylate (PMMA) blocks. The minimal image quality was defined as that giving a target contrast-to-noise ratio (CNR) of 5.4. Several evaluations of this objective method for evaluating image quality in mammography quality assurance programmes have been considered on computed radiography (CR) and digital radiography (DR) mammography systems. The measurement gives a threshold CNR necessary to reach the minimum standard image quality required with regards to the visibility of a 0.2-mm microcalcification. This method may replace the CDMAM image evaluation and simplify the threshold contrast visibility test used in mammography quality.

Application of detection probabilities to the design of amphibian monitoring programs in temporary ponds

Failure to detect a species in an area where it is present is a major source of error in biological surveys. We assessed whether it is possible to optimize single-visit biological monitoring surveys of highly dynamic freshwater ecosystems by framing them a priori within a particular period of time. Alternatively, we also searched for the optimal number of visits and when they should be conducted. We developed single-species occupancy models to estimate the monthly probability of detection of pond-breeding amphibians during a four-year monitoring program. Our results revealed that detection probability was species-specific and changed among sampling visits within a breeding season and also among breeding seasons. Thereby, the optimization of biological surveys with minimal survey effort (a single visit) is not feasible as it proves impossible to select a priori an adequate sampling period that remains robust across years. Alternatively, a two-survey combination at the beginning of the sampling season yielded optimal results and constituted an acceptable compromise between sampling efficacy and survey effort. Our study provides evidence of the variability and uncertainty that likely affects the efficacy of monitoring surveys, highlighting the need of repeated sampling in both ecological studies and conservation management.