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La présente étude vise à poursuivre la validation du construit d’habilitation comportementale, en examinant non seulement sa structure factorielle, mais en examinant les différences conceptuelles et empiriques entre ce type de comportements et trois autres types de comportements organisationnels, à savoir les comportements de citoyenneté organisationnelle, d’innovation et d’autogestion. Des analyses factorielles confirmatoires ont été effectuées afin d’examiner la structure du construit (N = 274) alors que des analyses corrélationnelles ont permis de statuer sur le caractère distinctif des mesures (N = 104). Les résultats démontrent que les concepts sont distincts (.19

Personalized medicine is based on: 1) improved clinical or non-clinical methods (including biomarkers) for a more discriminating and precise diagnosis of diseases; 2) targeted therapies of the choice or the best drug for each patient among those available; 3) dose adjustment methods to optimize the benefit-risk ratio of the drugs chosen; 4) biomarkers of efficacy, toxicity, treatment discontinuation, relapse, etc. Unfortunately, it is still too often a theoretical concept because of the lack of convenient diagnostic methods or treatments, particularly of drugs corresponding to each subtype of pathology, hence to each patient. Stratified medicine is a component of personalized medicine employing biomarkers and companion diagnostics to target the patients likely to present the best benefit-risk balance for a given active compound. The concept of targeted therapy, mostly used in cancer treatment, relies on the existence of a defined molecular target, involved or not in the pathological process, and/or on the existence of a biomarker able to identify the target population, which should logically be small as compared to the population presenting the disease considered. Targeted therapies and biomarkers represent important stakes for the pharmaceutical industry, in terms of market access, of return on investment and of image among the prescribers. At the same time, they probably represent only the first generation of products resulting from the combination of clinical, pathophysiological and molecular research, i.e.of translational research.

La médecine personnalisée repose sur : 1) des méthodes cliniques et paracliniques (y compris des biomarqueurs) pour un diagnostic plus discriminant et plus précis des maladies ; 2) des thérapies ciblées ou le choix du meilleur traitement parmi ceux possibles pour chaque patient ; 3) des méthodes d’ajustement de posologie pour maximiser le rapport bénéfice/risque des médicaments choisis ; 4) des biomarqueurs d’efficacité, de toxicité, d’arrêt de traitement, de rechute, etc. Malheureusement, c’est encore trop souvent un concept théorique faute de méthodes diagnostiques et de traitements adaptés, en particulier des médicaments correspondant à chaque sous-type pathologique et donc pour chaque patient. La médecine stratifiée en est une composante, utilisant des biomarqueurs et des tests diagnostiques compagnons pour cibler les patients susceptibles de présenter la meilleure balance bénéfice-risque pour un principe actif donné. Le concept de thérapie ciblée, surtout utilisé en oncologie, repose sur l’existence d’une cible moléculaire définie, impliquée ou non dans le processus pathologique, et/ou sur l’existence d’un biomarqueur permettant d’identifier la population cible, qui devrait être logiquement restreinte par rapport à la population atteinte de la pathologie considérée. Thérapies ciblées et biomarqueurs représentent des enjeux importants pour l’industrie pharmaceutique, en termes d’accès au marché, de retour sur investissement et d’image auprès des prescripteurs. En même temps, ils ne représentent probablement que la première génération de produits issus de la combinaison de la recherche clinique et de la recherche physiopathologique et moléculaire, c’est-à-dire de la recherche translationnelle.

The European Commission has introduced new risk management tools in the rural development pillar 2 of the Common Agricultural Policy. One of them consists in providing co-financing support to mutual funds compensating farmers who experience a severe drop in their income. This paper analyses this income stabilisation tool for a region in Belgium by means of a skew normal linear mixed model. Relying on the farm accountancy data network, this analysis focuses on estimating the probability that such a fund would need to intervene and, in that case, the expected amount of each farm income compensation. The predictive distribution of future incomes given past revenues trajectory is derived and used for evaluation purposes. Particular attention is paid to additional requirements that could be imposed to the income stabilisation tool.

Patients with posttraumatic stress disorder (PTSD) have significant medical morbidity, which may be mediated by hypothalamic pituitary axis (HPA) dysfunction and reflected in cortisol output. Many veterans with PTSD are hesitant to engage in trauma-focused exposure treatments; therefore briefer, non–exposure-based treatments are needed; one such promising approach is an abbreviated Primary Care brief Mindfulness Program (PCbMP).

Insomnia is common, but undertreated, among primary care patients. Within the Veterans Health Administration (VA), increasing attention has been given to the treatment of insomnia within primary care settings, but little research has examined Veterans' treatment preferences. We examined preferences for sleep treatment among VA primary care patients. Participants (N = 126: 98% male, 89% white; M age = 60 years) completed a brief survey. On the basis of Insomnia Severity Index scores, 22% reported subthreshold and 13% moderate insomnia. Fifty percent reported having issues with sleep (falling asleep, staying asleep, or sleeping too much) in the past 12 months; among these, only 44% reported any discussion of medication (34%) or other strategies (32%) to improve sleep with medical providers. The most preferred treatment approach was to work it out on one's own, followed by consulting the primary care provider (PCP). The most preferred modality was a one-on-one meeting with the PCP, followed by a one-on-one meeting with the behavioral health provider. In conclusion, VA primary care patients preferred handling sleep problems on their own, but if seeking help, they preferred working with PCPs over behavioral health providers. The majority of Veterans preferred individual treatment and strategies other than medication.

Decree No. 2012-1116 of 2 October 2012 on medico-economic assignments of the French National Authority for Health (Haute autorité de santé, HAS) significantly alters the conditions for accessing the health products market in France. This paper presents a theoretical framework for interpreting the results of the economic evaluation of health technologies and summarises the facts available in France for developing benchmarks that will be used to interpret incremental cost-effectiveness ratios. This literature review shows that it is difficult to determine a threshold value but it is also difficult to interpret then incremental cost effectiveness ratio (ICER) results without a threshold value. In this context, round table participants favour a pragmatic approach based on “benchmarks” as opposed to a threshold value, based on an interpretative and normative perspective, i.e.benchmarks that can change over time based on feedback.

Le décret n° 2012-1116 du 2 octobre 2012 relatif aux missions médico-économiques de la Haute autorité de santé modifie significativement les conditions d’accès au marché des biens de santé en France. Cet article présente le cadre théorique d’interprétation des résultats de l’évaluation économique des technologies de santé et synthétise les éléments factuels disponibles en France pour l’élaboration de référentiels pour l’interprétation des ratios différentiels coût/résultats. Cette revue de littérature montre qu’il est difficile de déterminer une valeur-seuil mais qu’il est également difficile d’interpréter des résultats de ratio différentiel coût/résultats (RDCR) sans valeur-seuil. Dans ce contexte, les participants à la table ronde privilégient une approche pragmatique reposant sur « des référentiels » et non une valeur-seuil, dans une perspective interprétative et non normative, référentiels qui pourront évoluer dans le temps au regard des retours d’expérience.

We report on the generation of supercontinuum radiation from 2 to 20 μm in a 67 mm long GaAs crystal pumped by a train of 3 ps CO_2 laser pulses. Temporal measurements indicate that sub-picosecond pulse splitting is involved in the production of such wide-bandwidth radiation in GaAs. The results show that the observed spectral broadening is heavily influenced by four-wave mixing and stimulated Raman scattering.

Suicide is a major public health focus with increasing importance among veterans. Post-traumatic stress disorder (PTSD), depression, and alcohol use are associated with increased rates of suicidal thoughts, with some indications that suicide is also linked to sleep disturbance. The current study examined the association of sleep disturbance with suicidal ideation (SI) among 654 veterans. Logistic regression revealed that after controlling for age, alcohol dependence, depression, and PTSD, sleep disturbance remained associated with SI. In this sample of veterans, the relationship of sleep disturbance to SI does not appear to be solely attributable to comorbid factors. Identification of sleep difficulties may aid in the early detection of SI, allowing for intervention prior to symptom escalation.

To provide an overview of foundational theories on the psychosocial and neurobiological mechanisms that underlie the pathophysiology of insomnia, a review of recent findings from across the spectrum of sleep sciences that are germane to conceptualizations of insomnia, and how such findings contribute to newer integrative models.

Les anticorps monoclonaux (AcMo) sont très différents des autres médicaments. Notre objectif a été d’évaluer si leurs spécificités ont des conséquences sur leur développement clinique, leur évaluation par les autorités de santé et leur suivi à long terme. En ce qui concerne la relation structure-activité des AcMo, il est plus pertinent de les classer selon leur mécanisme d’action (AcMo neutralisants ou agonistes, AcMo cytolytiques) que selon leur degré d’humanisation. Des recommandations sur leur développement clinique seraient souhaitables car les phases précoces posent un certain nombre de problèmes et sont mal codifiées. La pharmacocinétique est très différente de celle des autres médicaments. L’étude de la relation concentrationeffet est difficile car les biomarqueurs sont souvent déconnectés de l’effet thérapeutique. La méthodologie de l’évaluation des AcMo par les agences et leur suivi post-autorisation de mise sur le marché (post-AMM) ne sont pas différents de ceux des autres médicaments mais les AcMo associent un ensemble de particularités.

Une cohorte est la réunion d’un groupe de sujets partageant ensemble un certain nombre de caractéristiques, suivis longitudinalement, à l’échelle individuelle. Outils essentiels de l’épidémiologie, ces études permettent notamment d’argumenter sur l’éventuelle causalité entre une exposition et la survenue d’événements et d’orienter ainsi des politiques de santé publique.

Monoclonal antibodies (MoAb) are very different from other drugs. The Round Table aimed to determine whether the specific characteristics of MoAb have repercussions on their clinical development, evaluation by the health authorities, and long-term monitoring. As regards the structure-activity relationship of MoAb, classification according to mechanism of action (neutralising or agonist MoAb, cytolytic MoAb) is more relevant than to their degree of humanisation. Recommendations on their clinical development would be useful since the early phases give rise to a number of problems and are insufficiently codified. The pharmacokinetic profile is very different from that of other drugs. The concentration-effect relationship is difficult to study since the biomarkers may be apparently disconnected from the therapeutic effect. The methodology for evaluation of MoAb by the agencies, and postmarketing surveillance do not differ from the procedures used for other drugs; however, MoAb bring together a number of specific characteristics as compared with other drugs.

The problem of efficiently adapting JPEG images to satisfy given constraints such as maximum file size and resolution arises in a number of applications, from universal media access for mobile browsing to multimedia messaging services. However, optimizing for perceived quality (user experience) commands a non-negligible computational cost which in the authors work, they aim to minimize by the use of low-cost predictors. In previous work, the authors presented predictors and predictor-based systems to achieve low-cost and near-optimal adaption of JPEG images under given constraints of file size and resolution. In this work, they extend and improve these solutions by including more information about images to obtain more accurate predictions of file size and quality resulting from transcoding. The authors show that the proposed method, based on the clustering of transcoding operations represented as high-dimensional vectors, significantly outperforms previous methods in accuracy.

Abstract: Aim: Previous studies have demonstrated relationships between sleep and both obesity and diabetes. Additionally, exercise may improve sleep and daytime function, in addition to weight and metabolic function. The present study extends these findings by examining how general sleep-related complaints are associated with body mass index (BMI), diabetes diagnosis, and exercise in a large, nationally representative sample. Subject and methods: Participants were respondents to the Behavioral Risk Factor Surveillance System (BRFSS). Sleep complaint (SC) was measured with “Over the last 2 weeks, how many days have you had trouble falling asleep or staying asleep or sleeping too much?” Daytime complaint (DC) was measured with “Over the last 2 weeks, how many days have you felt tired or had little energy?” Responses were dichotomized, with ≥6 days indicating complaint. Covariates included age, race/ethnicity, income, and education. Results: Being overweight was associated with DC in women only. Obesity was significantly associated with SC and DC in women, and DC in men. Diabetes was associated with SC and DC in both genders. Any exercise in the past 30 days did not attenuate any BMI or diabetes relationships, but was independently associated with a decrease in SC and DC in both men and women. Conclusion: These results suggest that for both men and women diabetes is a significant predictor of sleep and daytime complaints, and there is a relationship between obesity and sleep and complaints for women to a greater extent than men. Finally, exercise was associated with much fewer sleep and daytime complaints in both genders.

This paper presents a controller design for a class of MIMO nonlinear systems involving some uncertainties. The latter is particularly composed by cascade subsystems and each subsystem is associated to a subset of the system outputs and assumes a triangular dependence on its own state variables and may depend on the state variables of all other subsystems. The main contribution consists in extending the available control results to allow more interconnections between the subsystems. Of fundamental interest, it is shown that the underlying tracking error exponentially converges to zero in the absence of uncertainties, and can be made as small as desired by properly specifying the control design parameter in the presence of uncertainties.

L’évaluation pour l’admission au remboursement faite par la Commission de la Transparence de la Haute Autorité de Santé (HAS) comporte une cotation du Service Médical Rendu (SMR) qui donne l’accès au remboursement, de l’Amélioration du Service Médical Rendu (ASMR) qui détermine la valeur thérapeutique ajoutée et une définition de la population cible. L’évaluation au remboursement des anticancéreux ne diffère pas de celle des autres classes thérapeutiques exceptés certains éléments spécifiques. La survie globale (OS) considérée par la commission de la transparence comme le critère d’évaluation du bénéfice clinique, n’est pas applicable en tant que critère principal dans tous les types de cancer. L’existence de lignes ultérieures de traitement peut rendre difficilement interprétable une OS prise comme critère principal. La survie sans progression (PFS) pour les situations métastatiques et la survie sans maladie (DFS) dans les situations adjuvantes sont des critères tout à fait pertinents pour statuer sur le remboursement d’un nouvel anticancéreux. L’évaluation de la quantité d’effet se fait sur les courbes de survie actuarielles du produit par rapport à son comparateur. L’interprétation des résultats se fait en général sur la médiane de survie qui n’est pas un bon critère puisqu’elle ne mesure qu’un seul point de la courbe. Le hazard ratiomesure l’effet du traitement sur toute la durée du suivi et est ainsi plus global pour quantifier le bénéfice clinique. La détermination d’un seuil de quantité d’effet pour l’octroi du remboursement est difficile, compte tenu de la diversité des situations cliniques des cancers et du niveau de besoin thérapeutique. L’évolutivité rapide des comparateurs ainsi que l’apparition et la recherche en cours de développement de facteurs prédictifs d’efficacité (biomarqueurs, histologie…), peuvent amener à des ASMR différentes selon les populations voire à la restriction de la population cible à un sous groupe de la population de l’Autorisation de Mise sur le Marché (AMM), où la quantité d’effet attendue est plus importante. Pour répondre à ces enjeux, la Table Ronde recommande la possibilité d’avis scientifiques précoces auprès du bureau de la commission de la transparence, pour discuter des comparateurs et de la pertinence de sous groupes de répondeurs. Elle recommande aussi la possibilité d’octroi d’une ASMR temporaire, sous condition de confirmation ultérieure par production de données, lorsque le remboursement semble justifié dans une sous population de l’AMM pour laquelle seule une analyse en sous groupe est disponible.

Reimbursement is assessed by the Transparency Commission from the Health Authority (HAS) using a medical benefit (SMR) score that gives access to reimbursement, an “improvement of medical service rendered” (ASMR) that determines the added therapeutic value, and the target population. Assessing cancer drugs for reimbursement raises the same issues as other therapeutic classes, with some key differences. Overall survival (OS) is considered by the Transparency Commission as theendpoint for assessing clinical benefit, and yet it is not an applicable primary endpoint in all types of cancer. Later lines of treatment, particularly during the development process, may make it difficult to interpret OS as the primary endpoint. Therefore, progression-free survival (PFS) for metastatic situations and disease-free survival (DFS) in adjuvant situations are wholly relevant endpoints for decisions on the reimbursement of a new cancer drug. Effect size is assessed using actuarial survival curves of the product versusthe comparator, and it is difficult to summarise them into one single parameter. Results are generally interpreted based on median survival, which is fragmented because it only measures one point of the curve. The hazard ratio measures the effect of treatment throughout the duration of survival and is therefore more comprehensivein quantifying clinical benefit. Determining an effect size threshold for granting reimbursement is difficult given the diversity of cancer settings and the level of medical need, which influences assessment of the clinical relevance of the observed difference. Rapid progress in comparators (700 molecules in development) and the identification of predictive factors of efficacy (biomarkers, histology, etc.) during development may lead to different ASMR scores per population, or to the restriction of the target population to a subgroup of the marketing authorisation (MA) population in which the expected effect size is greater. To address these issues, the roundtable recommends the possibility of early scientific opinions by the office of the Transparency Commission in order to discuss comparators and the relevance of responder subgroups. It also recommends the possibility of granting a temporary ASMR, on condition of subsequent confirmation by production of data, when reimbursement appears justified in a subpopulation of the MA for which only subgroup analysis is available.

Eins geht verloren, eins bleibt!Eine Vielzahl an cyclischen und acyclischen β‐Aminofluoralkenen konnte mit der Titelreaktion hergestellt werden. Das entscheidende fluorierte Palladium‐π‐Allyl‐Intermediat entsteht durch katalytische Aktivierung einer allylischen C‐F‐Bindung.

No Abstract

The ferrocenyl diphenol 1 [1,1‐bis(4‐hydroxyphenyl)‐2‐ferrocenyl‐but‐1‐ene] displays strong cytotoxic effects against a variety of cancer cells. In the present study we have evaluated the immunomodulatory and antiparasitic activities of compound 1 and its protected dipalmitate analogue 2. We have furthermore compared the antiparasitic results of 1 and 2 with the organic analogue, 3 [1,1‐bis(4‐hydroxyphenyl)‐2‐phenyl‐but‐1‐ene], where the ferrocenyl group has been replaced by a phenyl ring. When assayed against normal (noncancerous) splenocytes, all compounds were considered nontoxic. Compound 1 inhibited NO production by macrophages, inhibited concanavalin A‐induced lymphoproliferation, and was active against Leishmania amazonensisand Trypanosoma cruzi. Compound 2 had lower activity in all assays performed. Surprisingly, compounds 1 and 2 exhibited similar and significant activity against Plasmodium falciparum, with IC50values of 3.50 and 1.33 µM, respectively. Compound 3 showed an inverse activity profile, being active against T. cruzibut far less active against P. falciparum. Drug Dev Res 71: 69–75, 2010. © 2009 Wiley‐Liss, Inc.

Cet article évalue la validité de construit et la fiabilité d'une version québécoise de l'échelle de dépression postnatale d'Edimbourg (EPDS) auprès d'une population de mères de statut socio-économique faible. Cette échelle a été conçue spécifiquement pour mesurer la symptomatologie dépressive des mères è la période postnatale dans le but de pallier les problèmes de validité apparente que peuvent comporter les échelles conçues pour une population générale. Deux cent vingt-quatre mères recrutées dans le cadre du programme intégré de prévention et de promotion en périnatalité «Naitre égaux, grandir en santé» (Martin & Boyer, 1995) ont répondu è l'EPDS entre le 22 et le 35 jour postpartum. L'analyse factorielle confirmative, effectuée avec LISREL, fait ressortir un modèle è 2 facteurs, le premier reflétant la présence de symptômes dépressifs et le second, celle d'anxiété cognitive. Cette structure est differente de celle proposée par Cox, Holden et Sagovsky (1987), auteurs et auteures de l'EPDS. Elle correspond cependant aux résultats d'autres auteures et auteurs qui se sont penchés sur la structure factorielle de l'EPDS en utilisant l'analyse factorielle confirmative (Pop, Komproe, & van Son, 1992) et est le signe d'une bonne validité de construit. La fiabilité de l'instrument s'est également révélée satisfaisante, avec un indice alpha de Cronbach de 0.82 pour l'ensemble des questions.

Les données cliniques soumises au Comité des Médicaments à Usage Humain (CHMP) pour autorisation de mise sur le marché manquent fréquemment de comparaisons directes pertinentes des produits. Ces comparaisons peuvent permettre aux autorités nationales chargées de l’approbation du remboursement d’apprécier l’Amélioration du Service Médical Rendu (ASMR) d’une substance active nouvelle ou d’une entité pharmaceutique existante en cas d’extension d’indication. Les comparaisons indirectes et comparaisons mixtes sont des procédés issus du domaine de la méta-analyse et conçus pour aborder ce problème. Les comparaisons indirectes ajustées, les méta-régressions, les modèles mixtes, les analyses en réseaux bayésiens regroupent les résultats d’essais contrôlés randomisés permettant une synthèse quantitative des données.

Frequently, in data packages submitted for Marketing Approval to the CHMP, there is a lack of relevant head-tohead comparisons of medicinal products that could enable national authorities responsible for the approval of reimbursement to assess the Added Therapeutic Value (ASMR) of new clinical entities or line extensions of existing therapies.

We report here the synthesis and cell‐proliferation properties of derivatives of the breast cancer drug tamoxifen, in which the O(CH2)2N(CH3)2side chain, responsible for the drug's antiestrogenic properties, has been modified by a ferrocenyl moiety. We recently reported the diphenol compound 5, in which this amino chain had been replaced with an acyl‐ferrocenyl (O(CH2)2C(O)[(η5‐C5H4)FeCp]) group, and which showed antiproliferative effects against both the hormone‐dependent MCF‐7 and ‐independent MDA‐MB‐231 breast cancer cell lines. We now report the results of a structure–activity relationship (SAR) study, in which the lateral chain length has been varied, the ketone group has been omitted, and the number of phenol groups has been varied. Compounds 1–4, with a side chain lacking the carbonyl function (O(CH2)n[(η5‐C5H4)FeCp], n=1–4) and which show a decreasing affinity for ERα (ER=estrogen receptor) with increasing chain length, act as estrogens on MCF‐7 cells, and mild cytotoxics on PC‐3 prostate cancer cells, with IC50values around 10 μM. The two monophenolic derivatives of 2, 2 aand 2 b, which show a reduced affinity for ERα compared to 2, are also estrogenic, but are only slightly cytotoxic. Finally, we have reexamined compound 5and discovered that its antiproliferative effect against the MCF‐7 cell line does not arise from antiestrogenicity as we had originally suspected, but by means of a cytotoxic pathway. This compound is also sensitive to the number of phenol groups as cell death is diminished when one of the hydroxyl groups is omitted (5 aand 5 b). Molecular modeling studies of the ligand–ERα binding stability are broadly consistent with the experimental binding affinity results for compounds 2, 2 a, 2 b, 5, 5 a, and 5 b. Electrochemical experiments show that 1–4, 2 a, and 2 bare stable to oxidation on the electrochemical timescale, unlike 5, 5 a, and 5 b, and that cytotoxicity is related to less positive phenol oxidation potentials. The SAR study shows that the presence of a ketone group and two phenol groups is necessary for strong receptor binding and cytotoxic effects, and that all compounds are estrogenic, despite the presence of a bulky side chain.

Considerable spatial variability in snow properties exists within apparently uniform slopes, often resulting from microscale weather patterns determined by local terrain. Since it is costly to establish abundant weather stations in a region, local lapse rates may offer an alternative for predicting snowpack characteristics. For two Castle Mountain Resort weather stations, we present the 2003–2004 winter season weather and snow profile data and the 1999–2004 winter season lapse rates. A third site was sampled for small-scale spatial variability. Layer thickness, stratigraphy, temperature gradients, crusts, wind drift layers, stability, and settlement were compared between the sites and correlated with temperature, wind, and lapse rates. Average yearly snowfall was 470 cm at the Base and 740 cm at the Upper station. Average daily maximum and minimum temperature lapse rates are −6.1°C km−1and −5.7°C km−1when inversions are removed. Inversions occur mostly at night, adversely affecting lapse rate averages. Lapse rate modes are unaffected and most often −6.3°C km−1. Snowpack spatial variability is ∼25% of layer thickness and is controlled by wind and topography. Layer settlement is primarily related to initial snow thickness and wind drift. Snowpacks stabilize with age, unless rain crusts are present, which are important low-force failure horizons.

Resolution III fractional factorial designs permit the uncorrelated estimation of all main effects under the assumption of no interactions among the factors and are often used in the initial phases of an experimental program to screen factors. Even in these experimental situations, it may be desirable to include partial replication of the design, thereby allowing for the unbiased estimation of the experimental error while maintaining the orthogonality of the main effects. It is often then possible to assess the no-interactions assumption by comparing the sample of confounded interactions with the pure error estimate. In this paper, a new class of partially replicated two-level fractional factorial designs based on Hadamard matrices is proposed. A method of constructing these designs is given and the relative performance of the designs is evaluated by comparing them with competing fractional factorial designs.

The relative added value of a drug is currently evaluated in France by the Transparency Commission (TC) of the National Health Authority (HAS), by assigning a level of Improvement in Actual Benefit (IAB). IAB is based on two parameters, efficacy and safety of the product, in a defined target population, either as compared to one or more other drugs with similar indications, or within therapeutic strategy.

La valeur ajoutée relative d’un médicament est actuellement évaluée en France par la Commission de la Transparence au sein de la HAS (Haute Autorité de Santé), par l’attribution d’un niveau d’Amélioration du Service Médical Rendu (ASMR). L’ASMR est obtenue sur la base de deux paramètres que sont l’efficacité et la tolérance du produit, dans une population cible définie, soit par rapport à un ou plusieurs autres médicaments comparables en termes d’indication, soit dans la stratégie thérapeutique.

Patients with myotonic dystrophy type 1 (DM1) frequently have symptoms of excessive daytime sleepiness (EDS). Some patients with DM1 show sleep-onset REM, similar to that observed in narcolepsy. Narcolepsy is characterized by impaired hypocretin (Hcrt) neurotransmission.

L’intérêt de santé publique des médicaments (ISP) est un critère d’évaluation récent (décret d’octobre 1999) et spécifiquement français qui, faute d’éléments disponibles au moment de son appréciation, reste à ce jour souvent incomplètement documenté dans les dossiers de transparence. En effet, lors de la demande de première inscription d’un médicament sur la liste des spécialités remboursables, les données cliniques dont on dispose sont en général les seules contenues dans le dossier d’enregistrement. Ces données sont issues d’un programme de développement désormais global, construit bien longtemps avant le dépôt du dossier d’inscription au remboursement, qui ne prévoit pas de façon systématique de renseigner les données nécessaires à l’évaluation de l’ISP. On comprend donc la difficulté d’anticipation et de documentation de ce critère récent et hexagonal. En France, l’ISP est à la fois l’un des critères d’admission au remboursement des médicaments et un élément de pilotage d’une politique de santé nationale. Son évaluation permet par ailleurs d’identifier les besoins et les objectifs des études post-inscription qui font l’objet d’une clause conventionnelle lors du passage au Comité Économique des Produits de Santé (CEPS). Située en aval de l’évaluation de l’autorisation de mise sur le marché (AMM), l’évaluation du critère ISP lui fait suite et la complète.

The Public Health Benefit (PHB) of new medicines is a recent and French-specific criterion (October 1999 decree) which is often only partially documented in the transparency files due to a lack of timely information. At the time of the first reimbursement application for a new medicine to the “Transparency Committee”, the file is exclusively based on data from randomised clinical trials. These data are generated from a global clinical development plan which was designed a long time before the new medicine’s submission for reimbursement. And this plan does not systematically provide the data needed to assess the PHB. Thus, one easily understands the difficulty to anticipate and document this recent French criterion. In France, the PHB is both one of the necessary criteria for the reimbursement submission and an indicator for the national health policy management. Its assessment also helps to identify the needs and objectives of the post-registration studies (nowadays in the scope of responsibilities of the “Drug Economics Committee”). The assessment of the PHB criterion is carried through after the marketing authorization process and is an addition to it.

De plus en plus souvent, les autorités de santé et les agences d’évaluation françaises sont conduites à délivrer des AMM (Autorisation de Mise sur le Marché), à rendre des avis sur l’admission au remboursement de médicaments ou à élaborer des recommandations pour la pratique clinique à partir de résultats d’études étrangères. Les résultats de ces études sont plus ou moins difficiles à transposer à la pratique française. Ces difficultés génèrent une incertitude de degré variable sur l’effet à attendre d’un médicament. Une perte d’effet plus ou moins importante est quelquefois même prévisible. Quelques unes des difficultés de transposition sont discutées dans cet article et des propositions d’actions sont formulées pour permettre, à terme, de prédire de la façon la plus précise possible les effets à attendre d’un médicament en population française et de pouvoir vérifier cette prédiction à distance de son admission au remboursement.

More and more frequently, the health authorities and the French assessment agencies are led to issue Marketing Authorizations (MAs), give opinions on the eligibility for reimbursement of drugs or to draft recommendations for clinical practice based on the results of foreign studies. The results of these studies are more or less difficult to transpose to French practice. These difficulties generate varying degrees of uncertainty concerning the effect to be expected of a drug. A more or less extensive loss of effect is sometimes even predictable. Some of the difficulties in transposition are discussed in this article and proposals for action are made in order to allow one, in the long term, to predict in the most precise manner possible the effects to be expected from a drug in the French population and be able to verify this prediction at an interval from its eligibility for reimbursement.

AbstractA real-time monitoring methodology to determine diesel fine particles in diesel emissions has been evaluated. The range of particle size captured by the monitor was ∼0.1 μm to 1 μm. DustTrak real-time monitors were connected to the dilution tunnel of the vehicle exhaust to measure the emissions during the vehicle tests under both dynamic and steady-state driving conditions, and concentration data were recorded every 5 sec. Test variation of the real-time monitoring among different test days was similar to that measured by traditional filter-based gravi-metric method, whereas the repeatability of the monitor data within the same-day tests was better than that of gravimetric method. Correlations between the two methods were established for different fuels tested on a single light duty vehicle. When the emissions from the reference fuel was used to convert the monitor’s response to diesel fuels, the levels determined by the real-time monitor were consistent with those measured by gravimetric method among different fuels tested. Use of the real-time monitor could provide information on the levels of fine particles that is more relevant to the public health than the total particles.

Presents the short story "That Obscure Desire," by Marguerite Pigeon.

Hepcidin, which has been recently identified both by biochemical and genomic approaches, is a 25 amino acid polypeptide synthesized mainly by hepatocytes and secreted into the plasma. Besides its potential activity in antimicrobial defense, hepcidin plays a major role in iron metabolism. It controls two key steps of iron bioavailability, likely through a hormonal action: digestive iron absorption by enterocytes and iron recycling by macrophages. In humans, this could explain that low levels of hepcidin found during juvenile haemochromatosis and HFE-1 genetic haemochromatosis are associated with an iron overload phenotype. Conversely, an increase of hepcidin expression is suspected to play a major role in the development of anemia of chronic inflammatory diseases. However, the regulatory mechanisms of hepcidin expression are multiple, including iron-related parameters, anemia, hypoxia, inflammation and hepatocyte function. Therefore, many physiological and pathological situations may modulate hepcidin expression and subsequently iron metabolism. A better knowledge of the biological effects of hepcidin and of its expression regulatory mechanisms will clarify the place of hepcidin in the diagnosis and treatment of iron-related diseases.

We report here the synthesis and the strong and unexpected antiproliferative effect of the organometallic diphenolic compound 1,1-bis(4‘-hydroxyphenyl)-2-ferrocenyl-but-1-ene (4) on both hormone-dependent (MCF7) and -independent (MDA-MB231) breast cancer cells (IC50 = 0.7 and 0.6 μM). Surprisingly, 6 [1,2-bis(4‘-hydroxyphenyl)-2-ferrocenyl-but-1-ene], the regioisomer of 4, shows only a modest effect on these cell lines. This pertinent organometallic modification seems to trigger an intracellular oxidation of the structurally favorable compound 4, leading to the generation of a potent cytotoxic compound.

A series of ruthenocene derivatives, 1-[4-(O(CH2)nN(CH3)2)phenyl]-1-(4-hydroxyphenyl)-2-ruthenocenylbut-1-ene, with n = 2−5, based on the structure of the breast cancer drug tamoxifen has been prepared. These compounds were obtained, via a McMurry cross-coupling reaction, as a mixture of Z and E isomers that could not be separated by HPLC. The relative binding affinity values for estrogen receptor α (ERα) for n = 2 and 3 were very high (85 and 53%) and surpassed even that of hydroxytamoxifen (38.5%), the active metabolite of tamoxifen. Ruthenocene derivatives act as anti-estrogens as effective (n = 2) or slightly more effective (n = 3−5) than hydroxytamoxifen on ERα-positive breast cancer cell lines but, unlike ferrocifens, do not show antiproliferative effects on ERα-negative breast cancer cell lines. Electrochemical studies showed that the ruthenocifen radical cations are unstable, which may account for this behavior. Some of these compounds could be useful as radiopharmaceuticals for ERα-positive breast cancer tumors.

Presents the short story "Slag," by Marguerite Pigeon, illustrated by Dee Rimbaud.

When reaching movements involve simultaneous trunk rotation, additional interaction torques are generated on the arm that are absent when the trunk is stable. To explore whether the CNS compensates for such self-generated interaction torques, we recorded hand trajectories in reaching tasks involving various amplitudes and velocities of arm extension and trunk rotation. Subjects pointed to three targets on a surface slightly above waist level. Two of the target locations were chosen so that a similar arm configuration relative to the trunk would be required for reaching to them, one of these targets requiring substantial trunk rotation, the other very little. Significant trunk rotation was necessary to reach the third target, but the arm's radial distance to the body remained virtually unchanged. Subjects reached at two speeds—a natural pace (slow) and rapidly (fast)—under normal lighting and in total darkness. Trunk angular velocity and finger velocity relative to the trunk were higher in the fast conditions but were not affected by the presence or absence of vision. Peak trunk velocity increased with increasing trunk rotation up to a maximum of 200°/s. In slow movements, peak finger velocity relative to the trunk was smaller when trunk rotation was necessary to reach the targets. In fast movements, peak finger velocity was ∼1.7 m/s for all targets. Finger trajectories were more curved when reaching movements involved substantial trunk rotation; however, the terminal errors and the maximal deviation of the trajectory from a straight line were comparable in slow and fast movements. This pattern indicates that the larger Coriolis, centripetal, and inertial interaction torques generated during rapid reaches were compensated by additional joint torques. Trajectory characteristics did not vary with the presence or absence of vision, indicating that visual feedback was unnecessary for anticipatory compensations. In all reaches involving trunk rotation, the finger movement generally occurred entirely during the trunk movement, indicating that the CNS did not minimize Coriolis forces incumbent on trunk rotation by sequencing the arm and trunk motions into a turn followed by a reach. A simplified model of the arm/trunk system revealed that additional interaction torques generated on the arm during voluntary turning and reaching were equivalent to ≤1.8 g(1 g= 9.81 m/s2) of external force at the elbow but did not degrade performance. In slow-rotation room studies involving reaching movements during passive rotation, Coriolis forces as small as 0.2ggreatly deflect movement trajectories and endpoints. We conclude that compensatory motor innervations are engaged in a predictive fashion to counteract impending self-generated interaction torques during voluntary reaching movements.