Which available transapical transcatheter valve fits into degenerated aortic bioprostheses?

The transapical transcatheter aortic valve implantation (TA-TAVI) in degenerated aortic bioprosthesis is an emerging therapy for surgically non-amenable patients. However, the presence of different types of aortic bioprostheses (stented and stentless), available in different sizes (19-27 mm), can be at the origin of important mismatches between the malfunctioning, degenerated aortic valves and the inner stent-valves implanted through transapical accesses (23 and 26 mm Edwards Sapien transcatheter stent-valves). We report an emergency TA-TAVI treatment of a severely regurgitant degenerated 23 mm Mitroflow aortic bioprosthesis (Sorin Group, Milano, Italy) implanted seven years earlier in an 80-year-old lady, and we reviewed the current available literature about transapical 'valve-in-valve' procedures to analyze the hemodynamic results and the ideal 'prosthesis-to-prosthesis' match.

Physician behavioral adaptability: A model to outstrip a "one size fits all" approach

Objective: Based on a literature review, we propose a model of physician behavioral adaptability (PBA) with the goal of inspiring new research. PBA means that the physician adapts his or her behavior according to patients' different preferences. The PBA model shows how physicians infer patients' preferences and adapt their interaction behavior from one patient to the other. We claim that patients will benefit from better outcomes if their physicians show behavioral adaptability rather than a "one size fits all" approach. Method: This literature review is based on a literature search of the PsycINFO1 and MEDLINE1 databases. Results: The literature review and first results stemming from the authors' research support the validity and viability of parts of the PBA model. There is evidence suggesting that physicians are able to show behavioral flexibility when interacting with their different patients, that a match between patients' preferences and physician behavior is related to better consultation outcomes, and that physician behavioral adaptability is related to better consultation outcomes. Practice implications: Training of physicians' behavioral flexibility and their ability to infer patients' preferences can facilitate physician behavioral adaptability and positive patient outcomes.

Photodynamic therapy : a pathway for enhanced delivery of liposomal doxorubicin to tumors

Abstract Part I : Background : Isolated lung perfusion (ILP) was designed for the treatment of loco-regional malignancies of the lung. In contrast to intravenous (IV) drug application, ILP allows for a selective administration of cytostatic agents such as doxorubicin to the lung while sparing non-affected tissues. However, the clinical results with ILP were disappointing. Doxorubicinbased ILP on sarcoma rodent lungs suggested high overall doxorubicin concentrations within the perfused lung but a poor penetration of the cytostatic agent into tumors. The same holds true for liposomal-encapsulated macromolecular doxorubicin (LiporubicinTM) In specific conditions, low-dose photodynamic therapy (PDT) can enhance the distribution of macromolecules across the endothelial bamer in solid tumors. It was recently postulated that tumor neovessels were more responsive to PDT than the normal vasculature. We therefore hypothesized that Visudyne®-mediated PDT could selectively increase liposomal doxorubicin (LiporubicinTM) uptake in sarcoma tumors to rodent lungs during intravenous (IV) drug administration and isolated lung perfusion (ILP). Material and Methods : A sarcoma tumor was generated in the left lung of Fisher rats by subpleural injection of a sarcoma cell ,suspension via thoracotomy. Ten days later, LiporubicinTM is administered IV or by single pass antegrade ILP, with or without Visudyne® -mediated low-dose PDT pre-treatment of the sarcoma bearing lung. The drug concentration and distribution were assessed separately in tumors and lung tissues by high pressure liquid chromatography (HPLC) and fluorescence microscopy (FNI~, respectively. Results : PDT pretreatment before IV LiporubicinTM administration resulted in a significantly higher tumor drug uptake and tumor to lung drug ratio compared to IV drug injection alone without affecting the blood flow and drug distribution in the lung. PDT pre-treatment before LiporubicinTM-based ILP also resulted in a higher tumor drug uptake and a higher tumor to lung drug ratio compared to ILP alone, however, these differences were not significant due to a heterogeneous blood flow drug distribution during ILP which was further accentuated by PDT. Conclusions : Low-dose Visudyne®-mediated PDT pre-treatment has the potential to selectively enhance liposomal encapsulated doxorubicin uptake in tumors but not in normal lung tissue after IV drug application in a rat model of sarcoma tumors to the lung which opens new perspectives for the treatment of superficially spreading chemoresistant tumors of the chest cavity such as mesothelioma or malignant effusion. However, the impact of PDT on macromolecular drug uptake during ILP is limited since its therapeutic advantage is circumvented by ILP-induced heterogeneicity of blood flow and drug distribution Abstract Part II Background : Photodynamic therapy (PDT) with Visudyne® acts by direct cellular phototoxicity and/or by an indirect vascular-mediated effect. Here, we demonstrate that the vessel integrity interruption by PDT can promote the extravasation of a macromolecular agent in normal tissue. To obtain extravasation in normal tissue PDT conditions were one order of magnitude more intensive than the ones in tissue containing neovessels reported in the literature. Material and Methods : Fluorescein isothiocyanate dextran (FITC-D, 2000kDa), a macromolecular agent, was intravenously injected 10 minutes before (LKO group, n=14) or 2 hours (LK2 group, n=16) after Visudyne® mediated PDT in nude mice bearing a dorsal skin fold chamber. Control animals had no PDT (CTRL group, n=8). The extravasation of FITC-D from blood vessels in striated muscle tissue was observed in both groups in real-time for up to 2500 seconds after injection. We also monitored PDT-induced leukocyte rolling in-vivo and assessed, by histology, the corresponding inflammatory reaction score in the dorsal skin fold chambers. Results : In all animals, at the applied PDT conditions, FITC-D extravasation was significantly enhanced in the PDT treated areas as compared to the surrounding non-treated areas (p<0.0001). There was no FITC-D leakage in the control animals. Animals from the LKO group had significantly less FITC-D extravasation than those from the LK2 group (p = 0.0002). In the LKO group FITC-D leakage correlated significantly with the inflammation (p < 0.001). Conclusions: At the selected conditions, Visudyne-mediated PDT promotes vascular leakage and FITC-D extravasation into the interstitial space of normal tissue. The intensity of vascular leakage depends on the time interval between PDT and FITC-D injection. This concept could be used to locally modulate the delivery of macromolecules in vivo. Résumé : La perfusion cytostatique isolée du poumon permet une administration sélective des agents cytostatiques sans implication de la circulation systémique avec une forte accumulation au niveau du poumon mais une faible pénétration dans les tumeurs. La thérapie photodynamique (PDT) qui consiste en l'application d'un sensibilisateur activé par lumière laser non- thermique d'une longueur d'onde définie permet dans certaines conditions, une augmentation de la pénétration des agents cytostatiques macromoléculaires à travers la barrière endothéliale tumorale. Nous avons exploré cet avantage thérapeutique de la PDT dans un modèle expérimental afin d'augmenter d'une manière sélective la pénétration tumorale de la doxorubicin pegylée, liposomal- encapsulée macromoléculaire (Liporubicin). Une tumeur sarcomateuse a été générée au niveau du poumon de rongeur suivie d'administration de Liporubicin, soit par voie intraveineuse soit par perfusion isolée du poumon (ILP). Une partie des animaux ont reçus un prétraitement de la tumeur et du poumon sous jacent par PDT avec Visudyne comme photosensibilisateur. Les résultats ont démontrés que la PDT permet, sous certaines conditions, une augmentation sélective de Liporubicin dans les tumeurs mais pas dans le parenchyme pulmonaire sous jacent. Après administration intraveineuse de Liporubicin et prétraitement par PDT, l'accumulation dans les tumeurs était significative par rapport au poumon, et aux tumeurs sans PDT. Le même phénomène est observé après ILP du poumon. Cependant, les différences avec ou sans PDT n'étaient pas significatives lié à und distribution hétérogène de Liporubicin dans le poumon perfusé après ILP. Dans une deuxième partie de l'expérimentation, nous avons exploré la microscopie intra-vitale pour déterminer l'extravasion des substances macromoléculaires (FITS) à travers la barrière endothéliale avec ou sans Visudyne-PDT au niveau des chambres dorsales des souris nues. Les résultats montrent qu'après PDT, l'extravasion de FITS a été augmentée de manière significative par rapport au tissu non traité. L'intensité de l'extravasion de FITS dépendait également de l'intervalle entre PDT et injection de FITS. En conclusion, les expérimentations montrent que la PDT est capable, sous certaines conditions, d'augmenter de manière significative l'extravasion des macromolécules à travers la barrière endothéliale et leur accumulation dans des tumeurs mais pas dans le parenchyme pulmonaire. Ces résultats permettent une nouvelle perspective de traitement pour des tumeurs superficielles intrathoraciques chimio-résistent comme l'épanchement pleural malin ou le mésothéliome pleural.

A toxicokinetic model to assess exposure to folpet fungicide from urinary biomarkers

Folpet is one of the most widely employed fungicides in agriculture. It is typically used in the culture of vegetables, fruits and ornamental plants. Once absorbed in the human body, it has been found to be very reactive, especially in acid conditions. According to various in vitro and in vivo experiments in animals, Folpet is first fractioned at the N-S link when in contact with aqueous solutions and thiol groups. From this non-enzymatic process a phthalimide (PI) molecule is formed, which may be used as a biomarker of exposure, along with the short-lived thiophosgene. We have built a human toxicokinetic model to account for the biotransformation of Folpet into PI and its subsequent excretion while accounting for other non-monitored metabolites. The mathematical parameters of the model were determined accordingly from best-fits to the time courses of PI in blood and urine of five volunteers administered orally 1 mg/kg and dermally 10 mg/kg of Folpet. In both cases, the mean elimination half-life of PI from the body (either through faeces, urine or metabolism) was found to be 31.6 h. The average final fractions of administered dose recovered in urine as PI were 0.025% and 0.002%, for oral and dermal administration, respectively after 96 h. According to the model, when orally administered, PI rapidly hydrolyzes to phthalamic and phthalic acids such that only 0.04% of the PI found in the gastrointestinal tract is absorbed into the blood stream. Likewise, after dermal application, model predicts that only 7.4% of the applied Folpet dose crosses the epidermis. In the model, the PI initial metabolite of Folpet is formed in the dermis and further metabolized prior to reaching systemic circulation, such that only 0.125% of PI formed at the site-of-entry reaches systemic blood. Our mathematical model is in accordance with both measures of blood (R2=0.57 for dermal and R2=0.66 for oral) and urine (R2 =0.98 for dermal and R2=0.99 for oral).

Origin of Early Carboniferous pseudo-adakites in northern Brittany (France) through massive amphibole fractionation from hydrous basalt

P>The first Variscan pseudo-adakites were identified in close association with the Saint-Jean-du-Doigt (SJDD) mafic intrusion (Brittany, France) in a geodynamic context unrelated to subduction. These rocks are trondhjemites emplaced 347 +/- 4 Ma ago as 2-3 km2 bodies and dykes. Trace-element concentrations and Sr-Nd-Pb isotope ratios indicate that the SJDD pseudo-adakites probably resulted from extreme differentiation of an SJDD-type hydrous basaltic magma in a lower continental crust of normal thickness (0.8 GPa). Modelling shows that garnet is not a required phase, which was commonly believed to be the case for continental arc-derived adakite-like rocks. A massive fractionation of amphibole fits the data much better and does not require high pressures, in agreement with the inferred extensional tectonic regime at the time of pluton emplacement. Alternatively, the SJDD pseudo-adakites could have resulted from the melting of newly underplated SJDD mafic precursors, but thermal considerations lead us to believe that this was not the case.

La gestion des services environnementaux: entre règles et régulation négociée. Six études de cas de services forestiers pour la production d'eau potable dans trois pays

Cette thèse est construite en quatre parties : trois annexes qui présentent six études de cas (env. 800 pages), précédées par une analyse transversale, plus synthétique (env. 150 pages), dont traite ce résumé. Chaque annexe contient une synthèse détaillée des études de cas. Cette thèse aborde la « gestion des ressources naturelles » en affirmant d'emblée que l'appellation est inappropriée, car ce ne sont pas les ressources qui sont gérées, mais leurs usages. Il s'agit donc d'identifier et d'analyser ce qui influence les comportements humains en lien avec la ressource. Cette affirmation fonde la perspective des sciences sociales sur la gestion des ressources naturelles, dans laquelle s'inscrit cette thèse. L'approche néo-institutionnaliste considère que les usages sont influencés par des institutions, qui sont elles-mêmes influencées par les usagers. Ces institutions sont des constructions humaines qui composent le contexte institutionnel dans lequel les acteurs décident de leurs usages (abattre un arbre, prélever de l'eau, etc.). Les usages des ressources ne sont donc jamais libres et il s'agit de comprendre comment ces règles du jeu influencent les pratiques. Elles sont nombreuses, interdépendantes et forment la trame sur laquelle se décident les usages. Pour saisir cette complexité, l'auteur applique le cadre d'analyse des régimes institutionnels des ressources (RIR) qui se limite à l'analyse de deux types de droits d'usages : ceux issues des règles de la propriété (titres de propriété, servitudes, etc.) et ceux issus des politiques publiques (lois, ordonnances, etc.). Le RIR permet d'identifier un « régime institutionnel », spécifique à la ressource étudiée, dont les évolutions peuvent être comparées dans le temps ou entre plusieurs lieux. Dans cette recherche, ce cadre d'analyse a été appliqué au même objet - la gestion forestière dans les zones de captage d'eau souterraine destinée au réseau public - dans trois pays : en France, en Suisse et en Indonésie. Trois années de recherche de terrain ont permis à l'auteur de s'intéresser non seulement aux règles prédéterminées (la réglementation), mais aussi aux règles effectivement activées sur le terrain (la régulation) par les acteurs rencontrés. Les études de cas montrent que les règles prévues sont inégalement activées et que les acteurs privilégient parfois la négociation directe pour résoudre leurs rivalités d'usages, à la place d'invoquer leurs droits acquis. Ce constat conduit l'auteur à proposer un élargissement de la focale du RIR, qui constitue le coeur de sa thèse. On ne s'intéresse plus seulement à ce qui « est » régulé, mais aussi à ce qui ne l'« est pas » et qui échappe à l'application classique du RIR. Ce renversement de perspective est crucial pour comprendre les usages concrets des ressources dans les régimes peu intégrés, où les pratiques s'expliquent davantage par la marge de manoeuvre laissée aux acteurs que par les règles prédéterminées. Cette relecture, testée avec succès dans cette thèse, permet d'intégrer la marge de manoeuvre à l'analyse au moyen du RIR. Elle se concrétise par l'identification des lacunes et incohérences dans les régimes institutionnels étudiés. Le champ d'application du RIR s'en trouve élargi et sa vulgarisation pour des non-spécialistes est facilitée, notamment pour les environnementalistes. La complémentarité entre les approches s'en trouve renforcée. Les résultats montrent deux choses : premièrement les acteurs disposent toujours d'une marge de manoeuvre pour négocier des régulations ponctuelles, qui sont autant d'alternatives à l'application des règles prévues. Deuxièmement, la conclusion d'accords issus de la négociation bi-/multilatérale dépend directement de la marge de manoeuvre laissée par le contexte institutionnel. Ceci explique pourquoi la négociation entre les propriétaires forestiers et les exploitants de captages s'imposent en Indonésie, est envisageable en France, mais n'aboutit pas en Suisse. Les nombreuses tentatives infructueuses de mise en oeuvre de solutions négociées, notamment sous forme de paiements pour services environnementaux (PSE), trouvent ici une explication. - This thesis (written in French) is built in four parts: three annexes that present six case studies (approx. 800 pages), preceded by a transverse, more conceptual analysis (approx. 150 pages), which this summary is about. Each annexe contains a detailed summary of the case studies. 'Natural resource management' is an inappropriate designation because it is not the resources that are managed but the uses made of them, therefore this thesis addresses the identification and analysis of the influences on human behaviour in relation to the resource. This statement roots the social sciences perspective on the management of natural resources, in which this thesis fits. A neoinstitutionalist approach considers that the uses are influenced by institutions, which are themselves influenced by users. These institutions are human constructions that form the institutional context in which the actors decide on the use of resources (felling a tree, collecting water, etc.). Thus, the uses of resources are never independent from institutional influences and it becomes necessary to understand how these rules of the game affect practices. They are numerous, interrelated and form the basis for the uses of resources. To understand this complexity, the author applies the institutional regime resource framework (IRR) which limits the analysis to two types of use rights: those resulting from the property rights (deeds, easements, etc.) and those from public policies (laws, ordinances, etc.). The IRR identifies an 'institutional regime', specific to the resource, from which developments can be compared over time or between several places. In this research, this analytical framework has been applied to the same topic - forest management in the recharging areas of groundwater piped for public supply - in three countries: France, Switzerland and Indonesia. Three years of field research allow the author to look not only at predetermined rules (rules), but also at regulations that are actually activated on the ground (rules-in-use). The case studies show that the predetermined rules are unevenly applied and that sometimes actors favour direct negotiation to resolve their rivalry of uses, instead of invoking their vested rights. From this observation the author proposes an enlargement of the IRR's scope, forming the core of his thesis. The interest covers not only what 'is' regulated, but what 'is not' and so is beyond the classical application of the IRR. This shift in perspective is crucial to understand the concrete uses of resources in poorly integrated regimes, where practices are explained by the margin of manoeuvre left to the actors rather than predetermined rules. This reinterpretation, tested successfully in this research, allows the margin of manoeuvre to be integrated in the analysis using the IRR and is made concrete by the identification of gaps and inconsistencies in the investigated institutional context. The new interpretation of the IRR in this thesis complements and enhances its classical application. In particular, its use and understanding by non-specialists, especially environmentalists, is facilitated. The results show two things: first the actors always have leeway to negotiate ad hoc regulations, which are alternatives to the application of the predefined rules. Second, the conclusion of bi/multilateral negotiated agreements depends directly on the leeway left by the institutional context. This explains why the negotiation between forest owners and operators of water catchments is needed in Indonesia, is possible in France, but does not succeed in Switzerland. This offers an explanation for many unsuccessful attempts to implement negotiated solutions, notably payments for environmental services (PES).

The metaphysics of quantum gravity : a causal approach

The dissertation investigates some relevant metaphysical issues arising in the context of spacetime theories. In particular, the inquiry focuses on general relativity and canonical quantum gravity. A formal definition of spacetime theory is proposed and, against this framework, an analysis of the notions of general covariance, symmetry and background independence is performed. It is argued that many conceptual issues in general relativity and canonical quantum gravity derive from putting excessive emphasis on general covariance as an ontological prin-ciple. An original metaphysical position grounded in scientific essential- ism and causal realism (weak essentialism) is developed and defended. It is argued that, in the context of general relativity, weak essentialism supports spacetime substantivalism. It is also shown that weak essentialism escapes arguments from metaphysical underdetermination by positing a particular kind of causation, dubbed geometric. The proposed interpretive framework is then applied to Bohmian mechanics, pointing out that weak essentialism nicely fits into this theory. In the end, a possible Bohmian implementation of loop quantum gravity is considered, and such a Bohmian approach is interpreted in a geometric causal fashion. Under this interpretation, Bohmian loop quantum gravity straightforwardly commits us to an ontology of elementary extensions of space whose evolution is described by a non-local law. The causal mechanism underlying this evolution clarifies many conceptual issues related to the emergence of classical spacetime from the quantum regime. Although there is as yet no fully worked out physical theory of quantum gravity, it is argued that the proposed approach sets up a standard that proposals for a serious ontology in this field should meet.

Cloning and expression of rat pancreatic beta-cell malonyl-CoA decarboxylase.

To gain insight into the function and regulation of malonyl-CoA decarboxylase (MCD) we have cloned rat MCD cDNA from a differentiated insulin-secreting pancreatic beta-cell-line cDNA library. The full-length cDNA sequence shows 69% identity with the cDNA cloned previously from the goose uropygial gland, and predicts a 492 amino acid protein of 54.7 kDa. The open reading frame contains an N-terminal mitochondrial targeting sequence and the C-terminal part of the enzyme ends with a peroxisomal (Ser-Lys-Leu) targeting motif. Since the sequence does not reveal hydrophobic domains, MCD is most likely expressed in the mitochondrial matrix and inside the peroxisomes. A second methionine residue, located 3' of the mitochondrial presequence, might be the first amino acid of a putative cytosolic MCD, since the nucleotide sequence around it fits fairly well with a consensus Kozak site for translation initiation. However, primer extension detects the presence of only one transcript initiating upstream of the first ATG, indicating that the major, if not exclusive, transcript expressed in the pancreatic beta-cell encodes MCD with its mitochondrial presequence. The sequence also shows multiple possible sites of phosphorylation by casein kinase II and protein kinase C. mRNA tissue-distribution analysis indicates a transcript of 2.2 kb, and that the MCD gene is expressed over a wide range of rat tissues. The distribution of the enzyme shows a broad range of activities from very low in the brain to elevated in the liver and heart. The results provide the foundations for further studies of the role of MCD in lipid metabolism and metabolic signalling in various tissues.

Enterprise Architecture Management Design: Towards Understanding Organizational Contingencies, Design Principles and Effectiveness

Despite the increasing popularity of enterprise architecture management (EAM) in practice, many EAM initiatives either do not fully meet the expected targets or fail. Several frameworks have been suggested as guidelines to EA implementation, but companies seldom follow prescriptive frameworks. Instead, they follow very diverse implementation approaches that depend on their organizational contingencies and the way of adopting and evolving EAM over time. This research strives for a broader understanding of EAM by exploring context-dependent EAM adoption approaches as well as identifying the main EA principles that affect EA effectiveness. Based on two studies, this dissertation aims to address two main questions: (1) EAM design: Which approaches do companies follow when adopting EAM? (2) EA principles and their impact: What impact does EA principles have on EA effectiveness/quality? By utilizing both qualitative and quantitative research methods, this research contributes to exploring different EAM designs in different organizational contingencies as well as using EA principles as an effective means to achieve principle-based EAM design. My research can help companies identify a suitable EAM design that fits their organizational settings and shape their EA through a set of principles.

Unorthodox Humeanism

The thesis is situated in the domain of contemporary metaphysics of science. The question is which ontology fits best with our knowledge of the world. The method chosen is the one of evaluating the consequences of different ontological frameworks against the background of our scientific knowledge of the world. The thesis analyses the two main frameworks in today's metaphysics of science, Humeanism and dispositionalism. It advocates that only an unorthodox version of Humeanism and only an unorthodox version of dispositionalism can be defended, the unorthodox character of these versions consisting in taking the fundamental properties to be relations rather than intrinsic properties. The thesis then sets out in detail what such an unorthodox version of Humeanism amounts to. Chapters 1 and 2 introduce the standard versions of Humeanism and dispositionalism, focussing on the accounts of laws of nature and causation. Chapter 3 compares both these positions and concludes that as far as the orthodox versions are concerned, dispositionalism fares better than Humeanism, since it can avoid Humeanism's commitments to quidditism and humility. However, as is argued in chapter 4, instead of replying to the objections from quidditism and humility by switching to dispositionalism, there is an unorthodox version of Humeanism available that does not run into these problematic consequences and that is supported by science: if one takes the fundamental physical properties to be relations instead of intrinsic properties, the objection from quidditism is avoided, since there is no hidden intrinsic essence of relations. As regards the objection from humility, one can maintain that science is in principle able to provide knowledge of the fundamental relations that there are in the world so that there is no principled ignorance. Consequently, the thesis concludes that Humeanism and dispositionalism are on a par as regards the remaining charge of humility. Unorthodox Humeanism provides a competitive and adequate ontology in the light of contemporary science.

A generalized mechanistic codon model.

Models of codon evolution have attracted particular interest because of their unique capabilities to detect selection forces and their high fit when applied to sequence evolution. We described here a novel approach for modeling codon evolution, which is based on Kronecker product of matrices. The 61 × 61 codon substitution rate matrix is created using Kronecker product of three 4 × 4 nucleotide substitution matrices, the equilibrium frequency of codons, and the selection rate parameter. The entities of the nucleotide substitution matrices and selection rate are considered as parameters of the model, which are optimized by maximum likelihood. Our fully mechanistic model allows the instantaneous substitution matrix between codons to be fully estimated with only 19 parameters instead of 3,721, by using the biological interdependence existing between positions within codons. We illustrate the properties of our models using computer simulations and assessed its relevance by comparing the AICc measures of our model and other models of codon evolution on simulations and a large range of empirical data sets. We show that our model fits most biological data better compared with the current codon models. Furthermore, the parameters in our model can be interpreted in a similar way as the exchangeability rates found in empirical codon models.

Determining the best population-level alcohol consumption model and its impact on estimates of alcohol-attributable harms.

BACKGROUND: The goals of our study are to determine the most appropriate model for alcohol consumption as an exposure for burden of disease, to analyze the effect of the chosen alcohol consumption distribution on the estimation of the alcohol Population- Attributable Fractions (PAFs), and to characterize the chosen alcohol consumption distribution by exploring if there is a global relationship within the distribution. METHODS: To identify the best model, the Log-Normal, Gamma, and Weibull prevalence distributions were examined using data from 41 surveys from Gender, Alcohol and Culture: An International Study (GENACIS) and from the European Comparative Alcohol Study. To assess the effect of these distributions on the estimated alcohol PAFs, we calculated the alcohol PAF for diabetes, breast cancer, and pancreatitis using the three above-named distributions and using the more traditional approach based on categories. The relationship between the mean and the standard deviation from the Gamma distribution was estimated using data from 851 datasets for 66 countries from GENACIS and from the STEPwise approach to Surveillance from the World Health Organization. RESULTS: The Log-Normal distribution provided a poor fit for the survey data, with Gamma and Weibull distributions providing better fits. Additionally, our analyses showed that there were no marked differences for the alcohol PAF estimates based on the Gamma or Weibull distributions compared to PAFs based on categorical alcohol consumption estimates. The standard deviation of the alcohol distribution was highly dependent on the mean, with a unit increase in alcohol consumption associated with a unit increase in the mean of 1.258 (95% CI: 1.223 to 1.293) (R2 = 0.9207) for women and 1.171 (95% CI: 1.144 to 1.197) (R2 = 0. 9474) for men. CONCLUSIONS: Although the Gamma distribution and the Weibull distribution provided similar results, the Gamma distribution is recommended to model alcohol consumption from population surveys due to its fit, flexibility, and the ease with which it can be modified. The results showed that a large degree of variance of the standard deviation of the alcohol consumption Gamma distribution was explained by the mean alcohol consumption, allowing for alcohol consumption to be modeled through a Gamma distribution using only average consumption.

New validated prognostic models and prognostic calculators in patients with low-grade gliomas diagnosed by central pathology review: a pooled analysis of EORTC/RTOG/NCCTG phase III clinical trials.

Background In a previous study, the European Organisation for Research and Treatment of Cancer (EORTC) reported a scoring system to predict survival of patients with low-grade gliomas (LGGs). A major issue in the diagnosis of brain tumors is the lack of agreement among pathologists. New models in patients with LGGs diagnosed by central pathology review are needed. Methods Data from 339 EORTC patients with LGGs diagnosed by central pathology review were used to develop new prognostic models for progression-free survival (PFS) and overall survival (OS). Data from 450 patients with centrally diagnosed LGGs recruited into 2 large studies conducted by North American cooperative groups were used to validate the models. Results Both PFS and OS were negatively influenced by the presence of baseline neurological deficits, a shorter time since first symptoms (<30 wk), an astrocytic tumor type, and tumors larger than 5 cm in diameter. Early irradiation improved PFS but not OS. Three risk groups have been identified (low, intermediate, and high) and validated. Conclusions We have developed new prognostic models in a more homogeneous LGG population diagnosed by central pathology review. This population better fits with modern practice, where patients are enrolled in clinical trials based on central or panel pathology review. We could validate the models in a large, external, and independent dataset. The models can divide LGG patients into 3 risk groups and provide reliable individual survival predictions. Inclusion of other clinical and molecular factors might still improve models' predictions.