The effect of health care expenditures on survival in locally advanced and metastatic Non Small Cell Lung Cancer

Context: The significant survival benefit of chemotherapy over best supportive care for locally advanced and metastatic NSCLC has been amply demonstrated in the literature. However, there is no clear evidence of the impact of the type of chemotherapy or of a superiority of combination chemotherapy over single-agent chemotherapy.Objective: The present study empirically examines, in real-life practise and using multiple proxies, the impact of health care expenditures on overall survival in locally advanced and metastatic NSCLC in order to guide medical decision-making.Methods: Disease characteristics, the resources used, the costs of treatment and survival data were retrospectively collected from the records of 175 patients treated between 2000 and 2004 at Léon Bérard Regional Cancer Center (Lyon, France). Survival data were modelled using multivariate Cox models and controlled for endogeneity with the instrumental variable method.Results: The median survival for the whole cohort was 289 days. The average total cost of treatment reached €35,160. Survival was significantly shorter for patients with stage IV disease, poor performance status, and past or concomitant cardiovascular disease and/or diabetes, for current smokers, and for patients with adenocarcinoma compared to large cell carcinoma. Survival duration was not significantly associated with the total cost of treatment per day of hospitalisation, the number of chemotherapy drugs administered, nor inpatient length of stay.Conclusion: Higher care expenditures do not appear to improve survival for patients with locally advanced or metastatic NSCLC. Hence, maintaining patient quality of life and tailoring therapy to stage, histology and comorbidities appears to be the less bad choice.Cost; NSCLC; Oncology; Survival

The effect of health care expenditures on survival in locally advanced and metastatic Non Small Cell Lung Cancer

Working Paper GATE 2009-03Context: The significant survival benefit of chemotherapy over best supportive care for locally advanced and metastatic NSCLC has been amply demonstrated in the literature. However, there is no clear evidence of the impact of the type of chemotherapy or of a superiority of combination chemotherapy over single-agent chemotherapy.Objective: The present study empirically examines, in real-life practise and using multiple proxies, the impact of health care expenditures on overall survival in locally advanced and metastatic NSCLC in order to guide medical decision-making.Methods: Disease characteristics, the resources used, the costs of treatment and survival data were retrospectively collected from the records of 175 patients treated between 2000 and 2004 at Léon Bérard Regional Cancer Center (Lyon, France). Survival data were modelled using multivariate Cox models and controlled for endogeneity with the instrumental variable method.Results: The median survival for the whole cohort was 289 days. The average total cost of treatment reached €35,160. Survival was significantly shorter for patients with stage IV disease, poor performance status, and past or concomitant cardiovascular disease and/or diabetes, for current smokers, and for patients with adenocarcinoma compared to large cell carcinoma. Survival duration was not significantly associated with the total cost of treatment per day of hospitalisation, the number of chemotherapy drugs administered, nor inpatient length of stay.Conclusion: Higher care expenditures do not appear to improve survival for patients with locally advanced or metastatic NSCLC. Hence, maintaining patient quality of life and tailoring therapy to stage, histology and comorbidities appears to be the less bad choice

Coupling electron capture dissociation and the modified Kendrick mass defect for sequencing of a poly(2-ethyl-2-oxazoline) polymer

With increasing focus on the structural elucidation of polymers, advanced tandem mass spectrometry techniques will play a crucial role in the characterization of these compounds. In this contribution, synthesis and analysis of methyl initiated and xan-thate terminated poly (2-ethyl-2-oxazoline) using Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry was achieved. Electron capture dissociation (ECD) produced full end group characterization as well as back bone fragmentation including complete sequence coverage of the polymer. A method of fragment ion characterization is also presented with the use of the high resolution modified Kendrick mass defect plots as a means of grouping fragments from the same fragmentation pathways together. This type of data processing is applicable to all tandem mass spectrometry techniques for polymer analysis but is made more effective with high mass accuracy methods. ECD FT-ICR MS demonstrates its promising role as a structural characterization technique for polyoxazoline species

Recruitment of a lineage-specific virulence regulatory pathway promotes intracellular infection by a plant pathogen experimentally evolved into a legume symbiont

Ajuts: We are grateful to Lidwine Trouilh for helping in NimbleGen microarray hybridizations and Loic Escoriza for mutant construction. J.P.C. and C.C. were supported by the Initiative d'Excellence IDEX UNITI Actions Thématiques Stratégiques program (RHIZOWHEAT 2014) and by the French National Research Agency (ANR-12-ADAP-0014-01). This work was supported by funds from the French National Institute for Agricultural Research (Plant Health and the Environment Division), the French National Research Agency (ANR-12-ADAP-0014-01) and the French Laboratory of Excellence project TULIP (ANR-10-LABX-41). The complete collections of events generated for all the clones from this study are available on the Microscope platform (https://www.genoscope.cns.fr/agc/microscope/expdata/NGSProjectEvo.php, SYMPA tag).Ecological transitions between different lifestyles, such as pathogenicity, mutualism and saprophytism, have been very frequent in the course of microbial evolution, and often driven by horizontal gene transfer. Yet, how genomes achieve the ecological transition initiated by the transfer of complex biological traits remains poorly known. Here we used experimental evolution, genomics, transcriptomics and high-resolution phenotyping to analyze the evolution of the plant pathogen Ralstonia solanacearum into legume symbionts, following the transfer of a natural plasmid encoding the essential mutualistic genes. We show that a regulatory pathway of the recipient R. solanacearum genome involved in extracellular infection of natural hosts was reused to improve intracellular symbiosis with the Mimosa pudica legume. Optimization of intracellular infection capacity was gained through mutations affecting two components of a new regulatory pathway, the transcriptional regulator efpR and a region upstream from the RSc0965-0967 genes of unknown functions. Adaptive mutations caused the downregulation of efpR and the over-expression of a downstream regulatory module, the three unknown genes RSc3146-3148, two of which encoding proteins likely associated to the membrane. This over-expression led to important metabolic and transcriptomic changes and a drastic qualitative and quantitative improvement of nodule intracellular infection. In addition, these adaptive mutations decreased the virulence of the original pathogen. The complete efpR/RSc3146-3148 pathway could only be identified in the genomes of the pathogenic R. solanacearum species complex. Our findings illustrate how the rewiring of a genetic network regulating virulence allows a radically different type of symbiotic interaction and contributes to ecological transitions and trade-offs

Notch Promotes Neural Lineage Entry by Pluripotent Embryonic Stem Cells

A central challenge in embryonic stem (ES) cell biology is to understand how to impose direction on primary lineage commitment. In basal culture conditions, the majority of ES cells convert asynchronously into neural cells. However, many cells resist differentiation and others adopt nonneural fates. Mosaic activation of the neural reporter Sox-green fluorescent protein suggests regulation by cell-cell interactions. We detected expression of Notch receptors and ligands in mouse ES cells and investigated the role of this pathway. Genetic manipulation to activate Notch constitutively does not alter the stem cell phenotype. However, upon withdrawal of self-renewal stimuli, differentiation is directed rapidly and exclusively into the neural lineage. Conversely, pharmacological or genetic interference with Notch signalling suppresses the neural fate choice. Notch promotion of neural commitment requires parallel signalling through the fibroblast growth factor receptor. Stromal cells expressing Notch ligand stimulate neural specification of human ES cells, indicating that this is a conserved pathway in pluripotent stem cells. These findings define an unexpected and decisive role for Notch in ES cell fate determination. Limiting activation of endogenous Notch results in heterogeneous lineage commitment. Manipulation of Notch signalling is therefore likely to be a key factor in taking command of ES cell lineage choice

An asymmetry detected in the disk of Kappa CMa with the AMBER/VLTI

International audienceAims. We study the geometry and kinematics of the circumstellar environment of the Be star Kappa CMa in the Br gamma emission line and its nearby continuum. Methods. We use the VLTI/AMBER instrument operating in the K band which provides a spatial resolution of about 6 mas with a spectral resolution of 1500 to study the kinematics within the disk and to infer its rotation law. In order to obtain more kinematical constraints we also use an high spectral resolution Pa beta line profile obtain in December 2005 at the Observatorio do Pico do Dios, Brazil and we compile V/R line profile variations and spectral energy distribution data points from the literature. Results. Using differential visibilities and differential phases across the Br gamma line we detect an asymmetry in the disk. Moreover, we found that kappa CMa seems difficult to fit within the classical scenario for Be stars, illustrated recently by alpha Arae observations, i.e. a fast rotating B star close to its breakup velocity surrounded by a Keplerian circumstellar disk with an enhanced polar wind. Finally we discuss the possibility for kappa CMa to be a critical rotator with a Keplerian rotating disk and try to see if the detected asymmetry can be interpreted within the "one-armed" viscous disk framework

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

International Society of Sports Nutrition Position Stand: Nutritional recommendations for single-stage ultra-marathon; training and racing

Background. In this Position Statement, the International Society of Sports Nutrition (ISSN) provides an objective and critical review of the literature pertinent to nutritional considerations for training and racing in single-stage ultra-marathon. Recommendations for Training. i) Ultra-marathon runners should aim to meet the caloric demands of training by following an individualized and periodized strategy, comprising a varied, food-first approach; ii) Athletes should plan and implement their nutrition strategy with sufficient time to permit adaptations that enhance fat oxidative capacity; iii) The evidence overwhelmingly supports the inclusion of a moderate-to-high carbohydrate diet (i.e., ~60% of energy intake, 5 – 8 g⸱kg−1·d−1) to mitigate the negative effects of chronic, training-induced glycogen depletion; iv) Limiting carbohydrate intake before selected low-intensity sessions, and/or moderating daily carbohydrate intake, may enhance mitochondrial function and fat oxidative capacity. Nevertheless, this approach may compromise performance during high-intensity efforts; v) Protein intakes of ~1.6 g·kg−1·d−1 are necessary to maintain lean mass and support recovery from training, but amounts up to 2.5 g⸱kg−1·d−1 may be warranted during demanding training when calorie requirements are greater; Recommendations for Racing. vi) To attenuate caloric deficits, runners should aim to consume 150 - 400 kcal⸱h−1 (carbohydrate, 30 – 50 g⸱h−1; protein, 5 – 10 g⸱h−1) from a variety of calorie-dense foods. Consideration must be given to food palatability, individual tolerance, and the increased preference for savory foods in longer races; vii) Fluid volumes of 450 – 750 mL⸱h−1 (~150 – 250 mL every 20 min) are recommended during racing. To minimize the likelihood of hyponatraemia, electrolytes (mainly sodium) may be needed in concentrations greater than that provided by most commercial products (i.e., >575 mg·L−1 sodium). Fluid and electrolyte requirements will be elevated when running in hot and/or humid conditions; viii) Evidence supports progressive gut-training and/or low-FODMAP diets (fermentable oligosaccharide, disaccharide, monosaccharide and polyol) to alleviate symptoms of gastrointestinal distress during racing; ix) The evidence in support of ketogenic diets and/or ketone esters to improve ultra-marathon performance is lacking, with further research warranted; x) Evidence supports the strategic use of caffeine to sustain performance in the latter stages of racing, particularly when sleep deprivation may compromise athlete safety