dataesr/scientific-paragraphs-categorization huggingface dataset:
This work was supported by the  Austrian Science Foundation FWF  through the  ERA-Net Pathogenomics project FunPath  to KK ( FWF-API-0125 ), SR (BMBF:  0313931A ), TG, CD, DF and BH, and in part by the  Christian Doppler Society  to KK. BC and BM were supported in part by  NIH   RO1AI46223. BH and SB were supported by the  German Federal Ministry of Education and Research (BMBF)  through FKZ:  01EO1002. TG was funded in part by grants from the  Spanish ministry of science and innovation  ( GEN2006-27784E ,  BFU2009-09168 ). KH was funded by the  BBSRC  ( BB/F005210/1 ). DF was also partly supported by  CNRS  and the  Fondation pour la recherche Medicale  ( Programme Equipe FRM ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Testing the relevance of the European Curriculum version 2. 0: a prospective European survey A prospective continuous survey would be the ideal next step in assessing the present and future impact of the European Curriculum on hematology training in Europe. If implemented as a self-assessment tool for hematology trainees at all stages of training, competence information could be gathered at any time from the beginning of training until up to two years following completion of training. The competence data registered in this survey would, first and foremost, enable trainees to monitor their own progress and ensure they have covered all the diverse areas which hematology encompasses. The survey would also enable the generation of national or regional reports, providing important information regarding the patterns of hematology competence in various regions of Europe.
Single versus tandem transplant? In the absence of new treatments in the 1990s, the only possibility to attempt to improve outcome was to further increase dose intensity by developing the concept of double intensive therapy, which was pioneered by the Arkansas group. 59 Three randomized trials showed a benefit in favor of double ASCT in terms of PFS, but 2 of them failed to show an OS benefit. 3 In the trial carried out by Attal et al. , double ASCT resulted in an OS benefit in patients who did not achieve a VGPR after the first transplant. 60 In a recently published Cochrane Database systematic review of first-line tandem ASCT versus single HDT/ASCT studies, the authors concluded that none of the studies included in the analysis was sufficiently informative to support treatment decisions concerning the question of single versus tandem ASCT.
Acknowledgments: MM would like to thank  Prof. J. V. de Melo  ( Adelaide, Australia ) for critical reading of the manuscript. We also thank the " Association pour la Recherche sur le Cancer (ARC) , the  "Fondation de France" , the " Fondation contre la Leucémie ", the  "Agence de Biomédecine", the "Association Cent pour Sang la Vie", the "Association Laurette Fuguain", the "IRGHET" and the "Ligue contre le Cancer  ( Comités Départementaux de l'Inter région Grand-Ouest Bretagne, Centre, Pays-de-Loire, Poitou-Charentes )", for their generous and continuous support for our clinical and basic research work.
We built a data set of CDS data from 44 representative species of vertebrates including the newly sequenced transcriptomes of seven sauropsids (five reptiles and two birds) and one amphibian. We report that reptiles, and particularly the green anole, exhibit a level of GC3-heterogeneity comparable to that of mammals and birds, revealing a conflicting signal between third-codon positions and noncoding DNA. We also report a significant impact of chromosome and genome size on GC3 dynamics in vertebrates, including the green anole. Our results suggest that gBGC is of ancient origin in vertebrates and has impacted the neutral nucleotide substitution process in all vertebrate lineages, even though this is not always reflected by a strong GC-heterogeneity in the genomic landscapes of extant species.
(2011). Nonnormalized cDNA libraries were prepared and sequenced on a Hiseq 2000 (Illumina, Inc. ) to produce 100-bp reads. Reads were trimmed for low quality (phred quality score < 30) and minimum size (60 bp). All reads are available on the ncbi website (http://www. ncbi. nlm. nih. gov/, last accessed January 13, 2015) through the BioProject PRJNA268920.
Transcriptome Assembly and Coding Sequence Prediction In 15 additional reptile species, RNA sequencing (RNA-seq) reads or contigs were obtained from the literature: Podarcis sp. , Phrynops hilarii, Caretta caretta, Emys orbicularis, Chelonoidis nigra, Caiman crocodilus, Alligator mississipiensis De novo transcriptome assembly was performed with a combination of Abyss and Cap3 programs following the strategy B of  Cahais et al. (2012). Open reading frames (ORFs) were predicted using the program getORF included in the EMBOSS package. ORFs shorter than 200 bp were discarded. This transcriptome-based data set includes 30 species of which 20 reptiles (supplementary table  S2 , Supplementary Material online).
Annotated CDS from Complete Genomes In addition, we also built a data set of CDS annotated from complete genomes-the genome-based data set (supplementary table  S3 , Supplementary Material online). Complete sets of CDS were retrieved from Ensembl using the biomart tool for 21 vertebrate species of which seven sauropsids (two reptiles and five birds), six mammals, one amphibian and seven bony fish, eight of these species being also present in the transcriptomic data set (A. carolinensis, Pe. sinensis, G. gallus, Ana. platyrhynchos, H. sapiens, M. musculus, Bos taurus, and Mo. domestica). When several transcripts were obtained for a single gene, we retained the longest one. All identified mRNA from the complete genome of the western painted turtle Chr. picta  (Shaffer et al. 2013).
Orthologous Genes and Alignments A set of orthologous sequences was built with the OrthoMCL software  (Li et al. 2003 ) on amino acid-translated sequences with default parameters. We run the program only using the 21 reptiles of this study to maximize the number of shared clusters for these species. We selected among all returned orthologous clusters the ones including at least 18 of the 21 reptilian species and no more than four ORFs per cluster for a particular species. When several ORFs were returned in a cluster for a single species, we retained the longest one. This procedure resulted in a total of 1,025 genes. Orthologous genes from all other vertebrates taken from Ensembl (19 species) were added to the above defined clusters thanks to the Ensembl predictions of orthology with A. carolinensis and Pe.
Phylogeny and Divergence Dates The topology of the phylogenetic tree for our set of vertebrate species was adapted from reference phylogenies:  Near et al. (2012)  for actinopterygii (ray-finned fishes),  Meredith et al. (2011)   Divergence dates were retrieved from the TimeTree of Life database (http://www. timetree. org, last accessed December 18, 2014 ) that combines both paleontological and molecular dating estimates. When divergence dates were inconsistent with the topology (older nodes being assigned an earlier divergence), all the concerned nodes were placed at the most ancient date and when no date was available (Emys-Chrysemys and Anolis-Iguana ancestral nodes), we used the mean between the two neighboring nodes. The effect of phylogenetic dependence on correlations was tested through the method of phylogenetically independent contrasts  (Felsenstein 1985)  with the "ape" R package, using divergence dates as branch lengths.
Ancestral GC3 Estimation Ancestral GC3 was estimated for all nodes of the tree separately for each of the 1,025 genes using the NHML program  (Galtier and Gouy 1998) , implemented in the bpp_ML programs  (Dutheil and Boussau 2008). This method uses a nonhomogeneous and nonstationary Markov model of nucleotide evolution to estimate branch-specific GC-content in a maximum-likelihood framework. This program has been used and tested in a large variety of studies  (Romiguier et al. 2010 (Romiguier et al. , 2013;; Fujita et al. 2011 ).
C-Value and Karyotypes We retrieved all available C-values from the Animal Genome Size database  (Gregory et al. 2007 ) as a proxy for genome size. When several measures were available for a given species, we took their mean, and the mean of the genera if the species was not available. C-values were obtained for 20 of the 22 species of the genome-based data set. Karyotypic information provided by Ensembl was used for the 11 species for which it was available and the standard deviation in chromosome length was calculated (excluding the mitochondrial genome). To improve the sampling, karyotypic heterogeneity was also obtained in five additional species by measuring chromosome size from karyotype pictures (A. mississipiensis:  Valleley et al. 1994  For the green anole and the chicken, which both exhibit a clear distinction in size between micro-and macrochromosomes, we also calculated the mean GC3 value of genes associated with each type of chromosomes using the chromosomal assignation of genes provided by Ensembl.
(assembled from National Center for Biotechnology Information [NCBI] SRA SRX012365) from Chiari et al. 2012, Pelodiscus sinensis (NCBI SRA DRX001551), Sphenodon punctatus (Miller et al. 2012), Chamaeleo chamaeleon (Bar-Yaacov et al. 2013), Pogona vitticeps (Tzika et al. 2011), Elaphe guttata (Tzika et al. 2011), Thamnophis elegans (Schwartz et al. 2010), Ophiophagus hannah (NCBI SRA SRX365144), and A. carolinensis (NCBI SRA SRR391650). Four representatives mammals (Homo sapiens, Mus musculus, Monodelphis domestica: Perry et al. 2012, and Bos taurus: NCBI SRA SRX477519) as well as two birds (Gallus gallus: NCBI SRA SRX191158 and Anas platyrhynchos: NCBI SRA SRX255765). and one basal sarcopterygian (Protopterus annectens: Chiari et al. 2012) species were also retrieved from public databases.
Acknowledgments The authors thank the  GBE Editorial Board  for accepting to consider this submission accompanied with reviews. They thank four anonymous reviewers, who had done the job for another journal. They do not thank the Editorial Board of this other journal for rejecting our submission based on the review of another manuscript. They are grateful to  Pierrelatte zoo "La  ferme aux crocodiles," Montpellier zoo, Cedric Libert,  Benjamin Rey ,  Ylenia Chiari ,  Claire Doutrelan , and  Philippe Peret  for their help with sampling. They also thank  Laurent Duret  for useful advice and the  Montpellier Bioinformatics & Biodiversity  platform for support regarding computational aspects. This work was supported by  European Research Council  advanced grant  232971  (PopPhyl) and  Agence Nationale de la Recherche  grant  ANR-10-BINF-01-01  (Ancestrome).
All models were compared using the likelihood test ratio and Akaike's information criterion (AIC). The discriminant performance of models was measured using the timedependent area under the curve (AUC) using the Surviv-alROC R package  [32]. This criterion allows evaluating whether a model may correctly classify a patient with an event and a patient without event at a time point; AUC close to 1 indicating a better classification. The performance of the final model was also evaluated in deriving risk groups from the prognostic index (PI) (sum of weighted regression coefficients estimated from derivation set). The discrimination of the observed survival curves of risk groups (Kaplan-Meier) and the comparison with final model-based predicted mean survival curves were studied. The final model was evaluated through internal and external validation.
We estimated the observed survival curves (Kaplan-Meier) into the three risk groups and evaluated whether they were well separated and reported the hazard ratios across these risk groups. The comparison with the predicted survival curves allowed evaluating the accuracy prediction of the model (calibration). Less importance was attached to this point since our aim was to define a risk score with good ability to separate patients with different prognoses. An update of the final prognostic model was performed on the pool of the derivation and validation set with adjustment by dataset, thus providing more accurate estimate of regression coefficients. For all analyses, we categorized continuous miRNA expression levels as measured by qRT-PCR into two classes (<1, ≥1), using as cutoff the expression level of IGR-N-835 cell line taken as one  [19].
If patients were younger (P = 0. 05) with higher number of MYCN amplification (P = 0. 04) in the validation set, no significant difference into the standard risk stratification between the two datasets was observed (P = 0. 38). There is no significant difference between derivation and validation set in terms of OS (P = 0. 06) contrary to DFS (P = 0. 04) (Fig. S1  reporting the log-rank test). These last two comparisons were performed after controlling for stage, age, and MYCN amplification but considering the analysis of retrospective data some important omitted confounders; for example, the difference of treatments in the institutions where these archival cohorts were obtained, could explain the observed difference in term of DFS. Figure  1A  shows the updated survival curves reported in Gattolliat and coworkers with a significant log-rank test (P < 0.
Each model corresponds to a separate column in the table. The models including both miR-487b and miR-516a-5p for OS (column "model 4") and including only miR-487b for DFS (column "model 2") fit the data considerably better than the reference model: likelihood ratio test P = 0. 002 with lowest AIC = 629. 002 for OS and P = 0. 007 with lowest AIC = 862. 645 for DFS compared to the reference model. In these two models, high expression of miR-487b is associated with a 69% decrease in the hazard of death (HR = 0. 31, 95% CI = [0. 13-0. 75]) and 54% decrease in the hazard of disease-related event (HR = 0. 46, 95% CI = [0. 25-0. 84]). High expression of miR-516a-5p is associated with a 98% increase in the hazard of death (HR = 1. 98, 95% CI = [1. 00-3. 92]). In "model 5," a significant interaction term (P = 0.
In term of calibration, the inaccuracy prediction between observed and predicted survival curves may result by substantial different baseline survival function in the two populations (derivation and validation sets). This last point is, however, less important regarding the aim focusing on a risk score able to well-discriminate neuroblastoma patients. We also provided an update of regression coefficients of model 5 (adjusted by dataset) in carrying out a pooling of the two datasets. Column "Combined" of Table  3  shows similar regression coefficients.
Introduction: Methylphenidate is a piperidine derivative structurally and pharmacologically similar to amphetamine. Methylphenidate is indicated for Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 years of age and over when remedial measures alone prove insufficient. In adults, its indication, except in narcolepsy, is not defined. Methylphenidate received regulatory approval almost sixty years ago with a first registration in Switzerland in October 1954. Objective: To evaluate the off-label use of methylphenidate and its characteristics from a database of spontaneous reports. Methods: This study analysed data from the French Pharmacovigilance Database of adverse drug reactions spontaneously reported by health professionals from 1985 to December 2011. Off-label use was evaluated according to age.
Results: In the French Pharmacovigilance database, 181 cases of adverse drug reactions were reported with methylphenidate. Neuropsychiatric effects were the most frequent adverse event reported (41%) followed by cardiovascular and cutaneous side effects (14%). 143 reports concerned children (113 boys, 30 girls, mean age 10. 6 ± 3. 3 years) of which 46 (30%) were off-label uses. There were 38 adults (20 men, 18 women), of which 32 (88%) off-label use. In adults, methylphenidate was prescribed for depression, and this practice was associated with serious adverse events of drug dependence, overdose and suicide attempt. Overall, off-label use was detected in 43% (78/181) of all cases reported. Conclusion: More than 40% of the patients with drug reactions received methylphenidate for off-label indications.
Moreover, pharmacies are only allowed to dispense methylphenidate on presentation of the two prescriptions, namely the initial hospital prescription and the renewal prescription. A contract of care is established between the pharmacist, the practitioner, and the patient. The names of the three individuals are listed on the renewal prescription, and the diagnosis must be reevaluated each year by the specialist. Despite the limited indications, and the stringent conditions of its prescription and dispensing, off-label use of methylphenidate exists. The guidelines of the European Medicines Agency define off-label use as "medicinal product intentionally used for a medical purpose not in accordance with the authorised product information" (European Medicines Agency 2012). In this context, we aimed to evaluate the off-label use of methylphenidate, and describe the features of off-label use from a database of spontaneous reports for methylphenidate in France.
Methods This study used data from the French National Pharmacovigilance Database of all Adverse Drug Reactions (ADRs) spontaneously reported with commercially approved drugs in France. This database was established in 1985 to register all ADRs spontaneously reported by health professionals to the French Pharmacovigilance System, but not those reported to manufacturers. The national database includes data from 31 regional pharmacovigilance centres. Reports are reviewed by medically qualified personnel in the regional centres before being entered into the national database. ADRs are coded according to the Medical Dictionary for Regulatory Activities (MedDRA®, version 12. 1)  (Brown and Sexson 1988). Seriousness of the reaction is also recorded in the Pharmacovigilance database: ADRs are considered serious when they result in death, are life-threatening, require patient hospitalisation or prolongation of existing hospitalisation, or any reaction that results in persistent or significant disability or incapacity, congenital anomaly or birth defect.
All other ADRs are considered nonserious (European Medicines Agency 2012). All cases reported between 1 January 1985 and 31 December 2011 and citing methylphenidate (in any of its forms) were selected. All cases were assessed from the computerised data and reviewed by two pharmacovigilance specialists (TT, EH) to determine whether the use was off-label. The criteria for classifying the use as offlabel were as follows: all patients below six years of age treated with methylphenidate were considered as off-label use, all adults (18 years and above) treated with methylphenidate for indications other than narcolepsy were considered as off-label use, for narcolepsy, only the immediate-release form (Ritaline®) is approved for use in adults.
Results From 1 January 1985 to 31 December 2011, in the French National Pharmacovigilance database, 181 spontaneous reports were collected citing methylphenidate as the culprit drug. Among these, 78 (43%) were considered to be offlabel uses of the drug. Overall, 143 children were involved (113 boys, 30 girls), mean age 10 years, of which 46 (32%) were offlabel use. In children, when used in accordance with its indications, serious adverse effects represented 31. 3% of all spontaneous ADRs, and 43% of the spontaneous reports in the context of off-label use. There were 38 spontaneous reports in adults (20 men, 18 women) of which 32 (84%) were considered as off-label use. Reports in adults first appeared in 2005 and now represent 27% of the spontaneous notifications. In adults, when used in accordance with its indications, serious adverse effects represented 33% of all spontaneous reports, and 52% of the spontaneous reports in the context of off-label use.
The number of spontaneous reports with methylphenidate is increasing regularly, and doubled over the year 2011 (Figure  1 ). By 2011, off-label use notifications represented half of the total spontaneous notifications reported to the national pharmacovigilance database with methylphenidate. For patients aged <6 years, the main indications for prescribing methylphenidate were ADHD, autism and psychomotor activity. In the 6-18 year age group, the offlabel indications for methylphenidate prescription were: behavioural disorders (38%), narcolepsy (Concerta®) (13%), instability (19%), autism (13%) and intellectual disability (8. 8%). Off-label uses of the drug, with presence of a contraindication, were observed in 9 cases (i. e. 20% of off-label use in children) (child aged <6 years, n = 6; prior history of epilepsy, n = 3).
Discussion In our study, we investigated prescriptions of methylphenidate outside of the described product characteristics, using data from the French National Pharmacovigilance Database. Despite very restrictive conditions for its prescription in France, over 40% of the spontaneous ADRs with methylphenidate could be considered as off-label use (age <6 years, or prescription in adults outside of the only approved indication, namely narcolepsy). The ADRs observed were more often classed as serious when the use was off-label. In our study, we chose to take into account only the criteria based on age and indication, as this information is generally always recorded in pharmacovigilance databases. Thus, it is likely that the high rate of off-label use observed is actually an under-estimation of the true rate.
Possible sources for identifying off-label prescriptions are manifold, but unfortunately, not well structured. First among these sources are the pharmacovigilance databases, but other sources are also available, such as hospital databases, sales information or marketing studies, and data on reimbursement of medications through the social security system. The data from our study were taken only from the French National Pharmacovigilance Database. Spontaneous reporting systems are associated with under-reporting. The tendency of physicians to under-report is heightened by the fear of revealing an off-label (unapproved) use of the drug  (Inman 1996). The motives for prescription of methylphenidate in adults varied widely in this study, with prescription for ADHD representing only 1/6 of all reports.
The use of methylphenidate in adults is not codified, and there are currently almost 300 studies ongoing with this drug (http://clinicaltrials. gov, accessed 23/08/2013). 1991 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011  Figure  1  Profile of the number of spontaneous reports of adverse effects occurring during off-label use of methylphenidate in the French National Pharmacovigilance Database from 1991 to 2011. Our data are in line with the few studies of methylphenidate prescription reported to date  (Frauger et al. 2011; Knellwolf et al. 2008; Wilens et al. 2008 ). Among psychiatric drugs, off-label use is reportedly as high as 31%  (Radley et al. 2006). Identifying off-label use is difficult, as this is not a specific item in databases that record ADRs.
A case-control study performed by  Gould et al. (2009)  on mortality data from 1985-1996 in the USA among children aged 7 to 19 years of age, showed an association between the use of psychostimulants and sudden death in children and adolescents, with a relative risk of 7. However, the methodology of this study has come in for some criticism. Data from the WHO for the period 1999-2003 report the occurrence of 25 sudden deaths under psychostimulants, of which 8 were with methylphenidate (7 children, 1 adult)  (Wilens et al. 2006). On 1 November 2011, the FDA published a statement for the general public emphasizing the absence of any relation between the use of psychostimulant drugs for the treatment of ADHD, and the appearance of adverse cardiovascular effects. A study by  Cooper et al. (2011)  that included 1,200,438 children and young adults aged 2 to 24 years undergoing treatment, corresponding to a followup of 2,579,104 person-years, reported a rate of 3.