dataesr/scientific-paragraphs-categorization huggingface dataset:
In addition, toxicology study findings for terminated molecules rarely get published by the sponsoring company, an unfortunate situation, as such data (e. g. , showing class effects) might influence the need for extensive nonclinical testing of subsequent similar drugs by other companies. This comprehensive evaluation of cross-industry and cross-drug modalities toxicology data enabled a retrospective evaluation of whether comparable decisions could have been reached on the toxicology profile of a new molecule using only one species (purposely working outside current regulatory guideline recommendations). From these data, the incidence of similar toxicities identified in both species at FIH stage indicated a wider number of drug modalities could potentially reduce to a single species for longer-term post-FIH studies.
, 2015). Several additional issues need to be resolved before use of a single species can be routinely considered for all drug modalities after the FIH toxicology package is completed. It is acknowledged that for a few of the drug candidates in the survey (five small molecules), new toxicities were identified in the longer-term toxicity studies which would potentially have been missed had only a single species been tested. Other reviews of chronic (> 3-month dosing duration) toxicity studies from individual company portfolios indicate that additional target organ toxicities are occasionally revealed  (Galijatovic-Idrizbegovic et al. , 2016; Roberts et al. , 2015)  and that this information can lead to decisions to terminate late-stage drug candidates. Therefore, further work to establish a larger dataset would be necessary to provide scientific justification to adopt this flexibility for the use of a single species within longer-term post-FIH toxicology studies across a wider range of drug modalities, whilst still retaining the use of two species where both are necessary to fully identify the toxicity profile of an individual drug candidate.
The use of target safety evaluations early in drug discovery is an effective way to increase knowledge of safety risks from literature and databases, to reduce the need for in vivo studies and prioritise resources  (Hornberg et al. , 2014). It is hoped that the emergence of non-animal technologies (such as in silico modelling and in vitro human 3D-tissue models) could provide more relevant and predictive data and thus replace the need for data in a second species in the future  (Ewart et al. , 2018). In the meantime, continued sharing of experiences of different approaches to enable and support clinical drug development, and further international data-sharing and analysis activities (to also include other regions within ICH) are required to identify the criteria for justifying the use of a single species, or conversely, justifying the use of two species.
Acknowledgements This article reflects the views of the authors and in particular should not be construed to represent views or policies of the FDA. At the time of initiation and conduct of the research/data gathering/analysis,  K Jones  was employed by  Chugai Pharma Europe Ltd. , and subsequently in the latter stages of the manuscript preparation is a consultant to  Chugai Pharmaceutical. , Japan. The project was co-funded by member companies of the ABPI, working in partnership with the NC3Rs. ABPI represents the researchbased pharmaceutical industry in the UK, developing strategy, monitoring policy and responding to consultations. Expert groups cover nonclinical issues in pharmaceutical research and drug development, in particular, focussing on discovery, preclinical safety, animal research and welfare.
Statistical analysis Results were analysed using the RStudio Version 1. 1. 453 (https://www. rstudio. com/). To analyse the behaviour of piglets over the 15 interaction sessions in the home pen, we first calculated the mean values for data by pen. We proceeded in two steps and had to use non-parametric statistics due to the nonnormal distributions of residuals. First we tested the effect of treatment during each first interaction session of each week (D5, D12, D19 corresponding to sessions 1, 6 and 11) with Mann-Whitney tests. Then we calculated the effect of treatment, session and their interaction within each week. To do so, we used non-parametric tests for repeated measures, using the nparLD package  (Noguchi et al. , 2012). Treatment was tested as an independent factor and session was tested as the repeated factor.
When treatment*session revealed significant effects, we analysed the session effect within a treatment via Friedman tests and compared the data between sessions by treatment using a Nemenyi multiple comparison test from the PMCMR package  (Pohlert, 2014). Differences were considered statistically significant when P < 0. 05. We dissociated the period when the human was standing (to stimulate piglet's attention) and the period when the human was sitting. Results are presented as medians and interquartile ranges (Md (IQ1-IQ3)). Data obtained during the reactivity tests (test 1 and test 2) were analysed by test phase (1: before the entrance of the experimenter; 2: with the presence of the experimenter) as in De Oliveira et al. (de Oliveira et al. , 2015)  to determine the effect of the treatments on the piglets' behaviour.
According to the distribution of the data and the residuals of the models, we had to use three methods to test the treatment effects (Table  4 ): -We used linear mixed models (lme of the package lme4) with treatment as a fixed effect and pen and repetition as random effects. This model was built using data or transformed data (square root). Pairwise comparisons were tested with the lsmeans package  (Lenth, 2015). -When the distribution of the data resembled an inverse distribution, it was analysed with generalised linear models with a gamma error structure and an inverse link function was used. Pairwise comparisons were tested with the lsmeans package  (Lenth, 2015).
11 -Data not fitting the parametric models hypothesis were analysed using non-parametric methods. We tested the effect of treatment with kws of the coin package (non-parametric method using permutations rather than rank) and post hoc comparisons were performed using nparcomp of the nparcomp package. Results are expressed as means and s. e. m. for non-transformed data analysed using parametric statistics, and as medians and interquartile ranges for all other variables. One animal from the HPV treatment died during the treatment application period, so 29 HPV, 30 HP and 30 CTRL piglets were used in the tests.
Acknowledgments The authors would like to thank Michel Lefebvre for building the apparatus and Carole Guérin for her participation in the project. We would like to acknowledge the piggery staff of UEPR that were involved in the work. We really appreciated the help with the English language of Lauren C Dawson, and the comments from the reviewers which helped to highly increased the quality of the article. This project was funded by the INRA PHASE department (Crédits Incitatifs 2015). We received grant n°30000937 SB from the INRA institute and the Brittany regional council. Comment citer ce document : Bensoussan, S. , Tigeot, R. , Meunier-Salaün, M. -C. ,  Tallet, C. (2020). Broadcasting human voice to piglets (Sus Scrofa domestica) modifies their behavioural reaction to human presence in the home pen and in arena tests.
| Case documentation and data collection The appendix lists data categories and items to be collected in the The anonymised electronic case report form will be accessible through www. clini calsu rveys. net. ClinicalSurveys. net employs a customised version of Questback's internationally acclaimed EFS Survey ® and EFS Leadership ® technology to provide the user with an easy-to-use online documentation system. Personnel who will be entering data will receive training on the system via telephone or web conference, after which each person will be issued a unique user identification (ID) and password.
Epistatic incompatibilities of archaic functional alleles To characterize the regulatory effects of archaic haplotypes, McCoy et al. have compared the relative expression of archaic and non-archaic alleles in a collection of 44 diverse tissues from the Gene-Tissue Expression database (GTEx)  [8]. Neanderthal haplotypes tend to be generally biased towards lower expression levels, this effect being most pronounced in the brain and testis. This observation has been interpreted as supporting the occurrence of genetic incompatibilities between Neanderthals and modern humans, due to epistatic interactions as predicted by the Dobzhansky-Muller model of speciation (i. e. , the fixation of incompatible mutations in two offspring lineages that share a common parental lineage). A weaker archaic ancestry on the X chromosome and near testis-expressed genes supports further the notion of a high rate of infertility among firstgeneration hybrids  [1].
Acknowledgements The laboratory of L. Q. -M. is supported by the  Institut Pasteur , the  Collège de France , the  French Government 's  Investissement d'Avenir program ,  Laboratoires d'Excellence "Integrative Biology of Emerging Infectious Diseases"  ( ANR-10-LABX-62-IBEID ) and " Milieu Intérieur " ( ANR-10-LABX-69-01 ), and the  Fondation pour la Recherche Médicale  (Equipe FRM  DEQ20180339214 ).
2 MIN 18 through MIN 33 correspond to Tandem Repeat identified in the study of Dauchy et al. [35]. PCR products (441 bp) were visualized by electrophoresis using 1. 5% agarose gels (agarose electrophoresis grade; Invitrogen), purified using NucleoSpin Extract II (Macherey-Nagel) and sequenced by GenomExpress (Grenoble, France). Sequences were analyzed using the leBIBI-QBPP website https://umr5558-bibiserv. univ-lyon1. fr/lebibi/lebibi. cgi. Phylogeny was performed with a concatenate of SNP using the software Bionumerics®v. 7. 6. 3 (Applied Maths).
PCR DNA Fragment Analysis To confirm in silico data from available genomes, detection and size analysis of the hbhA and lbp genes was investigated by PCR as described  [20]. The sizes of the PCR products corresponding to hbhA and lbp were determined after the amplification of genomic DNA of all isolates with primers described in Table  2. The fragments were amplified after a denaturation cycle of 5 min at 94 • C by using only 23 cycles of 94 • C for 30 s, 61 • C for 30 s and 72 • C for 30 s, followed by a final elongation cycle at 72 • C for 5 min. The size of the PCR products was analyzed by electrophoresis using 1. 5% agarose gels (agarose electrophoresis grade; Invitrogen, Carlsbad, CA, USA).
Images were taken with a 40× objective. To quantify the cytoadherence of M. intracellulare to A549 cells luminescence was measured using a Berthold Lumat LB 9507 luminometer. As needed, the crude cell lysates were diluted in PBS containing 0. 05% Tween 80. Aliquots (100 µL) of each sample were transferred into a polystyrene test tube (Falcon, PLAM0908) containing 900 mL dilution buffer and the luciferase activity was measured. Raw data were collected in triplicate and the mean Relative Luminescence Unit (RLU) readings were automatically calculated by the luminometer in-core software. Adhesion assays were performed in triplicate repeated in three independent experiments. The percentage of adhesion was calculated by the following formula: (cell-associated RLU/RLU of the inoculum) × 100. The average and the standard deviation were calculated with the GraphPad Prism software version 6.
Nucleotide Sequence Accession Numbers The hbhA and lbp genes were amplified by PCR using primers P19, P22, P23 and P24 (Sigma) (Table  2 ) and chromosomal DNA of M. intracellulare 13950 as a template by using Pfu DNA polymerase (Promega). The sequences of hbhA and lbp (Genome Express, Takeley, UK). have been deposited in the GenBank databases under the following accession numbers: KY748358 and KY748359.
| Statistical analyses Statistical analyses were performed using the MedCalc (Ostend, Belgium) and Microsoft Excel (Redmond, United States) statistical software. Continuous variables were described as median, range, mean ± SD. Categorical variables were compared using the Pearson chi-square test and continuous variables with an ANOVA test (one-way analysis of variance). CS rates of two independent groups were compared using the Pearson chi-square test with reporting of the odds ratio (OR), its confidence interval (95% CI) and the P value. A P value of strictly less than. 05 was considered significant.
ACKNOWLEDGEMENTS This work was supported by the  French National Cancer Institute (INCa, Institut National du Cancer)  with a grant for translational research ( INCa-DHOS 2010 ,  Prof M. Campone ) and one grant for PhD students on translational research (Grant No 201108; 2011); and by  Roche Diagnostics GmbH, Germany , which provided financial and technical support for the immunohistochemical characterization of the carcinomas. The authors deeply acknowledge  Prof Laura Peña  ( Department of Animal Medicine, Surgery and Pathology, Complutense University of Madrid, Spain ) and  Prof Adelina Gama  ( Animal and Veterinary Research Centre CECAV, University of Trásos-Montes and Alto Douro [UTAD], Vila Real, Portugal ) who participated in the histopathological and immunohistochemical evaluation of the canine mammary carcinomas included in this study;  Prof Mario Campone  ( Integrated Center for Oncology Nantes/Angers, France ) for his input in comparative oncology and funding acquisition;  Dr Claire Hanzenne ,  Dr Ingrid Bemelmans ,  Dr Floriane Morio  and  Dr Clotilde de Brito , who helped in collecting the clinical and follow-up data;  Dr Laëtitia Jaillardon  for her involvement in data analysis;  Dr Jean-Loïc Le Net ,  Dr Virginie Théau ,  Dr Pierre Lagourette ,  Dr Olivier Albaric  and  Dr Sophie Labrut , the veterinary pathologists who performed the initial diagnoses of canine and feline mammary carcinomas, as well as  Mr Bernard Fernandez ,  Mrs Florence Lezin , and  Mrs Catherine Guéreaud , the technicians in histopathology who made the slides.
With the advent of whole-genome sequencing (WGS), comparative analysis has led to the use of core genome MLST (cgMLST) schemes for the high-resolution reproducible typing of bacterial isolates. In cgMLST, hundreds of loci are used for gene-by-gene comparisons of assembled genomes for studying the genetic diversity of clinically important pathogens. Combination of the cgMLST data and metadata of the isolates is useful for epidemiological investigations. Here we present a cgMLST scheme for the high-resolution typing of isolates from the whole Leptospira genus, enabling identification at the level of species, clades, clonal groups and sequence types. We show several examples how the cgMLST Leptospira database, which is a publicly available web-based database, can be used for the analyses of WGS data of Leptospira isolates.
First, cgMLST can be applied to pathogenic (sub-clade P1), intermediate (sub-clade P2), and saprophytic isolates (sub-clades S1 and S2) and, thus, has a potential to elucidate the role of intermediates, which is a group of strains phylogenetically related to pathogens of unclear pathogenicity from the clinical perspective. cgMLST has a high discrimination power resulting in the identification of species, clades, clonal groups (CGs), sequencing types (STs) and most probable serogroups. This would allow tracking of Leptospira strains and could help, for example, the detection of new genotypes and length of time for which a given genotype persists. The widespread use of this cgMLST scheme should enable the identification of such relationships at the global level and over time. The Leptospira cgMLST database (https://bigsdb.
pasteur. fr/leptospira/) is a publicly available web-based database hosted at the Institute Pasteur. At present, the database contains data from 1007 Leptospira strains (08/28/2019). The Bacterial Isolate Genome Sequence Database platform (BIGSdb) was initially developed by Jolley and Maiden in 2010  [7]  for automatic ST and CG assignments; for determination of new alleles; for storage of sample metadata; for identification of new associations between genotypes and metadata using various tools; and for user-friendly visualization of molecular typing data using breakdown options and external plugins such as interactive tree of life (iTOL)  [8]  and GrapeTree  [9]. This chapter presents some examples of how the WGS data can be used in BIGSdb for user-friendly visualization of phylogenic relationships among STs of Leptospira.
Data submission New users can contact the curators by e-mail (leptospiraMLST@pasteur. fr). Subsequently, the curators will create an account and provide the login details to new users, who are then able to submit their data (see  Note 5). Whole genome sequence data in FASTA format can be submitted to BIGSdb as i. ) a single contig of a closed chromosome; ii. ) a multi-fasta file with closed chromosome and plasmids from the same isolate; iii. ) multi-contig files (whole genome shotgun) or iv. ) scaffold files. There are number of fields that must be filled in so the curators know how the data were obtained; e. g. , the sequencing platform used, read length, coverage, and assembly (de novo or mapped). Make sure the 'e-mail submission updates' box is checked if you wish to receive e-mail notification of the result of your submission.
Data export Different data can be exported from BIGSdb. You can export the isolate recordsets by clicking the "Export dataset" link in the Export section of the main contents page or you can export recordsets of isolates returned from a database query by clicking the "Dataset" button in the Export list at the bottom of the results table. You can then download the data in tab-delimited text or Excel formats. In the advanced options, chose the cgMLST scheme in order to export cgSTs and "Test-40" under the "Classification scheme" to obtain the cgCGs. Similarly, the original submitted data as well as the sequences of core genes extracted from the original data can be exported. By default, the data will be extracted unaligned, but you can also chose to align the sequences by checking the "Align sequences" checkbox (use the MAFFT as the aligner).
General overview An easy way to get a general overview of all or selected data present in BIGSdb, is to use the breakdown option plugins. For example, when you want to know the prevalence of different Leptospira species in different geographical areas, you can click the "Two field breakdown" link on the main contents page. This plugin exports a table breaking down one field against another (the breakdown of "species" by "country") (Fig. 1 ) (see Note 6).
GrapeTree GrapeTree allows for exploration of the fine-grained population structure and phenotypic properties of large number of genomes (more than 200) in a web browser. It generates and displays the minimum spanning tree (MSTree) based on cgSTs  [9]. The GrapeTree algorithm is able to export large datasets and is compatible to handle larger amount of missing sequences thus is perfect for handling cgMLST data. The datasets can include metadata, which allows nodes in the result tree to be colored interactively. It can be accessed from the contents page or following the query by clicking the "GrapeTree" link. In the Leptospira setting, it could be very useful in an easy identification of the potential source of infection by determination of cgCGs which are shared among human and animal isolates (Fig.
4. A simulation of the effect of missing data (uncalled cgMLST alleles) on the clustering results showed that cluster assignment is robust even with high amounts of missing data (affecting up to 400 loci out of 545)  [5] ; indicating that even incomplete genomes should be typeable by cgMLST. 5. One of the features of BIGSdb is that the stored data sets have been manually curated to provide researchers with more accurate results. 6. A BIGSdb manual for a detailed description of BIGSdb function is available (https://bigsdb. readthedocs. io/en/latest/).
Furthermore, the durability of a surveillance system depends on a reasonable cost to ensure its financing. Therefore, we also assessed each protocol's cost. Among methods to evaluate the sensitivity of a surveillance system, scenario tree modelling  (Martin et al. , 2007)  has been frequently used  (Hadorn et al. , 2009; Christensen et al. , 2011; Foddai et al. , 2016). It is possible with this approach to use various and complex data that can be easily updated. Besides, the variability and uncertainty about the surveillance parameters can be accounted for with a stochastic approach  (Martin et al. , 2007). Finally, this method allows the concomitance estimation of the costs of the system  (Hadorn et al. , 2009; Rivière et al. , 2015; Hénaux and Calavas, 2017). We thus used this method to evaluate quantitatively the efficiency of bTB ante mortem surveillance in France.
These costs and distributions are detailed in the complementary materials (C4). For indirect costs, the estimation of daily immobilisation cost of animals within the suspected herd, from each production type and animal category (calves, female over or under 24 months, male over or under 6 months old)  (Buczinski and Reuillon, 2015)  (C5) was used. These costs were weighted by the number of animals of each category sold each month (by herd type, from the BDNI database) and by the duration between each protocol's steps (estimated for the SIGAL database, C6). We adapted the model with the following distribution for variables related to the use of IFNMIX. To model the costs for IFNMIX, we used the same probability distribution as for the bTB IFN test (PERT(min =3 4, mode = 53, max = 68))  (Poirier et al.
, 2019) , given that laboratories declared they would charge the same price for an IFNMIX as for the usual IFNγ. The times to obtain the IFNMIX and IFNγ results (in days) in the two alternative protocols were modelled similarly (personal communication, NLR) (PERT(min = 2, mode = 2, max = 7))  (Poirier et al. , 2019). In the compliant slow-path and alternative protocols, the times (in days) between a positive IFNMIX result or a positive IFNγ result, respectively, and the culling of the corresponding animal were modelled using the same probability distribution (PERT(min = 3, mode = 24, max = 136)). The parameters of this distribution were estimated from the time intervals reported in 2016 in the French national database for disease regulation (SIGAL)  (Poirier et al. , 2019; complementary materials C6).
of the tests performed by the NRL (bacteriology, spoligotyping and PCR) were assumed to be perfect M-L. Boschiroli, director of the French NRL Legend: β(a; b) = beta distribution; N asym (mean; min; max) = Normal asymetric distribution (Sicard, 2013); N(mean; sd) = normal distribution; PERT(min; mode; max) = Pert distribution; Se = sensitivity, Sp = specificity; ICCT = intradermal cervical comparative tuberculin test; IFN = interferon test; NRL = national laboratory of reference for bTB. Parameters taking into account the ICCT practice in our evaluation of the periodic screening protocols (method's details in Guétin-Poirier et al. , 2020). *BDNI = National database of bovine identification = French data base in which all bovine are register associated with their age, race and all commercial exchanges of live animals.
Parameter DistribuƟon Comments Reference ProducƟon type Analyses of SIGAL*** database showed a minimum of one adult and a maximum of 100% of the adults tested with ICCT2. In most of small herds all adults were tested with ICCT2, whereas a mean of 53 adults tested with ICCT2 was found for big herds. Limited data about the number of tested animals did not allow to fit normal distribuƟons for veterinarians) FiƩed to the real reparƟƟon of herd types (data from the BDNI*) in 2016, in Cantal, a French administraƟve area which has the proporƟon (Poirier et al. , 2019) (C3; Poirier et al. , 2019) of each herd type closest to the naƟonal mean this parameter These parameters were idenƟfied as influent on either ICCT pracƟces or We assumed that the result for the second ICCT has the same percepƟon of bTB surveillance (posiƟve or negaƟve) by the veterinarian (GuéƟn-Poirier et al.