dataesr/scientific-paragraphs-categorization huggingface dataset:
The patient is followed until one of three endpoints is reached: 1. the patient changes progression stage (only changes from pre-progression to post-progression are possible); 2. the patient dies in hospital, which is recorded in the database; 3. censure at the end of the follow-up period (31st December 2013). In the last case it is not known whether the patient has died at home or is still alive, since out-of-hospital deaths are not recorded in the database. Between the index hospitalisation and any one of these endpoints, the patient may undergo one or more hospitalisations (H) which are accounted separately for the pre-progression stage and the post-progression stages calendar year. For the number of patients assumed to have died in each calendar year, the duration of the remaining follow-up time from the 1st January of the year of death to the end of the follow-up period (date of censure: 31st December 2013) was determined and subtracted from the unadjusted cumulative follow-up duration as follows: Adjusted cumulative follow-up duration days ð Þ ¼ Unadjusted cumulativ follow-up duration days ð Þ -Number of estimated deaths in 2011 ½ Ã 365 Â 3 -Number of estimated deaths in 2012 ½ Ã 365 Â 2 -Number of estimated deaths in 2013 ½ Ã 365 Â 1 The presentation of the data is descriptive and no a priori statistical hypotheses were tested.
Patient cohort Overall, 78,750 hospital stays by 10,337 patients with metastatic melanoma (and no other primary cancer) identified in the SDS were identified in the PMSI database for the 3 years of the study (2011-2013). Of these, 8294 stays (10. 5%) were excluded since they were not directly related to melanoma. Of the remaining 70,456 stays, 63,268 (89. 8%) were made by 8862 patients who had not received chemotherapy for melanoma in the previous 2 years, and these formed the study population (Fig. 2 ). The overall mean number of melanoma-related stays per patient was 7. 14. The annual number of stays increased somewhat over the 3 years of the study. The vast majority of the stays were in acute stays in general hospitals (96. 6%). A total of 26,843 stays (42. 4%) concerned 7332 patients who were at the pre-progression stage and the remaining stays concerned 5062 patients at the post-progression stage.
Costs of chemotherapy or immunotherapy Annual per capita costs were assessed for hospitalisations related to metastatic melanoma with administration of ipilimumab or fotemustine (both specifically identified in the FICHCOMP database), or of all other chemotherapeutic agents. These costs are presented in Table  4. Of the 7332 patients in the pre-progression stage, 55 (0. 8%) received ipilimumab at 165 individual stays. During this stage, the per capita cost of ipilimumab using national tariffs was € 64,585. During the postprogression stage, 348 patients (6. 9%) received ipilimumab at a mean per capita cost of € 44,124. In both stages, when the ENCC unit costs were used for the valuation, the costs of therapy were estimated to be sixteen-fold lower. When the ENCC unit cost was adjusted for the real reimbursable cost of the treatment actually delivered, a per capita cost close to that estimated from national tariffs was obtained (Table  4 ).
Nevertheless, this still remains a small proportion of the total direct healthcare expenditure on cancer in France, which amounted to € 7000 million in 2009  [14]. The annual per capita costs of treatment were also determined. Ipilimumab (an anti-CTLA-4 immunotherapy for advanced melanoma) and fotemustine (a chemotherapy for melanoma with cerebral metastases) are the only two drugs that could be individualised, as these are the only two treatments of advanced melanoma documented in the FICHCOMP database. Ipilimumab was only used in 402 patients (<5%), principally in the post-progression stage (348 patients). The limited use of ipilimumab in this study reflects the fact that it was only available through a named-patient early access scheme prior to its commercialisation in France in March 2013 for half the period of the study.
The annual per capita costs of these events corresponded to € 3762 in the pre-progression stage and to € 5523 in the post-progression stage. However, it should be noted that costs per stay with ADR were highly variable depending on the type of adverse event reaction considered, being most expensive for infections and least expensive for neuropathies. The actual costs of managing adverse drug reactions related to immunotherapy or chemotherapy for melanoma determined in our study are much lower than the costs estimated in a recent literature review of the costs of in-hospital management of toxicities associated with treating metastatic melanoma in eight countries, including France  [19] , which ranged from € 1416/event for cutaneous squamous cell carcinoma to € 6913 for hepatotoxicity. Similarly high costs associated with adverse drug reactions to metastatic melanoma treatments have also been reported in an analysis of data from a North American prescription claims database  [20].
In this study, we compared cost valuation using national tariffs to valuation using mean real-world costs obtained from the ENCC surveys. With respect to total costs, the two valuation methods provided very similar estimates, suggesting that, for the treatment of metastatic melanoma, national tariffs accurately reflect the actual cost of in-hospital management. However, when treatment costs were considered, large discrepancies between the two methods were observed. In the case of patients treated with ipilimumab, cost estimates based on national tariffs and including ipilimumab acquisition costs from the FICHCOMP database were twenty-fold higher than the cost estimates based on the ENCC mean unit costs. This can be explained by the fact that the ENCC costs are generated from patients treated with a range of cancer therapies with different acquisition costs, such that the cost of ipilimumab is diluted by that of less expensive drugs.
In contrast, in patients with other chemotherapies that do not figure on the FICHCOMP list (and are therefore in principle inexpensive) the costs estimated from ENCC mean unit costs were nearly twice as high as those estimated from national tariffs. In this case, the ENCC mean unit costs are inflated by the acquisition costs of recent innovative therapies commanding a premium price. In consequence, the best way to estimate the real costs of cancer therapies may be to adjust the ENCC mean unit cost for the cost of the individual treatments received by each patient as documented in the FICHCOMP database. In our study, performing such an adjustment abolished nearly all the difference between costs estimates bases on national tariffs and those based on the ENCC mean unit costs. Around one-quarter of patients with post-progression metastatic melanoma underwent hospitalisation including palliative care, and this carried a high annual per capita cost (€ 20,107).
It is noteworthy that only a minority of patients who finally died in hospital of metastatic melanoma received any palliative care. Data for the study were obtained from the PMSI database which contains exhaustive information on inhospital healthcare consumption for all beneficiaries of the principal public health insurance schemes in the country, covering around 97% of the population. For this reason, we are confident that essentially all stays related to melanoma will have been captured in our analysis. The costs obtained in the valuation using national tariffs are relevant as these correspond to the tariffs used for resource allocation in the French health system. Nonetheless, the PMSI database does have several limitations from the perspective of economic analyses. Firstly, it is not possible to be sure that all resource use during hospitalisation was effectively for the treatment of metastatic melanoma or that all hospitalisations in which melanoma was documented as a SAD in the SDS were related to melanoma.
Fourthly, in the analysis of costs attributed to adverse drug reactions to chemotherapy, the relationship of such events to the chemotherapy is not specified in the SDS and cannot be ascertained independently. For this reason, all hospitalisations for one of a list of pre-specified clinical events corresponding to a characterised chemotherapy adverse drug reaction was considered to be treatment-related. Nonetheless, it is possible that not all infections requiring hospitalisations, for example, were in reality attributable to treatment of metastatic melanoma. Fifthly, costs accrued in community and outpatient care are not captured in the PMSI database and are thus not considered in our analysis. In particular, the B-RAF inhibitors vemurafenib and dabrafenib are administered orally and hospitalisation is not required for their use.
The acquisition costs of these drugs, which will be substantial, has not been included in our analysis. In addition, prior use of these agents will not have been documented in the PMSI database and thus certain patients that we have considered as treatmentnaïve may in reality have previous experience with B-RAF inhibitors. In this respect, it would be interesting to replicate this analysis in the SNIIRAM claims database, which has recently become more readily available for medicoeconomic studies and covers all reimbursed healthcare resource consumption by all national health insurance beneficiaries in France both in hospital and in community medicine. Finally, a lag time is needed in order to consolidate all expenditures in the PMSI database, and it is thus not possible to measure health expenditure, and changes in expenditure, in real time.
Availability of data and materials The analysis described in this manuscript was performed in a national database (Programme de Médicalisation des Systèmes d'Information; PMSI) belonging to a third-party, namely the French Ministry of Health. Access to this database is freely available to researchers on reasonable demand, upon request to the relevant agency, the Agence technique de l'information sur l'hospitalisation, 117 boulevard Marius Vivier Merle, 69,329 Lyon CEDEX 03 (demande_base@atih. sante. fr), on.
Trypanosoma congolense, the causative agent of the most important livestock disease in Africa, expresses specific surface proteins involved in its parasitic lifestyle. Unfortunately, the complete repertoire of such molecules is far from being deciphered. As these membrane components are exposed to the host environment, they could be used as therapeutic or diagnostic targets. By mining the T. congolense genome database, we identified a novel family of lectin-like glycoproteins (TcoClecs). These molecules are predicted to have a transmembrane domain, a tandem repeat amino acid motif, a signal peptide and a C-type lectin-like domain (CTLD). This paper depicts several experimental arguments in favor of a surface localization in bloodstream forms of T. congolense. A TcoClec gene was heterologously expressed in U-2 OS cells and the product could be partially found at the plasma membrane.
b. brucei does not  [9]. Interestingly, in vitro T. congolense BSF adhere directly to the flask but not T. b. brucei. This could reflect a different composition or property of the plasma membrane. Actually, in both species, the entire surface is covered by millions of copies of a single variant surface glycoprotein (VSG) which constitute a « coat » that masks other antigens and fools the immune system of the host  [10, 11]. Nevertheless, VSG are not responsible for adhesion and the repertoire of surface proteins is not completely well-known. Our study aimed to discover such new molecules in T. congolense BSF. As lectins are exposed on the surface of cells, we performed a search in the African trypanosomes genome database in order to identify candidates. We found a family of proteins that possesses several features of surface molecules, i.
In silico identification of new putative T. congolense lectins Our first goal was to identify in silico new genes that could code for surface proteins of T. congolense BSF. In order to minimize the number of potential candidates, we focused our search on lectins. We chose the C-type lectin-like domain (CTLD, InterPro IPR016187) because in metazoan parasites, lectins that contain this motif are involved in host-parasite interaction  [16]. In protozoans, this domain was only described in the human pathogen Cryptosporidium parvum  [17]. We restricted our search to multigene families of proteins with a transmembrane domain and a signal peptide. These last features are common to many unicellular surface proteins  [18]. By mining the T. congolense genome with the Tritryp website (Tritrypdb. org), we found genes (see the materials and methods section) corresponding to a unique family.
Fluorescence microscopy T. congolense BSF Plastic-adherent trypanosomes grown in culture were scrapped, collected by centrifugation (500 g, 5 min, RT) and washed in gPBS. For whole-cell and « shaving » experiments, trypanosomes were fixed with paraformaldehyde (PFA, 3%) as described elsewhere  [22]. For cytoskeleton-extracted cell experiments, parasites were extracted with Pipes buffer (100 mM Pipes pH 6. 9, 1 mM MgCl 2 , 0. 05% NP40) for 3 min, washed and fixed with PFA (3%). Slides were incubated with mouse anti-TcoRep (diluted 1:100) or mouse anti-beta tubulin (diluted 1:200) followed by Alexa Fluor 596-conjugated goat anti-mouse secondary antibody (diluted 1:100) (Invitrogen). The nucleus and the kinetoplast were stained with DAPI (10 µg/mL). Cells were viewed using a Zeiss Axio Imager Z1 fluorescent microscope; images were captured using the MetaMorph® software (Molecular Devices) and processed using ImageJ software.
ACKNOWLEDGMENTS We would like to acknowledge  J. Izotte  for technical help with immunizations, and  V. Coustou ,  M. Bonhivers ,  D. R. Robinson  and  B. Roger  for discussions and technical help. This work was supported by the  CNRS, the Ministère de l'Education Nationale de la Recherche et de l'Enseignement Supérieur , the  University of Bordeaux , the  Laboratoire d'Excellence (LabEx) ParaFrap   ANR-11-LABX-0024  and the  Fédération de Recherche TransBioMed.
An amount of 20 ml of scintillation cocktail was added and the incorporated radioactivity was determined using a microtiter plate scintillation counter. The IC 50 values were calculated using SigmaPlot 13 (Systat Software Inc. ) according to the Hill function (four parameters). In vitro speed of action. The in vitro speed of action of SC81458, SC83288, artemisinin and atovaquone on Dd2 P. falciparum parasites was assessed according to two different protocols: first, we adapted the previously established protocol by Sanz et al. 26  and performed the assay using standardized conditions. Briefly, asynchronous cultures (0. 5% parasitemia and 2% haematocrit) with a predominant ring population were treated with the selected drugs at concentrations corresponding to 10 times their respective IC 50 values.
The sequence data have been deposited in the European Nucleotide Archive (ENA) under the accession code ERP005793 (https://www. ebi. ac. uk/ena/data/search?query=ERP005793). The accession numbers of the reads are compiled in Supplementary Table  10. Bioinformatics analysis. The analysis was performed as described  13, 14. In short, to improve mapability the P. falciparum reference genome 3D7 was transformed into the Dd2 parent clone by repeatedly mapping the reads and correcting the differences using iCORN2 (ref. 51). Next, this new reference was annotated with RATT  52. Reads from all samples (Supplementary Table  10 ) were mapped against to the new reference genomes using bowtie2 (ref. 53). Variants were called using two methods: (i) the genome analysis toolkit (GATK) single-nucleotide polymorphism calling pipeline  54  , using the settings for Plasmodium; and (ii) mpileup and varfilter (varFilter -D 2000; Quality Z60) from the SAMtools package  55.
A bespoke PERL script returns genes where just drug-resistant sample had single-nucleotide polymorphisms. Last, large deletions, insertions and duplications were manually detected using BAMview  56. Ca 2 þ live imaging. Trophozoite-stage P. falciparum HB3 parasites were incubated with 10 mM of Fluo-4-AM in RPMI 1640 medium (Life Technologies) with Pluoronic F-127 (0. 1% (v/v)) and 40 mM of probenecid for 40 min at 37 °C, as previously described  57. Dye-loaded parasites were washed two times before settling onto poly-L-lysine-coated glass slides. Confocal laser scanning fluorescence microscopy was performed using a Leica TCS SP5 (Leica Microsystems CMS GmbH). Fluo-4-AM was excited at 488 nm (argon laser, 0. 03%) and the emitted fluorescence was collected from 505-520 nm. Single images were obtained using a 63 Â objective, with a fivefold software zoom, 1,024 Â 1,024 pixels, every 2 s over a time span of 120 s.
The Ca 2 þ ATPase inhibitor CPA, the Na þ /K þ ATPase inhibitor oubain, SC81458 and SC83288 were added to a final concentration of 10 mM at 45 s. The calcium signal was further analysed using Fiji, and the mean fluorescence signals were compared using one-way analysis of variance in SigmaPlot 13 (Systat Software Inc. ). Gametocytocidal activity. Activity against early-and late-stage gametocytes was determined in miniaturized 384-wells plate assays as previously described  58, 59. Briefly, gametocytes from a recombinant line NF54 Pfs16 , expressing a green fluorescent protein-luciferase reporter gene under the gametocyte-specific Pfs16 promoter were induced and purified as previously described  60  ; gametocytes were then treated either on day 1 (stage I gametocytes) or day 8 of gametocytogenesis (stage IV gametocytes) with serially diluted SC81458 or SC83288 to achieve a final top concentration of 40 mM (0.
Acknowledgements The research leading to these results has received funding from the  Bundesministerium fu ¨r Bildung und Forschung  under the portfolio of the  German Centre for Infectious Research (DZIF) , the  Wellcome Trust  (grant number  098051 ), the  Australian Research Council  (grant number  LP120200557 ), and the  European Commission  under the portfolio of the  FP6- integrated project AntiMal (contract number  LSHP-CT-2005-0188 ) and the 7th framework  Center of Excellence EVIMalaR. We thank  Matt Berriman  and  Mandy Sanders  (both from the  Welcome Trust Sanger Institute ) for processing the samples for sequencing. We thank  Marina Mu  ¨ller and  Stefan Prior  (both from  Heidelberg University ), and  Christian Portaluppi ,  Liliana Gustini ,  Sandra Rath  and  Sabrina Wittlinger  (all from  4SC AG ) for excellent technical assistance.
Data availability. The authors declare that the data supporting the findings of this study are available within the article and its supplementary information files, or available from the authors upon request. The whole genome sequences of the P. falciparum clone Dd2 and 8 P. falciparum clones resistant to SC83288 and SC81458 have been deposited in the European Nucleotide Archive (ENA) under the accession code ERP005793 (https://www. ebi. ac. uk/ena/data/search?query= ERP005793).
An amplitude analysis of the decay Λ 0 b → D 0 pπ -is performed in the part of the phase space containing resonances in the D 0 p channel. The study is based on a data sample corresponding to an integrated luminosity of 3. 0 fb -1 of pp collisions recorded by the LHCb experiment. The spectrum of excited Λ + c states that decay into D 0 p is studied. The masses, widths and quantum numbers of the Λ c (2880) + and Λ c (2940) + resonances are measured. The constraints on the spin and parity for the Λ c (2940) + state are obtained for the first time. A near-threshold enhancement in the D 0 p amplitude is investigated and found to be consistent with a new resonance, denoted the Λ c (2860) + , of spin 3/2 and positive parity.
84 GeV 1 , which could be the missing member of the D-wave doublet  [30]. This analysis is based on a data sample corresponding to an integrated luminosity of 3. 0 fb -1 of pp collisions recorded by the LHCb detector, with 1. 0 fb -1 collected at centre-of-mass energy √ s = 7 TeV in 2011 and 2. 0 fb -1 at √ s = 8 TeV in 2012. The paper is organised as follows. Section 2 gives a brief description of the LHCb experiment and its reconstruction and simulation software. The amplitude analysis formalism and fitting technique is introduced in Sec. 3. The selection of Λ 0 b → D 0 pπ - candidates is described in Sec. 4, followed by the measurement of signal and background yields (Sec. 5), evaluation of the efficiency (Sec. 6), determination of the shape of the background distribution (Sec. 7), and discussion of the effects of momentum resolution (Sec.
The uncertainty due to differences between data and simulation in the input variables of the BDT is estimated by varying the scaling factors for these variables. In addition, the replacement of simulated proton and pion PID variables with values drawn from control samples in the data with matching kinematics, described in Section 4, introduces further systematic uncertainties. The uncertainty associated with the limited size of these control samples is evaluated again with a bootstrapping procedure, and the uncertainty associated with the kinematic matching process is assessed by changing the kernel size in the nonparametric algorithm used to estimate the PID response as a function of the kinematic properties of the track. 3. Uncertainty on the background shape (Sec. 7). This is assessed by varying the density estimation procedure (changing the number of Gaussian cores in the mixture model, or using kernel density estimation instead of a Gaussian mixture model), and by using only a narrower upper sideband of the M (D 0 pπ -) distribution, 5680 < M (D 0 pπ -) < 5780 MeV.
The phase motion of the 3/2 + component with respect to the nonresonant amplitudes is obtained in a model-independent way and is consistent with resonant behaviour. With a larger dataset, it should be possible to constrain the phase motion of the 3/2 + partial wave using the Λ c (2880) + amplitude as a reference, without making assumptions on the nonresonant amplitude behaviour. The mass of the Λ c (2860) + state is consistent with recent predictions for an orbital D-wave Λ + c excitation with quantum numbers 3/2 + based on the nonrelativistic heavy quark-light diquark model  [24]  and from QCD sum rules in the HQET framework  [26]. First constraints on the spin and parity of the Λ c (2940) + state are obtained in this analysis, and its mass and width are measured. The most likely spin-parity assignment for Λ c (2940) + is J P = 3/2 -but the other solutions with spins 1/2 to 7/2 cannot be excluded.
The mass and width of the Λ c (2940) + state are measured to be m(Λ c (2940) + ) = 2944. 8 +3. 5 -2. 5 (stat) ± 0. 4(syst) +0. 1 -4. 6 (model) MeV, Γ(Λ c (2940) + ) = 27. 7 +8. 2 -6. 0 (stat) ± 0. 9(syst) +5. 2 -10. 4 (model) MeV. The J P = 3/2 -assignment for Λ c (2940) + state is consistent with its interpretations as a D * N molecule  [16, 17, 19]  or a radial 2P excitation  [21]. GridPP (United Kingdom), RRCKI and Yandex LLC (Russia), CSCS (Switzerland), IFIN-HH (Romania), CBPF (Brazil), PL-GRID (Poland) and OSC (USA). We are indebted to the communities behind the multiple open source software packages on which we depend. Individual groups or members have received support from AvH Foundation (Germany), EPLANET, Marie Sk lodowska-Curie Actions and ERC (European Union), Conseil Général de Haute-Savoie, Labex ENIGMASS and OCEVU, Région Auvergne (France), RFBR and Yandex LLC (Russia), GVA, XuntaGal and GENCAT (Spain), Herchel Smith Fund, The Royal Society, Royal Commission for the Exhibition of 1851 and the Leverhulme Trust (United Kingdom).