dataesr/scientific-paragraphs-categorization huggingface dataset:
FUNDING This work was partially supported by  INSA Rouen ,  Rouen University ,  CNRS ,  EFRD, LabexSynOrg  ( ANR-11-LABX-0029 ),  Région Normandie  ( Crunch Network ) and the  IUF (Institut Universitaire de France ). EC thanks the  Labex SynOrg  ( ANR-11-LABX-0029 ) for a doctoral fellowship. TP thanks the  IUF  for support. TB thanks the  European Research Council (ERC)  under the European Union's  Horizon 2020 research and innovation programme  (grant agreement no. 758710 ).
Review of other cases reported to the French Regional Pharmacovigilance Centers Cases of hypothermia were identified from the French Pharmacovigilance Database (FPVD), which includes all adverse drug reactions (ADRs) reported to the 31 French Regional Pharmacovigilance Centers since 1985  [1]. For the present study, we collected all cases of hypothermia in children (0-15 years), recorded from 1985 to September 15, 2018, in which acetaminophen was involved. Hypothermia was defined by the preferred term "hypothermia" according to the Medical Dictionary for Regulatory Activities 11. 0. The causal relationship between hypothermia and acetaminophen was evaluated by applying the French drug reaction assessment method  [2]. Nine pediatric cases of hypothermia secondary to acetaminophen were selected and analyzed.
Infrared spectra were recorded on a FT/IR-4100 spectrometer (JASCO Corporation, Tokyo, Japan). HPLC analyses were performed on a JASCO PU-2080 Plus system using a 4. 6 × 250 mm CHIRALPAK IB-3 column and a CHIRALCEL OD-3 column. Optical rotations were measured on a SEPA-300 instrument (HORIBA Ltd, Kyoto, Japan). High resolution mass spectrometry were recorded on a Synapt G2 HDMS (ESI-MS) system (Waters Corporation, Milford, MA, USA). The chiral amines: (S)-(-)-α-methylbenzylamine (≥99. 5% ee), (S)-(-)-α-ethylbenzylamine (≥99. 0% ee), (S)-(-)-4-methoxy-α-methylbenzylamine (≥97. 5% ee) were purchased from Sigma Aldrich (St. Louis, MI, USA). (S)-(-)-1-(1-Naphthyl)ethylamine (>98. 0% ee), and (S)-(-)-1-(p-tolyl)ethylamine were purchased from TCI (Tokyo, Japan). The 1 H, 13 C and 19 F NMR spectra of compounds 3 and HPLC data of compounds 3 are available in the Supplementary Material.
Pre-inclusion: Patients will be screened by investigators according to eligibility criteria. Patients will sign a consent form after receiving oral and written information from a physician investigator involved in this project. After inclusion, they will be randomly assigned, using block randomization , by using Ennov clinical® software, based on a list prepared by the study statistician (using block randomization), to SC before IV paracetamol injection or IV before SC with a washout period of 24 hours between the 2 injections. This washout period was determined since half-life of paracetamol was commonly described (Summary of product characteristics) as ranging from 1 to 4 hours depending on the administration routes. An almost complete elimination may be considered after 5 to 6 half-lives.
Pharmacokinetic Data Pharmacokinetic sampling procedure. Blood samples (2 ml) will be collected in dry tubes free of gel at 0. 75, 1, 1. 5, 2, 4 and 8 hours after paracetamol intravenous administration or 0. 25, 0. 5, 0. 75, 1, 1. 5, 2, 4, 6 and 8 hours after SC administration. They will be rapidly transported to the laboratory. method. After centrifugation, samples will be immediately used for quanti cation of acetaminophen with the EMIT tox TM Acetaminophen Assay, which is a homogeneous enzyme immunoassay performed in AU 5800 clinical chemistry systems (Beckman Coulter, France). The limit of quanti cation is 0. 12 mg/L. Precision is better than 6% for three quality control levels. The quantitative analyses will be conducted according to the principles of Good Laboratory Practice (GLP) Pharmacokinetic calculations.
A non-parametric test (Wilcoxon signed-rank test) will be used for Tmax. The bioequivalence between the 2 modes of administration will be tested for AUC0-t, AUC0-¥ and Cmax, based on the 90% con dence interval of the ratio of the geometric means (SC vs IV). According to the recommendations of the European Medicines Agency,  9  we can conclude bioequivalence if the con dence interval is fully within the range [80%-125%]. Pain scores will be compared between the 2 modes of administration by paired T-tests or Wilcoxon signed-rank tests, depending on the form of the distribution. Data will be analyzed based on a per protocol analysis. Statistical signi cance will be set at P < 0. 05. Data will be analysed at the Biostatistics and Clinical Research Unit of Caen University Hospital, with SPSS and R software.
Adverse Events Data All adverse events will be collected, from consent to the end of patient participation, and reported to the sponsor. Serious adverse reactions (SAR) will be quali ed as expected or unexpected by the sponsor. Expected SAR related to paracetamol are thrombocytopenia, leucopenia, neutropenia, hypersensitivity, hypotension, increased transaminases, malaise, tachycardia, ushing, pruritus and erythema. Other SAR will be considered as unexpected. A Data Safety Monitoring Board (DSMB) will review the safety independently. The DSMB will include three experts: one pharmacologist, one physician pain specialist, and one dermatologist. The sponsor will request DSMB advice in case of Suspected Unexpected Serious Adverse Reaction or any new safety information. The DSMB is charged with providing advices to the sponsor recommendations that include (a) continuation of the study, (b) continuation with modi cation, and (c) termination of the study.
Acknowledgements We thank  Mr Ryohei Kikuchi  (SEM),  Ms Masayo Ishikawa  (Mass),  Mr Shohei Yamazaki  (DSC), and  Ms Mayuko Nara  (optical properties of the lms) for measurements. This work is partially supported by the  Grant-in-Aid for Scientic Research (B)  ( 18H02045 ),  Innovative Areas "p-System Figuration " ( 17H05145 ) and " So Crystals " ( 17H06371 ), and  The Cooperative Research Program "NJRC Mater. & Dev. " from  MEXT of Japan.
The effect of production speed and dwell time on tablets tensile strength, powder deformation and disintegration time was investigated. For each of the above mentioned studies, 400mg tablets were produced at 100-400 MPa using Styl'One ® rotary press simulator. Tablets tensile strength was calculated using hardness, thickness and diameter data measured by Pharmatron Multitest50 ® (Solothurn, Switzerland). Powder deformation behavior was assessed using Heckel model analysis and Py was used to compare different powder deformation behaviors (using Analis ® software). Tablet solid fraction was determined automatically using the compression simulator. In the compression studies, 3 reference powders were used as controls: chitin, Ludiflash ® and dry mix of chitin and CaCO3 at the same ratio used for the coprocessed excipient.
this Data Descriptor announces the submission to public repositories of the monoterpene indole alkaloid database (MIADB), a cumulative collection of 172 tandem mass spectrometry (MS/MS) spectra from multiple research projects conducted in eight natural product chemistry laboratories since the 1960s. All data have been annotated and organized to promote reuse by the community. Being a unique collection of these complex natural products, these data can be used to guide the dereplication and targeting of new related monoterpene indole alkaloids within complex mixtures when applying computer-based approaches, such as molecular networking. Each spectrum has its own accession number from CCMSLIB00004679916 to CCMSLIB00004680087 on the GNPS. The MIADB is available for download from MetaboLights under the identifier: MTBLS142 (https://www.
till the mid of the last century, quinine; the antihypertensive reserpine, and vincristine and vinblastine, which are used directly or as derivatives for the treatment of several cancer types. Recently, much effort was directed toward understanding and manipulating the underlying biosynthetic pathways of MIAs in order to engineer them in microorganisms to allow industrial production of medicinally relevant compounds  [3] [4] [5]. Although a large amount of knowledge has been accumulated concerning the early steps  [6] [7] [8]  and the assembly of key intermediates, many questions are still unanswered, and the discovery of new members of this family may illuminate unexpected enzymes involved in the biosynthesis of this intriguing group of natural products. As part of our continuing interest in MIA chemistry  [9] [10] [11] [12]  , we developed a streamlined molecular networking 13 dereplication pipeline based on the implementation of an in-house MS/MS database, constituted of a cumulative collection of MIAs  14.
In order to enrich this database, seven prominent practitioners from the global natural products research community shared their historical collections, leading to the construction of the largest MS/MS dataset of MIAs to date, that we named: Monoterpene Indole Alkaloids DataBase (MIADB) (Fig. 1 ). The MIADB contains MS/MS data of 172 standard compounds, comprising 128 monoindoles and 44 bisindoles (these compounds are presented in Supplementary Table  1 ) and covers more than 70% of the known (30/42) MIA skeletons. The information that can be drawn from this dataset is valuable for the scientific community that envisages the isolation of new MIAs. The purpose of this Data Descriptor is to announce the deposition of the MIADB on the Global Natural Product Social Molecular Networking (GNPS  15  ) and MetaboLights  16.
Methods Sample preparation. Each of the collected MIA was diluted to a concentration of 1 mg/mL using HPLCgrade (High Performance Liquid Chromatography) with MeOH (Methanol) as solvent. The solution was then transferred in 1. 5 mL HPLC vials and analyzed by LC-MS/MS (Liquid Chromatography-tandem Mass Spectrometry). Chemicals and solvents were purchased from Sigma-Aldrich. Data acquisition. Samples were analyzed using an Agilent LC-MS (Liquid Chromatography Mass Spectrometry) system composed of an Agilent 1260 Infinity HPLC coupled to an Agilent 6530 ESI-Q-TOF-MS (ElectroSpray Ionization Quadrupole Time of Flight Mass Spectrometry) operating in positive mode. A Sunfire ® analytical C 18 column (150 × 2. 1 mm; i. d. 3. 5 μm, Waters) was used, with a flow rate of 250 μL/min and a linear gradient from 5% B (A: H 2 O + 0.
Database constitution. The analysis of each of these substances resulted in 172 files with the standard. d format (Agilent standard data-format). A list of individual compounds for each sample was generated from an Auto MS/MS data mining process implemented in MassHunter ® software on every single file. Averaged as well as monocollisional energy MS/MS spectra were generated from the three retained collision energies (30, 50, and 70 eV). Within this list, the molecular formula (as well as the exact mass) of the expected compound (in its charged state) was identified. Then, depuration of the other features was carried out. Finally, each spectrum was converted into the. mgf (Mascot Generic Format) using the export tool of the MassHunter ® software.
Data Records All data described in this article have been uploaded to GNPS and MetaboLights. Each spectrum of the 172 compounds of the MIADB has its own accession number from CCMSLIB00004679916 to CCMSLIB00004680087 on the Global Natural Product Social Molecular Networking (GNPS) (accessed via: https://gnps. ucsd. edu/ ProteoSAFe/static/gnps-splash. jsp). The spectral collection in its two versions (i. e. averaged and separate collision energy MS/MS spectra at 30, 50, and 70 eV) is available for download from MetaboLights under the identifier: MTBLS142  17.
Metadata. The MS/MS spectra of the MIADB library are recorded with a variety of details including: LC-MS/ MS acquisition parameters, instrument details, organism, organism part, smiles and Inchi codes, CAS numbers, CHEBI IDs, retention times, and chemical formula. These metadata are available on the GNPS and MetaboLights websites. analyses were carried out by the various collaborators having contributed to the establishment of the database. The obtained mass spectra were individually inspected to verify the occurrence of either the protonated molecular or molecular ion as the precursor mass. Selected strategies for the validation of the MiaDB. The validation of the MIADB was achieved following two strategies: (i) dereplication of the profiled compounds from a methanol extract of the leaves of Catharanthus roseus (L.
Molecular networking-based dereplication of Catharanthus roseus methanol extract. Molecular networking-based dereplication using MIADB-uploaded GNPS libraries was attempted on the methanol extract of Catharanthus roseus, the MIAs content of which was thoroughly studied. Accordingly, more than 130 different compounds were reported from the different tissues of the plant  18. In the displayed network, the experimental data of C. roseus methanol extract are depicted as green rectangles and nodes representing a consensus of experimental data and database records (i. e. , MIADB-uploaded in the GNPS libraries) are displayed as red rectangles (Fig. 2 ). As expected, molecular networking of the C. roseus leaves methanol extract allowed dereplication of previously known metabolites within this plant including: tabersonine, catharanthine, vindolinine, perivine, geissoschizine, pericyclivine, serpentine, raubasine, and akuammigine (Table  1 ).
roseus, both these structural assignments can be deemed reasonable based on biosynthetic considerations. Being an akuammiline-derived MIA, such as akuammine  21  and the monomer precursors of the bisindoles vingramine and methylvingramine  22  that have been reported to occur in C. roseus, the detection of burnamine is not unexpected. Likewise, the co-dereplication in the depicted molecular network of the formerly described vobasane-type perivine supports the identification of vobasine within this plant. Such examples emphasize the dereplicative interest of MIADB especially on such a deeply dug plant model. Prior to its GNPS upload, i. e. , as an in-house database, the ability of the MIADB to pinpoint tentatively new MIAs was demonstrated through the streamlined isolation of geissolaevine along with its O-methylether derivative and 3′,4′,5′,6′-tetrahydr ogeissospermine from the formerly vastly studied Geissospermum leave (Vell.
) Miers (Apocynaceae)  14. Altogether, the currently garnered results support the valuable contribution of MIADB either for the straightforward identification of monoterpene indole alkaloids or to highlight putative structural novelty among this privileged structural class. The topology of the obtained network also reveals that a further extent of information could yet be accessed from C. roseus extracts. Indeed, most dereplicated MIAs are tightly associated within cluster A. Since clusterization depends on structural similarity, a single match to the MIADB-implemented GNPS allows for the propagation of the structure throughout an entire molecular family, indicating that most if not all the nodes of this cluster refer to MIAs. The seminal contribution of the MIADB to the tandem mass spectrometric databanks of MIA is expected to pave the way for the upload of such data by the numerous teams involved in MIA research all over the world, thereby contributing to making this tool more and more efficient to reach a quick and sharp insight into the MIAs content of any producing organism.
acknowledgements We gratefully acknowledge the productive collaborations and the fruitful contributions that allowed the generation of this natural products MS/MS database. This research was funded by  FONDECYT-CONCYTEC  (grant contract number  239-2015-FONDECYT ), and by the  French ANR  grant ( ANR-15-CE29-0001 ). We express our thanks to  Séverine Amand  ( MNHN ) for her assistance in the collection of the MIAs from the  MNHN chemical library.
Compound 5 was purified from fractions 50 to 55 with preparative HPLC (isocratic elution with 42% aqueous ACN), and 43 mg (yield 19. 73%) was obtained. Compound Characterization Data. Compounds 1-5 possessed a purity of >95% by means of HPLC-DAD. High-resolution MS (HRMS) and MS-MS analyses were performed on a Thermo Velos Pro Orbitrap Elite (Thermo Fisher Scientific) system. The ionization method was ESI operated in positive ion mode. The protonated molecular ion peaks were fragmented by CID at a normalized collision energy of 35%. For the CID experiment, helium was used as the collision gas. The samples were dissolved in methanol. The protonated molecular ion peaks were fragmented by CID at a normalized collision energy of 35%. Data acquisition and analysis were accomplished with Xcalibur software version 2.
0 (Thermo Fisher Scientific). NMR spectra of compounds 1, 2, 3, and 5 were recorded on a Bruker Avance NEO 500 MHz spectrometer equipped with a Prodigy BBO 5 mm CryoProbe. Compounds 1, 2, and 5 were dissolved in acetone-d 6 , and methanol-d 4 was used for 3 (VWR Chemicals, Belgium). Standard 1D and 2D spectra were processed with MestReNova v6. 0. 2-5475 software. NMR spectra of compound 4 were recorded at 25 °C on a Varian 800 MHz spectrometer equipped with a 13 C sensitivity-enhanced salt tolerant 1 H/ 13 C/ 15 N cryogenically cooled probe head. The sample was dissolved in methanol-d 4 (Eurisotop, France). Standard 1D and 2D spectra were acquired using pulse sequences available in the VNMJ 3. 2 library. Chemical shifts are reported in the delta scale using residual solvent signals (methanol-d 4 : 3.
31 or 49. 15 ppm, acetone-d 6 : 2. 05 or 29. 84 for 1 H or  13  C, respectively) as references. For spectral analysis and data reporting, the ACD/NMR Workbook 2015. 2. 9. software suite (ACD/Labs, Canada) was used. Compound 1. (30); 163(100); 153 (9); 135 (15); 107 (5). Chemicals. RPMI 1640 medium, Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS), antibiotic-antimycotic solution, penicillin-streptomycin solution, L-glutamine, and trypsin/ ethylenediaminetetraacetic acid (EDTA) were purchased from Bioind, Beit Haemek, Israel. MTT was purchased from Sigma, St. Louis, MO, USA. Dimethyl sulfoxide (DMSO) was obtained from Sigma-Aldrich Chemie Gmbh, Germany. The annexin-V-FITC (AV) apoptosis detection kit with PI was purchased from Abcam, Cambridge, UK. DHE was obtained from Molecular Probes, Invitrogen, USA.
The plates were incubated at 37 °C for 48 h, and then MTT solution was added to each well. After incubation at 37 °C for 4 h, the MTT-containing medium was removed, and 100 μL of DMSO was added to dissolve the formazan crystals. Cell viability was determined by measuring the optical density values (absorbance) of the chromogenic product at 550 nm with an enzyme-linked immunosorbent assay reader (Thermo Multiskan Ascent). Three plates were prepared on three different days, and averages of these three replicates were utilized to calculate the combination index (CI) values at several fix pcm vs H 2 O 2 ratios by using the CalcuSyn software. In Silico Calculations. Calculations were performed with the Gaussian09 package (Rev. A). Ground-state geometries were optimized using the B3P86 functional that has been shown to properly reproduce thermodynamics of polyphenol oxidative processes.
Background: For patients with recurrent flares of gout, tophi, urate crystal arthropathy, and renal stones, uratelowering therapies (ULTs, including allopurinol and febuxostat) are the first-line treatment. Due to the widespread use of these ULTs (especially in patients with impaired renal function), assessment of the associated renal risk is essential. Accordingly, we performed a disproportionality analysis of reported cases of acute renal failure (ARF) associated with allopurinol and febuxostat. Methods: We carried out a case/non-case study of the World Health Organization's VigiBase® pharmacovigilance database between January 1, 2008, and December 31, 2018. The frequency of reports of ARF as a standardized Medical Dictionary for Regulatory Activities query for allopurinol and febuxostat was compared with that of all other reports for the two drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)].
Data source Individual case safety reports (ICSRs) from VigiBase® (the World Health Organization (WHO)'s global database of suspected adverse drug reactions (ADRs)) were analyzed in a case/non-case disproportionality study. VigiBase® was established in 1968 and has been managed by the Uppsala Monitoring Centre  [22]  since 1978. It is the largest data resource of its kind in the world and contains over 20 million ICSRs on suspected ADRs submitted by more than 150 countries participating in the WHO's Program for International Drug Monitoring. The anonymized ICSRs are variously submitted by health professionals, patients, and pharmaceutical companies in the member countries. VigiBase® is continuously updated with the incoming ICSRs. Each ICSR includes anonymous administrative data (the country, and the reporter's qualification), patient information (age and gender), drug information (the international non-proprietary name or trade name, Anatomical Therapeutic Chemical (ATC) classification, indication, start date, withdrawal date, dosage, and administration route), and information on the suspected ADR (coded according to the Medical Dictionary for Regulatory Activities (MedDRA))  [23].
In fact, the small number of corresponding ICSRs in international databases suggests that this reaction is rare. However, we believe that it is important to inform allopurinol and febuxostat prescribers about this potential ADR-especially when they are treating atrisk patients (i. e. , women and patients with CKD). A significant ROR was found for each subgroup studied in our secondary analyses. Women had a higher ROR than men-especially for febuxostat. A number of recent literature results are controversial; although most clinical studies predominantly include male patients  [45] [46] [47] , recent findings indicate that specific physiologic features in women might impact the response to injury and/or treatment  [45]. Depending on the situation, women might be less protected  [47]. Our results suggest that caution is required when considering the prescription of febuxostat and allopurinol in women at risk of AKI.
The RORs were still significant for both drugs and were even higher than in the primary analysis. Our study suffers from the inherent limitations of all pharmacovigilance studies  [30, 31]  and case-control designs. We did not have any data on the number of patients exposed to a particular drug, which prevents one from calculating the absolute frequency of ARF on the basis of ICSRs (notably because of underreporting  [50] ). Moreover, the data collection differed from one country to another for legislative and regulatory reasons. However, widespread underreporting would not affect the results of this kind of study  [30]. Furthermore, it is known that underreporting is similar for drugs within a given class  [51] , and so, a comparison of allopurinol and febuxostat is possible. Also, pharmacovigilance databases are designed to detect signals, rather than to exhaustively record all ADRs  [30, 31].
Likewise, VigiBase® does not contain detailed information on the patient's clinical status, such as the seriousness or etiology of previous AKI or CKD. In contrast, our study has several important strengths linked to its case/non-case design  [30, 31]. Firstly, we studied the world's largest pharmacovigilance database. Second, more than 150 countries participate in the WHO Program for International Drug Monitoring, accounting for over 90% of the world's population. Hence, the data were exhaustive and reflected "real-life" medication use. Thirdly, the case/non-case study is a validated method of investigating disproportionality between reports and drugs. It has already been shown that this kind of study can detect signals for rare ADRs  [30, 31]. We choose to calculate ROR as a measure of disproportionality; a study of disproportionality indices in the FDA reporting database concluded that the ROR gives the best results  [53].