dataesr/scientific-paragraphs-categorization huggingface dataset:
by Elsevier Masson SAS. All rights reserved. Abbreviations ADRs adverse drug reactions ANSM French Drug Agency (Agence nationale de sécurité des medicaments et des produits de santé) AV atrio-ventricular AZI azithromycin COVID-19 coronavirus disease 2019 CQ chloroquine EAD early after-depolarizations ECGs electrocardiograms EMA European Medicines Agency FDA Food and Drug Administration FPVD French pharmacovigilance database HCQ hydroxychloroquine hERG human ether-a-go-go related gene IQR interquartile range LQTS long QT syndrome LOPI lopinavir-ritonavir MedDRA medical dictionary for regulatory activities RCPV Regional Center of Pharmacovigilance SARS-CoV-2 serious acute respiratory syndrome coronavirus 2 SD standard deviation SOC system organ class TdP torsades de pointes.
, only 20% of AICN cases were screened for AMX crystals in urine  [1]. As underlined above, given the declarative nature of RPV databases, AICN may be underestimated. Moreover, its real incidence remains to be determined, especially in patients receiving high AMX doses. Thus, the objective of the present study was to analyze the incidence of severe AKI Kidney Disease: Improving Global Outcome (KDIGO) 2 or 3) related to AICN by studying all consecutive patients treated with high dose AMX during a 3 year period in the University Hospital of Angers. The second objective was to describe AICN cases and identify potential risk factors in patients exposed to high AMX doses.
Selection of Patients We conducted a retrospective study between 1 January 2015 and 31 December 2017. Patients admitted to the Angers University Hospital during the period and who received at least one dose of AMX were screened through the prescription software database (Crossway, Boulogne Billancourt, France). The software has been implemented in all hospital units since 2013, except in critical care medicine units. Adult patients that received at least 8 g/day of AMX using IV route for at least 24 h were included in the study. Patients that were admitted directly to critical care units or that received AMX for less than 24 h were excluded. The protocol was approved by the ethics committee of our institution (authorization number 2018/40).
Data Collection For all patient included in the study, baseline characteristics, including demographic data and medical history were retrieved from medical records. Causes of admission (medical or surgical), infectious sites and identified germs, concomitant antibiotic use, and evolution of renal function from admission to discharge or death, daily dose, type of administration (discontinuous vs. continuous), duration of AMX treatment were also collected. Estimated glomerular filtration rate (GFR) was determined using the modified diet in renal disease (MDRD) formula. AKI was defined according to KDIGO classification based on creatinine variations, as urine outpout was not available for most patients  [15]. Patients that developed AKI of at least KDIGO stage 2 or 3 were identified and their medical records were extensively analyzed.
Statistical Analyses Continuous variables are presented as median and interquartile (IQR). Categorical variables are presented with their absolute value and percentage. Differences between groups were analyzed using the χ 2 test (or Fisher exact test when applicable) for categorical variables and the Mann-Whitney U test for continuous variables. Univariate logistic regression analysis was used to study risk factors associated with AICN development. All the statistical tests were performed to the two-sided 0. 05 level of significance. Statistical analysis was performed using SPSS software ® 23. 0 for Macintosh and Graphpad Prism ® for Macintosh.
Statistical Analyses Continuous variables are presented as median and interquartile (IQR). Categorical variables are presented with their absolute value and percentage. Differences between groups were analyzed using the χ 2 test (or Fisher exact test when applicable) for categorical variables and the Mann-Whitney U test for continuous variables. Univariate logistic regression analysis was used to study risk factors associated with AICN development. All the statistical tests were performed to the two-sided 0. 05 level of significance. Statistical analysis was performed using SPSS software® 23. 0 for Macintosh and Graphpad Prism® for Macintosh.
Acute Kidney Injury and Mortality We next analyzed renal function and identified patients that developed AKI episodes according to the KDIGO classification. Median eGFR on admission in the whole population was 91. 9 (67. 8-127. 6) mL/min/1. 73 m 2. AKI was present in 12. 6% of patients on admission and developed in 73 patients (20. 4%) during hospital stay. KDIGO stage 2-3 AKI was diagnosed in 42 patients (11. 7%), representing 56. 9% of all AKI episodes. Nine patients (2. 5%) required renal replacement therapy. None of the AKI patients underwent renal biopsy. These data are detailed in Table  3. As compared to patients that did not develop AKI, patients with AKI had more frequently hypertension, diabetes mellitus, were more frequently admitted for a surgical reason, and had more frequently endocarditis.
Liver disease is highly prevalent in Africa, especially in the western African country Burkina Faso, due to the presence of multiple biological and chemical aggressors of the liver. Furthermore, diagnosis and appropriate care for liver disease are uneven and usually insufficient. This drives local communities to turn to folk medicine based on medicinal plants from healers. Small scale, ethnopharmacological studies on reputed hepatoprotective plants have been carried out in defined regions worldwide, but so far, no study has been carried out on a countrywide scale. Therefore, we have explored traditional healers' practices in all thirteen regions of Burkina Faso. We interviewed 575 healers and we compiled a database with 2,006 plant entries. Here, we report results on liver nosology, liver pathologies, medicinal plants used for liver disease, and traditional practices through the lens of Burkinabe healers.
Thanks to the FENATRAB, guides were identified in each region to assist the survey and translations if necessary. Consequently, surveys were carried out in the local language and translated into both French and English. Data were recorded by nine investigators from the Department of Medicine and Traditional Pharmacopeia-Pharmacy (MEPHATRA-PH) of the Institute of Research in Health Science (IRSS) and from the University of Ouagadougou. The data collected included a long questionnaire with 31 main entries, as well as free discussions, field observations, and the geolocation of healers and plants. The questionnaire included five main sections: 1) information on the investigators, 2) information on the traditional healers, 3) the pathology treated and nosography, 4) information on plants, 5) plant harvesting, preparation, and administration of plants, and 6) information on plant toxicity.
Data Analysis Data storage was performed on Sphinx Plus v5 software. R was used for all analysis, computation, and graphical representation, including maps and drawings. R is open source, distributed by the Comprehensive R Archive Network. Version 3. 6. 3 was used under a Linux Debian 10 host platform. The main libraries and associated dependencies used were 1) readr, dplyr, tidyverse, stringr, and splitstackshape for data cleaning and analysis, 2) raster and sp for graphs, and 3) maptools, geosphere, GADMTools, and geoname for maps. Finally, georeferenced data for healers and plants were linked to GNSS coordinates (Global Navigation Satellite System), acquired through the GPS (United States Global Positioning System) constellation, using eTrex Venture® HC devices. Coordinates were serialized using N-S E-W designators over (decimal) floating point notation.
RESULTS Traditional Healers and Their Knowledge of Liver Disease in Burkina Faso 575 healers were interviewed throughout the country. They were evenly distributed across the 13 regions. Geographically, healers are more concentrated in the regions: Centre (12. 2%, which includes the capital Ouagadougou), Centre-Nord (10%), Boucle du Mouhoun (10%), and Hauts-Bassins (10%) (Figure  2 ). As a result, 48. 4% of the total traditional practitioners live in the central regions (Centre, Centre-Nord, Centre-Sud, Centre-Est, Centre-Ouest, and Plateau-Central), 32. 3% in the west regions (Boucle du Mouhoun, Hauts-Bassins, Cascades, and Sud-Ouest), 12% in the north regions (Nord and Sahel), and 7. 3% in the east region (Est). Among the 575 healers interviewed, 305 were women and 270 were male. Most healers were aged from 40 to 70 with a peak at age 50-60 (Supplementary Data S1).
5%), hepatitis A or B (0. 2%), hepatitis B or C (0. 15%), or hepatitis A, B, and C combined (0. 1%). However, no healers reported a case of viral hepatitis C alone nor hepatitis D or E although these diagnoses are present in Burkina Faso. According to the healers, region Centre contained most cases of hepatitis (196 out of 230) and the three main viral hepatitis types: A, B, or C which are familiar for some Centre healers. Hepatitis B was mentioned in nine of the 13 regions but was not described in regions Centre-Ouest, Plateau Central, Nord, and Sud-Ouest. Hepatitis A was reported in regions Centre, Centre-Ouest, Boucle du Mouhoun, and Hauts-Bassins. Hepatitis C was only mentioned in regions Centre and Cascades (Supplementary Data S3).
SELECTION AND COLLECTION OF MEDICINAL PLANTS FOR TREATMENT OF LIVER DISEASE IN BURKINA FASO By exploring the 13 regions of Burkina Faso, 2,006 plant entries were collected. Analysis of their geolocation showed that these medicinal plants are actually distributed across the whole country but in a higher proportion in some regions such as Hauts-Bassins (15. 3%), Cascades (14. 8%), Centre-Nord (12. 8%), and Boucle du Mouhoun (10. 3%) (Figure  4 ). We then analyzed the number of plants prescribed by healers against liver disease and found an average of 3. 3 plants per healer interviewed. When we analyzed the number of plants used by healers per region, it varied from 2. 4 (in Sahel) to 4. 4 (in Centre-Nord) (Supplementary Data S4). The number of plants recognized by healers ranged from one to 22.
Among them, 60% are   2 ; Supplementary Data S6). Regarding which plant parts were collected and used, roots and leaves are used the most, 32. 9% and 28. 2%, respectively, followed by the bark, leafy stems, and fruits (Supplementary Data S7). Seeds and flowers (1. 3%) are not used much. The use of young leaves or young stems was sometimes specified as well as combinations of plant parts with leaves and roots being the most frequent (3. 4%). In the case of Cochlospermum tinctorium Perr. ex A. Rich. , all plant parts were used except the flowers, seeds, and fruits, with the roots being most commonly used (93%) (Table  2 ). In the case of Cassia sieberiana DC. , all plant parts were used with roots being most commonly used (56. 8%), while for Anogeissus leiocarpa (DC. ) Guill. & Perr. , the leaves were most commonly used (50%).
& Perr. , Dichrostachys cinerea (L. ) Wight & Arn. , Cassia sieberiana DC. , and Carica papaya L. Healers may also travel very long distances within their region. For example, one healer in Sud-Ouest traveled 125 km to collect Piliostigma thonningii (Schumach. ) Milne-Redh. , and a healer in Est traveled 116 km to collect Balanites aegyptiaca (L. ) Delile. In total, 97 plants were harvested from further than 100 km, 85 plants between 50 and 100 km, and 1,043 plants between 1 and 50 km (Supplementary Data S8). In 7. 7% of cases, plants were harvested at a specific time in their life cycle. For example, leaves of Carica papaya L. and Combretum micranthum G. Don were described as being collected before the plant bloomed. Some roots were   Finally, some plants were harvested with spiritual practices (7.
PRACTICES AND USAGES OF MEDICINAL PLANTS FOR THE TREATMENT OF LIVER DISEASE IN BURKINA FASO During interviews, 139 plant species out of 212 (66%) were described as having other medicinal applications beyond treating liver disease. Again, we then searched for data consensus for each plant species (i. e. , mentioned by at least three different healers), and we found the main secondary medicinal applications to be malaria (31. 1%), chronic digestive illnesses including abdominal pain (9. 1%), hemorrhoids (5. 7%), and asthenia (4%) (Supplementary Data S9 and S10). Interestingly, the medicinal plants used to treat malaria were also most frequently used to treat liver disease. Conversely, 12 medicinal plants were described at least three times by healers without being associated with any pathology other than liver disease (Supplementary Data S10).
, possibly in association with six other medicinal plants. A third healer in Ouagadougou recommended the species Lippia chevalieri Moldenke which is reputedly preventative against liver cancer when patients have already contracted hepatitis. A fourth healer from Boucle du Mouhoun taught us that Securidaca longipedunculata Fresen. in association with Calotropis procera (Aiton) Dryand. could cure any cancerous wounds. Most of the time, plant parts are harvested and used as either fresh or dry material (51. 8%), or as specifically fresh material (30. 9%) or as specifically dry material (17. 3%). Plant preparations are mainly decoctions (69%), and then macerations are prepared in water or in local alcoholic beverages such as sorghum beers (8. 2%) or powders of dried plants (4. 6%) which are further mixed with soup, water, or millet porridge (Supplementary Data S11).
CONCLUSION This countrywide survey of plants used against liver disease was carried out with 575 traditional healers in all 13 regions of Burkina Faso. In total, 212 different plant species were reported with important details on the liver pathology targeted, geolocation of plants, preparation mode, and plant combinations. Data analysis of the resulting databank identified nine widely used plant species; the hepatoprotective activity of this group has been partially explored (four of the nine). Also, among six plant species reported as active against liver cancer, only two have been investigated to date. Therefore, this study paves the way for novel chemical and pharmacological assessments of plant extracts to validate plant-based traditional medicine and be of use to local and global patients.
ACKNOWLEDGMENTS This was the last project of  Dr. André Tibiri  before he died very prematurely from hepatocarcinoma. We commend him for the huge input and faith he gave to the project. We thank the  National Federation of Traditional Healers  and the  Direction Générale de la Pharmacie, du Médicament et de la Législation  (DGPML) of the Health Minister of  Burkina Faso  for giving their consent to the study and supporting us in carrying it out. We thank all traditional healers we interviewed, for their collaboration in answering the survey. We thank students from the  University of Ouagadougou , i. e. ,  Souleymane Compaore ,  Alimata Bance ,  René Dofini Magnini ,  Rakiatou Traore ,  Nouhoun Nignan ,  Roger Kabore , and  Lydia Kabore , for their help in carrying out the field studies. We thank  Pr.
Furthermore, these mutations did not abrogate the cleavage activity against the inactive form of uPa  [61]. Therefore, Pla could have different active sites, which could explain why Pla is such a broad-spectrum protease. Figure  5  shows the zoomed-in active site of Pla from Y. pestis and illustrates peculiarities of the local environment of four catalytic residues of this protein, Asp 84 , Asp 86 , Asp 206 , and His 208. This later generates a network of associations based on predicted and experimentally-validated information on the interaction partners of a protein of interest  [108]. In the corresponding network, the nodes correspond to proteins, whereas the edges show predicted or known functional associations. Seven types of evidence are used to build the corresponding network, where they are indicated by the different colored lines: a green line represents neighborhood evidence; a red line-the presence of fusion evidence; a purple lineexperimental evidence; a blue line-co-occurrence evidence; a light blue line-database evidence; a yellow line-text mining evidence; a black line-co-expression evidence  [108].
Seven types of evidence are used to build the corresponding network, where they are indicated by the different colored lines: a green line represents neighborhood evidence; a red line-the presence of fusion evidence; a purple line-experimental evidence; a blue line-co-occurrence evidence; a light blue line-database evidence; a yellow line-text mining evidence; a black line-co-expression evidence  [108]. activation of the host plasminogen uPA  [61]. Furthermore, these mutations did not abrogate the cleavage activity against the inactive form of uPa  [61]. Therefore, Pla could have different active sites, which could explain why Pla is such a broad-spectrum protease. Figure  5  shows the zoomed-in active site of Pla from Y. pestis and illustrates peculiarities of the local environment of four catalytic residues of this protein, Asp84, Asp86, Asp206, and His208.
Biomolecules 2020, 10 , 1554 3 of 33 Figure 1. 10331 Figure 1. 3D structure of the plasminogen activator Pla from Yersinia pestis determined by X-ray crystallography (PDB ID 2 × 55) [30]. Two side projections (plots A,C) and a top view from the extracellular side (plot B) of Pla are shown together with the set of C8E4 detergent molecules.
Acknowledgements The authors are very grateful to the  ANR  (The  French National Research Agency)  ( N • ANR 14-CE16-0025-01  and  ANR-14-CE16-00025-03 ) and to the INSERM (the  French National Institute of Health and Medical Research)  ("poste d'accueil 2016" for  Kevimy Agossa ) for their valuable support and also acknowledge the contribution of  Mrs. Aurélie Guillemette  to the microbiological tests.
The method offers a route to deliver qualitative and quantitative data analysis of chemical space for the metabolites present in complex bacteria fermentation extracts  [9]. A useful analytical technique that has been integrated into the metabolomics-guided microbial NPs discovery is HR-ESIMS and associated MS/MS fragmentation data. However, the complexity of HR-ESIMS/MS data prevents manual annotation of the presence of metabolites in the extracts. As such, several computing-based data mining tools have been applied; one of the widely used is the Molecular Networking (MN) database  [17] [18] [19] [20]. The MN database is a web-based server that is extremely useful for dereplicating natural product structures by comparing both experimental HR-ESIMS (MS/MS) spectra with the database  [17]. The method is useful for the effective dereplication and annotating of specialised metabolite (SM) families and individual molecules.
HRESIMS and molecular network analyses of the fractions identified five major compound families: indole alkaloids, phenols, surfactins, deferoxamines, phthalates, and cyclopeptides (Figure  S2 ). Manual dereplication  [23]  using MS 1 spectra of compounds against available databases (AntiBase, The Natural Products Atlas  [24] ) identified fraction S2 to harbor alkaloid metabolites that were not previously reported in literature (Table  S3 ). Disc diffusion assay of S2 against C. albicans ATCC 10,231 revealed zone of inhibition that was not observed in other fractions. Hence, S2 was further purified by high pressure liquid chromatography (HPLC) and led to the isolation of four compounds, one of which is a new alkaloid bearing a linear imide motif, legonimide 1 (2. 1 mg), and three known compounds: 2 (1.
General Experimental Procedures HR-ESIMS data were obtained in positive ESI mode with a mass range of 100-2000 m/z (maximum resolution 30,000) on a Thermo Scientific MS system (LTQ XL/LTQ Orbitrap Discovery, Waldbronn, Germany). Reserpine (m/z 609. 2807) was used as a lock mass for internal calibrant during data acquisition. The following instrument parameters were used: capillary voltage 45 V, spray voltage 4. 5 kV, capillary temperature 200 • C, auxiliary gas flow rate 10-20 arbitrary units, and sheath gas flow rate 5 arbitrary units; furthermore, an automated full dependent MS-MS scan was applied. The injected samples were chromatographically separated in Thermo Instrument HPLC system (Accela PDA detector (Waldbronn, Germany), Accela PDA autosampler and Accela Pump, Agilent Technologies, Waldbronn, Germany) using a C18 (Sunfire 150 × 46 mm) column.
Feature Based Molecular Networking The MS/MS data of S1-S6 fractions were converted from. RAW to. mzXML files using the ProteoWizard MSconvert software  [43]. A molecular network was generated using Feature-Based Molecular Networking (FBMN) workflow  [44]  on Global Natural Product Social networking (GNPS)  [17]  (https://gnps. ucsd. edu). The mass spectrometry data were preprocessed with MZMINE v2. 38  [45]  and exported to GNPS for FBMN analysis. The data were filtered to remove all MS/MS fragment ions within ±17 Da of the precursor m/z. MS/MS spectra were window filtered by choosing only the top 6 fragment ions in the ±50 Da window throughout the spectrum. The precursor ion mass tolerance was set to 0. 02 Da with an MS/MS fragment ion tolerance of 0. 02 Da to create consensus spectra. The consensus spectra that contained fewer than four spectra were discarded.
The edges were filtered to ensure a cosine score above 0. 65 and more than four matched peaks. The edges between two nodes were kept in the network if each of the nodes appeared in each other's respective top 15 most similar nodes. The spectra in the network were then searched against GNPS spectral libraries  [46]  and annotated by the DEREPLICATOR  [23]. The library spectra were filtered in the same manner as the input data, where a score above 0. 65 and at least 4 matched peaks are required. The created molecular network was visualized using Cytoscape software v3. 4. 0 (Seattle, WA, US).
Funding: Q. F. is grateful to the  University of Aberdeen Elphinstone Scholarship and Scottish Funding Council/ScotCHEM  for financial support through the  PEER/PERCE Funding. F. M. thanks the  University of the Philippines for the Faculty, Reps, and Staff Development Program (FRAS DP)  for the PhD grant fellowship. H. D. and K. K. thank the financial supports of  Leverhulme Trust-Royal Society   Africa award  ( AA090088 ) and the jointly funded  UK Medical Research Council-UK Department for International Development  ( MRC/DFID) Concordat agreement African Research Leaders Award  ( MR/S00520X/1 ).
Methods Here, we performed a pharmacovigilance analysis of VigiBase, the World Health Organization's individual case safety reports database, to describe hepatic impairment reports with remdesivir. 7 VigiBase contains more than 22 million spontaneous generated adverse drug reactions from 136 countries covering more than 90% of the world's population. VigiBase includes information on patient, medical history, country, and drugs taken with their initiation and stop dates. We considered only reports of patients with COVID-19 registered up to June 15, 2020. Disproportionality analysis was performed to assess a potential increased risk of reporting hepatic disorders with remdesivir compared with drugs prescribed in COVID-19 patients. 8 he risk of hepatic disorders was calculated by using the reporting odds ratios (ROR) with their 95% confidence interval (CI), a ratio similar in concept to the odds ratio in case-control studies.
Acknowledgments The authors thank the  Uppsala Monitoring Centre (UMC) , who provided and gave permission to use the data analyzed in the present study. Access to the World Health Organization global individual case safety report database, Vig-iBase®, is available without fees to  Drs Montastruc  and  Durrieu. The authors thank the National Pharmacovigilance Centers that contributed data. The opinions and conclusions in this study are not necessarily those of the various centers or of the  World Health Organization.