dataesr/scientific-paragraphs-categorization huggingface dataset:
| Data collection The PMSI database was started 30 years ago as the basis for the French national healthcare reimbursement system. This database describes each inpatient stay in a standardized dataset that summarizes information on the patient and the hospital stay (e. g. , diagnoses as diagnosis-related groups and procedures) and entrance at the hospital, especially if it was via an intensive care unit  [11]. For this study, data on hospital stays in the French Hospitals located in the 13 metropolitan regions and four overseas territories from 2010 to 2019 were used. To identify possible cocaine-related hospitalizations and their outcome, data were extracted using the International Classification of Diseases (10th edition ICD-10) codes F14. 0 to F14. 9 (mental and behavioral disorders due to use of cocaine), R78.
2 (cocaine detection in blood), and T40. 5 (cocaine poisoning). Nominative, sensitive, or personal data were not collected. As recommended by the French authorities, the study had a public interest and the used information were not linked to personal data and were within the scope of the French Reference Methodology MR-005 according to the 2018-256 law of June 7, 2018 on the modernization of the French health system [12].
| DISCUSSION The analysis of the PMSI data allowed monitoring cocaine-related hospitalizations in France, showing their increase by fourfold from 2010 to 2019. Cocaine pharmacoepidemiological surveys are usually done in the general population to assess the prevalence of cocaine use by sex and age, the frequency of consumption (experimentation, regular use, or daily use), and the type of cocaine used (cocaine or crack cocaine). The study by the Euro-DEN research group described the pharmacoepidemiology and cocaine-related complications observed specifically in emergency units, using data on substance use self-reported by patients. Between October 2013 and September 2014, cocaine was the second substance involved in acute psychoactive substance toxicity events leading to emergency hospitalization in Europe  [13].
However, data for France were obtained only from one hospital in Paris. In France, the FAN analyzed data on cocaine use, obtained using three different tools (spontaneous notifications, OPPIDUM, DRAMES), and found that cocaine-related complications are increasingly reported to the addiction monitoring centers, although the real frequency is certainly underestimated  [6, 10]. Using these three data sources provides complementary data: (1) cocaine-reported complications, (2) number of cocaine and crack cocaine users and number of patients with use disorders in addiction care centers, and (3) cocaine-related deaths  [5]. However, these epidemiologic approaches have some limitations, such as the lack of objectivity because information collected in some population surveys comes from users' selfreports.
A study evaluates the profile of drug users and characteristics of the psychoactive substances used in French overseas territories, using data  from the OPPIDUM survey from 2012 and 2013  [14]. Cocaine was frequently consumed in the French Americas, mainly in the "freebase" form, versus in metropolitan France. It is surprising not to observe more increase in hospitalization rates in these territories. An increase by 10-fold of pediatric cases of cocaine poisoning was observed in most of the regions over the study period. Pediatric cocaine poisoning could occur at birth because of the mother's addiction, by maternalinfant transmission through breast milk, or by accidental poisoning. Their strong increase is a marker of cocaine trivialization. Based on the PSMI database a similar study was realized by the FAN on pediatric cannabis poisoning.
A steady increase was reported, since 2014, in the number of pediatric cannabis poisoning mainly in children under 2 years of age, occurring in the family setting  [15]. Among the strengths of this study is the use of the PMSI database that collect data from all French healthcare facilities  [16]. Therefore, its exhaustive nature should guarantee the absence of selection bias. Nevertheless, the quality of data, which were not originally intended for pharmacoepidemiological studies, have been evaluated  [9]. This pilot study was performed in a single hospital and demonstrates how hospital databases could be used as a source for the identification of abuse and dependence cases  [9]. There are also some limits linked to the PMSI tool. First, as no information on the cause or role of cocaine use is reported, it is not possible to confirm that the cause(s) leading to each hospital stay was cocaine use.
Second, a coding error or coding with insufficient precision on the causal role of the substance or drug might have occurred. Third, we cannot rule out the improvement of coding efficiency by clinicians and the increasing use of actionable data in patient records by the hospital medical data teams during the study period. Moreover, it is possible that sometimes there was no mention of cocaine during hospitalizations for multiple reasons. However, these improvements should not be sufficient to explain the observed increase of hospitalizations related to cocaine use in France. The World Health Organization recommended that countries should develop vigilance systems specifically dedicated to substance use disorders  [17]. Many of the existing surveillance systems rely on spontaneous reporting of medical complications related to psychoactive substance use; in this context, PMSI, and other national health databases, can be a useful tool to complete data collection.
Fluorescence (560/590 nm) was recorded using a Clariostar plate reader (BMG Labtech, Ortenberg, Germany) for HepG2 cells and a Tecan Infinite 200 (Lyon, France) for HepaRG cells. Data were integrated with Mars Data Analysis software (v. 1. 51, BMG Labtech) and iControl V1. 30 software. Induced apoptosis was investigated by measuring caspase 3/7 activity with the Caspase-Glo ® 3/7 luminescent assay (Promega). Proportional luminescence was recorded using a plate reader. ATP content was assessed in cells cultured in high-glucose or galactose media with the CellTiter-Glo ® Luminescent Cell Viability Assay (Promega) after cell lysis.
The assay consisted in measuring basal respiration followed by the sequential addition of an ATP synthase inhibitor, oligomycin (2 µM), followed then by maximal stimulation of the mitochondrial electron transport chain by adding carbonyl cyanide m-chlorophenylhydrazone (CCCP, 2 µM, an uncoupling agent dissipating the proton gradient). Finally, adding rotenone-and antimycin A-(0. 5 µM each) inhibited mitochondrial complexes I and III, respectively, and allowed us to determine extramitochondrial respiration. Maximal respiratory capacity was calculated after subtracting extramitochondrial respiration. The assay was conducted over 96 min, and data were normalized to the protein content with the Pierce™ BCA Protein Assay Kit (ThermoFisher, Waltham, MA, USA).
Mitochondrial Superoxide Accumulation in HepG2 Cells The accumulation of mitochondrial superoxide was assessed in live cells using the selective MitoSOX™ Red Mitochondrial Superoxide Indicator (Invitrogen, Waltham, MA, USA). To evaluate the role of GSH in aldehyde detoxication, cells were exposed to an increasing range of reactive metabolites (1-50 µM) in either the presence or absence of BSO (250 µM), a specific inhibitor of GSH synthesis. Rotenone (50 µM) was used as a positive control. After treatment, cells were gently washed with PBS and covered with 2. 5 µM of MitoSOX reagent diluted in PBS. Fluorescence was recorded after incubation (excitation/emission wavelength 510 nm/580 nm), and data were normalized to the protein concentration.
Patients and Hepatotoxicity Data Correlations between plasma concentrations of P-CHO and liver parameters were evaluated in 15 patients treated with pazopanib for mRCC and included in the SUP-R clinical trial ((ClinicalTrials. gov Identifier: NCT02555748)), a French pilot study evaluating sunitinib and pazopanib pharmacokinetic parameters and toxicity. Patients were sampled on the first day of the first treatment cycle before intake (T0), and at two, four, six, and eight hours after intake (T2, T4, T6, T8). This schedule was repeated at T0, T2, and T6 on the 15th day of cycle 1 and cycle 2. Patients' hepatic biochemical parameters were collected before inclusion and during treatment and were graded according to the Common Terminology Criteria for Adverse Events (CTCAE, v. 4. 03).
UPLC-MS/MS Analysis Extracted samples were analyzed with a UPLC Waters Acquity system equipped with a Waters TQ-S micro mass spectrometer (triple quadrupole detector) added to an electrospray ionization source (ESI). Components were eluted in a linear gradient with sequential changes in the proportion of aqueous eluent (ammonium formate in ultrapure water, pH = 3. 2) and organic eluent (acetonitrile with formic acid 0. 1% [v/v]), as previously described  [6]. Data were analyzed with MassLynx software (version 4. 2, Waters, Milford, MA, USA). The multiple reaction monitoring (MRM) mode was used for mass spectrometry detection. Selected MRM characteristic transitions were 438. 0 > 357. 0 (loss of SO 2 NH 2 ) for pazopanib, 452. 0 > 328. 0 (loss of SO 2 NH 2 , CHO and CH 3 ) and 452. 0 > 343.
Statistical Analyses All experiments were conducted three times, so the data are given as the mean ± standard deviation (s. d. ). A one-way ANOVA followed by Dunnett's post-test procedure was used for comparison with vehicle control. A two-way ANOVA followed by Bonferroni's post-test procedure was used to compare multiple conditions. p value < 0. 05 was considered significant. Statistical analyses were performed with R ® version 4. 1. 0 (R Foundation for Statistical Computing, Vienna, Austria) and plots were created with GraphPad Prism 7. 0 (GraphPad Software, La Jolla, CA, USA).
Evaluation of Pazopanib and Sunitinib Aldehyde Cytotoxicity in Liver Cell Lines The chemical structures of pazopanib, sunitinib, and their derived aldehydes (P-CHO and S-CHO, respectively) are presented in Figure  1. sequential changes in the proportion of aqueous eluent (ammonium formate in ultrapure water, pH = 3. 2) and organic eluent (acetonitrile with formic acid 0. 1% [v/v]), as previously described  [6]. Data were analyzed with MassLynx software (version 4. 2, Waters, Milford, MA, USA). The multiple reaction monitoring (MRM) mode was used for mass spectrometry detection. Selected MRM characteristic transitions were 438. 0 > 357. 0 (loss of SO2NH2) for pazopanib, 452. 0 > 328. 0 (loss of SO2NH2, CHO and CH3) and 452. 0 > 343. 0 (loss of SO2NH2 and CHO) for P-CHO. S-CHO was detected with 413.
Author Contributions: Conceptualization, C. A. , C. C. , E. C. and F. T. ; formal analysis, M. M. , C. A. , F. P. and F. T. ; investigation, M. M. , C. V. , N. J. C. , F. P. , N. S. -L. and T. L. ; methodology, M. M. , C. A. and F. T. ; supervision, C. A. , E. C. and F. T. ; writing-original draft, M. M. , C. A. , E. C. and F. T. All authors have read and agreed to the published version of the manuscript. Funding: The clinical part of the study (plasma analysis in patients) was funded by a PHRCi grant from GIRCI-SOHO (Groupements Interrégionaux de Recherche Clinique et d'Innovation Sud Ouest Outre Mer Hospitaliers) (Study reference: EUDRACT 2015-001051-68). Institutional Review Board Statement: The clinical study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee Comité de Protection des Personnes Sud-Ouest et Outre-Mer III (2015/59).
Acknowledgments: The authors thank  Cathy Quelen  ( Centre de Recherches en Cancérologie de Toulouse, France ) for providing the HepG2 cell line and  C. Guguen-Guillouzo  ( INSERM 991, Rennes, France ) for providing the HepaRG cell line. The authors thank  Gail Taillefer ,  University of Toulouse I-Capitole (Toulouse, France ) for English-language editing of the manuscript.
Acknowledgements This research was supported financially by a grant to L. G. from the  French Ministry of Higher Education and Research delivered by the Doctoral school  ( ED 459 ) and the ICGM. We thank the  Centre National de la Recherche Scientifique (CNRS) , the  Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)  and the  Université de Montpellier  for financial support. We also thank the  Dr. R. M. de Figueiredo  for her help in the dipeptide synthesis.
Acknowledgements This work was financially supported by the  University of Rouen Normandie ,  INSA Rouen Normandy , the  Centre National de la Recherche Scientifique (CNRS) ,  European Regional Development Fund (ERDF) ,  Labex SynOrg  ( ANR-11-LABX-0029 ),  Carnot Institute I2C , the  graduate school for research Xl-Chem  ( ANR-18-EURE-0020 XL CHEM ), and by the  Région Normandie. A. N. N. and E. V. thank the  Région Normandie , respectively for a postdoctoral and doctoral fellowship (RIN- EMERGENCE-2020-RadFlurOx  and  RIN-100-2020-RRaFluR ).
Larrea tridentata antibacterial lignan 4,4 ′ -dihydroxy-3-methoxy-6,7 ′ -cyclolignan (1) was derivatized to obtain eleven new amino ether derivatives (2 A-12 C). The structural elucidation of compounds was performed by analysis of 1D-and 2D NMR spectral data and HRESIMS. The antibacterial activity of compounds was determined against nine drug-resistant bacteria and two strains of Mycobacterium tuberculosis (sensitive ATCC 27294 H37Rv and drug-resistant G122). Results showed that all derivatives were devoid of activity towards six gramnegative clinical isolates assayed. However, seven derivatives displayed antibacterial activity against three grampositive drug-resistant bacteria. Further, enhancement of antibacterial activity was only observed for the compounds 2 A and 10 C-12 C (MIC of 12.
Acknowledgements The authors gratefully acknowledge the research group IICiMed ( Nantes Université, France ) for recording the HRMS spectrometric data. Financial support is gratefully acknowledged to CONACYT through grant No. 603598  provided to carry out the PhD studies of  Hernández-Carrillo M. L. , and to FCQ-UANL  MEXICO  project  code FARDC-93765-MRCC-18/02 , which also provided financial support for the project.
Chromaticity and Luminance Analysis Chromaticity and luminance were measured with a UV-visible spectrophotometer (V670, Jasco Corporation ® , Lisses, France) using the mode Colour Diagnosis of the built-in software (Spectra Manager ® , version 2. 12. 00, Jasco Corporation ® , Lisses, France) with a quartz measuring cell. The CIE L*a*b* colour parameters were used to represent the colour changes  [22, 23]. Transmittance spectra were obtained by using a light source D65 (wavelength between 780 and 380 nm), data pitch 5 nm, colour matching JIS Z8701-1999 and scan speed 400 nm/min. The difference of colour perception (∆E) was calculated using the following equations for the spectrophotometric analysis  [24] : ∆a= a* -a 0 * (1) ∆b*= b* -b 0 * (2) ∆L*= L* -L 0 * (3).
The method was validated on a reverse-phase HPLC Prominence-I LC2030C 3D with diode array detection (Shimadzu France SAS, Marne La Vallée, France), and the associated software used to record and interpret chromatograms was LabSolutions ® version 5. 82 (Shimadzu France SAS, Marne La Vallée, France). The mobile phase was a gradient mixture of phases A and B. Mobile phase A was an aqueous ortho-phosphoric acid solution at 85% (0. 1 %, v/v). Mobile phase B was prepared by mixing 500 mL of ACN (Acetonitrile for HPLC, 99. 95% ref 412342 2. 5L) and 47 mL of MTBE (tert-Butyl methyl ether for HPLC, ≥99. 8%, Sigma Aldrich, Saint Quentin Fallavier, France), ref 34875-1L). The column oven was set at 70 • C and the mobile phase was stored at ambient temperature before reaching the column. The gradient used is presented in Table  3.
Data Analysis-Acceptability Criteria The stability of the tested tacrolimus formulations was evaluated using the following physicochemical parameters: visual aspect of the solution, turbidity and micelle size, viscosity, pH and osmolality, tacrolimus concentration and a research of BPs. The study was conducted following methodological guidelines issued by the International Conference on Harmonisation for stability studies  [33]  and recommendations issued by the French Society of Clinical Pharmacy (SFPC) and by the Evaluation and Research Group on Protection in Controlled Atmosphere (GERPAC)  [34]. A variation of concentration outside the 90-110% range of initial concentration (including the limits of a 95% confidence interval of the measurements) was considered as a sign of instability. The presence of BPs and the variation of the physicochemical parameters were also considered a sign of tacrolimus instability.
The compound at 7. 43 min was found possibly to be 3,5-Di-tert-butylphenol (CAS number 1138-52-9) or 2,4-Di-tertbutylphenol (CAS number 96-76-4). The peaks detected between 11. 07 and 17. 59 min seem to belong to the siloxane family. All these peaks presented common m/z values of 73, 147, 221 or 207, 281, 355, with a difference of 74 m/z units between the fragments. Analytical standards of 1,3-Di-tert-butylbenzene and 2,4-Di-tert-butylphenol were analysed using the tacrolimus HPLC method and the retention times and UV spectra of these products were compared with those of the leachable compound observed during the in-use assay. 2,4-Di-tert-butylphenol possessed a quasi-identical relative retention time (1. 069, relative to tacrolimus) and UV spectrum. In order to support the hypothesis that it is the same compound as that observed during the GC-MS analysis, 2,4-Di-tert-butylphenol was also reanalysed by GC-MS and was found to correspond (see Supplementary Data File S1).
Background and Objectives: Patients frequently complain of mild, transient, unpleasant skin sensations that cannot be diagnosed as common neuropathies. Dermatologists have termed these symptoms "sensitive skin syndrome. " This narrative review was performed for a better knowledge by other specialists. Databases and Data Treatment: Publications on pain in sensitive skin syndrome were obtained from PubMed. Results: There is a growing body of data supporting the concept that sensitive skin is a type of small-fiber neuropathy. The arguments are based on clinical data, a decrease in intra-epidermal nerve fiber density, quantitative sensory testing abnormalities and an association with irritable bowel syndrome and sensitive eyes. Sensitive skin is triggered by environmental factors. Sensitive skin is a frequent condition, with a lifetime prevalence of ∼50% according to self-reports.
EPIDEMIOLOGICAL DATA Following the first epidemiological study of sensitive skin was published on a United Kingdom cohort in 2001  (24) , other studies have been conducted in many countries throughout the world, including Belgium, France, Germany, Greece, Italy, Portugal, Spain, Switzerland, the United States, Brazil, Japan, Russia, Korea, and India  (25). Similar methodologies based on surveys of cohorts aged 15 years and older in accordance with quota sampling, were used in all these studies. The relevant collected information included gender, age, occupation of the head of the household, type of geographical area (rural vs. urban), and region. The relatively low non-response rate to the question "Do you have sensitive skin?" in all countries (<1. 5%, except in Russia and Brazil, for which the non-response rate was nearly 10%) suggests that the term "sensitive skin" is known by many individuals.
6 µs. 24 transients were coadded with a recycle delay of 5 s, corresponding to a total experimental time of ~4 h. First-principles calculations using a periodic-DFT approach. For calculations, input files were generated by taking molecular coordinates from previously published crystal structures deposited in the Cambridge database: Lhistidine. HCl. H2O (CCDC code: HISTCMO1)  1  and dopamine•HCl (CCDC code: DOPAMN). 2  All calculations were performed using the CASTEP 19. 11 code. 3 Geometry optimization was carried out using periodic density functional theory (DFT), and the NMR chemical shifts were computed using the gauge including projected augmented wave (GIPAW) method as described by Pickard and Mauri. 4, 5 The generalized density approximation DFT functional PBE (Perdew-Burke Ernzerhof) with the Tkatchenko-Scheffler (TS) dispersion correction scheme (DFT-D method) was applied with ultrasoft pseudopotentials.
Crystal structures of HsaD The structure of native HsaD was solved at a high resolution (1. 96 Å), and is identical to the one described by Lack et al. (PDB: 2VF2)  [21, 35] , with a root-mean-square deviation (RMSD) of 0. 317 over 259 alpha carbon atoms; making our HsaD structure the best resolution obtained so far. Crystals of native HsaD belong to space group P2221 with average unit cell axes of 76. 8 × 87. 4 × 106. 2 Å and two molecules per asymmetric unit. The biological assembly is a homo-tetramer, which can be generated by application of a crystallographic two-fold axis. The two monomers present in the asymmetric unit are nearly identical (RMSD 0. 248 Å over 266 alpha carbon atoms) and display an α/β-hydrolase fold, which contains the active site made-up by the catalytic triad Ser 114 , Asp 241 and His 269  [30].
In silico molecular docking study In order to better understand the absence of inhibitory activity of CyC32 at the molecular level, complementary in silico molecular docking experiments were conducted as described previously  [16, 32]  using our HsaD-CyC31 crystal structure (PDB ID: 7ZM4) as receptor (Fig. 6 ). Docking runs were performed using the Autodock Vina program  [36]  after removing the bound CyC31 and replacing the catalytic Ser 114 by a glycine residue in order to enable the docked inhibitor to adopt a suitable position corresponding to the prebound intermediate before the nucleophilic attack in the active site  [16, 32]. For CyC32, the best scoring position obtained (i. e. lowest energy complex) places this compound at the entrance of the active site cleft, with a predicted binding energy value ΔECyC32 = -7.
6C ). This redocking/crossdocking experiment thus confirms the validity and reliability of our computational approach. In addition, using a similar in silico approach with the reported crystal structure of HsaD bound to 3,5-dichloro-4-hydroxybenzoic acid (PDB: 5JZS -2. 27 Å resolution  [21] ), we had previously demonstrated that CyC17 adopted a productive orientation close to the catalytic Ser 114 (ΔECyC17 = -7. 4 kcal/mol; [Ser 114 -Oγ/P] distance ~2. 3 Å)  [16]. A good level of concordance was also observed between the favorable docked conformation of CyC17 and the 3D structure of the covalently bound CyC31-Ser 114 in HsaD active site (Fig. 6D ). Overall, such in silico molecular docking results not only corroborate our experimental biochemical data, but above all provide some clues that may explain the absence of inhibitory activity of CyC32 towards HsaD.
Plates were incubated at 37°C for 10-14 days. Then, 20 µL of a 0. 025% (w/v) resazurin solution was added to each well, and the plates were incubated at 37 °C for color change from blue to pink or violet and for a reading of fluorescence units (FU). Fluorescence corresponding to the resazurin reduction to its metabolite resorufin was quantified using a Tecan Spark 10M multimode microplate reader (Tecan Group Ltd, France) with excitation at 530 nm and emission at 590 nm. MIC values were determined by fitting the relative fluorescence unit (RFU%) sigmoidal dose-response curves in Kaleidagraph 4. 2 software (Synergy Software). The lowest drug concentration inhibiting 90% of M. tb growth was defined as the MIC90. Isoniazid (INH) was used as reference drug. Activity-based protein profiling (ABPP) -adapted from  [18, 19].