dataesr/scientific-paragraphs-categorization huggingface dataset:
Data collection The French pharmacovigilance database contains individual case safety reports (ICSR) reported to the CRPV. These 31 centers are located in the 13 regions of France. These noti cations come from healthcare professionals or patients and patient associations  (13). Medicinal products are listed as speciality or active substance based on available information. Adverse reactions are coded according to the international terminology of the Medical Dictionary for Regulatory Activities (MedDRA). Our study included spontaneous declarations noti ed from January 2011 to December 2020. Reports corresponding to follow-up were not considered. For this study, reports from overseas territories were not included, and Corsica was included the Provence Côte d'Azur region. For each noti cation, the following variables were extracted: sex, age, region, noti cation date, noti ed type, start date, effect type (e.
Multivariate analysis of patients versus health professionals: logistic regression The regression was performed using the BNPV variables: sex (F/M), age classes, severity (yes/no), reporting modality (web portal/other), reporting time, which is the time between the onset of an adverse event and its reporting. Data from patients and HCP were pooled together, the reporting time was dichotomized as < 46 days and ≥ 46 days, according to the median value. After describing, descending stepwise elimination was used to determine factors associated to patients' reporting. Variability in sampling associated with the estimated odds ratios was assessed by two-sided 95 percent con dence intervals. p values of less than 0. 05 were considered to indicate statistical signi cance.
Comparison of Patient Reports by Regional Characteristics: Principal Component Analysis (PCA) The PCA (  16 ) is a multivariate method of analysis that explores multidimensional datasets of quantitative variables. It allows to synthesize the information into only a few new variables called main components. The Kaiser criterion was chosen to determine the number of axes for the analysis(  16 ). The analysis by PCA of the reporting activity by region according to the characteristics of the regions allows to highlight the factors related to this activity; (table  3 ).
Qualitative Analysis A Top 10 list of the most reported drugs by patients and healthcare professionals was drawn as follows: prior to 2017, from 2017 through web portal reporting, from 2017 via the standard reporting tools noted «Others» in our study. A qualitative and comparative analysis was conducted between the complete Top 10 "Patients" and "Healthcare Professionals". All analyses were performed using SAS® studio software version 9. 4.
Results We defined a panel of 17 genetic polymorphisms selected for their association with drug pharmacokinetics, drug response or when dosing recommendations were available in international databases  [6, [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]. The assay was designed to identify clinically relevant variants in genes coding for drug metabolizing enzymes from the CYP450 system and for the membrane transporter ATP-binding cassette 1 (ABCB1 or P-gp) since many drugs are substrate of this efflux pump. It included bi-allelic and tri-allelic SNP and nucleotide deletions. Table  1  reports the selected variants and gives an overview of the molecular consequences and some examples of drugs impacted by these genetic polymorphisms.
Comparison of Cost and Analytical Workflow with Reference Methods Regarding the cost of the analysis, we included the cost of labware and reagents. Cost of instrument and personal was not included since it may depend on each center organization. As reported in Table  5 , the PCR-multiplex assay is cheaper than the two other methods, even for a large set of samples (48 samples). The workload to perform the PCR multiplex assay leads to a fast turnaround time with results available within 6. 5h whereas the analytical parameters remain good enough for the purpose of hotspot analysis. (1 These data are estimated based on our center experiences and usual literature reports. ($) are evaluated regarding cost of reagents and consumables. They do not include personal cost nor equipment acquisition since this part is inherent to laboratory policy.
DNA concentration was measured using a NanoDrop One spectrophotometer (NanoDrop Technologies Inc. , Wilmington, DE, USA). The multiplex PCR kit was provided by Qiagen ® (Courtaboeuf, France). Primers and fluorescent dyes were provided by Eurofins MWG (Operon, Les Ulis, France). The denaturant Formamide and the dye size internal standard GeneScan™ 500 ROX™ were purchased from Applied BiosystemsTM/Thermo Fisher Scientific (Illkirch, France). PCR reaction was performed on a thermocycler Veriti™ 96-Well Thermal Cycler and samples were analyzed on a sequencer ABI 3500 Genetic Analyzer, both from Applied BiosystemsTM/Thermo Fisher Scientific (Illkirch, France). Data were processed using the GeneMapper ® 6. 0 software (Applied Biosystems™, Illkirch, France).
2 µL) was added in each well. Samples were loaded on the analyzer. Each electrophoregram was visually checked for peak intensity and resolution. We defined the acceptance criterion of the results after migration on the sequencer as follows: the height of the signal of each fragment should be higher than 100 (intensity unit) and lower than 20,000 (intensity unit) to avoid saturation, and the length of each fragment should not differ from +/-1 base pair from the theoretical length of the fragment. Raw data were automatically processed using GeneMapper ® software (version 6) and were interpreted with a local Microsoft Excel ® interface providing a user-friendly and synthetic report of genotypes for each gene and samples. Illustration of the principle of the assay is reported in Figure  S1.
Genotyping results from control DNA samples were compared between samples analyzed with a freshly prepared pool solution and the same samples analyzed with the same pool frozen and thawed five times. The accuracy of the assay was assessed by comparing genotyping results provided by the multiplex assay compared to those previously reported by reference methods used in our center or in our partner subcontracting centers. The comparison was performed on at least 25 and up to 121 DNA samples per polymorphism included in the panel. Reference methods were Taqman TM assays (Thermo Fisher Scientific (Illkirch, France)) and NGS assays (in house panel, sequencing platform from Illumina (San Diego, CA, USA), Process on GATK Joint Genotyping and MiSeqReporter version 2. 4. 6 software (Illumina, San Diego, CA, USA)) depending on the origin of the samples.
Nuclei were stained using Hoechst reagent (ref. B2883; Sigma-Aldrich, Darmstadt, Germany) diluted 1,000 times in the same secondary antibody solution. Finally, the cells were washed 3 times during 5 min with PBS-CMF. Filters with BLECs for miniaturized model were directly placed in the microscope, while 12 TW inserts were cut and mounted on a glass slide under a coverslip. Stained preparations were observed with an ImageXpress Micro Confocal High-Content Imaging System (Molecular devices, San Jose, CA, USA), using blue DAPI filter (excitation/emission wavelength 358/461 nm) for nuclei, green Fluorescein isothiocyanate (FITC) filter (excitation/emission wavelength 480/530 nm) for ZO-1. Images were processed in MetaXpress software version 6. 5. 2 (2018, Molecular Devices, LLC, San Jose, CA, USA).
P36962, Thermo Fisher Scientific; Massachusetts, USA) under a coverslip. BLECs were observed from the luminal face. Stained preparations were observed by confocal microscopy using a Zeiss Axio Observer LSM 710 Scanning Module coupled with ZEN 2 (blue edition) software (Zeiss, Jena, Germany). The nanoparticles were visualized with an excitation/emission wavelength 561/629 nm, detection range 603-656 nm. The EEA-1 stained with Alexa Fluor 488 was visualized with an excitation/emission wavelength 488/525 nm, detection range 496-554 nm. The nuclei stained with DAPI were visualized with an excitation/emission wavelength 561/613 nm, detection range 410-507 nm.
Statistical analysis Results were expressed as mean ± standard deviation (SD). The number of replicates (n), performed through independent experiments (N), were detailed in each experiment. For analysis involving two groups, unpaired t-test, or one-way ANOVA, followed by Bonferroni's multiple comparison tests was used. For analysis of more than one condition in two groups, multiple t-test or two-way ANOVA were used. All data was analyzed by GraphPad Prism 8. 1 software (GraphPad Software, San Diego, CA, USA). The threshold for statistical significance was set to p-value < 0. 05.
Response to metabolic inhibitors of distinct vesicular endocytosis pathways The NPs internalization pathways were studied by testing a range of selected inhibitors involved in different metabolic internalization routes in the BLECs. Inhibitors for caveolae (filipin III and genistein), clathrin (dynasore and chlorpromazine) and macropinocytosis (cytochalasin D, and dimethylamiloride) pathways were tested (Fig. 7A ). Their non-toxic impact over the BLECs of the inhibitors was previously studied (data not shown). While a decrease of P188 NP uptake could be observed with genistein and chlorpromazine, no significant differences were found for any of the inhibitors. However, a significant decrease of the uptake could be observed for PS80 NP, with filipin III (*p = 0. 0145) and chlorpromazine (**p = 0.
Statistical Analysis Fluorescence data analysis was performed using the SoftMax Pro 5. 4. 1 software (Molecular Devices, Sunnyvale, CA, USA). The kinetic traces of Ca 2+ signals, monitored with Fura-2, were plotted as a ratio of fluorescence intensities measured at λ = 510 nm as emission, after a dual excitation at λ = 340 nm and 380 nm. The area under curve (AUC) was used for analysis. All graphs and statistical analysis were established using GraphPad Prism 7. 02 (GraphPad Software, San Diego, CA, USA). Data are presented as mean ± SEM. Nonlinear analysis was used to fit the concentration-response data with Langmuir-Hill equation with Hill coefficient. For this analysis, the integration of the fluorescence kinetics (AUC) obtained with increasing concentrations of ligands were used. IC50 or EC50 and Hill coefficient values were calculated from at least two experiments.
Labetalol is a drug that exhibits both alpha and beta-adrenergic receptor-blocking properties. The American Heart Association/American Stroke Association (AHA/ASA) has recommended labetalol as an initial treatment option for the management of severe hypertension. The physiologically based pharmacokinetic (PBPK) model is an in silico approach to determining the pharmacokinetics (PK) of a drug by incorporating blood flow and tissue composition of the organs. This study was conducted to evaluate the primary reasons for the difference in PK after intravenous (IV) and oral administration in healthy and diseased (renal and hepatic) populations. A comprehensive literature search was done using two databases, PubMed and Google Scholar. Various PK parameters were screened for the development of the PBPK model utilizing a population-based PK-Sim simulator.
Literature Review The systematic analysis was conducted by Cochrane Handbook guidelines to accomplish the study objective and was reported by using the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) statement  [21]. The search was done by using two databases i. e. , PubMed and Google Scholar, and the adopted search strategy has been illustrated in supplementary Figure  S1. The duplication of all the selected studies was removed by using EndNote X9. The articles related to labetalol in populations such as healthy, renal, liver, hypertension, or pregnancy-induced hypertension and the presence of plasma concentration versus time profile after oral and IV administration, were included in the study. Furthermore, articles were excluded based on title and abstract, the involvement of animals in the study, and if the articles were in open access or not.
Modeling Software The open-system pharmacology suite has been designed to allow efficient modeling and simulation. In this current study, the PBPK modeling of labetalol in healthy adults and diseased (liver and kidney) patients was carried out by using a population-based PK-Sim simulator (version 9. 1), which is a component of the computational Systems Biology Software Suite of Bayer Technology Services GmbH (Leverkusen, Germany) and is specifically for whole-body PBPK modeling [28].
Model Parameters Labetalol (C19H24N2O3) has a pKa value of 9. 38, a molecular weight of 328. 412 g/mol, and lipophilicity of 2. 79 log units, as mentioned previously in Table  2. In PBPK modeling, each organ is recognized by its physiological properties. For orally administered dosage forms, the specific intestinal permeability value of 4. 67 × 10 -5 was incorporated into the model. For the estimation of cellular permeability and tissue plasma partition coefficient, PK-Sim standard model was used. The value of specific organ permeability and specific clearance were optimized using the parameter estimation feature of PK-Sim software to 0. 1 L/min and 0. 10 L/min respectively. Finally, a total body clearance of 15 ml/min/kg was incorporated into the model (after drawing both oral and IV simulations by using all the values ranging from 10 to 25 mL/min/Kg) based on visual predictive checks and observed/predicted ratios  [10].
Model Parameters Labetalol (C19H24N2O3) has a pKa value of 9. 38, a molecular weight of 328. g/mol, and lipophilicity of 2. 79 log units, as mentioned previously in Table  2. In PB modeling, each organ is recognized by its physiological properties. For orally admin tered dosage forms, the specific intestinal permeability value of 4. 67 × 10 -5 was incor rated into the model. For the estimation of cellular permeability and tissue plasma pa tion coefficient, PK-Sim standard model was used. The value of specific organ perm bility and specific clearance were optimized using the parameter estimation feature PK-Sim software to 0. 1 L/min and 0. 10 L/min respectively. Finally, a total body cleara of 15 ml/min/kg was incorporated into the model (after drawing both oral and IV sim lations by using all the values ranging from 10 to 25 mL/min/Kg) based on visual pred tive checks and observed/predicted ratios  [10].
Acknowledgments e authors are grateful to the Ministry of External Affairs and to the  Department of Science and Technology, Government of India , who supported this work financially through the  Federation of Indian Chambers of Commerce , under the  CV Raman International Fellowship for African Researchers in India. Similar gratitude goes  to the  World Academy of Science  and the  Council for Scientific and Industrial Research, Government of India , for facilitating the completion of this project in India through the  TWAS-CSIR Sandwich Fellowship for Postgraduate Research.
75 mM; FeSSIF: taurocholate 15 mM (bile salts), phospholipids 3. 75 mM]. The surface tension determined at room temperature is 51. 7 ± 2. 5 mN/m for FaSSIF and 48. 6 ± 0. 4 mN/m for FeSSIF (data kindly provided by Biorelevant. com). Yet, similarly to the results obtained in the PBS, the percentage of ionization together with the milling time govern the shape of dissolution profiles more than the load of surface active compounds in these solvents. Thus, more than twice higher amount of bosentan dissolves in FaSSIF of a pH = 6. 50 and ionization = 95 % (SI = 0. 19) than in FeSSIF of a pH = 5. 00 and ionization = 90 % (SI = 0. 11). Fully amorphous samples show the most favorable dissolution profiles. After 120 min, 55. 48 ± 0. 67 μg/mL or 52. 07 ± 1. 63 μg/mL of bosentan dissolve in FaSSIF from samples milled for 4 or 6 h, respectively.
Medical staff and pharmacovigilance specialists matched their inclusions to ensure completeness of the cases included. Then, the pharmacovigilance specialist manually collected clinical and pharmacological data from the medical records. Medicinal herbs or homeopathy were noted in the abstract of reports and considered in the ADR assessment. Patients with suspected ADR-HA were followed for 1 month to collect the adverse reaction outcome. Patients who died within 24 hours of admission were not excluded. ADR-HAs were coded in the French Pharmacovigilance database according to the Medical Dictionary for Regulatory Activities and drugs according to the Anatomical Therapeutic Chemical classification. Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.
ACKNOWLEDGEMENTS The authors thank the hospitals and physicians who participated in this study as well as the investigators of RPVCs, the  ADR Review Committee , the  University Hospital of Limoges  and the  ANSM (Agence Nationale de Sécurité du Médicament et des produits de santé). The  IATROSTAT study group: Valérie Gras-Champel (RPVC Amiens ),  Laurence Lagarce  ( RPVC Angers ),  Marie-Blanche Valnet -.
) had been collected to test for saxitoxin. The link between the symptoms and exposure to paralytic toxins was established based on the report received by the RASFF from the product distributor, which was not mandatory since the measured concentrations were below the regulatory limit. This alert highlights the probable under-diagnosis of human poisoning cases with neurotoxic phycotoxins, since the link between shellfish consumption and neurological signs is, depending on the situation, neither routinely sought nor established. In this context, ANSES carried out a review of bivalve shellfish poisoning cases recorded by the French PCCs, looking for a link with environmental monitoring data when possible, specifically in order to identify those cases presenting neurological signs compatible with neurotoxic phycotoxins.
Case definition Cases were defined as symptomatic human poisoning in relation to bivalve mollusc consumption in France, regardless of symptomatology, registered by the PCCs. Cases of poisoning that occurred abroad, or with no causality between the suspected exposure agent and the symptoms, or without symptoms, were excluded from the study. Data were extracted from the French PCC national database (SICAP), where all PCC cases, corresponding to "patients", are collected in medical records, corresponding to "events", each event (or shellfish meal in this study) containing either a single case or collective cases related to the same exposure. Among included cases, those with neurological symptoms were selected. A toxicologist reviewed all the medical records in which at least one neurological symptom was reported to specifically search for and describe cases that could be related to neurotoxic phycotoxins, taking into account the type of symptoms and their time of onset after shellfish consumption.
Cases with symptoms suggestive of an allergic reaction were excluded. The diagnosis was made retrospectively based on the clinical signs recorded, as well as, when the origin of the shellfish was known, co-occurrence with shellfish contamination reported in the monitored production areas (based on REPHYTOX database) or RASFF notification of imported products. The REPHYTOX network, whose data are analysed by the French Research Institute for Exploitation of the Sea (Ifremer), under the authority of the Ministry of Agriculture and Food, collects samples from several hundred shellfish sites. This is sufficient to provide the authorities in charge of public health safety with information to make decisions on bans in harvesting areas.
ANSES, PCCs and Ifremer developed a specific guide to collect information when a person reports neurological signs after shellfish consumption and to recommend actions to take for further investigations. The patients should keep and freeze any meal leftovers for subsequent analyses. Measurement of toxin concentrations in unconsumed shellfish are key, especially when poisoning is associated with shellfish harvested from uncontrolled areas. The suspected cases should be referred to the emergency department of a hospital, for collection of biological samples that may be frozen (in particular for a posteriori testing for marine toxins, even those not yet regulated in European countries such as pinnatoxins and brevetoxins). These samples will help to confirm the poisoning. Daily automatic monitoring of cases of shellfish poisoning recorded in the PCC national database was also set up to detect any suspected case the day following the call to the PCC.
Hirshfeld Surface Analysis To better clarify the presence of weak intermolecular contacts occurring in the crystalline state, that may be complementary and relevant to the docking simulation shown in Section 2. 2, a Hirshfeld surface analysis  [48]  was carried out utilizing the CrystalExplorer21 software package  [49]. For molecule 4c, the Hirshfeld surface is mapped over d norm in the range from -0. 5804 to 1. 5493 (arbitrary units). As presented in Figure  5.
Molecular Dynamics and Binding Modes Analysis The binding mode of the six compounds was elucidated by molecular docking simulations in the active site of SARS-CoV-2 M pro (PDB: 6W63) [50] using GOLD 5. 8  [51, 52]  (Cambridge Crystallographic Data Centre, Cambridge, UK), as reported previously  [53]. Interestingly, the docking results of four compounds 4a, 4b, 4d and 4e converged to a similar binding mode. The oxindole ring occupies the S1 subsite while the pyrrolidine ring with its 4-substituted aryl group occupies the S1 subsite mimicking the imidazole ring of the cocrystallized ligand. The N-[(S)-(-)-methylbenzyl]-group appears, extending to the deep S2 subsite. Finally, the substituted 3-arylidene of the piperidone ring resides in the S3 subsite. The limited size of the S1 subsite will not be able to accommodate the extended methoxy phenyl group of the pyrrolidine ring found in the structures of 4c and 4f which explains the failure of these latter compounds to exhibit the same binding mode (Figure  6 ).
To further confirm the stability of these proposed binding modes, 80 ns molecular dynamics simulations were conducted for each M pro -ligand complex using the AMBER software package  [54]. In total, four ligands were studied (4a, 4b, 4d and 4e) to check the stability of their binding modes. Visual examination of the resultant trajectories showed the three compounds 4a, 4b and 4e capable of retaining GOLD docked pose (Figure  7 ). On the other hand, visual inspection of the resultant trajectory of compound 4d showed it completely detached from the binding site at the beginning of the production run and failing to reach a stable binding mode within the conducted simulation. Accordingly, compound 4d was not further considered in this study (Figure  7C ). It is worth mentioning that the dimeric state of M pro is the functional form of this protease protein  [55].
Apparatus and General Information The NMR (300 MHz for 1 H NMR, 75 MHz for 13 C { 1 H} NMR) spectra were recorded on Bruker Avance 300 machine (Rheinstetten, Germany. The chemical shifts δ were reported in ppm relative to tetramethylsilane (TMS). Data were described as follows: chemical shift (δ in ppm), multiplicity (s = singlet, d = doublet, m = multiplet, q = quartet), coupling constants (Hz), integration. Optical rotations were determined by a Perkin Elmer polarimeter. Elemental analyses were performed on a Perkin Elmer 2400 Series II Elemental CHNS analyzer (Waltham, MA, USA). Thin-layer chromatography (TLC) was performed on silica gel plates (Merck, silica gel 60 F 254 0. 2 mm, 200_200 nm) (Darmstadt, Germany) using UV light at 254 nm.