dataesr/scientific-paragraphs-categorization huggingface dataset:
34 These criteria were applied at a single time point during the hospitalization corresponding to the admission. In this assessment, Cohen's Kappa was used to measure the extent of agreement between the two experts. The Kappa value was 0. 72, indicating good agreement (defined as a value between 0. 6 and 0. 80). Inappropriateness of each prescription focused on medication overuse or misuse (dosage or duration), and was evaluated by using the "Screening Tool of Older People Prescriptions" (STOPP) criteria v. 2. 35 As STOPP criteria are based on diagnostic and/or prescription data, these criteria are explicit and do not require additional expert assessment. Avoidability of CA-AKI events was estimated by using the Hallas criteria. 36 The Hallas criteria are categorized into 4 classes as follows: "definitely avoidable": drug treatment was inconsistent with present-day knowledge; "possibly avoidable": prescription was not erroneous, but the event could have been avoided by an effort exceeding the obligatory demands; "not avoidable": the event could not have been avoided by any reasonable means, or was an unpredictable event in the course of a treatment fully with good medical practice; "unevaluable": data for which a rating could not be obtained or with conflicting evidence (Table  S5 ).
The probability of AKI occurring in this context, therefore, seemed low, especially among hospitalized older patients. Moreover, the period of study inclusion was 2012-2013 and some new drugs, such as sacubitril/valsartan, may have been identified in rare cases in a more recent period. However, 68 medications were associated with AKI in a recent study of pharmacovigilance database in France. 12 Nearly all medications were prescribed during our study period, except bendamustine (2014). Our study did not identify contrast-induced CA-AKI because of the lack of reliable data concerning the administration of contrast agents in the days before hospital admission. Items of the Naranjo scale were not all assessed in the study. Indeed, items 6 to 10 were scored "do not know" for most drugs because data were not most often available.
Acknowledgments We sincerely thank all the physicians who participated in the Patient Safety through  Intelligent Procedure (PSIP)  project in their respective departments, notably,  Dr. Pascale Leurs ,  Dr. Olivier Brimont ,  Dr. Zine Baarir , and  Dr. Philippe Lecocq. We thank  Renaud Perichon  and  Sophie Quenton  (health informatics engineers) for their invaluable assistance. We also thank  Laurie Ferret  and  Joanna Dupont  for preliminary work.
Tunable Resistive Pulse Sensing (TRPS) Measurements were made using a qNano system from IZON Science equipped with an upper and a lower fluid cell, each one containing an Ag/AgCl electrode. The measurements were done using electrolyte (standard provided with Izon kit) solution and a pressure of 0 mbar to allow the passage of the particles through the pore. The membrane stretch was comprised between 45 and 47 mm and the voltage were adjusted in order to have a baseline current between 120 and 145 nA. Data were acquired using Izon Control Suite V3. 1. Each acquisition presented is the result of the passage of at least 500 liposomes. The liposome size and concentration were calculated after the measurement of the calibrated particles solutions with Nano-pore (NP250) allowing a measurement of a total size range between 100 and 400 nm according to manufacturer.
Statistical analysis For the size measurement and the Stability test, the data was presented as the mean ± SD. The graph Pad Prism software was used to analyses the data and determine statistical significance between groups for cytotoxicity and release test. Cytotoxicity experiment data was treated with Gaussian nonlinear regression fit and two-way ANOVA was applied p<0. 001, ***. The release test graphs presented one phase decay nonlinear regression fit and student t test was applied p=0. 0001, ***. All the experiments were performed in triplicates.
Calorimetric assay (Baleux assay) To determine the quantity of poloxamer entrapped inside the liposomal shell, calorimetric assay was carried out by means of poloxamer/KI 3 interactions. This has been made possible since we demonstrated that DOPC presence does not influence the quantification of poloxamer by such a technic (results not shown). The estimated percentages of entrapped poloxamer for the filtrated HLP in and HLP out formulations were 67% and 45%, respectively. The distinguishable data between these two formulations confirm the TEM images previously described. Indeed, HLP in have higher amount of entrapped poloxamer than HLP out. Additionally, the results obtained us to interpret the DSC data.
Results mRNA expression of ABC transporters in resistant NCI-H295R and K562/R7 tumour cell lines RT-qPCR experiments made on NCI-H295R cells showed that P-gp/ MDR1 mRNA was the major product (1525 copies, normalised by G3PDH) whereas very low amounts of mRNAs were expressed for the other ABC transporters MRP1 (ABCC1) (0. 6 copy/G3PDH), BCRP (ABCG2) (0. 2 copy/G3PDH) and MRP2 (ABCC2) (0. 02 copy/G3PDH). These levels are much lower than reported for K562/R7 cells  15  but remain in similar ratios. The presence of P-gp in the two NCI-H295R and K562/R7 cell lines was confirmed by Western blot using C219 anti-P-gp antibody (data not shown). Measurements of the cytotoxicity of doxorubicin in K562/R7 cells in the presence of steroid modulators using a [ 3 H]thymidine assay Cytotoxicity of doxorubicin in NCI-H295R and K562/R7 cells was measured by a [ 3 H]thymidine incorporation assay less prone to steroid interferences than the MTT assay previously employed for non-steroidogenic K562/R7 cells  15  , owing to the risk of steroid interactions with the mitochondrial succinate dehydrogenase involved in MTT reduction  20.
Acknowledgements Jian Wang  greatly thanks  Chinese Scholarship Council  ( CSC ) for support. Parts of this work were carried out within the framework of  ALIBIOTECH (Agroalimentaire et Biotechnologie, Nord Pas-de-Calais region) program. The authors thank also the  Haut de France region, FEDER (Fonds européen de développement régional) ,  Conseil Départemental de l'Ain, and Bourg en Bresse Agglomération  for their financial supports.
Implant characterization The diameter of the implants was measured with a SMZ-U microscope (Nikon, Tokyo, Japan), equipped with an AxioCam ICc1 camera and the Axiovision Zeiss Software (Carl Zeiss, Jena Germany). The practical drug loading was determined as follows: Samples were dissolved in 5 mL of a 1:4 (v/v) ethanol:acetonitrile mixture. The drug content of the solutions was analyzed using a Thermo Fisher Scientific Ultimate 3000 Series HPLC, equipped with a LPG 3400 SD/RS pump, an auto sampler (WPS-3000 SL) and a UV-Vis detector (VWD-3400RS) (Thermo Fisher Scientific, Waltham, USA). Samples were centrifuged for 2. 5 min at 10,000 rpm (Centrifuge Universal 320; Hettich, Tuttlingen, Germany) and filtered with a 0. 45 µm PVDF syringe filter (Millex-HV, Merck Millipore, Tullagreen, Ireland).
, 2018) , complementing, rather than duplicating, national pharmacovigilance initiatives. WHO also launched a global aDSM database to collect a standard set of variables including anonymised individual-level patient data on serious AEs  (Halleux et al. , 2018) , and provided clear guidance on how to implement aDSM at a national level  (World Health Organization, 2015). National TB Programmes faced difficulties in implementing aDSM and contributing to the global database. Taking advantage of a newly implemented global network (Global Tuberculosis Network-GTN)  (Borisov et al. , 2017; Rossato Silva et al. , 2018)  a large aDSM project was launched to demonstrate the feasibility of implementing national aDSM registers. The GTN research addressed clinical centres with the goal of assessing the safety and tolerability profile, as well as the effectiveness of anti-TB drugs and regimens in MDR-TB patients treated with new drugs (bedaquiline, delamanid) worldwide.
The AEs of any drug involved in the treatment regimen were prospectively collected, ensuring a probabilistic mechanism of causality assignment (e. g. attribution of the AE to a specific drug based on its evidence-based profile). The data collection form in an electronic format was based on the WHO-recommended template, although more clinical details were requested  (World Health Organization, 2015). This article reports on the initial results of the aDSM project. As of January 31st 2019 (interim analysis), 41 centres in 27 countries (Figure  1 , Table  1 ) provided aDSM information on new anti-TB drugs: 14 in Europe, 6 in Latin America, 4 in Asia, 2 in Africa, and 1 in Oceania. 5 countries participated in the aDSM project although no case has yet been treated with bedaquiline and/or delamanid.
Acknowledgements The project is supported by the  Global Tuberculosis Network  (GTN; Committees on TB Treatment, Clinical trials and Global TB Consilium) and was part of the  European Respiratory Society Latin American  project in collaboration with  ALAT (Asociación Latino Americana de Torax -Latino American Thoracic Association)  and  SBPT (Brazilian Society of Pulmonology and Tuberculosis). This article belongs to the scientific activities of the  WHO Collaborating Centre for Tuberculosis and Lung Diseases, Tradate ,  ITA-80 ,  2017-2020-GBM/RC/LDA.
METHODS DECISION trial design and outcomes A comprehensive description of the inclusion and exclusion criteria, methods, and primary results of the phase III DECISION trial (NCT00984282; EudraCT 2009-012007-25) has been published elsewhere. 2 Briefly, patients were ≥ 18 years of age and had locally advanced metastatic RAIrefractory DTC that had progressed during the previous 14 months (according to Response Evaluation Criteria in Solid Tumors). 2  Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate bone marrow, hepatic and renal function, and serum thyroid-stimulating hormone level < 0. 5 mL U/L. Patients were randomized to either sorafenib 800 mg/day (400 mg twice daily (b. i. d. )) or matching placebo b. i. d. administered without food in a 28-day cycle.
DISCUSSION PK analysis It is tempting to speculate about the underlying cause of the higher sorafenib exposure in the DECISION trial compared with other studies. Obvious external reasons like different assays or different formulations have been investigated and can be ruled out. The comparison of the available PK data from all eight studies in patients with cancer (Figure  S1 ) illustrates that there were also patients with HCC and RCC who had unusually high plasma concentrations. Furthermore, as the single PK sample was obtained in the DECISION trial after unsupervised drug intake, it cannot be ruled out that patients may have taken their drugs shortly before visiting the clinic but recorded intake to be earlier. This could result in higher drug exposure than expected on the basis of the recorded time after dose.
Then, the influence of exposure on the hazard was tested by including the selected exposure covariates in the hazard model as continuous variables. The stratified pc-VPCs, however, were only stratified by exposure above and below the population median. Although it would have been more informative if pc-VPCs allowed the direct comparison between observed and model-simulated events under the influence of a continuous variable, such detailed qualification would have required the subdivision of exposure into more than two categories with fewer subjects and wider CIs, and the resulting display would have been less informative. Although dosing-related exposure parameters could be obtained directly from the clinical database, the AUC 12 measures for 156 patients were obtained from a single PK measurement, the patient's sex, the individual dosing history, and the individual post hoc estimates of the PK parameters derived from the population PK model.
Acknowledgments. Scientific writing support was provided by  Lisa M. Klumpp Callan, PhD , and  Alan J. Klopp, PhD , CMPP, of  C4 MedSolutions, LLC (Yardley, PA ), a  CHC Group company. Funding. The study was supported by  Bayer HealthCare Pharmaceuticals and Onyx  (a wholly owned subsidiary of Amgen). Scientific writing was funded by  Bayer HealthCare Pharmaceuticals.
pharmacoepidemiology, pharmacoeconomics. This enumeration gives a global picture of different scientific areas, which are however dealing with the same question. Another mindset should be a global interactive and continuous approach, which could be designed as "human pharmacology". An original and attractive way to illustrate this continuous approach is to combine pharmacodynamics and pharmacovigilance and/or pharmacoepidemiologic data. Coupling disproportionality analyses in pharmacovigilance databases or computerized health databases, with pharmacological characteristics of drugs (receptor affinity, for example) allows to investigate in humans, the mechanism of adverse drug reactions. Examples of such analyses investigating the risk of movement disorders, diabetes related to psychoactive drugs, or the risk of adverse cardiac outcomes with different drugs (classical drugs or protein kinase inhibitors) are given.
Brief overview of disproportionality analyses in large pharmacovigilance databases During the last decades, the databases collecting suspected adverse drug reaction (ADR) reports had grown, reaching sizes of more than several thousands or millions, thus making routine and regular quantitative screening a necessity. Data mining in these large databases has become a necessity in order to help pharmacovigilance systems to identify early signals for specific ADRs. Various statistical measures have been proposed for the application of computer-assisted quantitative signal detection procedures. Data mining encompasses a number of statistical techniques, including cluster analysis, link analysis, deviation detection and disproportionality assessment, which can be used to determine the presence of and to assess the strength of ADR signals.
Disproportionality in large pharmacovigilance databases is often investigated under the scope of a case-non case method, in which cases of a given ADR are compared to non-cases (other spontaneous reports except this given ADR) regarding prevalence of exposure to specific drugs and/or classes of drugs. Results are presented in the form of a reporting odds ratio (ROR) or a proportional ADR reporting ratio (PRR), the interpretation of which makes it possible to identify drug safety signals  [4, 5] , or to rank different drugs for a specific ADR risk. Many studies have been conducted at the international level, with data from the World health organization (WHO) database  [6] , the Food and drug administration (FDA) adverse event reporting system (FAERS), the European medicines agency (EMA) Eudravigilance database, or national pharmacovigilance databases  [7, 8].
Exploring the implication of neurotransmitter receptors in adverse drug reactions of psychoactive drugs Sekine in 1999 investigated the correlations between in vitro affinity of antipsychotic drugs (AP) to various receptors and clinical incidence of their adverse drug reactions  [10]. For that purpose, they analyzed safety data of 17 AP available in Japan. From both post-marketing ADR databases and the investigational clinical trials of eight pharmaceutical companies with data collected from 1960 to 1995, they estimated the frequency of 7 different ADR (akathisia, dyskinesia, tremor, rigidity, drowsiness, hypotension and dry mouth). Affinity constants (K i ) of the respective drugs toward dopamine D1 and D2 receptors, alpha1-adrenoceptors, histamine H1 receptors, serotonin 5HT2 receptors and muscarinic receptors were obtained from the literature, among studies determining these K i using rat brain synaptosomes.
Relationships between in vitro receptor-binding properties and in vivo incidences of the respective types of antipsychotic-related ADRs were analyzed using Spearman's rank correlation. They found statistically significant correlations between Ki values for dopamine D2 receptor and akathisia and dyskinesia as well as between the Ki values for alpha1-adrenoceptor and histamine H1 receptor and drowsiness and dry mouth. According to these results, the authors concluded that preclinical receptor-binding data might be useful for predicting not only in vivo antipsychotic potency but also clinical incidence of some ADRs. According to the results regarding D2-receptors affinities, they suggested that newly developed antipsychotic drugs with more potent and selective antagonist activity against the dopamine D2 receptor might not necessarily be associated with a lower incidence of extrapyramidal ADR, which was confirmed later by a study conducted on the WHO international pharmacovigilance database, Vigibase ®  [11].
The findings of this study supported that AP blocking both histamine H1 receptors and 5HT2C receptors are more frequently involved in drug-induced diabetes than that observed with other APs, and therefore that the role of these properties must be specifically anticipated when predicting the risk of glycemic and metabolic effects of candidate APs. More recently, researchers have investigated the possible receptor/transporter mechanisms involved in the risk of diabetes related to antidepressant drug use, through a disproportionality analysis of the FDA adverse events spontaneous reporting system database  [13]  and in Vigibase ®  (14). In the FDA database, authors extracted data from 2004 to 2017 using OpenVigil2 and calculated adjusted reporting odds ratio (aROR) for reporting diabetes for 22 antidepressant drugs.
The pharmacodynamic profile was extracted using the PDSP and Union of basic and clinical pharmacology / British pharmacological society (IUPHAR/BPS) databases and the occupancy to receptors (serotonin, α adrenergic receptors, dopaminergic, muscarinic, histamine) and transporters (SERT, NET, DAT) was estimated similarly to previous studies  [11, 12]. The relationship between aROR for diabetes and receptor occupancy investigated with Pearson's correlation coefficient and univariate linear regression suggested that higher degrees of occupancy to muscarinic receptors and H1 receptors might be a plausible pharmacological mechanism for antidepressant-induced diabetes. In this study, six imipraminic antidepressants were found associated with type 2 diabetes: nortriptyline, doxepin, imipramine, sertraline, mirtazapine and amitriptyline  [13].
Exploring the role of specific targets on the occurrence of cardiovascular adverse reactions To the best of our knowledge, one of the first application of the combination of pharmacodynamics data and disproportionality analysis in the WHO international pharmacovigilance database was performed by De Bruin et al in 2005  [15]. Drug-induced prolongation of the QTc-interval usually results from concentration-dependent blocking of cardiac human ether a go-go-related gene (hERG) potassium channels. The authors were interested in how inhibition of hERG potassium channels may lead to serious ventricular arrhythmias and sudden death observed in the real life context. For this purpose, they studied the quantitative anti-hERG activity of pro-arrhythmic drugs as a risk factor for this outcome, with a two-step analysis.
In the first step, they identified all case reports of suspected adverse drug reactions with known anti-HERG activity received by the International drug monitoring program of the World health organization-Uppsala monitoring center (WHO-UMC) up to the first quarter of 2003 and recorded in the international pharmacovigilance database (which was not yet called "Vigibase ® "). Cases of interest were all reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia, which were designed as "cases" and compared to all other cases (as non-cases), to calculate reporting odds ratios (ROR). The anti-hERG activity of the study drugs was regarded as the exposure. Anti-HERG activity was defined as the free plasma concentrations attained during clinical use (ETCP unbound) divided by the concentration which inhibits 50% of the potassium channels (IC50).
Anti-hERG activities of all study drugs which were assigned as 'suspect' were assessed. The authors hypothesized that increasing ETCP unbound/IC50 ratio led to an increased risk of an adverse event of interest. To control for potential confounding factors, the estimation of ROR was done by adjusting on several secondary factors including age, sex, several concomitant diseases (heart disease, pulmonary disease, and diabetes mellitus), pharmacokinetic drug-drug interactions, concomitant use of drugs which may lower blood potassium levels, year of reporting, and time since first marketing for each respective drug. Results highlighted a significant association between the anti-hERG activity of drugs (with an ROR of 2), measured as log10 (ETCP unbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHOinternational pharmacovigilance database.
These findings confirmed the value of pre-clinical hERG testing to predict pro-arrhythmic effects of drugs. Other authors investigated the same question whether non-cardiovascular hERG channel blockers were associated with an increased risk of sudden cardiac death and whether hERG-channelinhibiting capacity should be an indicator for this risk  [16] , not investigated through a pharmacovigilance database. Indeed, the originality of this study was that it was performed in the Integrated Primary Care Information database, a longitudinal general practice research database in Netherlands. A case-control study was performed, matched for age, gender and calendar time. Odds ratios were calculated with conditional logistic regression. The hERG-channel-inhibiting capacity of the different drugs, defined as the effective free therapeutic plasma concentration (ETCP unbound divided by the concentration that inhibits 50% of the potassium channels (IC50) and computed in the same way that in the De Bruin 's study  [15]  and was compared according to the risk of sudden cardiac death among 1424 cases and 14 443 controls.
Conclusion These different examples underline the importance of coupling disproportionality analyses in pharmacovigilance databases or pharmacoepidemiologic studies in large health care databases, with pharmacological characteristics of drugs (receptor affinity, for example); The PE-PD method could be interesting not only to better understand the mechanisms of adverse drug reactions but also to prevent the use or the development of drugs susceptible of inducing a given adverse drug reaction. The increasing number of research works investigating this topic underlines the importance of this relatively novel approach, which gives significant inputs for the better appraisal of drug safety.
in March 2015 and the package leaflet of Selincro® in September 2016 on this misuse. Material and method. -We analyzed the observations regarding a use of nalmefene with an opioid between September 2014 and August 2017 in the French pharmacovigilance database and the laboratory. Results. -The combination nalmefene and methadone was reported in about half of the cases (46/90). Observations were highest between October 2015 and March 2016 (29/90) and then decreased. Those with self-medication have increased. From October 2016, declarations become rarer. Conclusion. -The effect of modifications in the SPC and the package leaflet on the use of nalmefene with ODS was real and progressive. KEYWORDS Nalmefene; Opioids; Contraindication; Pharmacovigilance Résumé Introduction. -Le nalméfène, antagoniste opiacé, provoque un syndrome de sevrage chez le patient exposé à un agoniste opiacé.