dataesr/scientific-paragraphs-categorization huggingface dataset:
On the other hand, the false positives were due to (1) imprecise normalization of symptoms to MedDRA terms, (2) spelling and grammatical mistakes in colloquial expression. In our dataset, the proportion of drug-event combinations of methylphenidate with one, two, three and four or more reports was  64. 1, 17. 9, 15. 4, and 2. 6% respectively, compared to 50. 6, 27. 8, 6. 7, and 14. 9% for all drug-event combinations, showing that methylphenidate is a less than average reported medication and that most of the ADRs are of very small frequencies, which makes it unsuitable to apply signal detection methods with criteria "3 or more cases" as decision rule. As our main objective was to illustrate with methylphenidate our methods of using text-mining tools for social media data, but not to compare different signal detection methods or to compare signals of methylphenidate with other drugs, we just listed the signals of methylphenidate with four most common used signal detection methods based on disproportionality, and did not explore all the signals in this work.
Conflict of Interest Statement: The Vidal drug database is owned by the Vidal Company, which employs SP. The Luxid Annotation server and the Skill Cartridge are owned by the Expert System Company, which employs CH. Kappa Santé, the company that developed the Detec't tool, employs CF, PF, SS, and NT. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Image analysis and quantification of radioactivity uptake were performed using PMOD ® software (version 3. 5, PMOD Technologies LLC, Switzerland). A 5 mm diameter sphere was drawn on the upper part of the median lobe of the liver to generate the corresponding time-activity curves (TACs) with a time frame duration of 0. 25 min; 0. 5 min × 2; 0. 75 min; 1 min × 4; 1. 5 min; 2 min × 4; and 2. 5 and 3 min × 4. Radioactivity was corrected for carbon-11 decay, injected dose, and animal weight to express the measurements in standardized uptake value (SUV).
Data Analysis. Liver exposure to [ 11 C]metoclopramide was estimated in all conditions using the mean area under the curve of the tissue radioactivity from 0 to 30 min (AUC; SUV•min). Imaging data were interpreted in the light of [ 11 C] metoclopramide plasma kinetics measured from 0 to 60 min, previously reported in the same experimental conditions (n � 3 animals per condition)  [14]. [ 11 C]metoclopramide AUC in plasma from 0 to 60 min was calculated in all conditions to assess the respective impact of pharmacologic dose and P-gp inhibition on [ 11 C]metoclopramide plasma exposure. Plasma AUC was corrected for injected radioactivity and animal weight (SUV•min units) and is therefore inversely correlated to [ 11 C]metoclopramide plasma clearance (plasma clearance � dose/AUC plasma ). e mean plasma kinetics of parent [ 11 C]metoclopramide obtained in each respective condition (4 conditions, n � 3 per condition)  [14]  were fitted using a one-phase exponential decay function.
Statistical Analysis. Statistical analysis was performed using the GraphPad Prism 7. 0 software (GraphPad Inc. , CA, USA). Variance homogeneity was assessed using Levene's test (p > 0. 05). Data were compared using a one-way Contrast Media & Molecular Imaging ANOVA followed by a Tukey post hoc test. A result was deemed significant when a two-tailed p value was less than 0. 05.
Acknowledgments e authors thank  ierry Lekieffre  for technical assistance. Catriona Wimberley  kindly reviewed the English text. Sylvain Auvity received a public grant overseen by the  French National Research Agency (ANR)  as part of the  "Investissements d'Avenir" Program, through the "Lidex-PIM " Project funded by the  IDEX Paris-Saclay ,  ANR-11-IDEX-0003-02. is work was performed on a platform of  France Life Imaging Network partly funded by the grant  " ANR-11-INBS-0006. ".
| Measurements Following sampling, the tape is positioned onto a flat and rigid cardboard of a black background (nil luminance value, L*=0). A scanner (Scanjet G4010, HP, USA) allows the image of the tape to being recorded and stored. (Settings: Original Type: Photo, File Format: JPEG, Resolution: 600 dpi, Sharpness: Sharpen) Image is further selected from root up to the distance where sebum cannot be any more detected. The progressive decrease in blackness along the tape is quantified as black levels (=gray levels of a virgin F I G U R E 2 Illustrations of the hair sebum sampling procedure, from root to longer distances (A) and appearance of an applied mat tape post sampling (B) (A) (B) tape minus gray levels of a sampled tape), using the Photoshop™ CS4 Extended software. Repeated readings of the same tape led to comparable values of gray levels, ie, of low (2% to 3%) coefficients of variation (SD/mean x100), irrespective with the warming time of the scanner.
| Agreement of measurements with selfdeclarations of subjects Forty-seven subjects were selected for their different selfdeclarations with regard to their own feeling of hair greasiness: 23 self-declared presenting low hair greasiness, whereas 24 complained of greasy scalp or hairs. Sebum amounts were determined in the same conditions as mentioned above at 24 and 48 hours. Figure  7  summarizes the data obtained on these two cohorts, indicating that the values of a. u. c statistically differ (P <. 0005), at both times. The "greasy scalp" group shows increased values by about 46% between 24 and 48 hours, whereas about twice more (+119%) in the "nongreasy scalp" cohort. Of note, at 24 hours, the greasy scalp cohort shows a much higher (about twice) and significant sebum-coating than the one observed in the "nongreasy" scalp cohort.
All the participants benefited from a specific centralized training in order to harmonize their practices in each period. This training was performed over three days, the week before the study started. After data collection, controls will be carried out to ensure that pharmaceutical interventions have not been misclassified. Patients aged at least 65 years, hospitalized in one of the participating care units, and having given their agreement to be called for a 30-day and 90-day follow-up could be enrolled. In each 14-day period, 15 patients will be recruited in each care unit no more than 24 h or 48 h after admission, respectively, in the week or weekend/public holiday. Finally, a total of 630 patients will be enrolled in the study. We will exclude patients with a hospital stay > 21 days, as there is a risk of there being too many medication modifications during the hospital stay.
After the follow-up, the medication reconciliation and review will be retrospectively conducted by the clinical pharmacists who have participated in the interventional period in each investigator center. Finally, experts will retrospectively assess the potential clinical harm of each medication error detected. In the interventional period, a senior clinical pharmacist based in the care unit will perform medication reconciliation by comparing the BPMH to the AMO and notifying the prescriber of any possible discrepancies. He/She will collect all relevant bioclinical data and perform medication review of the AMO by using the STOPP and START tools  [18] , the French list of potentially inappropriate medications in elderly  [36] , and the PAPA guide about medication prescription adapted to the elderly, published by the French Society of Geriatric and Gerontology  [37].
Data management Only persons who will be involved in the research project and identified will have access to the data entry software: OpenClinica. The data entry in the electronic case report form (e-CRF) will be controlled and formatted to prevent the entry of data out of bounds or outliers. In the event of an input change, traceability and activity tracking is ensured. An electronic signature committing the responsibility of the investigator of each center will allow the validation of the visit and the e-CRF. This software is hosted on a website within Nîmes University Hospital. Access to this application is secured and is via http://www. bespim. fr with a login and password. The data collected through this software is backed up daily on a secure network. The network is connected to the Internet and access is protected by a firewall.
If the results of global cost are unchanged, then the robustness could be deduced. The Tornado diagram will be used to evaluate and sort the most sensitive parameter. The Department of Biostatistics, Epidemiology, Public Health, and Health Economics of Nîmes Hospital Center will perform the statistical analysis using R. 4. 0. (R Development Core Team [2017], R Foundation for Statistical Computing, Vienna, Austria; https://www. r-project. org) and TreeAge Pro 2017 (TreeAge Software, Williamstown, MA, USA; https://www. treeage. com).
Background Hepatotoxicity may be a concern when prescribing antidepressants. Nevertheless, this risk remains poorly understood for serotonin and noradrenaline reuptake inhibitors (SNRIs: venlafaxine, milnacipran, duloxetine) and 'other antidepressants' (mianserin, mirtazapine, tianeptine and agomelatine), particularly in comparison with selective serotonin reuptake inhibitors (SSRIs: fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, escitalopram), which are by far the most commonly prescribed antidepressants. Objective We quantified the risk of serious liver injury associated with new use of SNRIs and 'other antidepressants' compared with SSRIs in real-life practice. Methods Based on the French national health insurance database, this cohort study included 4,966,825 individuals aged 25 years and older with a first reimbursement of SSRIs, SNRIs or 'other antidepressants' between January 2010 and June 2015.
Data Sources A cohort study was conducted using the French national health insurance database [Système National d'Information Inter-Régimes de l'Assurance Maladie (SNIIRAM)]. Individuals were enrolled from January 1, 2010 to June 30, 2015. This health insurance database covers almost the entire French population (65. 3 million inhabitants) with different affiliation schemes based on types of employment. For the present study, the data relating to beneficiaries of the main scheme (the general scheme covering approximately 77% of the French population) were used. The SNIIRAM comprehensively records the following with corresponding dates: outpatient drugs [Anatomical Therapeutic Classification (ATC) codes] and medical devices prescribed, reimbursed services and procedures, as well as demographic data such as age, sex, area of residence (postcode), complementary universal health insurance (free access to healthcare for people with an annual income < 50% of the poverty threshold) and date of death.
The database does not stipulate the medical indication for each reimbursement. However, it includes information on severe and costly long-term disease (LTD) for which health expenses are fully reimbursed; these are coded according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) and the date of LTD diagnosis is recorded. An anonymous unique identifier for each patient links SNIIRAM information to the national hospital discharge database [Programme de Médicalisation des Systèmes d'Information (PMSI)], which covers all hospitals and provides reasons for admission (in the format of the ICD-10) and surgical procedures. Previous observational studies using the SNIIRAM and the PMSI have been published elsewhere  [11] [12] [13] [14] [15] [16] [17].
Secondary Approach: Study Using a Case-Time-Control Design A study using a case-time-control design was undertaken as a secondary approach to challenge the conclusions of the main cohort approach and to better control for residual unmeasured confounding; that is, related to variables not directly recorded in automated databases and considered as unchanged over the study period (e. g. , disorders related to alcohol abuse, smoking, morbid obesity etc. ). One analysis was performed for each antidepressant of interest compared with SSRIs. In each analysis, incident cases of serious liver injury occurring between September 1, 2011 and June 30, 2015 were identified using the same criteria as for the main cohort approach. Exposure to antidepressants of interest and SSRIs was measured both during a 'risk' and a 'reference' period corresponding respectively to the 6 months preceding the liver-related event date and to the period from the 9th to the 15th month before this date, a 3-month wash-out period separating these two time windows.
g. , launch of a new drug, introduction of safety warnings, seasonality, etc. ). Therefore, for each case, 20 controls of the same sex and age (± 1 year) were randomly sampled from the 'non-case' population. Exposure was measured as for the matched case, and, taking into account exposure temporal trends, ORs were derived from the coefficient of the interaction between exposure and case or control status introduced in the conditional logistic regressions models  [28]. All statistical tests were two-tailed with an α-risk of 5%. Statistical analyses were performed using SAS Enterprise Guide software, version 7. 1 (SAS Institute Inc. ).
To our knowledge, the present study is the first to compare the risk of the hepatotoxicity of antidepressants both in real life and on the basis of such a large (5 million treatment initiators) representative nationwide sample. Its sample size warranted identifying rare outcomes such as serious, including fatal, DILIs. The study also utilized the large amount of information provided by the SNIIRAM database to control for the main potential confounders by means of propensity scores, thereby providing more reliable estimates compared with classic multivariate models in the event of rare outcomes  [40]. It is also likely that using an active comparator minimized the influence of measured and unmeasured differences in patient characteristics linked with both antidepressant use and the risk of hepatotoxicity  [41].
The short chain dehydrogenase/reductase superfamily (SDR) is a large family of NAD(P)H-dependent enzymes found in all kingdoms of life. SDRs are particularly well-represented in plants, playing diverse roles in both primary and secondary metabolism. In addition, some plant SDRs are also able to catalyse a reductive cyclisation reaction critical for the biosynthesis of the iridoid backbone that contains a fused 5 and 6-membered ring scaffold. Mining the EST database of Plantago major, a medicinal plant that makes iridoids, we identified a putative 5β-progesterone reductase gene, PmMOR (P. major multisubstrate oxido-reductase), that is 60% identical to the iridoid synthase gene from Catharanthus roseus. The PmMOR protein was recombinantly expressed and its enzymatic activity assayed against three putative substrates, 8-oxogeranial, citral and progesterone.
Results Identification of PRISE family genes from P. major and protein expression. Based on sequence conservation with CrIS (GB JX974564) and Dl5ß-POR (GB AIF73578. 1) we searched GenBank for putative PRISE family members from P. major using PSI-BLAST  21. Although a complete genome of P. major is not yet available, an EST database is accessible and a gene annotated as a 5ß-POR was identified (ADG56541. 1) with an E value of 3e -164 based on sequence identity to CrIS, with no other genes with significant homology in the search results  22. This is consistent with the high degree of sequence similarity between CrIS and 5ß-PORs from other plants  4. Given the known production of iridoids, the lack of a cardenolide pathway in P. major, and that some 5ß-PORs have been shown to also have IS activity  23  , we therefore reasoned that the gene annotated as a 5ß-POR from P.
None of these datasets yielded interpretable electron density for the ligand. We were, however, able to obtain higher quality ligand electron density using the PmMOR V150M mutant instead of wild type. PmMOR V150M replaces a small hydrophobic residue in the active site substrate-binding pocket with a larger residue, which is present in Dl5ß-POR (Fig. 3C ). We reasoned that this change in the active site might lead to better quality electron density for the substrate molecules by restricting the size of the ligand binding site. In the PmMOR V150M /NADP + /citral structure, the hydrophobic citral substrate is found in two distinct conformations, one of which is similar to the binding mode observed in the PmMOR 8-oxogeranial structure and a second conformation in which the molecule is flipped downwards into the active site (Fig.
Thus, it is likely that the enzyme is able to form both reduction products. The 1. 86 Å crystal structure of the ternary complex with NADP + and 8-oxogeranial and the 1. 46 Å ternary structure with citral shows the 8-oxogeranial molecule in the same relative position as citral with the same residues contributing to substrate sequestration. Thus, it is likely to be a physiologically relevant binding mode. Progesterone binding. PmMOR shares higher sequence identity to progesterone reductases and may represent a more promiscuous enzyme with greater substrate versatility than either the CrIS or Dl5ß-POR enzymes. To investigate this, we co-crystallized PmMOR V150M with progesterone and NADP +. Several datasets were collected which showed significant difference density in the Fo-Fc electron density maps.
The V150M point mutation yielded the best results (similar to what we observed for citral binding). Omit maps showed density in the active site, defining the location of the bound steroid (Fig. 6 ). Progesterone was modeled into this density, however, despite the relatively high resolution of the data (2. 56 Å). The resulting density was of poor quality, so the exact position of the ligand should be treated with caution. A second dataset of wild-type protein in complex with progesterone also yielded an extended difference map peak in the same region, into which progesterone could be modeled and refined, however the crystals diffracted to lower resolution and the map was of poorer quality. It is likely that the size of the pocket allows for significant movement of the ligand, and the observed density is an average of multiple conformations.
roseus iridoid synthase, with similar specific activity, but with a much higher K m of 368 μM vs. 4 μM, for PmMOR and CrIS, respectively. The relatively poor substrate specificity may be due to PmMOR being an evolutionary snapshot with promiscuous activity towards a variety of different molecules and the ability to perform simple alkene reductions as well as reductive cyclisation. Based on 1 H NMR characterization of the reaction of PmMOR with 8-oxogeranial, we could identify nepetalactol and observe a minor secondary product. Examination of the P. major genome reveals no other IS candidates based on homology to CrIS  22. In addition, searching the EST P. major database identifies a homolog to the C. roseus upstream enzyme in the iridoid pathway, 8-hydroxygeraniol oxido-reductase. Thus, it is likely that iridoid biosynthetic pathway recently characterized in C.
For determination of kinetic constants for the wild type enzymes (PmMOR and 5ß-POR) substrate concentrations were varied. Specific activity assays were performed using a substrate concentration of 1 μM and 0. 1 μg of protein, well above the K m as determined for the wild type proteins. The reaction was monitored by the reduction in absorbance of NADPH at 340 nm and measured using a Shimadzu UV-VIS recording spectrophotometer according to Geu-Flores 4. All assays were performed in quadruplicate. Results were analysed using Kaleidagraph software. Crystallization and data collection. The protein was crystallized using the hanging drop vapour diffusion method. Protein (wild type or PmMOR V150M ) at 16 mg/mL was pre-incubated for approximately 1 h with 1-5 mM NADP + and either 5 mM citral or 8-oxogeranial or a saturated solution of progesterone (<5 mM).
The reservoir conditions for wild type/NADP + /8-oxogeranial, PmMOR V150M /NADP + /progesterone and PmMOR V150M / NADP + /citral were 0. 1 M Bis-Tris Propane, 5% glycerol, and 16. 5% to 19% PEG 5000 MME. For the wild type PmMOR/NAD + /progesterone, crystals were obtained in 0. 1 M sodium acetate pH 4. 6, 0. 2 M ammonium acetate and 30% PEG 4000. Glycerol (15%) was added directly to the drops as a cryoprotectant, the crystals were harvested and flash frozen in liquid nitrogen. Data collection, processing, and refinement. All datasets were collected at 100 K on beamline ID23-2 of the ESRF, Grenoble, France. Indexing was performed using EDNA  38  and the default optimized oscillation range and collection parameters used for data collection. The data sets were integrated and scaled using the programs XDS and XSCALE  39, 40.
Molecular replacement was performed using PHASER  41  with the structure of the D. lanata 5ß-POR as a search model (PDB 2V6F) for the PmMOR apo dataset. All subsequent datasets were phased using the PmMOR apo structure as a molecular replacement model. All refinements were performed using BUSTER  42  and PHENIX  43. The structures are deposited under PDB codes 5MLH, 5MLR, 5MLM and 6GSD for PmMOR/ NADP + /8-oxogeranial, PmMOR V150M /NADP + /citral, PmMOR V150M /NADP + /progesterone and PmMOR/NAD + / progesterone, respectively. Omit maps were produced by deleting the ligand, followed by phenix. dynamics to introduce random coordinate shifts followed by refinement in BUSTER. Thin Layer Chromatography. Enzyme reactions were monitored using TLC assays and R f values compared to starting material and product.
Evaluation of the kinase inhibitory activity of lead compounds 15 and 22 Due to the common reports of bisindolylmaleimides as kinase inhibitors and the reported polypharmacology of the class, as discussed in the introduction, the standard maleimide 15 and novel hydroxymaleimide 22 were evaluated by a preliminary kinase screen. 28 SK-3β has been shown to reduce apoptosis signals it may be useful for the treatment of Alzheimer's disease and protection against cell death. 29, 30 In addition to the data above, there are reports of bisindolylmaleimide involvement with GSK-3β in the regulation of murine embryonic stem cell self-renewal so it is an obvious starting point. 27 nterestingly, inhibitors of GSK-3 have also been shown to enhance apoptotic signal transduction induced by TRAIL (TNF-related apoptosis inducing ligand TRAIL).
Acknowledgments The authors would like to acknowledge the  Irish Research Council for Science, Engineering and Technology  and the  Ulysses scheme  for funding this research, the  National Cancer Institute (NCI)  screening program for 60-cell line testing. The authors also thank the  Cancéropôle Grand-Ouest  (axis: Natural sea products in cancer treatment), the  Ligue Contre le Cancer  ( CD29 ,  35 ,  22  and  75 ),  GIS IBiSA  ( Infrastructures en Biologie Santé et Agronomie, France ) and  Biogenouest (Western France life science and environment core facilty network) for supporting KISSf screening facility (Roscoff, France ). This article is based upon work from  COST Action   CA15135 , supported by  COST.
Clinical data were obtained from medical records and associations with receipt of antibiotics in the prior 12 months made. To control for confounding and assess for modifying effects of healthcare setting type, multivariable logistic regression models were constructed with interaction terms included. Results: Of 3483 patients, 56% were from the AH, 23. 4% from ITC and 20. 4% from LTC institutions. Age was similar between institutions(AH:mean 70. 5[SD 15. 1] years; ITC:70. 5[12. 6]; LTC:69. 9[14. 0]; P = 0. 16). Patients in the AH had more comorbidities, with 26. 6% having a Charlson's comorbidity index > 5, compared to 12. 6% in ITC(P < 0. 001) and 13. 2% in LTC(P < 0. 001) institutions. Significantly more patients in the AH(84. 4%) than ITC(73. 2%)(P < 0. 001) and LTC(58. 8%)(P < 0. 001) had received antibiotics in the preceding 12 months.