dataesr/scientific-paragraphs-categorization huggingface dataset:
Background Drug-related problems are an important cause of morbidity and mortality and a significant burden on healthcare resources. A high rate of adverse drug reactions (ADRs) has been demonstrated in hospitalized patients  [1] [2] [3] [4] , potentially leading to death. As patients with severe or acute unexpected symptoms frequently present to emergency departments (EDs), some epidemiological studies of ADRs have been successfully conducted in this setting, showing that approximately 10-17 % of ED visits were related to an ADR  [5, 6]. The definition of self-medication is still debated. According to the National Library of Medicines' MeSH (Medical Subject Headings) database, self-medication refers to self-administration of a medication not prescribed by a physician, or in a manner not directed by a physician.
The diagnosis of ADR and the drug causality assessment were then documented in the e-CRF. If necessary, notification of cases of drug toxicity was provided to the pharmacovigilance regional centre at the discretion of the local investigator. All contentious issues transmitted by local investigators, every ADR-SM case (whether contentious or not), and some randomly assigned files were reviewed by an expert committee comprised of therapeutics professors, clinical pharmacists and emergency physicians, whose meetings and minutes were managed by the clinical research pharmacist. Furthermore, the entire database was scrutinized by the clinical research pharmacist in order to detect each case potentially related to an ADR; the expert committee was asked to assess such cases and to confirm drug causality (in order to validate the main outcome).
Every local investigator was also asked to verify each subject file and to transmit all useful information regarding the possibility of an ADR to the expert committee. This committee was finally able to resolve each contentious case, and to validate the entire database. Last, the expert committee determined, for each ADR-SM case, the type of selfmedication leading to the adverse event: self-modification of a prescribed treatment, discontinuation of treatment, non-prescribed drugs, or a drug interaction with non-prescribed drugs (i. e. self-prescription).
The context and objectives of this study have generated some bias that requires discussion. Because of the focus of this study, the self-medication behaviours are explored by self-report, restricting those enrolled to patients able to answer the standardized questionnaire. Therefore, the sample of included patients could not exactly represent the entire ED population, particularly along the lines of the severity of illness. Moreover, the collection of declarative data could lead to recall and reporting bias. The known discrepancies in self-medication access, depending on local rules and on the financial ability of patients to pay for their drugs, could also have influenced our results. Despite these recognized limits, the overall quality of this survey renders our results strong enough to be considered as quantitative of the frequency of ADR-SM in patients admitted to the ED.
Acknowledgments The authors thank the MEDQUAL office for its logistic and technical support,  Bioscience Writers ,  LLC , for editing support and  Dr Herve  ´Maisonneuve for his contribution to the manuscript. We are also grateful to the  National Medicine Academy  and the  French Society for Clinical Pharmacy  for their support, to the  French Association of Therapeutics' Professors (APNET)  for promoting this study, and to all members of the collaborative study group. This article was published in a supplement sponsored by the  Foundation for the National Institutes of Health (FNIH). The supplement was guest edited by  Stephen J. W. Evans. It was peer.
04 m 2 ; mean number of traps per station: 355. 25; mean area per station: 28. 42 m 2 ; mean number of traps per 10-day period: 284). Sampled sandflies were placed in a 90°alcohol solution and identified. For each species, imago densities were calculated on the basis of the number of sandflies (P# + $) counted per m 2 of sticky paper  [2, 23, 27, 32]. The statistical analysis was focused on P. ariasi and P. perniciosus, the only confirmed vectors sampled at the site, using Kolmogorof-Smirnov, Wilcoxon and Friedman, Cochran and McNemar tests (SYSTAT Ò 9 software)  [33, 35].
Acknowledgements. We warmly thank  Anne-Laure Ban  ˜uls,  Bulent Alten ,  Nathalie Barras ,  Jean Cousserans ,  Henri Descamps ,  Jean-Charles Gantier ,  Christian Jean ,  Nicole Leger ,  Michele Maroli ,  Georges Metge ,  Pierre Quezel ,  Joseph Trave  ´and  Marco Zito.
Y The significant differences in the antineoplastic activity values of structurally similar thiopyrano  [2,3-d] thiazol-2-ones 4e, 4f, and 4i encouraged us to investigate their molecular mechanisms of action. For this purpose, we have used an accessible online tool -the NCI COMPARE analysis  [16]. The COMPARE analysis evaluates the similarity of the compounds' cytotoxicity patterns with those of known anticancer standard agents and NCI synthetic compounds present in public databases  [17] [18] [19]. The COMPARE analysis revealed moderate correlations at the GI 50 level of the 4f pattern with panсratistatin (Pearson correlation coefficient, PCC = 0. 603), didemnin B (PCC = 0. 525), S-trityl-L-cysteine (PCC = 0. 473), and the compound 4i pattern with trimethyltrimethylolmelamine (PCC = 0. 473).
Acknowledgement We thank  Dr. V. L. Narayanan  from the  Drug Synthesis  and  Chemistry Branch ,  National Cancer Institute, Bethesda, MD, USA , for the in vitro evaluation of anticancer activity. Antimycobacterial data were provided by the  Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF)  through a research and development contract with the  US National Institute of Allergy and Infectious Diseases.
for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). Results In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1. 59 (95 % CI 1. 1-2. 2) for all NSAIDs pooled, 2. 3 (95 % CI 1. 2-3. 9) for ibuprofen, 1.
Patients and Methods The SALT study was a multicentre, multinational, casepopulation study  [8]  conducted in seven countries, and designed to provide estimates of the population rates of registration on transplantation lists for ALFT patients exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms of liver disease (index date). The study protocol was approved by the CHMP, the data protections authorities in each of the seven countries, and by Ethics Committees and Research and Development (R&D) committees as required  [9]. The study period for inclusion in the liver transplant registries was 2005-2007, the 3-year period preceding the last nimesulide referral to regulatory authorities. Data were collected from January 2009 to October 2011.
ALFT status was verified by the local transplant centre hepatologist, and validated by a national case classification hepatologist. For all ALFT cases, symptoms and dates, laboratory results, viral workups, autoantibodies, concomitant factors and diseases that could help to identify clinically relevant aetiologies, and drug exposure history were extracted from all available data and verified by the local hepatologist. Relevant documents were anonymized and scanned for further reference. Data were then reviewed and validated by the national case classification hepatologist, who also defined the date of onset of liver disease (index date) and classified patients as ALFT with or without an identified clinical aetiology. Typical identified clinical aetiologies were viral or autoimmune hepatitis, mushroom toxicity, vascular causes and other, as described in the medical charts.
g. diclofenac ? misoprostol) or paracetamol (e. g. paracetamol ? codeine) were attributed to the main component of interest (NSAID or paracetamol). When paracetamol was associated with an NSAID (e. g. fixed-dose paracetamol ? ibuprofen), the cases and sales were attributed to both drugs. Event rates are reported as the number of cases per billion DDD, and as the number of cases per million patient-years of treatment, with exact 95 % Poisson confidence intervals (95 % CI). All statistical analyses were performed using SAS software (SAS Institute, NC, USA), version 9. 1.
This assumes that the different NSAIDs included in the analysis were expected to be used in subpopulations with similar risk factors of developing ALF. Ibuprofen might be used in younger patients for a shorter duration of time  [21] , which could contribute to a lower event rate. The other NSAIDs are used in mostly similar populations in countries where this information exists  [21, 22]. Because we did not have access to the actual number of users in each country, we chose to use overall population exposure measures, in DDD or treatment-years. The same data source (IMS) was used for all countries and all NSAIDs or paracetamol. This includes all sales to pharmacies, including OTC resale, but not sales in supermarkets, convenience stores or petrol stations, which are possible in the UK, Ireland or The Netherlands.
Nevertheless, these two drugs did not seem to be associated with excess risk of hepatotoxicity in the present study. In other registries of drug-induced liver injury (DILI), antibiotics seem to be more often associated with DILI than NSAIDs. This might be related to the recording of less severe toxicity or cholestatic liver disease not leading to transplantation, which would not appear in our study. It might also be related to real differences in drug toxicity between countries, for unidentified reasons. We found a 2-to 3-fold higher event rate for nonoverdose paracetamol compared with all NSAIDs pooled, based on the same criteria used for NSAIDs. This has not been generally described, paracetamol toxicity being reported as essentially associated with overdose. There may be several reasons for this: OTC paracetamol is usually not recorded in claims databases or in medical databases; and in field studies there may be underascertainment or dismissal of non-overdose paracetamol exposure.
Acknowledgments The authors wish to thank all the physicians and staff at the transplant centres, all the patients whose acceptance of this study made it possible, and the various people in administrative positions, data protection, ethics and the  British R&D committees. The corresponding authors had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis, which was conducted independently from the funder. The manuscript was reviewed by  Philip Robinson, PhD , a medical writer employed by the  University of Bordeaux, Department of Pharmacology.
Except if we hypothesize that the sensitive skin syndrome should be provoked by different bacterial species in men and women we can exclude these germs as determinants of this disorder. Acinetobacter and Proteus were not detected in samples from sensitive skin patients and the percentage of Staphylococci even decreased. Consequently, although a total of 495 bacterial isolates was collected on sensitive skin patients, there was no detectable correlation between a phylum, a genus or even a dominant bacterial species and the sensitive skin phenotype. This is in contradiction with data showing that a partial elimination of the skin bacterial population is improving itch and pain in sensitive skin patients  (Masako et al. 2005; Berardesca et al. 2009). In order to understand these results, it should be essential to remember that bacterial virulence is highly variable  (Henderson and Martin 2011)  and that a same bacterium can switch from harmless to virulent under the effect of environmental factors, including host communication molecules  (Lesouhaitier et al.
Conflict of Interest This work was supported by public funds obtained in the framework of the FUI program Skin-O-Flor certified by the world's leading perfumery cosmetic network Cosmetic Valley. Elian Lati is employed by Bio-EC Laboratory and Luc Lefeuvre by the Dermatologic Laboratories Uriage. There are no patents, products in development of marketed products to declare. This does not alter our adherence to all MicrobiologyOpen policies on sharing data and materials, as detailed in the guide for authors.
Data analysis The data were entered in the software R version 2. 12. 0 (R Foundation for Statistical Computing, Vienna, Austria). The distribution of allelic families of msp-1 and msp-2 genes was determined by the number of PCR products corresponding to each family within the total number of samples. The number of patients with more than one amplified PCR fragment within the total population is defined as the frequency of polyclonal infections. The MOI was determined as the number of different msp-1 and msp-2 genotypes per isolate, and the mean MOI was calculated as the total number of detected P. falciparum msp-1, msp-2 genotypes/total number of infected children  [16]. Each codon was characterized as wild type (no mutation present), pure mutant (only mutant genotypes detected). Cases of mixed infection (wild type and mutant) were categorized as mutant throughout the analysis.
Demographic and parasitological data of the study population During five months, 1,642 asymptomatic children were screened, from which 214 positive samples for P. falciparum were collected on filter paper. The prevalence of asymptomatic parasitaemia detected by microscopy was 13%, P. falciparum being the only infecting Plasmodium species found. After the withdrawal of children above 15, 195 samples were selected for molecular analysis. Characteristics of the study population are detailed in Table  1. Children's ages ranged from two to 15 years (mean age: 7. 9 ± 0. 4 years). The parasite density ranged from 12 to 86,570 parasites/μl with a geometric mean density of 209. 6 (161. 2-272. 5). The parasite DNA from the 195 P. falciparum isolates were analysed for msp-1 and msp-2 genes. The efficiency of msp-1 and msp-2 genes amplification reactions with family-specific primers was 99% (193/195) and 99.
Future research priorities including strategies between the US Food and Drugs Administration and the European Medicines Agency These case histories illustrate why it is crucial for researchers and commercial organizations to obtain data from trials demonstrating any association between biomarkers and disease outcomes to enhance future endorsement and funding of diagnostic tests. The same holds for new targeted treatments. Alongside this, a cohesive vision of what personalized medicine will constitute must be developed. The instigation of groups such as the Personalized Medicine Consortium and European Medical Research Council and the combining of research group activities should help with this  [1, 16, 46, 47]. European initiatives such as Information and Telecommunication for the Future of Medicine  [202]  should also help with study design through developing methodologies incorporating multiple forms of evidence such as those from different genetic databases  [27].
Medico-economic assessment Cost-effectiveness studies will now be part of market access requirements for all drugs satisfying the selection criteria for medico-economic assessment. At the time of drug approval, the scope of assessment will be relatively narrow, and outstanding questions will be addressed during reassessments 5 years later or possibly earlier if warranted. Both HAS committees, the CT and the Economic and Public Health Assessment Committee (Commission Evaluation Economique et de SantePublique, or CEESP), will continue to work independently. Health economics data will be taken into account by the CEPS, and the price setting will take into account the results of the medico-economic assessment performed by the CEESP. In October 2011, the HAS published a guideline related to methodological choices for economic assessments.
Cell cycle analysis To measure the cellular DNA content, adherent cells transfected by si-Orai3 or si-CTL for 72-h were collected by trypsinization. Cells were pelleted, resuspended in PBS/EDTA, treated with 20 mg/ml RNase A (Sigma-Aldrich), and stained with 50 mg/ml of Propidium Iodide (Sigma-Aldrich). Samples were analyzed on BD Accuri C6 flow cytometer. The percentage of cells in different phases was calculated using FlowJo software (Tree Star, Inc).
Statistical analysis Data are presented as Mean 6 S. E. M. , ''n'' refers to the number of experiments. Statistical analyses were performed using Mann-Whitney or paired t-tests, as appropriate using Sigma-Stat 3. 0 (Systat Software, Inc. ). When more than two conditions were compared, a Kruskal-Wallis one way ANOVA was employed followed by Dunn's Method post-hoc tests using SigmaStat 3. 0 (Systat Software, Inc. ). Differences were considered significant at p,0. 05.
Reporting rates in those actually exposed patients and their 95% confidence intervals (CIs) were calculated. These rates were estimated by dividing the number of reports by the number of exposed patientyears; the number of patient-years, in turn, was calculated from sales data expressed as defined daily dose (DDD) per 1000 inhabitants per year -365 DDDs account for a patient treated per 1 year. These reporting rates were estimated on the assumption that the exposed population was large and the number of ADRs reports was small. Midi-Pyr en ees consumption data were obtained from the medical regional department of the French Health Insurance System (Caisse Nationale d'Assurance Maladie des Travailleurs Salari es: CNAM-TS); Italian consumption data were obtained from Cineca (Centro di Supercalcolo, Consorzio di Universit a); and Spanish data consumption was obtained from the CON-CYLIA database (Sistema de Informaci on de Farmacia.
Gerencia Regional de Salud de Castilla y Le on). Descriptive statistics were used to summarize the general characteristics of the reports for psychotropic drugs of interest and the reference group. To compare categorical variables between women and men, the Pearson's chi-squared test was used; a P-value of <0. 05 was considered statistically significant. The statistical analyses were performed with Epi-Info software (3. 5. 1 version).
Sequence analysis All sequences were retrieved from the Joint Genome Institute (JGI) database (http://genome. jgi-psf. org/programs/fungi/index. jsf) from the fungal genomic database MycoCosm. The sequences have been obtained with Blastp (BLOSUM matrix applying default parameters) using all P. chrysosporium GSTFuA sequences as template. Fungi showed in the phylogenetic analysis have been chosen according to their saprotrophic properties. The sequence of PcGSTFuA4 has been modified compared to the one available on JGI and the new sequence has been deposited to Genbank under the KC192375 identity number. Sequence alignments have been done using ClustalW and phylogenetic analysis were conducted using Muscle and MEGA5 (Neighbour-joining) programs  [11]. The pairwise deletion option was active to handle alignment gaps and the Poisson correction model was used for distance computation.
5 with an identical GSH concentration. Peroxidase activities were monitored as follows: 1 mM peroxide (hydrogen peroxide, terbutyl hydroperoxide or cumene hydroperoxide) in 30 mM Tris-HCl, pH 8. 0, was incubated in presence of 2 mM GSH, 200 mM NADPH, 0. 5 IU glutathione reductase. The activity was followed by monitoring the decrease in absorbance arising from NADPH oxidation in this coupled enzyme assay system showing the formation of oxidized glutathione (GSSG). All the reactions were started by addition of the purified enzyme (500 nM) and monitored with a Cary 50 UV-Visible spectrophotometer (VARIAN). To determine the catalytic properties of the enzyme, steady state assays were performed using variable substrate concentrations (from 10 mM to 10 mM) and the catalytic parameters were calculated using the GraphPadH software.
Inhibition Kinetics Competition assays between CcGSTFuAs and potential ligands were performed by measuring esterase activity on MUA without glutathione. Activities were monitored in a total volume of 200 mL containing 0 to 500 mM MUA and 0 to 10 mM of ligand. The reactions were started by the addition of purified enzyme (2 mM), and the catalytic parameters were calculated using the GraphPadH software. For noncompetitive inhibition, K i values were calculated resolving the non-linear noncompetitive inhibition equation: V maxInh = V max /(1+I/K i ); Y = V maxInh 6X/(K m +X). V max and K m represent the maximum enzyme velocity and the Michaelis-Menten constant without inhibitor, whereas V maxInh represents the maximum enzyme velocity for one concentration of inhibitor, and K i is the inhibition constant.
Crystallization, Data Collection, Structure Determination and Refinement Crystallization experiments of PcGSTFuA2 and PcGSTFuA3 were performed by the microbatch under oil (paraffin) method at 4uC and 20uC, respectively. Drops were prepared by mixing equal volumes (2 ml) of protein and precipitating agent solutions. TE buffered solutions of PcGSTFuA2 and PcGSTFuA3 had protein concentrations of 20 mg. mL 21 and 28. 3 mg. mL 21 , respectively. Suitable crystals for x-ray diffraction were obtained without optimization using Hampton crystallization screen 1. PcGSTFuA2 crystallized in condition 9 (0. 2 M ammonium acetate, 0,1 M sodium citrate tribasic dehydrate, pH 5,6 and 30% w/v polyethylene glycol 4,000) and PCGSTFuA3 crystals were obtained in condition 34 (0. 1 M sodium acetate trihydrate, pH 4.
6, 2. 0 M sodium formate solution). X-ray diffraction experiments were performed at 100 K with crystals soaked briefly in crystallization solution supplemented with 20% (v/v) glycerol prior to flash cooling. X-ray data sets were collected on beamline PROXIMA-1 at the French national Synchrotron facility SOLEIL (Gif-sur-Yvette, France). The data were indexed and processed using XDS  [13] , scaled and merged with SCALA from the CCP4 program package  [14, 15]. Both structures were solved by molecular replacement with MOLREP  [16]  using the coordinates of PcGSTFUA1 in complex with GSH (Protein Data Bank code 4G19). The models were refined using PHENIX  [17]  interspersed with manual inspection and corrections using COOT  [18]. The validation of both crystal structures was performed with MOLPROBITY  [19].
Genomic analysis of GSTFUA coding sequences The fungal genomic portal access Mycocosm on JGI is currently providing an increasing dataset of fungal genome sequences. GSTFuA sequences have been collected from the JGI database in all available genomes of Chytridiomycota, Mucoromycotina, Saccharomycotina, Pezizomycotina, Pucciniomycotina, Ustilagomycotina and Agaricomycotina. The number of detected GSTFuA sequences is highly variable between and inside fungal phyla and is not related to the number of predicted gene models in the genome (Table  S1 ). Among Ascomycota, no GSTFuA-related sequence was identified in Saccharomycotina genomes, while 0 to 6 sequences were found in Pezizomycotina genomes. Similarly, among Basidiomycota, GSTFuA sequences were only detected in Agaricomycotina genomes (from 0 to 17 sequences).