dataesr/scientific-paragraphs-categorization huggingface dataset:
Outcome Measures A list of trigger events, adapted from Rozich et al. [29]  and Mehta et al. [30] , was used during the initial screening of ADRs (see electronic supplementary material 2). The investigators did not know when an ADR was involved in the hospitalization. Whether the patients were admitted because of an ADR was first assessed by the Lao medical doctor and the pharmacovigilance specialist during the collection of the data on medication use, medical history, and history of the current condition. Some unknown medicines used prior to hospitalization were suspected to be involved in ADR-related hospitalizations, based on chronology, reason of use and hospital diagnosis. After identification of API(s) for these unknown medicines, each initially suspected ADR was reviewed and causality assessment was performed, using the WHO criteria, by three pharmacovigilance specialists until consensus was reached  [31].
Statistical Analysis Data were entered into an MS Access Database 2010 (Microsoft Corporation, Redmond, WA, USA) created specifically for the study. Qualitative variables were expressed in numbers and percentages [n (%)] and compared between patients with or without ADR-related hospitalization using Chi-square tests or Fisher's exact tests, as appropriate. Quantitative variables were expressed as mean ± 95% CI, or median and first and third quartiles (Q1-Q3), and were compared between the two groups using t tests or Wilcoxon-Mann-Whitney tests, as appropriate. A backward logistic regression model was performed to assess factors associated with ADR-related hospitalizations. All variables associated with ADRs with a p value \0. 20 on univariate analysis were entered into a multivariate logistic regression model, in addition to age and sex, factors commonly associated with ADR-related hospitalizations  [26].
The goodness-of-fit of the final model was assessed using the Hosmer and Lemeshow test. The results are presented as odds ratio (OR) and adjusted ORs (aOR) and their 95% CIs. Only ADRs assessed as possible, probable and certain were included in the analysis. Data analysis was carried out using SAS 9. 3 software (SAS Institute, Cary, NC, USA). The level of significance was set at 0. 05 (two-sided).
Funding This work was supported by the  Pierre Fabre Foundation, The L'Oreal Foundation-Unesco , the  French Ministry of Superior Education and Research , and the  French National Agency for the Safety of Medicines and Health Products (ANSM , Project  AAP-2012-082 ). Paul Newton  and  Mayfong Mayxay  are funded by the  Wellcome Trust. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Patients and setting The division of clinical pharmacology of Geneva University Hospitals give pharmacological advices to physicians on individual clinical situations, such as the appropriate drug in case of pregnancy or breastfeeding, in case of weight gain, in case of drug interactions, adverse effects or treatment failure, among others. Questions come from hospitals physicians as well as from private practices, and this for all medical specialities. Individual propositions are summarized in a report and when considered appropriate by a senior clinical pharmacologist, genetic and/or phenotypic investigations are proposed. If the tests are performed, their results are analysed according to the clinical context and summarized in a second report. We retrospectively collected results of genetic and/or phenotypic investigations performed between January 2005 and November 2014 and selected all data related to psychotropic drugs (N = 250).
Evaluation criteria All clinical pharmacology reports were carefully reviewed and classified into different categories according to clinical events, such as ADR and lack of response to the prescribed drug. Two experienced clinical pharmacologists assessed the possible association between these clinical events and the genetic and phenotypic results independently according to a semi-quantitative scale and their clinical judgment (Appendix A). The semi-quantitative scale was mainly built on scientific databases (e. g. http://www. hugge. ch/sites/interhug/files/structures/pharmacologie et toxicologie cliniques/documents/substrats et inhibiteurs a5; DrugBank, http://www. drugbank. ca/; 'The Human Cytochrome P450 (CYP) Allele Nomenclature Database', http://cypalleles. ki. se). For a given drug, each relevant metabolic pathway, whether major or minor, was considered and a global rating was made according to a 3-point scale: 0 = no or low probability of genetic and phenotypic results being linked with a clinical or biological problem; 1 = intermediate probability; 2 = high probability.
Genotyping The following variants of the CYP2D6 gene were genotyped: CYP2D6*3, *4, *5, *6, *35, *41 and duplications, until 2007, when the AmpliChip CYP450 test allowed the simultaneous analysis of 33 CYP2D6 alleles. For the CYP2C9 and CYP2C19 genes, the following variants were genotyped: CYP2C9 *2 and *3, CYP2C19*2 and *17 (since 2009). The predicted phenotypes were based on enzyme activities of these alleles, as listed in 'The Human Cytochrome P450 (CYP) Allele Nomenclature Database' (http://cypalleles. ki. se) or the Phar-mGKB database (http://www. pharmgkb. org/index. jsp), or in the AmpliChip CYP450 2D6 test. Patients were classified as poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM) and ultra-rapid metabolizer (UM) for CYP2C19 and CYP2D6 and as induced, normal or reduced activity for CYP2C9.
Isolation of Y. pestis in chott. To investigate the presence of Y. pestis in chotts in Algeria, we collected 208 soil samples comprising: 120 soil samples collected in chotts (salinity, 25 to 70 g/L) and 88 soil samples collected outside chotts (salinity, 0. 5 to 5 g/L); and 144 water samples of which 98 contained salt water (50 g/L NaCl) and 46 contained freshwater (0. 05 to 5 g/L NaCl) (Supplementary Table  1 ). Culturing these 352 samples in a safety level 3 laboratory yielded one Y. pestis isolate (named Y. pestis Algeria3) in one chott soil specimen containing 4% NaCl against zero isolates from low salinity control soil samples. The genome of Y. pestis Algeria3 (GenBank accession number FAUR00000000) (Fig. 2 ) is 4,637 Mbp-long and composed of 48 scaffolds with a GC content of 47. 65%.
The predicted ORFs were excluded if they spanned a sequencing gap region (containing N). The predicted bacterial protein sequences were searched against the GenBank database and the Clusters of Orthologous Groups (COGs) database using BLASTP (E value 1e -03 , coverage 0. 7 and 30% identity). If no hit was found, search was then done against the NR database using BLASTP with an E value of 1e -03 , coverage 0. 7 and 30% identity. The tRNAs and rRNAs were predicted using the tRNA Scan-SE and RNAmmer tools, respectively  55, 56. SignalP and TMHMM were used to screen the signal peptides and the number of transmembrane helices, respectively  57, 58. For each selected genome, complete genome sequence, proteome genome sequence and Orfeome genome sequence were retrieved from the FTP site of National Center for Biotechnology Information (NCBI).
All proteomes were analyzed using proteinOrtho  59. An annotation of the entire proteome was performed to define the distribution of functional classes of predicted genes according to the clusters of orthologous groups of proteins. For phylogenetic tree construction, sequences were recovered by nucleotide blast against the 16S RNA Database of "The All-Species Living Tree" Project of Silva. Sequences were aligned using Muscle and phylogenetic inferences obtained using the approximately-maximum-likelihood method within the FastTree software  60. Numbers at the nodes are support local values computed with the Shimodaira-Hasegawa test. For core genome SNPs analysis, all 133 genomes analyzed by Cui et al. along with the one of Y. pestis Algeria3 were downloaded from NCBI or European Bioinformatics Institute (EMBL-EBI).
Each sample was labeled for 30 min on ice in the dark and the reaction was quenched by the addition of 1 μ l of 10 mM lysine. CyDye-labeled samples were combined during 2-D gel electrophoresis so that each gel contained a Cy2, a Cy3 and a Cy5 labeled sample. Two dimensional gel electrophoresis was carried out as previously described  61. After electrophoresis, gels were scanned at appropriate wavelengths to cyanines using the Typhoon FLA 9000 Imager according to the manufacturer's protocol (GE Healthcare). Scans were acquired at 100 μ m resolution. Images were cropped with Image Quant TM software (GE Healthcare) and further analyzed using the Progenesis SameSpots software version 4. 0. 3779 from Nonlinear Dynamics (Newcastle upon Tyne, UK) as described by the manufacturers. To determine significant differences in 2D spot abundance, an ANNOVA score (p-value) lower or close to 0.
207 patients with moderate to severe dry eye disease were enrolled. Both CyclASol Ò groups showed a significant improvement in corneal staining compared with the vehicle over the 4-month treatment period. In particular, the central area of the cornea seemed to benefit most, an important aspect for visual function in dry eye patients. All treatment groups demonstrated improvement in symptoms, with CyclASol Ò showing improvements over vehicle in subgroups. The data further indicated an early onset of action by reduction in corneal and conjunctival staining in as little as 14 days. It is worth noting that the vehicle group also showed significant improvements in symptoms. Novaliq (through Ursapharm) currently markets EvoTears Ò , which are also eye drops based on the EyeSol TM SFA technology, designed as a nonblurring wetting lubricant for the ocular surface  [64].
Another liver disease that is increasingly recognized to favor DILI is nonalcoholic fatty liver disease (NAFLD), at least for some drugs such as acetaminophen, halothane, some antiretroviral drugs and methotrexate  [7, 8]. The main objective of the present review is to present the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a PubMed search of literature published in the English language using the following terms: "drug-induced liver injury", "drug-induced hepatotoxicity", "fatty liver", "nonalcoholic fatty liver disease", "steatosis" and "obesity". This data-mining analysis was also completed by using Google Scholar ®. Before presenting the collected data concerning the present topic, some major features of NAFLD pathophysiology will be briefly recalled.
, 2003)  in the tsiperifery sector. The proposed strategy takes its inspiration from Douthwaite et al. (2001)  'Follow the Technology' concept. It consists of relaying to local communities and economic operators credible technical solutions which, whilst not completely finalised, offer 'plausible promises' of success. Follow-up and evaluation of adoption, refusal or adaptation of these technical solutions will feed into the recurring innovation process. Preliminary results currently in the pipeline will allow the authors to consider implementing the concept at a local level at several sites and in two complementary and connected spheres: (i) development of a 'label' of quality and origin of tsiperifery, and (ii) a process of domestication drawn from a pool of selected plant matter. We are currently working on these two major areas of research within various projects funded by (or accountable to) different financing bodies: the European Union through projects supported by the European Development Fund (EDF), the French Ministry of Foreign Affairs and International Development (PISCCA fund for civil society: 'Innovative projects from Civil Societies and Coalitions of Actors').
Acknowledgments This study was carried out by the  DP 'Forêts et Biodiversité ', a partnership between FOFIFA, the  University of Antananarivo and CIRAD. It was supported by  'France Volontaires '. The authors would like to thank the  FSP 'Parrur'  (project ' InnovEpice ') funded by the  French Ministry of Foreign Affairs and International Development, the QualiReg network , and  CIRAD  which funded this study. The association 'Words for Solidarity' is gratefully acknowledged for the translation.
Statistical analysis All analyses were descriptive and produced using SAS version 9. 2 (SAS Institute, Cary, North Carolina). Verbatim ARs were coded with Medical Dictionary for Regulatory Activities terminology (version 19. 0). No confirmatory hypothesis testing was conducted for the analyses. The frequency and percentage of VRR (primary endpoint) and ARR were presented according to their PTs and system organ class (SOC). For VRR, two-sided 95% confidence intervals (CIs) were calculated using the Wald method if the number of vaccinees who reported 1 AR was 5 otherwise the exact method was used (number of vaccinees who reported 1 AR being <5). All VRRs and ARRs were estimated by age groups (for Vaxigrip: 6 months to <6 years, 6 to <13 years, 13 to <18 years, 18 to 65 years, and >65 years; for Intanza 15 mg: 60 years), seriousness (yes/no), severity (mild, moderate, severe, or unknown as per protocol), by day of onset since vaccination (7, >7 days), and per brand in total.
Acknowledgments The authors acknowledge all of the vaccinees, physicians, and nurses who participated in the ESS in the United Kingdom and the  Republic of Ireland. The authors would like to thank the  Sanofi Pasteur MSD study team (St ephane Thomas ,  Judith Rayner ,  Ian Gray ,  Janice Murtagh ) and the PPD team for providing operational support to conduct the study as well as medical writing and editorial support to prepare this manuscript (supported by SPMSD).
Procedures and data collection method A paper SRC specific to Vaxigrip or Intanza 15 µg provided the following information to the vaccinee: details regarding the ESS, instructions on how to report suspected ARs, the dedicated local toll-free telephone number, the site identifier, a unique SRC identification number, vaccine brand and batch, vaccination date and name of the treating physician. Vaccine coverage data were collected at practice level by the HCP/vaccinator(s) on a real-time basis (at least once a day) using an electronic data capture system. Vaccinees were encouraged to report any suspected post-vaccination ARs, especially those occurring within 7 days (although reports of ARs after 7 days were also considered for the analysis). A structured telephone interview was developed to ensure the appropriateness and completeness of data collection when vaccinees called to report suspected ARs.
Statistical analysis The ESS population included all vaccinees who were vaccinated in routine practice with either Vaxigrip or Intanza 15 µg and who received the SRC. No confirmatory hypothesis testing was conducted for the analyses. All analyses were descriptive and were produced using SAS version 9. 2. Verbatim ARs were coded with Medical Dictionary for Regulatory Activities terminology (version 18. 0) and processed according to routine pharmacovigilance processes. ESS reporting rates were calculated per brand using the following formula: ESS reporting rate = (Number of vaccinees reporting ARs within 7 days x 100) / total number of SRCs distributed Suspected AR reporting rates were estimated per brand using the following method: Suspected AR reporting rate = (Number of ARs within 7 days x 100) / total number of SRCs distributed Confidence intervals (CIs) for ESS reporting rates were computed using the Wald method if the AR count was ≥ 5 and using exact method if the AR count was < 5.
All suspected ARs (including PRAC AEIs, serious suspected ARs and other suspected ARs) and corresponding AR reporting rates were reported and summarised by vaccine, age groups (Vaxigrip: 6 months to < 6 years;  The mean number of ARs per vaccinee who reported at least one suspected AR was also calculated. For each brand, weekly reports for signal detection were generated and analysed. A 1-month interim report (1 month after the first SRCs were distributed) and a final report were compiled and submitted to the relevant health authorities. AR reporting rates were calculated and compared with the frequency of the AEIs reported during the NH 2014/15 influenza season clinical trials and with the expected rates based on current product-specific data from the Summary of Product Characteristics (SmPC)  [10].
Intanza safety data Among the Intanza 15 µg vaccinees, 31 (3. 0%) reported 114 suspected ARs (3. 7 ARs/vaccinee who reported at least one AR), including 99 suspected ARs that occurred within 7 days post vaccination (Table  2 ). All of the suspected ARs were non-serious. One vaccinee could not be included in the analysis because of insufficient information to identify the SRC number. This vaccinee had reported the non-serious suspected ARs of cough and pain. The most frequently reported suspected ARs within 7 days post vaccination (those reported by ≥ 1% of vaccinees) are listed in Table  3. Overall, 56 suspected PRAC AEIs were reported by 28 vaccinees (2 AEIs/vaccinee who reported at least one AR). Of these AEIs, 53 AEIs occurred within 7 days post vaccination (Table  2 ). All AEIs were considered nonserious.
Approximately 1. 5-2 hours per HCP were dedicated to protocol training, processes to be used, management of vaccinees, site management and the end of the ESS process, depending on staff involved. The contact centre needed ca 15 min per vaccinee to record the suspected AR. However, information on the time spent per vaccinee by the HCP to explain the ESS, distribute the SRCs, and explain how ARs were to be reported was not collected as part of this ESS. The strengths of this ESS were that the number of SRCs distributed was consistent with the estimated sample size and that weekly analyses were performed, which allowed for near real-time investigation of the reactogenicity of Vaxigrip and Intanza 15 µg. The safety reports received were well documented in terms of exposure data (brand, batch and date of vaccination), which is not always the case with routine pharmacovigilance.
The estimated AR reporting rates will provide baseline AR reporting rates to improve comparison during the next NH influenza season (2016/17) using a similar passive methodology. A limitation in the current comparison is that the reference data from ESS NH 2014/15 were obtained from active safety surveillance (clinical trial) and not from spontaneous reporting. The finalisation of the guidance related to ESS is currently under discussion at EMA, and current passive ESS pilot experiences will provide data to further support recommendations. Despite the historic success of immunisation in reducing the morbidity and mortality of several diseases, some public concerns about the safety of vaccines remain. These concerns occasionally erode public confidence in immunisation and sometimes lead to vaccine hesitancy and disease outbreaks.
Data collection Data collected at inclusion included demographic characteristics: gender, age, weight, height, and BMI; confounding factors for salt intake or urinary excretion of sodium: smoking, hypertension, diuretic treatment, hypothyroid, and cardiac failure; and disease characteristics: disease duration, presence of rheumatoid factor (RF), and/or anti-citrullinated protein antibody (ACPA), presence or absence of radiographic erosions, rheumatoid nodule, activity evaluated by Disease Activity in 28 joints-C-reactive protein level (DAS28-CRP) and CRP level at inclusion (mg/L).
24-hr urinary sodium excretion was estimated at 2,533±788 mg/day, on average, in French women  [12]. We hypothesized a one-standard deviation difference between patients with early RA and matched controls, thus a difference of 788 mg/day. This choice is clinically relevant because reducing the mean sodium consumption by 400 mg in the population has been projected to prevent up to 28,000 deaths from any cause  [13]. With an alpha risk of 5% and a power of 90%, the number of patients needed to demonstrate increased consumption of salt in those with early RA was 22 patients per group. All raw data are available on S1 Dataset.
All patients were seen in a hospital, which led to a selection bias. Indeed, 7/24 (29%) of those with early RA showed erosive disease, which is higher than the literature data  [16]. Another limitation is that sodium consumption was assessed at diagnosis and we cannot exclude that patients have modified their diet after symptom onset. Finally, whilst 24-hour sodium excretion is the gold-standard to assess sodium consumption in the general population, variability can be observed. Repeated measurements of 24-hour sodium excretion might have improved precision  [17]. However, this would have been difficult to conduct in patients and could have been influenced by treatment with disease-modifying anti-rheumatic drugs after diagnosis. No study has clearly evaluated the influence of rheumatoid arthritis on sodium excretion.
Acknowledgments This work was supported by the  Passerelle grant  ( Pfizer ). This does not alter our adherence to PLOS ONE policies on sharing data and materials. The funder had no role in the study design, performance, data analysis or decision to publish. We thank  Elodie Derbord  for food questionnaire analysis and  Sumaiya Hoque  for english revision. We also thank  Pascale Vergne ,  Christophe Richez ,  Gae ¨l Mouterde, Charlotte Hua, Helène Che  and « le Projet Jeune Chercheur ». This work was supported by  Passerelle grant  ( Pfizer ).
Genotyping The activity of the enzymes and transporters involved in drug PK parameters may be influenced by their genetic variation. For a subset of alleles in vivo and in vitro studies have elucidated enzyme activities that are listed as increased, normal, decreased, absent or unknown. This list is available in 'The Human Cytochrome P450 (CYP) Allele Nomenclature Database' (http://www. PharmVar. org), which catalogues genetic variability in CYP enzymes. This information can be used, along with the number of functional alleles and the presence of gene duplications, to predict the metabolic phenotypes. Poor or slow metabolizers (PMs) have deficient metabolizing ability compared with persons with normal activity. PMs relative to more rapid metabolizers are more likely to suffer from adverse drug effects when taking normal doses of drugs that are active per se and are metabolized mainly via these pathways.
Recruitment and design All 11 recruitment sites are coordinated by the Fonda-Mental foundation (www. fondation. fondamental. org) and belong to the Network of expert centres for Resistant Depression. Comprehensive assessment is offered to patients with resistant depression and data are entered into dedicated web-based application (e-DR). Patients are referred to the expert centre by a general practitioner or a psychiatrist. Psychiatrists recruit patients in hospital or ambulatory setting. Two rating scales for depression are performed during the selection visit; the Montgomery and Asberg Depression Rating Scale (MADRS) and the Hamilton Rating Scale for Depression (HAM-D). Dependent upon psychiatric evaluation and in accordance with usual practice, the psychiatrist (and investigator) propose an increase in dosage if this is indicated.
In anticipation of potential large disproportions between responders and non-responders (which will only be defined after study inclusion) we decided to include 205 patients. This will allow controlling for type I and typing II error rates in the comparison of the prevalence of CYP2C19 UMs among these groups. In addition the sample size will allow to study sufficient numbers of CYP2D6 PMs, IMs, and UMs to determine the effects of CYP2D6 variations on VLX and ODV plasma levels and their efficacy or risk of adverse events. The type I error rate will be fixed at 0. 05. All tests will be two-sided and compared thus to 0. 05. Multiple imputation, which is a popular approach for handling the pervasive problem of missing data in biostatistics, will be used  [49]. It is usually performed under a missing at random assumption  [50].