dataesr/scientific-paragraphs-categorization huggingface dataset:
Data Analysis Data for each outcome were analyzed using Comprehensive Meta-Analysis Software, version 3. 0 (Biostat, Englewood, NJ, USA). Fixed or random effect meta-analysis were conducted to assess test/placebo differences across studies, with effect size measured as difference in means (DM) with 95% confidence intervals (random effect meta-analysis was used when high heterogeneity across studies was present). Heterogeneity of studies was assessed by the Cochran's Q statistic (a chi-squared test with n -1 degrees of freedom) and the inconsistency index I 2 , with a value higher than 75% being considered substantial heterogeneity  [27]. Funnel plots were used to assess for evidence of publication bias. For outcomes with sufficient number of studies, the interindividual variability was assessed by exploring effects in subgroups: sex, age, country of origin and health status (BMI, healthy, with disease, and baseline values of measured outcomes and risk of cardiovascular disease).
Description of the Included Studies A total of 671 studies were retrieved from database search and two others from additional sources. After screening and application of exclusion criteria, 32 trials were selected for data extraction. Fifteen of these studies were rejected after detailed analysis of the full text. Many of the rejected studies in this phase were studies where the test food had a significant content in flavonols but was richer in other flavonoids or phenolic acids (for example, apple, cocoa and tea have a higher content of flavanols than flavonols; grape and berries have a higher content of anthocyanins or phenolic acids and, thus, the observed results in the outcomes cannot be imputed to the flavonols, which is the objective of this meta-analysis). Finally, 18 RCTs were included in the systematic review and meta-analysis.
Subgroup Analyses for Identification of Factors Affecting Inter-Individual Variability To explore the factors that could influence the individual response to flavonol intake on the studied outcomes, subgroup analysis was performed on blood lipids. Studies with high risk of bias were excluded from the subgroup analysis  [32, 41]. As in the sensitivity analysis (Section 3. 3. 1), another study was also excluded in LDL and HDL subgroup analyses  [42]. Subgroup analysis on blood pressure was not performed due to a lower number of studies and evidence of publication bias. Subgroup analysis on fasting glucose was also not undertaken due to the low number of studies available. Table  3  presents a summary of the results obtained for subgroup analysis performed on participant characteristics such as age, sex, country of origin, and health status (BMI, diagnosed disease, baseline lipid levels and cardiovascular risk) (the complete data of the subgroup analyses are presented on Supplementary Materials Table  S2 ).
More RCTs need to be performed, assuring a low risk of bias and reporting all the characteristics that may influence the response, preferably differentiated for men and women: mean and range of age and BMI, presence of genetic polymorphisms, number and percentage of different ethnicities, health status (including disease, medication, baseline levels of cardiometabolic markers) and lifestyle factors such as smoking habits, baseline diet and baseline physical activity level. Finally, to allow a pooled analysis of a high number of studies and a higher power of systematic reviews and meta-analysis, a database of pre and post data for each analyzed outcome should be created and made available for the scientific community.
Background: Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Classical Pharmacovigilance process is limited by underreporting which justifies the current interest in new knowledge sources such as social media. The Adverse Drug Reactions from Patient Reports in Social Media (ADR-PRISM) project aims to extract ADRs reported by patients in these media. We identified 5 major challenges to overcome to operationalize the analysis of patient posts: (1) variable quality of information on social media, (2) guarantee of data privacy, (3) response to pharmacovigilance expert expectations, (4) identification of relevant information within Web pages, and (5) robust and evolutive architecture. Objective: This article aims to describe the current state of advancement of the ADR-PRISM project by focusing on the solutions we have chosen to address these 5 major challenges.
Variable Quality of Information on Social Media In order to carry out our study about the quality of information on social media, we first sought to identify potential sources of interest. An initial analysis was conducted exploring the functioning and content of a selected sample of websites as well as the behavior and interactions of their users  [10]. To identify relevant forums for the project (ie, providing messages about drug use and safety), we conducted research through search engines such as Google with the terms "network," "forum," "health," "patient," and "medicine," and 11 sites were identified. In addition, to identify specialized forums about a disease or group of diseases, for example, we used the Catalogue et Index des Sites Médicaux de langue Française (CISMeF) website  [11, 12] , a catalog and index of French language health resources on the Internet that conducts appraisals of the websites of patient associations.
Identification and Processing of Relevant Information Within Web Pages Information extraction is the process of extracting and analyzing information in order to discover buried knowledge, leading to intelligence from large volume of unstructured text content. Our extraction process involves several subtasks: (1) text preprocessing, including text formatting tasks, (2) morphosyntactic tagging, performed by the XeLDA (Naver Labs Corp) tagger, which identifies the language, splits the text into sentences and words, and attaches to them their lemma and part of speech category, (3) extraction rules compiled in semantic components, which model the relevant information to extract, and (4) postprocessing, to normalize the information extracted. All analysis steps are packaged in components that build a Skill Cartridge (Expert System France SA).
It can be imagined as a cascade of extraction modules that condense the textual data into meaning. The analysis is based on finite state technology  [19]. Skill Cartridges are domain-specific knowledge resources that may embed lexicon, morphological rules, context rules, semantic rules, syntactic rules, and postanalysis processing. They are plugged into the Expert System Luxid (Expert System France SA) extraction server to perform annotations. The processing unit is the sentence. The information to be extracted by the Skill Cartridge is modeled according to the Luxid Data Model, which is made up of Luxid Objects. A Luxid Object is qualified by a type, either entity, relationship, or structure. Objects of the same type share the same behavior, meaning, and attributes. A type may have a parent type from which it inherits meaning, attributes, and behavior.
A working group has been created to develop a process to analyze data and extract some pharmacovigilance information and has identified 3 medical terminologies from the HeTOP terminology server (Health Terminology/Ontology Portal)  [20, 21]  and data from the Vidal Drug Database for the project. The identified terminologies are shown in Table  4  In the ADR-PRISM project context, the Anatomical Therapeutic Chemical (ATC) classification enables drugs class and substance entities extraction. Racine Pharma enables extraction of common drug names and abbreviations used by patients. It is a terminology developed by CISMeF from a file of French brand names where "racine" is the French word for "root. " A root corresponds to its brand name label without its strength or form or the name of the company in the case of a generic drug.
This terminology is revised monthly according to new updates to the French public drug database. New potential roots are extracted by an informatics process and presented to a pharmacist for curation. Several roots are linked to their ATC code. This terminology is not currently available in open access. The Medical Dictionary for Regulatory Activities (MedDRA) identifies ADRs. Vidal data contains all the regulatory information about drugs (names, indications, contraindications, expected adverse reactions, dosage, posology, interactions, precautions, etc).
Robust and Evolutive Architecture The method used to define the system architecture was based on the information system architectures part of the Open Group Architecture Framework. After having defined inputs and outputs provided by each partner of the ADR-PRISM consortium, data and application architecture have been combined to propose a service-oriented architecture. Regarding the storage software, a study comparing several solutions was conducted. Different big data storage technologies have been subject to the project constraints concerning relational or object-oriented database management system as well as non-structured query language solutions: columns oriented, documents oriented, key/value, graphs oriented, in-memory data grids, and triplestores. The first prototype of the ADR-PRISM project is based on Expert System Luxid repository technology, in which both posts and their indexing metadata (structural metadata and semantic annotations coming from the annotation service) are stored in order to support the search and browse functionalities from Luxid: (1) keywords (full text search), (  2 ) concepts (terms from the thesauri), and (3) relations linking the concepts.
" This article also defines exceptions to this law, for example, for "processing that relates to personal data that the concerned person has made public" or if the personal data are subject to an anonymization procedure which the French data protection authority, Commission Nationale de l'Informatique et des Libertés (CNIL), has earlier approved. In that case, the CNIL provides a specific procedure for processing in the scope of conventional pharmacovigilance (number AU-013 unique authorization of the CNIL). One of the specificities of the ADR-PRISM project lies in the fact that its purposes and the data processing natively refer to several legal and sometimes conflicting environments. Indeed,.
Obtaining the necessary authorizations To respond to this complexity we have chosen an approach that involves: • Breaking the global treatment related to the ADR-PRISM project into several treatment units that will then be positioned in a known and mastered legal framework • Articulating the treatment units in order to match them to the global treatment This approach, subject to the approval of the CNIL, led to the identification of 2 different treatment units: • Data collection from forums. Data collected are considered as indirectly identifying data (as the pseudonym is collected). Data considered at this stage are the copy of data found on public forums and haven't been enriched by processing yet. • Data processing and enrichment. Data are enriched by text mining analyses. Health data emerges at this stage from raw data.
• Restrictive access to the posts (cleaned by algorithms aiming to remove all directly identifying data before storage, such as email, telephone number, or addresses), the pseudonym, and the forum This second access allows the treatment covered by the processing of personal data and data processing steps related to pharmacovigilance requirements (defined by number AU-013 single authorization of the CNIL). These include preserving the possibility of making contact with the author of the message describing the adverse reaction (via its account) to investigate the case report and if necessary to intervene for a medical emergency. This second access is the most sensitive, which explains why it benefits from the highest modalities of information security. We have completed the process of computer data security with organizational procedures.
• Text annotation module: the Luxid Annotation server provides Web services to launch the automatic annotation of posts passed as parameter. The administrators of the annotation server punctually supply it with data from the terminology repositories to update the Skill Cartridges. After the call to this annotation service by the controller, posts are labeled with known controlled vocabulary concepts (provided by terminology servers). • Terminology standards: exports are made from the Vidal terminology servers and HeTOP  [20]. The HeTOP portal includes more than 69 health terminologies and provides services to export those data with standard formats. These exports are loaded in the modules requiring terminological information scraping and annotation tools but also the common database (data source for the graphical user interface).
Terminological data can be used in several steps of the ADR-PRISM information system: to preselect posts, to create a Skill Cartridge, or for data mining or querying purposes. • Common database: this serves to host the data necessary to the ADR-PRISM application server, whether batch process (controller jobs) or graphical user interface. This database especially contains monitored URLs, forums related metadata (name, last analysis dates, etc), crawling results (threads and posts to annotate and related metadata), annotation results, terminological data, and necessary information for the user interface (users, alerts, statistics, etc). The chosen solution for big data storage is PostgreSQL, which offers the best compromise for ADR-PRISM problematics-besides its proven reliability, it especially combines horizontal scalability features and advanced querying capabilities.
• Controller: this application server is a client of the data collection and annotation services. Batch processes are initiated at regular intervals: they consult the common database to respectively identify the URLs to process and posts to annotate, after which they query the required services and store the response in the database. Given that this batch process regularly launches the scraping, a lag can occur with the initial data in proportion of the time interval between each passage. The server also hosts the graphical interface Web application and the administration application. It also sends alerts to users according to their preferences and communicates through the interoperable Web services that allow access to the ADR-PRISM system-collected data for third-party applications.
For example, the seriousness of the reaction will be assessed, adverse reactions concerning specific populations (pregnant women, etc) will be identified, and pharmacovigilance signals will be detected. Specific drug use may also be identified to detect possible cases of nonmedical use of pharmaceutical products  [49]. Regarding languages processed by the ADR-PRISM system, the application scope of the project is focused on French and English data. But more languages could be added in the future (terminological data are multilingual; for example, MeSH or MedDRA are available respectively in 16 and 11 languages in HeTOP  [21] ). Other applications such as identification of counterfeiting and eReputation analysis for pharmaceutical companies should also be considered.
Acknowledgments This work was labeled by the competitiveness cluster  Cap Digital  and funded by the  Direction générale des entreprises and territorial collectivities (Ile de France and Haute Normandie)  under the 16th Fond Unique Interministériel request for proposal through the ADR- PRISM  project. The authors acknowledge the work of  Redhouane Abdellaoui ,  Anita Burgun ,  Myrtille Deldossi ,  Jean François Forget ,  Alain Gourarié ,  Armelle Guenegou-Arnoux ,  Olivier Haxaire ,  Marie-Christine Jaulent ,  Pierre Karapetianz ,  Gaetan Kerdelhue ,  Jérémy Lardon , and  Damien Leprovost.
Statistical Analysis Instant software (GraphpAd Prism 5, GraphPad Software Inc. , San Diego, CA, USA) was used to analyse data. One-way analysis of variance (ANOVA) with post hoc analysis using Tukey's multiple comparison test was used for parametric data. The results of multiple observations were presented as the means ± S. D. of three experiments. A p value of <0. 05 was considered statistically significant.
Membrane-Bound Forms of CPR Expression of the full-length membrane bound CPR mutants was obtained in BTC bacteria and membrane fractions of the different strains were prepared and characterized for protein content as described previously  (Marohnic et al. , 2010; Palma et al. , 2013). CPR content of membrane fractions was quantified by immunodetection against a standard curve of purified human, full-length WT CPR, using polyclonal rabbit anti-CPR primary antibody and biotin-goat anti-rabbit antibody in combination with the fluorescent streptavidin conjugate (WesternDot 625 Western Blot Kit; Invitrogen). Densitometry of CPR signals was performed using LabWorks 4. 6 software (UVP, Cambridge, United Kingdom).
Assay Conditions Our study was designed to test the variation of cytochrome c reduction in various salt concentration conditions for nine CPR enzymes variants (WT + eight mutants) in the context of the soluble or membrane bound forms. We therefore developed and optimized a 96-well plate format assay to follow cytochrome c reduction. These experiments were performed at 37 • C, contrarily to the primary test realized at room temperature in cuvette with the WT, soluble form of human CPR (Figure  1 ). Optimal conditions of the microplate rate assay were determined to ensure the linearity of the reaction traces. Initially, assays were performed at two cytochrome c concentrations (100 and 200 µM) in order to ensure that saturation was reached at all salt concentrations, which virtually gave the same velocities (data not shown).
Acknowledgments: We thank  Dr. Ahmed El Shobaky  for his valuable discussions and  Marie Granjon  for her technical assistance. This work was supported by the  Action Intégrée of the Comité Mixte Inter-universitaire Franco-Marocain  (CMIFM,  MA/14/310 ) from the  PHC Volubilis/Toubkal program , the  Ministère de l'enseignement Supérieur  and the  Centre National Pour la Recherche Scientifique et Technique (CNRST) Morocco , the  Institut Français D'Egypte au Caire , the  Ministère des Affaires Etrangères , the  Conseil Régional de Bourgogne and the Ministère de l'enseignement et de la Recherche , the  Institut National de la Santé et de la Recherche Médicale  ( INSERM, Centre de Recherches   U866 ), and the  French Government Grant  managed by the  French National Research Agency  under the program " Investissements d'Avenir "  ANR-11-LABX-0021.
Survival was recorded every 8 h after treatment. Our data indicated that for both compounds, the survival rate was markedly higher in the treated group than in a control, nontreated group (Ն80% versus ~7%, respectively [Fig. 4A] ). Eighteen hours after the end of the treatment, all the survivors showed festering or signs of inflammation at the inoculation site, and most had (sometimes severe) lymphadenopathy. In agreement with the autopsy data, Y. pestis was isolated from the skin, draining lymph nodes, and spleen (Fig. 4A ). LPC-058-and LPC-069-treated mice had similar bacterial loads in the various organs, with the exception of the lymph node, where the bacterial burden was higher in LPC-069-treated mice. The latter observation was correlated with the more severe lymphadenopathy in LPC-069-treated mice, which showed suppuration-considered to be a sign in recovery in human plague  (16).
4B ). In view of these efficacy data and the lack of any obvious adverse drug reactions for LPC-069 but not for LPC-058, we next tested the therapeutic effect of LPC-069 at a higher but nontoxic dose of 200 mg/kg q8h. Survival rates and organ sterility were assessed for up to 15 days after the end of the treatment. In contrast to nontreated mice (which all died), all the treated mice survived the 5-day treatment period, and posttreatment relapse was detected in only one of the 15 animals (Fig. 4C ). An autopsy and bacteriological testing performed 2 weeks after the end of the 5-day treatment period showed that all surviving mice were free of any signs of bacterial organ colonization (Fig. 4C ). Last, the LPC-069 The survival of mice treated with LPC-058 (gray squares) or LPC-069 (white squares) and nontreated mice (black circles) was recorded every 8 h.
The survival curves plotted for treated mice differed significantly from the curve plotted for untreated mice (P Ͻ 0. 0001 in a log rank test). Bacterial loads in the survivors' skin, draining lymph nodes, spleen, and blood were determined 18 h after the end of the treatment. Horizontal bars indicate the median of the individual data points. A total of 15 mice were used. (B) Bacterial loads in the skin, draining lymph nodes, spleen, and blood of eight mice at the start of treatment and in eight mice treated with LPC-058 (light gray boxes) or LPC-069 (dark gray boxes) and nontreated mice (white boxes) 24, 48, and 72 h after the start of the treatment (i. e. , 42, 66, and 90 h postinfection). The bacterial loads given at the 138-h time point are those from the experiment shown in panel A. The boxes represent the interquartile range of the bacterial load, and the lines crossing the boxes indicate the median bacterial load.
pestis were higher at 28°C than at 37°C. This may be due to structural differences in Y. pestis' lipooligosaccharide (LOS) at these temperatures; at 28°C, the phosphate groups in Y. pestis' lipid A are glycosylated with 4-aminoarabinose-thus resulting in a more closely packed LOS layer and a less fluid outer membrane  (28, 29). This lack of fluidity at 28°C might block the access of hydrophobic LpxC inhibitors to the cytoplasmic LpxC enzyme. In other words, our data indicate that a MIC should be measured at the host temperature (rather than the optimal growth temperature) when the structure of the bacterium's LOS or lipopolysaccharide is known to be affected by the growth temperature. In conclusion, we showed that LpxC inhibitors constitute a new class of antibiotics that may be capable of treating a number of infectious diseases, including the most severe ones such as plague, and infections caused by MDR/XDR carbapenemaseproducing strains.
The protein-inhibitor mixture was then mixed with an equivalent volume of crystallization reservoir solution containing 2. 49 M diammonium hydrogen phosphate, 0. 1 M Tris (pH 7. 7), and 5% glycerol. LpxC-LPC-069 complex crystals were obtained with the sitting-drop vapor diffusion method at 20°C. Crystals were harvested and cryoprotected using the mother liquor solution containing 30% ethylene glycol, prior to flash-freezing. Diffraction data were collected at the SER-CAT 22-ID beamline at the Advanced Photon Source at Argonne National Laboratory and were processed with XDS software  (33). The crystal structure of the A. aeolicus LpxC/LPC-069 complex was solved by molecular replacement using the Phaser program  (34)  and with Protein Data Bank (PDB) entry 5DRO as the search model. The inhibitor's restraints were generated with eLBOW  (35)  and then edited manually.
Iterative model building and refinement were carried out using Coot  (36)  and PHENIX  (37). The coordinates of the A. aeolicus LpxC/LPC-069 complex have been deposited in the PDB (accession code 5U86). In vitro susceptibility testing of LpxC inhibitors. MIC values were determined by using the broth microdilution method in 96-well plates containing Mueller-Hinton (MH) broth (supplemented or not with 2% bovine serum albumin [Sigma-Aldrich]) and the agar dilution method, according to the Clinical and Laboratory Standards Institute's guidelines  (38). The final concentration of LpxC inhibitor ranged from 0. 012 to 6. 4 g/ml. Plates were incubated for 48 h at 28°C and 37°C for Yersinia species and for 24 h at 37°C for the other organisms. The MIC was defined as the lowest concentration at which no visible growth occurred.