dataesr/scientific-paragraphs-categorization huggingface dataset:
The PPS excluded FAS patients with any major protocol deviation. Further efficacy endpoints were analyzed on the FAS and the PPS. The CFS, OSDI, global VAS, and combined CFS-VAS responder rates and complete corneal clearing rate were analyzed using the logistic model described above. Analysis of CFS, OSDI, global VAS, and lissamine green score change from baseline was performed using a repeated-measures analysis of variance with the following fixed factors: treatment, visit, pooled country, and treatment by visit interaction. Schirmer test, TBUT, NEI-VQF-25, HLA-DR expression, and tear film osmolarity were analyzed using an analysis of covariance model with the fixed factors treatment and pooled country, and the corresponding baseline data as covariate. A supportive analysis was conducted using a CMH test stratified on pooled country.
This test was also used to analyze the investigator global evaluation of efficacy. Sample size calculations were based on the results of a previous phase III study performed in patients with moderate to severe DED  (24). The expected CFS-OSDI responder rates at 6 months were 28% and 10% with CsA CE and its vehicle, respectively. Setting the risk α at 5% and the power at 90%, around 225 evaluable patients were needed (150 in the CsA CE group and 75 in the vehicle group) to detect a significant difference between groups. Accounting for nonevaluable patients (approximately 10%), a total of 252 patients were to be recruited. The safety analysis set was used for reporting safety data; this included all randomized patients for whom there was any evidence they used study medication and for whom any follow-up data were available.
1%) than of patients assigned to vehicle (49 patients, 57. 0%), but this difference did not reach statistical significance (p = 0. 319). A progressive decrease in the use of AT over time was recorded in both treatment groups. Median use of AT during the month 3-month 6 period was 4. 4 drops/ day/eye with CsA CE (n = 80) and 5. 4 drops/day/eye with vehicle (n = 55). Lissamine green conjunctival staining, TBUT, and NEI-VFQ-25 data (Tab. IV) displayed a similar trend to that observed for most of the secondary efficacy variables. A 40. 5% and 22. 2% improvement in TBUT was observed with CsA CE and vehicle, respectively, but the difference between treatments was not statistically significant (Fig. 6B ). A global trend of improvement in both signs and symptoms was found, with improvements generally greater (without reaching statistical significance) in the CsA CE group than in the vehicle group.
Supplementary Table II. Summary of adverse events recorded during the study If a patient had multiple occurrences of an event, the patient was counted only once in the corresponding patient count. a This category is about TEAEs that led to permanent discontinuation of treatment. All patients who stopped treatment were also discontinued from the study, except one patient who continued the study and completed the 6-month randomised treatment phase. b There was 1 SAE that started during the double-masked period (up to Month 6) but its seriousness (i. e. event requiring hospitalization) was known by the investigators after the double-masked period database lock.
Acknowledgment The authors thank  Pr. Françoise Brignole-Baudouin  and  Luisa Riancho  for analyses and interpretation of HLA-DR results;  Maëva Deniaud  ( MD Stat consulting ) for statistical and methodology ad-vice;  Pr. Michael Lemp  for help in study design; Scinopsis for medical writing support; and  Chameleon Communications International  for medical copyediting support.
This susceptibility to infection is caused, at least in part, by defects in the host's defense, which manifests as "sepsis-like" immune paralysis with reduced cellular immune function  [16, 17]. The aim of this study was to analyze whether cirrhotic patients with CHC have a greater tendency to die in ICU than non-CHC cirrhotic subjects through the use of comprehensive records of the Minimum Basic Data Set (MBDS) in Spain.
Study design and data source A retrospective study with nationwide population-based diagnoses from the Spanish MBDS was performed. We identified all consecutive cirrhotic patients with a record of CHC (CHC-group) and aged >18 years who were admitted to ICUs in Spanish hospitals between January 1, 2005 and December 31, 2010. A control-group of cirrhotic patients without CHC was selected at a proportion of 4:1 with regards to the CHC-group. This control-group contained patients aged >18 years and admitted to the ICU with no record of being tested for HCV, HIV, or HBV; they were randomly selected according to the same frequencies of age, gender, trauma and surgical conditions, and comorbidities (see Additional file 1: Supplementary Digital Content (SDC)-Appendix 1-6) as occurred in the CHC-group  [18].
Data were obtained from records in the MBDS of the National Surveillance System for Hospital Data in Spain, provided by the Spanish Ministry of Health. The MBDS is a clinical and administrative database containing clinical information recorded at the time of hospital discharge, which has an estimated coverage of total admissions to public hospitals of 97. 7 %  [19]. The MBDS provides the encrypted patient identification number, gender, date of birth, dates of hospital admission and discharge, medical institutions providing the services, the diagnosis and procedure codes according to the International Classification of Diseases 9th edn, Clinical Modification (ICD-9-CM), as well as the outcome at discharge  [20]. Length of stay was obtained as the difference, in days, between the date of hospital admission and date of discharge or death in the ICU.
The day of hospital admission was considered as day 0. Discharge on the same day was considered as a 1-day stay. For patients admitted several times to the ICU, only the first admission (also called the index episode) was analyzed. The data were treated with full confidentiality according to Spanish legislation. MBDS is regulated by an law, which explains how institutions have to proceed with health-related personal data. Informed consent is not required because personal data are collected for official usage by public administrations. The study was approved by the Research Ethics Committee (Comité de Ética de la Investigación y de Bienestar Animal) of the Instituto de Salud Carlos III (Madrid, Spain).
Statistical analyses For descriptive analysis, the results are presented as medians and their interquartile ranges for continuous variables; and as absolute numbers and percentages for categorical data. Categorical data and proportions were analyzed using chi-squared test or Fisher's exact test, as required. Student's t-test or the Mann-Whitney U tests were used to compare continuous variables. The primary outcome variable was ICU mortality. The cumulative mortality rate on days 7, 30, and 90 in patients admitted to the ICUs was calculated without considering censoring. This rate was estimated by dividing the number of deaths by the number of patients admitted to the ICU. Log-linear modeling for contingency tables was used to estimate the main and interaction (moderator) effects independently.
Note that several baseline clinical characteristics showed statistically significant differences between groups, but these variables were included in the model to adjust the competitive risks. There is controversial about whether patients with cirrhosis may benefit from the ICU management. In our study, the mortality was extremely high (merely 80 %) in comparison to data reported in the review of Saliba et al. [18]. There also are several important series published during the last 5 years with a mortality about 50 % [59 % Das et al. [27] , 70. 1 % Galbois et al. [28] , 58. 8 % Pan et al. [29] , 68. 1 % Bao et al. [30] , 60 % McPhail et al. [31] ]. These differences in death rates could be due to the designs of the studies used to obtain the data, which were very different, especially in our study carried out with data of Spanish MBDS from 2005 to 2010 and with a higher number of patients.
Neither do we know if these patients were admitted due to severe sepsis or acquired the sepsis in the ICU prior to death. Secondly, the time until death or discharge was calculated from entry into the hospital rather than the ICU because the date of ICU admission was not recorded in the MBDS. A time bias could have occurred  [37] , since some patients may have been admitted directly into an ICU whereas others may have had a period of time between hospital admission and entry into an ICU, and this time period was included in the observation time. However, this theoretical bias should be well-balanced between the groups, and should only affect survival time. Thirdly, due to the use of the administrative databases, was the inaccuracy in differentiating the etiologies of the diseases and the reporting of organ dysfunction, which could have engendered a confusion bias.
In this context, grouping of ICD-9-CM codes into comorbidities, organ dysfunction, and site of infection (Additional file 1: SDC-Appendixes 1-6) may have been the best approach to solve this issue. On the other hand, MBDS has already proven its usefulness in the previous assessments of outcomes among patients admitted to ICU  [39, 40]. This database has advantages being a national clinical administrative database, which allows analyze the trends in important public health issues.
Cell toxicity estimation. Cell toxicity was measured by analysis of chromatin condensation and fragmen- tation in the cell nucleus, and ATP quantification, as previously described  21. Real time cell impedance measurement. The xCELLigence system was used according to the manufacturer's instructions (Roche Applied Science). Briefly, 2500 cells/well were seeded in 96-well E-plates in Williams' E medium supplemented with 10% FCS, 2 mM L-glutamine. Twenty-four hours later, cells were treated with 50 nM B[a]P in the same medium. Cell impedance was measured in each well every 5 minutes for 80 hours. Impedance signals were analyzed by an integrated software (RTCA Analyzer), and expressed as a Cell Index (CI) value that reflects cell number, cell adhesion and/or cell morphology. The changes of cell impedance between control and treated cells were determined by calculating the slope of the line between two given time points.
Statistical analysis. All data were obtained from a minimum of three independent experiments. The mean ± standard deviation (SD) is shown in the figures. Analysis of variance followed by Newman-Keuls test was used to test the effects of B[a]P. Differences were considered significant at the level of P < 0. 05. All statistical analyses were performed using GraphPad Prism 5. 01 Software (GraphPad Software, San Diego, USA).
Results Glycolytic shift induced by B[a]P. We first looked for evidence of glycolytic reprogramming using data from a previously published study of the effects of 2 μM B[a]P (72 h) on the transcriptome of human hepatocarcinoma HepG2 cells (GSE40117)  26. More precisely, in order to identify the pathways that were differentially affected by exposure to B[a]P, we performed single-sample gene set enrichment analysis (ssGSEA) projection as a hypothesis-generating gene set identification tool. ssGSEA analysis revealed that the expression of an OXPHOS-related gene set was globally down-regulated, in contrast to glycolysis and xenobiotic metabolism-related genes which were up-regulated, thus indicating a B[a]P-induced metabolic reprogramming in hepatic cells (Supplementary Fig. S1 ). On the basis of these results, we then conducted a thorough characterization of the impact of a low concentration of B[a]P on energy metabolism in F258 cells.
Oxygen consumption rate (OCR) analysis showed a strong inhibition of basal respiration following exposure to 50 nM B[a]P for 48 h (Fig. 1A, B ). Although evaluation of the maximal respiration capacity with the uncoupler molecule FCCP showed a similar OCR between control and B[a]P-treated cells, the reserve capacity was significantly higher in B[a]P-treated cells (Fig. 1A, B ). Therefore, B[a]P-treated cells would be better able to consume O 2 upon increased ATP demand or during a stress, which suggests that these cells are better adapted to cope with other stress. Altogether, these data indicate that exposure to B[a]P leads to a change in energy metabolism. We next measured the extracellular acidification rate (ECAR) and found that it was increased by B[a]P (Fig. 1C ). Since extracellular acidification could reflect an accumulation of intracellular glycolytic by-products, we measured lactate release, a well-known indicator of glycolysis.
5C ). Finally, we looked for an EMT-like process upon B[a]P exposure. We first analyzed the same previously published transcriptome study (GSE40117  26  ) as we did for the metabolic studies. The ssGSEA analysis revealed that the expression of an EMT-related gene set was globally up-regulated, notably the mesenchymal marker vimentin (Supplementary Fig. S5 ). In line with this, an increase in the level of vimentin protein was detected in F258 cells exposed to B[a]P (50 nM, 24 h), along with a downregulation of the epithelial marker E-cadherin (48 h) (Fig. 6A ). Thus, B[a]P appeared to induce an EMT under our experimental conditions. Further support for this shift was obtained by using the xCELLigence technology with CIM plates to investigate the B[a]P impact on the F258 cell migration. Although we observed a trend toward an increase in migratory capacity of the cells after exposure to 50 nM B[a]P, a large variability in the response failed to give statistically significant results (data not shown).
Acknowledgements We wish to thank  Dr J. E. Ricci  ( University Nice-Sophia Antipolis ) for his scientific advice on lactate measurements. KH was a recipient of a fellowship from  French Ministry for Education and Research. We are also very grateful to the  Faculté des Sciences Pharmaceutiques et Biologiques de Rennes  ( University of Rennes 1 ) for further financial support to KH, and to the  Université Paris Descartes  for the PhD fellowship of ES. We wish to thank the Ligue contre le cancer (committees 22,35,49,85; DLG, OS), the  French National Academy of Medicine (DLG) ,  ANR  ( STEATOX project ; " ANR-13-CESA-0009 ";  DLG, BM, OS) , the  ITMO Cancer AVIESAN (National Alliance for Life Sciences and Health)  within the framework of the  Cancer Plan (SB) ,  Association for Cancer Research (ARC, CANC '  AIR Genexposomic  project) (BM), " Region Provence Alpes Côte d' Azur" (BM) ,  "Agence régionale santé Provence Alpes Côte d' Azur" (BM) , " Direction régionale de l'Environnement, de l'aménagement et du logement Provence Alpes Côte d' Azur " (BM, plan régional santé environnement PRSE PACA n°6.
Natural Anti-Oxidants and Inflammasomes The appearance of a new biological target always leads to a wave of patents and publications in fundamental and applied domains. The inflammasomes do not escape to this tradition. Considering patents, one major limitation for the use of the inflammasomes as an argument for originality is the patent from Tschopp and Martinon  [24]  in which the authors described the method for identification of inhibitors of the inflammasomes. This patent rendered the target itself extremely difficult to use without risking an anteriority problem. However, a few published patents identified by "inflammasomes" in the title or the summary can be identified knowing that the word "inflammasomes" itself is not in the thesaurus of the patent database. Table  2  summarizes the main results for compounds or compositions with antioxidant capacity claimed as useful for the treatment of inflammatory disorders involving direct or indirect effect on the inflammasomes.
When the anti-oxidant activity is studied in vitro in cellular or acellular conditions, a classification of compounds or mixtures according to their activity can be done. However, as soon as these compounds are administered orally or parenterally to a patient, there is no simple correlation between the initial antioxidant profiling and the final biological activity. The example of Oxygen Radical Absorbance Capacity (ORAC) illustrates perfectly the situation. ORAC value is well-known and used as a kind of calibrator for the anti-oxidant activities of compounds. Companies and final users are aware of it. However, the database on antioxidant profiling of foods with ORAC of the U. S. Department of Agriculture  [89]  is no longer available online due to the absence of a clear correlation between in vitro and in vivo activities.
Acknowledgements G. Guidoboni  and  S. Cassani  were partially supported by the  National Science Foundation  with grants  NSF-DMS  and , by the chair Gutenberg funds of the  Cercle Gutenberg of the Region Alsace (France)  and by  LABEX IRMIA at the University of Strasbourg (France). A. Harris  and  B. Siesky  were partially supported by  National Institutes of Health  Grant R EY A , unrestricted grant from  Research to Prevent Blindness, Inc.
Acknowledgements This investigation was supported by  SC1CA138176  ( NIH/NCI ;  SFW) award ,  Centre National de la Recherche Scientifique (CNRS)  through " Action CNRS-USA n° 4020 ", and  Aix-Marseille  and  Claude Bernard Lyon 1 Universities. We also thank  FIU Graduate School  for the  Dissertation Year Fellowship  (RR), and  NIH MARC U*STAR  ( GM083688-02 ) scholarship program (PT) as well as  Romain Simon ,  Christian Duchet  and  Nathalie Enriques  from the  Centre Commun de Spectrométrie de Masse (CCSM)  of  Claude Bernard Lyon 1 Université , for the assistance and access to the mass spectrometry facility. JB, AGT, TT and PV express their thanks to  Vincent Remusat  and the  Spectropole (Fédération des Sciences Chimiques de Marseille)  for NMR and HRMS analyses.
In summary, these results demonstrate that basic cell health endpoints will not predict hepatotoxic risk in simple hepatic cells in the absence of pharmacokinetic data and that a multicenter Abstract Assessing the potential of a new drug to cause drug-induced liver injury (DILI) is a challenge for the pharmaceutical industry. We therefore determined whether cell models currently used in safety assessment (HepG2, HepaRG, Upcyte and primary human hepatocytes in conjunction with basic but commonly used endpoints) are actually able to distinguish between novel chemical entities (NCEs) with respect to their potential to cause DILI. A panel of thirteen compounds (nine DILI implicated and 1-12. Members of the Innovative Medicines Initiative MIP-DILI (Mechanism-based Integrated systems for the Prediction of Drug-Induced Liver Injury) Consortium.
Since DILI continues to pose significant problems in drug development, this suggests that currently used in vitro models are not appropriate for effective screening, but a comprehensive, multicenter, unbiased assessment to test this unequivocally has never been performed. Therefore, the Innovative Medicines Initiative (IMI)-funded consortium 'Mechanism-based Integrated Systems for the Prediction of Drug-Induced Liver Injury' (MIP-DILI) has assessed current in vitro cell models, using an evidencebased panel of compounds implicated in DILI in man, in order to determine whether any of these simple cell models per se are actually predictive of human DILI. Furthermore, by using a small panel of DILI-and non-DILI-implicated compounds, and basic measures of cell health, we were able to monitor reproducibility across different sites, thereby ensuring that our data should be more definitive than any currently available.
Cell culture The different seeding densities used are the optimal for each cell type. Data generated from each cell model was first analyzed relative to the corresponding untreated controls and then comparisons were made across the different cell models. Donor details for the fresh and cryopreserved PHH as well as the Upcyte cells are summarized in Table  3. Allocation of PHH donors for each test site is also summarized in Table  3. Pre-qualification for choosing the five cryopreserved PHH donors was based on their viability post-thawing, ability to adhere to cell culture plates, metabolic profile and material availability to ensure there was sufficient supply for the planned experimental work and any future studies. Donor demographics were collected as summarized in Table  3 ; however, these were not considered a priority during the pre-qualification stage as the aim was to select a cohort of the population in an unbiased manner.
Data analysis Cell viability was determined as the percentage of the fluorescent resorufin after incubation with resazurin in the treated cells compared with vehicle control or the percentage of ATP detected in the treated cells compared with vehicle control. Individual EC 50 values from all participants were calculated using GraphPad Prism 6 (version 6. 03) at one partner site. Concentration series for each compound and cell type were log-transformed and fitted with a sigmoidal regression function assuming a lower viability plateau with increasing compound concentration of 0 and a Hill coefficient of -1 using Python and Prism (GraphPad Software). Differences between two dilution series were computed using F-tests. Differences were considered significant when p < 0. 05 and, to compensate for biological significance, when relative EC 50 -differences > three-fold.
'No fit' indicates no decrease in viability of at least one compound in the respective pairwise comparison. Variability coefficients were calculated by dividing the number of tests with significantly different responses by the number of all pairwise comparisons. Hierarchical clustering was performed using Qlucore Omics Explorer 3. 1 on mean-centered sigma-normalized data using maximum linkage. Correlation of ATP and resorufin values was calculated using Pearson correlation. Statistical difference between 24 and 72 h toxicity measurements was computed using a paired.
2014). Another aim of this study was to ensure that the data set generated was sufficiently robust for use as a reference tool for the evaluation of initial markers of chemical insult in simple cell models, and to benchmark more complex models of DILI. Importantly, we detected different degrees of inter-laboratory variation across the cell types assessed (Fig. 4 ). The largest inter-laboratory variation was observed in the PHH (48. 5 %), followed by the HepG2/ECACC cells (23. 4 %). It is not unexpected that the most complex and sophisticated cell in our study, the hepatocyte, shows the greatest inter-laboratory variation among the different cell models, despite the use of common reagents, plasticware and protocols. However, the variation in the HepG2 data was surprising particularly as these cells also demonstrated the highest level of intra-laboratory variation (11.
The specificity of each gene amplification was verified at the end of qPCR reactions through analysis of dissociation curves of the PCR products. Amplification curves were analyzed with CFX Manager software (Bio-Rad), using the comparative cycle threshold method. Relative quantification of the steady-state target mRNA levels was calculated after normalization of the total amount of cDNA tested to the 18S rRNA endogenous reference using the 2 (-∆∆Ct) method. Data were finally expressed in arbitrary units relative to 18S rRNA content as described previously  [34]  or, alternatively, for transporter regulation studies, as percentages of mRNA expression found in control untreated cells.
Cells were finally lysed in distilled water and intracellular levels of fluorescence dyes were quantified by spectrofluorimetry using a SpectraMax Gemini SX spectrofluorimeter (Molecular Devices, Sunnyvale, CA, USA) (excitation and emission wavelengths were 485 and 535 nm, respectively, for rhodamine 123 and CF, and 355 and 460 nm, respectively, for Hoechst 33342). Data were expressed as fluorescence arbitrary units/mg protein.