dataesr/scientific-paragraphs-categorization huggingface dataset:
Drug imputability was assessed by Roussel Uclaf Causality Assessment Method (RUCAM) scale  [4, 17] , a widely used method to quantify the strength of association between liver injury and implicated medication. The RUCAM scale is composed of several different criteria including: temporal relationship between the drug intake and development of an abnormal LFT, evolution of LFTs following drug withdrawal, alcohol consumption, age, previous case reports of DILI, concomitant medication, exclusion of all potential causes of liver damage, drug rechallenge. A semiquantitative score was calculated and an association between AD drug use and liver injury was defined as follows: highly probable (score>8); probable (score = 6-8); possible (score = 3-5); unlikely (score = 1-2); excluded (score<0). Data collection was carried out independently by two investigators (CSV and SM) under the supervision of GP and EC.
Moreover, NAFLD was the major cause of abnormal LFT in this group of patients. Acute alcohol consumption and chronic hepatitis C virus infection were also involved. Alcohol dependence is present in up 20% of patients with depression and may negatively affect the course of depressive disorders  [22]. The METADAP cohort included patients without ongoing alcohol consumption. Nevertheless, alcohol relapse was the second most common cause of LFT abnormalities and should be considered in antidepressant-treated patients. These data suggest that an increase in aminotransferase levels (before any antidepressant treatment or during treatment) may be related to an underlying liver disease, not necessarily severe, that does not contraindicate antidepressant treatment. Therefore, assessment of baseline LFTs may be useful as they help to interpret the abnormal LFT results during antidepressant treatment.
A more recent study conducted in medical inpatients reported a DILI incidence of 1. 4%  [27]. Carvajal Garcia-Pando and colleagues  [28]  reported an incidence of DILI associated with antidepressants requiring hospitalization of 1,28-29 cases per 100,000 patient-years. This estimation was based on cases of hepatic damage collected via spontaneous reporting and included in the Spanish Pharmacovigilance database, suggesting a possible underestimation of the disease. In our study, we report one case of symptomatic DILI associated to escitalopram and two cases of asymptomatic LFT abnormalities which fulfilled the criteria of DILI attributable to venlafaxine and amitriptyline use. The three patients developed increased ALT serum levels > 5xULN following antidepressant initiation that normalized upon treatment withdrawal and liver biopsy was unnecessary.
LFT normalized despite continuation of concomitant medication (Table  3 ). However, drug-drug interactions involving CYP450 pathway cannot be excluded in these cases of DILI. In our cohort of depressed patients, the frequency of DILI associated with antidepressant use was 0. 9% during the first six months of treatment. Considering that LFT were assessed in a minority of antidepressanttreated patients, undiagnosed cases of asymptomatic DILI may exist. Treatment continuation despite hepatotoxicity development could lead to severe hepatic failure or chronic hepatocellular dysfunction  [8, [29] [30] [31]. All these data suggest that DILI related to antidepressant use is probably underestimated and surveillance of LFT in the first six months of treatment could improve detection of asymptomatic cases.
The CYP2D6 Ã 10 allele was found in a homozygous status in a patient with DILI related to venlafaxine use. The patient was a homozygous carrier for the deletion GST M1 which leads to complete absence of enzymatic activity and potentially higher susceptibility to toxic liver injury. CYP450 and GST polymorphisms may therefore play a role in the pathogenesis of hepatic toxicity related to antidepressant use, but further studies are needed. Our study has several limitations. First, it is a retrospective review of a prospectively acquired database. Nevertheless, a primary goal was to assess frequency of LFT availability in depressed patients requiring antidepressants in psychiatric clinical practices. Second, the number of patients was relatively low to evaluate DILI associated with antidepressant drug use which is a rare condition.
Twenty-seven experiments were performed according to the surface response models method (Equation (  5 )) with a complete factorial matrix (16 experiments) (Table  3 ), 8 points on the axis and 3 points in domain's centre. All regressions were analysed by Modde software. The regression quality was evaluated by the same statistical indicator. After verifying the validity of the model by classical statistical tests  [45] , the vitamin C encapsulation could be predicted in each point of the defined domain. Analysis of variance (ANOVA) was performed to determine the significance of the fitted equation. The multiple correlation coefficient statistic (R 2 ) revealed the part of the variation of Y 1 explained by the model.
Optimisation Once all the experiments were performed, the calculation of the optimal point was given by Modde software with the following constraints:  The study of response surface is very interesting in three responses: encapsulation efficiency, yield, and release of vitamin C. Table  7  summarises the best level to optimize each reply individually. As shown by Table  7 , monomers and vitamin C amounts have the most important impact on all responses, whereas the amount of cyclohexane and the addition rate of monomers have a smaller effects. It is interesting to note that vitamin and monomer concentrations have antagonistic effects (Table  7 ).
Optimisation Once all the experiments were performed, the calculation of the optimal point was given by Modde software with the following constraints: • Y2 (encapsulation efficiency): objectives 100%, minimum 60% • Y3 (encapsulation yield): objectives 100%, minimum 65% • Y4 (release): objectives 0% maximum 15% The study of response surface is very interesting in three responses: encapsulation efficiency, yield, and release of vitamin C. Table  7  summarises the best level to optimize each reply individually. As shown by Table  7 , monomers and vitamin C amounts have the most important impact on all responses, whereas the amount of cyclohexane and the addition rate of monomers have a smaller effects. It is interesting to note that vitamin and monomer concentrations have antagonistic effects (Table  7 ).
Identification of the Components Identification of the components was based on computer matching against commercial libraries (Wiley, MassFinder 2. 1 Library, and NIST98), laboratory mass spectra libraries built up from pure substances, and MS literature data  [66] [67] [68] [69]  combined with comparison of GC retention indices (RI) on apolar and polar column. RIs were calculated with the help of a series of linear alkanes C8-C24 on apolar and polar column (HP-1 and HP-INNOWAX). Compounds available in the laboratory were confirmed by external standard compound co-injection.
Data of 7072 patients from prospective studies investigating DP efficiency were pooled. Those without molecular evidence for failure or with follow-up less than 28 days were excluded. The primary endpoint was the PCRadjusted risk of P. falciparum recrudescence at the end of the study follow-up. Secondary endpoints included new P. falciparum infections, parasitological clearance rates, and gametocyte carriage. No patient was heavier than 100 kg. Twenty-eight patients weighed from 75 to 100 kg, and the median cumulative dose in this group was 37. 4 mg/kg (32. 8-48. 3) for PPQ and 4. 7 mg/kg (4. 1-6. 4) for DHA; these were close to the rates in the present patient and corresponded to 71. 4 % (20/28) of patients below the WHO recommended dose  [22]. The WWARN DP Study Group clearly showed that a total PPQ dose below 40 mg/kg predicted risk of recrudescence failure  [23].
Study design and participants This was a phase III, randomized, active-controlled, investigator-masked, multicenter study with a run-in period, conducted in France (14 active centers) and Tunisia (4 centers), comparing HA-trehalose and HA eyedrops (ClinicalTrials. gov identifier: NCT02023268). The study was conducted in accordance with Good Clinical Practice and applicable International Conference on Harmonisation and the European directive 2001/20/CE guidance documents and practices, and in compliance with the ethical principles of the Declaration of Helsinki (2004) and local regulations (including independent ethics committee approvals before starting the study). Prior to enrollment, written informed consent was obtained from each participant. The study took place between October 2013 and December 2014.
Safety assessments Ocular symptoms (irritation/burning/stinging, photophobia, foreign body sensation, eye dryness feeling, pain, and other symptoms) and global tolerability were assessed at days 35 and 84. Ocular symptoms were assessed by asking if any sensation was felt upon instillation; if yes, an assessment of duration and severity was completed. Global tolerability was assessed by the investigator as very satisfactory, satisfactory, not very satisfactory, or unsatisfactory. Adverse event (AE) data were collected at days 0, 7, 35, and 84. All AEs observed by the investigator or reported by patients were recorded, along with their severity and potential relationship to study treatment. Best-corrected visual acuity (BCVA) was measured at the screening visit (baseline) and days 35 and 84 with the patient's best correction using a Snellen chart.
5%. An estimated attrition rate of 15% meant that it was planned to enroll a total of 90 patients. Other quantitative variables were analyzed using the same ANCOVA model for group comparison. Ordinal variables were analyzed using a 2-tailed Wilcoxon signed-ranked test or chi-square test. Missing data were handled using a last available assessment carried forward approach. Comparisons were performed 2-sided at the 5% α level of significance. A subanalysis for OSDI was performed at day 35 and day 84 for the percentage of patients with scores 0-13, 14-23, 24-33, and 34-100, corresponding to OSDI classes of none, mild, moderate, and severe, respectively  (23). Another subanalysis was performed at day 35 and day 84 to compare the evolution (improvement, no improvement) of each ocular symptom (burning, pain, stinging, itching, dryness feeling, foreign body sensation, light sensitivity, and blurred vision) between groups.
However, the small population size was validated statistically for the purposes of this study, and an investigator-masked design was used rather than a double-masked study design since the latter was not possible due to differences in the presentation of the 2 products. Notably, the primary criterion was assessed by the investigator masked to treatment, limiting bias regarding the primary analysis. Overall these data demonstrate that HA-trehalose is at least as efficacious as HA which, together with other eyedrops containing 0. 18% sodium hyaluronate  (36) , has proven efficacy in the treatment of dry eye syndrome  (37). Additionally, HA-trehalose is better appreciated by both the investigator and the patient, and is better tolerated than HA, with its advantageous effects on DED symptoms (both symptoms of ocular discomfort and visual disturbance linked to dry eye) being evident as early as day 35.
Acknowledgment The authors thank the patients for their participation in this study; all study site personnel;  Marielle Estrade  for managing the study;  Claire Billard  and  Sylvie Nisslé  for statistical analyses; and  Dr. Andrew Lane  (Lane Medical Writing) and  Hervé Chabanon , who provided professional medical writing assistance in the preparation and development of this manuscript in accordance with the European Medical Writers Association guidelines and Good Publication Practice.
The trial was designed using a modified two-stage Simon's design  [14] , allowing with small sample sizes of 40 patients per arm in the first stage to control the type I error accurately at the pre-specified level of 0. 15 with a statistical power of 0. 80. At the end of this first stage, no decision of dropping any arm was made. We wondered whether the use of a Bayes approach may have modified the design, and subsequent analyses. Thus, the objective of this paper was to redesign the Bayesian adaptive design originally proposed by Xie, Ji and Tremmel for seamless phase I/II trials  [13] , focusing on the comparison of multiple experimental drugs to a control drug on a binary criterion measure. First, we applied our design to the real dataset from the ongoing phase II randomized trial conducted on 120 patients that motivated this work.
Motivating example We used data from a phase II clinical trial of an international study conducted in 120 patients with myelodysplastic syndrome (MDS) who were randomized across three treatment arms. Although the original design was non-Bayesian  [14] , we reanalyzed data from the first stage of this trial to illustrate the interest of Bayes approaches. Because the trial is still ongoing in a second stage, no further details about the treatment arms will be provided. Each group of 40 patients received one of the following treatments: A (reference treatment, control group), B or C (two combinations of new drugs with the reference treatment, experimental groups). It was hypothesized that the response rate in the control group would be 0. 30 and that a response rate of at least 0. 45 would indicate that a combination was sufficiently promising to be included in further studies.
This setting in which several treatments are compared to a single control allows heterogeneity in patient populations and disease courses to be considered  [24, 25]. However, the heterogeneity in objectives, design, data analysis, and reporting of these multi-arm randomized trials has recently been highlighted  [26]. Moreover, in ascertaining which treatment modalities are most effective, the presence of K experimental arms also introduces complexity. We used a binary outcome measure, given that it appears to be the most widely used endpoint in phase II trials. Of note, such a binary criterion in MAMS has been used only in frequentist designs  [6, 27]. Indeed, most of the proposed MAMS designs, including optimal designs, used a frequentist framework for inference  [4-8, 14, 28]. The application of Bayesian adaptive design methods has recently been advocated to maximize the knowledge-creating opportunity of a learning phase study  [13].
PATIENTS AND METHODS This study was conducted by retrospective, observational review of hospital medical and electronic records. Consecutive patients who had been admitted to the Liver Unit and had been prescribed anidulafungin for IFI between July 1, 2009 and February 3, 2011 were included in the study. Patients who had participated in any other interventional clinical trial during the episode of sepsis when anidulafungin was used and patients who had received anidulafungin prophylactically or empirically were excluded. Patient consent was not sought for this study as permitted by United Kingdom Data Protection legislation  [15]  because it involved no intervention, and the data were collected by NHS staff with access to the patient case notes as part of normal clinical care. The study was given a favorable opinion by the Central London Research Ethics Committee (reference 10/H0716/65) and approved by the King's College Hospital NHS Trust Research and Development committee.
All study data were sourced retrospectively between February and May 2011 from patients' case notes and electronic databases at King's College Hospital. The data collected included patient and disease characteristics, Model for End-Stage Liver Disease (MELD) score  [16]  for patients with chronic liver disease, biochemical parameters at start date to 5 days after stopping anidulafungin; liver function tests (LFTs), international normalized ratio, platelets, white blood count, C-reactive protein, creatinine, urea, concomitant viral and bacterial infections, comorbidities, concomitant drugs, details of invasive fungal infection site and infecting species, previous antifungal exposure within 30 days before start of anidulafungin, outcome of antifungal treatment, clinical and microbiological response to anidulafungin treatment, anidulafungin-related adverse events, and hospital mortality.
Candida isolates in blood culture and in sterile body fluids were identified to species level, but isolates from sputum, bronchoalveolar lavage, throat swabs, and wound swabs were not identified to species. "Proven invasive candidiasis" was defined as isolation of Candida species (spp) from peripheral blood or normally sterile body site or histopathological or culture evidence of tissue invasion. "Probable invasive fungal infection" was based on inclusion of a host factor that identified patients at risk, clinical signs and symptoms consistent with the disease entity, mycological evidence that encompassed culture and microscopic analysis, and also indirect tests, such as antigen detection. Study data were recorded on study case report forms. The anonymized-coded case report forms were then transcribed into the study database and analyzed using descriptive statistics.
Both distributions and descriptive statistics of both central tendency and dispersion are presented for quantitative and ordinal variables, whereas nominal variables are described with frequencies and percentages. The primary outcome measure was the proportion of patients with a "favorable outcome" of anidulafungin treatment. Secondary outcome measures included the proportion of patients with a favorable clinical response, unfavorable outcome, lack of clinical response, death (all causes), death attributable to fungal infection, and death cause unrelated to fungal infection. To minimize bias from clinical judgment, the main study outcomes were defined as follows: (1) favorable outcome was defined as "favorable clinical response" and "documented or presumed microbiologic eradication"; (2) favorable clinical response was defined as the clinical resolution of signs and symptoms of infection or the transition to oral antifungal agent for completion of therapy and with no need to change or add to parenteral antifungal therapy; (3) documented or presumed microbiologic eradication was defined as 2 negative follow-up blood cultures for bloodstream infections or a successful clinical response without follow-up cultures for other infections; (4) "unfavorable outcome" was defined as the need to change to another antifungal agent because of a lack of clinical response or death due to the fungal infection or microbiologic persistence of the fungus or superinfection with a new Candida, Aspergillus, or other fungal strain occurring after at least 3 days and up to 14 days of anidulafungin therapy, or a lack of follow-up data about clinical and microbiologic responses at the end of anidulafungin therapy; (5) "abnormal" LFT results were defined as those above the normal range (bilirubin >20 μmol/L, aspartate transaminase >50 IU/L, alkaline phosphatase >130 IU/L, and gamma glutamyl transferase >55 IU/L); (6) deterioration in liver function was defined as at least a 2-fold increase in 1 or more LFTs during anidulafungin treatment compared with the start of treatment.
Acknowledgments Financial support. This work was funded by  Pfizer UK  Limited. Potential conflicts of interest. A. V. has received educational grants from  Astellas Pharma  and  Gilead  and is a study Investigator for  Pfizer. G. A. has worked in an advisory role on behalf of  Pfizer  and has given paid talks at national and international conferences. M. K. is a full-time employee of  Pfizer PFE (Paris, France ). J. C. and D. S. are full-time employees of Pfizer Ltd, UK. F. P. is an employee of pH Associates Ltd, which was commissioned by the study sponsor to provide support with study design, analysis, and reporting, under a commercial contract. N. H. has been paid for speaking on behalf of  Astellas Pharma. All authors have submitted the  ICMJE Form for Disclosure of Potential Conflicts of Interest.
Proposed criteria for conflicts of interest 1. CEs that are members of an ERN can receive unrestricted grants as well as research grants from a pharmaceutical company provided full and timely (i. e. , advance) disclosure of receiving such grants is given to the ERN's Steering Committee and the amount does not conflict with other criteria 2. Centres of Expertise (CEs) cannot become a member of an ERN if it is primarily funded by and financially dependent on industry for a substantial part (to be defined by an independent body) 3. Healthcare professionals and patient representatives involved in CEs and ERNs cannot take part in the development of clinical guidelines and protocols, such as care pathways, treatment guidelines and diagnostic strategies, if they have the following serious conflicts of interest relevant to the CE or ERN: a.
Acknowledgments: With the support of the  Lifelong Learning program  of the  European Union :  527194-LLP-1-2012-1-BE-ERASMUS-EMCR , this project has been funded with support from the  European Commission. This publication reflects the views only of the author; the Commission cannot be held responsible for any use which may be made of the information contained therein. The authors thank  Jane Nicholson  of the  European Industrial Pharmacists' Group (EIPG) ,  Vivian Moffat  of the  European Federation of Pharmaceutical Industries and Associations (EFPIA) , and  Hans Linden  of the  European Federation for Pharmaceutical Sciences (EUFEPS)  for distributing the PHAR-QA questionnaire to the members of their associations.
| Quantitative evaluation of the labelled cell surfaces Measurements of the extent of cell margin labelling observed with SEM were carried out using ImageJ free online software on samples from the eight different donors with five markers at three SC depths (superficial, intermediate and deep SC). At least 10 cells per D-squame strip were evaluated. On each cell, the width of the marginal labelling zone was measured at four different points. The results were expressed as a mean width of the marginal zone ± standard deviation (SD) and compared using ANOVA oneway test.
For instance, it is estimated that 34 % of medicines in sub-Saharan Africa are of poor quality  [4]. In the field of malaria, the analysis of a database collating customized summaries of 251 published anti-malarial quality reports showed that out of 9,348 anti-malarials sampled, 30. 1 % (2,813) failed chemical/packaging quality  [5]. In addition, because of the complexity of the supply channels in the global market and the consequent difficulty to trace the origin of medicines, poor-quality products may exceptionally reach highincome countries, and in a few case they have even been used in clinical trials  [6]. Poor-quality medicines include substandard medicines, i. e. genuine medicines that are produced by manufacturers authorized by a National Regulatory Authority but do not meet quality specifications, and falsified or counterfeit medicines, i.
ACKNOWLEDGMENT This work was supported in part by a  LabEx CSC "Chemistry of Complex Systems " grant and the  Marie Curie Actions FP7-PEOPLE Program  ( CIG-2012-326112 ). M. D. thanks the  Région Alsace  for a fellowship. We thank  Stéphanie Kouaho  ( Service de Spectrométrie de masse, Université de Strasbourg ),  Yann Simon  and  Benedicte Gauriat  ( Thermo Fisher Scientific ) for HRMS analysis.