dataesr/scientific-paragraphs-categorization huggingface dataset:
7A ; one-way ANOVA, F (3,56) ϭ 7. 12, p Ͻ 0. 001) at the dose of 150 mg/kg ( p Ͻ 0. 01), without altering water intake (Fig. 7B ; one-way ANOVA, F (3,56) ϭ 2. 07, p ϭ 0. 11). We further tested whether systemic administration of LM11A-31 attenuates binge drinking of sucrose. To do so, rats had IA to 1% sucrose in a 2BC paradigm for 7 weeks, and sucrose consumption was measured after 30 min access following LM11A-31 injection. As shown in Figure  7C , LM11A-31 (150 mg/kg) did not alter binge consumption of sucrose, and the corresponding water intake was also unaltered (Fig. 7D ; sucrose, t (13) ϭ 0. 93, p ϭ 0. 37; water, t (13) ϭ 0. 39, p ϭ 0. 71). Together these data suggest that pharmacological targeting of p75NTR is a potential treatment of alcohol abuse disorder by attenuating alcohol intake without affecting the consumption of a natural rewarding substance.
Introduction The European Medicines Agency included doxorubicin on the 'priority list' (doc. ref. EMEA/197972/2007 , London, June 2007) for medications with a high priority for further research on pediatric use, with the absence of pharmacokinetic knowledge being the most critical point. Based on this document, the European Paediatric Oncology Off-Patent Medicines Consortium (EPOC) set up a trial to investigate the pharmacokinetics of doxorubicin in children. The pharmacokinetic phase-II-trial (EudraCT number 2009-011454-17, short title: EPOC) was funded under the European Commission's Seventh Framework Program, grant agreement number 222910. These regulatory and political activities had the objective of including more detailed dosing information in the summary of product characteristics and the package leaflets.
Acknowledgments The authors wish to thank all clinical investigators and clinical trial centers that participated in the EPOC-MS-001-Doxo trial. This trial and all accompanying research were funded by the  European Community 's  Seventh Framework Programme  ( FP7/ 2009-2013 ) under Grant Agreement Number  222910. Miriam Krischke  and  Gudrun Wu  ¨rthwein are supported by the  German Federal Ministry of Research and Education (BMBF  Grant  01KN1105 ).
PATIENTS AND METHODS Patients and study design. PSUMMIT 1 (NCT01009086) and PSUMMIT 2 (NCT01077362) were conducted according to the principles of the Declaration of Helsinki. Governing ethical bodies at each study site approved the protocols, and patients provided written informed consent prior to the conduct of any study-specific procedures. Patient eligibility criteria and the study designs of the phase 3, randomized, placebo-controlled PSUMMIT 1  (10)  and PSUMMIT 2 (11) trials have been described. Briefly, both trials enrolled adult patients with active PsA for $6 months despite previous treatment with disease-modifying antirheumatic drugs (DMARDs; $3 months) or nonsteroidal antiinflammatory drugs (NSAIDs; $4 weeks), or ,3 months or 4 weeks, respectively, if DMARDS or NSAIDs were discontinued due to intolerance.
Additionally, a DLQI score #1 was defined as no impact of disease on HRQoL. The impact of disease on daily productivity at work, school, or home was evaluated using a visual analog scale (VAS; where 0 5 did not affect at all and 10 5 affected very much). Patient assessments of pain and disease activity also were assessed with a VAS ranging from 0 to 10. Statistical analysis. Data from the PSUMMIT 1 and PSUMMIT 2 trials were pooled for these post hoc analyses. Descriptive statistics, including counts (percentages), means (SDs), and mean changes from baseline are reported. Outcomes were analyzed according to 3 mutually exclusive antecedent-exposure groups: 1) patients who were biologic agent-and MTX naive, 2) patients who were biologic agent naive, but had been treated with MTX, and 3) patients who had been treated with an anti-TNF agent with or without MTX.
CONCLUSIONS Airborne lidar measurements were performed over several temperate and tropical forests sites, which allowed building a representative database of lidar vertical profiles. We extracted the structural and ecological parameters (canopy height, quadratic mean canopy height and apparent foliage) from lidar backscattered signal, and then evaluate the aboveground carbon and leaf area index. Even though UV lidar is not a good candidate for spaceborne missions due to the weak atmospheric transmission and the strong absorption by the vegetation in the UV domain, we confirm that the UV wavelength is a good candidate for airborne lidar measurements, and can be a very interesting reference for a spaceborne mission dedicated to forest studies at the global scale.
ACKNOWLEDGMENTS The experiments have been funded by the  Centre National d'Etudes Spatiales (CNES) , the  Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA) , and the  Université de la Réunion through the federation Observatoire des Milieux Naturels et des Changements Globaux (OMNCG) of the Observatoire des Sciences de l'Univers de la Réunion (OSU-R). We are also grateful for the support offered by the  Direction Générale de l'Armement (DGA). We finally thank our ULA pilot F. Toussaint.
Time-lapse confocal microscopy mGb4 cells were grown in 35 mm glass dish coated with poly-D-lysine/laminin and imaged on LSM5 live duo inverted Microscope (Zeiss) equipped for time-lapse microscopy with CCD camera, temperature controller (37°C) and CO2 (5%) incubation chamber. Cell divisions were imaged as stack images at 0. 5-1 μm z-spacing with an objective EC Plan-Neofluar 40x/1. 30 Oil DIC M27 (Zeiss). After acquisition, images were analysed using LSM5 images browser (Zeiss). For best viewing of proteins distribution, all z-planes were merged in one single plane projection. Raw data have been deposited on the public repository Figshare and are available at this link https://figshare. com/s/b332c725ae0695770cfb.
Statistical analysis of asymmetry GFAP asymmetric repartition events were scored in mitotic cells engaged in the late mitosis steps i. e. in anaphase or telophase with two separate chromatid sets but still sharing a common cytoplasm. Z acquisitions were systemically performed to ascertain that GFAP asymmetry was present in all or most cell planes to avoid artefact with cells displaying a 3D peculiar shape. To quantify the asymmetry in IF and videomicroscopy experiments, we determined the percent (%) deviation previously described in  [18]  using this formula: (F1-F2)/ (F1+F2) x 100 where F1 and F2 represent the fluorescence of each cells (using CTCF, i. e. integrated density-(area of selected cell X mean fluorescence of background readings) obtained with imageJ software). Fluorescence of β-tubulin (which is equally expressed in both daughter cells) was used to determine the asymmetry cell division cutoff.
Acknowledgments This work was supported by the  "Association pour la Recherche sur le Cancer" (ARC, France) , the  "Association pour la Recherche contre les Tumeurs Cérébrales" (ARTC Sud, France)  and  "l'Institut National pour la Recherche sur le Cancer" (INCA, France). We thank  Dr. D. Pham Dinh  ( Paris, France ) for kindly providing all hGFAP-EGFP constructions. RIO and RHEM Montpellier facilities were used for this work. This work has benefited from the facilities and expertise of the  CCBH-M Collection (glioma collection ) of the  University Hospital of Montpellier-France  (www. chu-montpellier. fr).
MATERIALS AND METHODS We pooled individual-level questionnaire data from the seven IMMC case-control studies that collected information on reproductive factors among women (1,072 cases and 3,541 controls). Within each study, we computed odds ratios (ORs) with corresponding 95% confidence intervals (CI) using unconditional logistic regression, adjusting for age group (four categories), race (except for Epilymph, which did not collect these data), and study center (for multicentric studies: Epilymph and FHCRC 1980s). Random-effects models were used to calculate pooled estimates using the DerSimonian & Laird method. Heterogeneity between studies was assessed using the I 2 statistic and p-heterogeneity using the Mantel-Haenszel method. Analyses on parity and gravidity were restricted to women aged 45 or older, as they are likely to have completed their reproductive history.
Our study was based on a large dataset with individual-level information on reproductive factors and exogenous hormone use, yet we did not observe consistent patterns with these factors and MM risk. We had the ability to control for a variety of potential confounders, including education, BMI and alcohol use. Ignoring these variables may have biased previous studies of HT and cancer, due to the potential for selection bias and a healthy user effect. We did not observe clear evidence of confounding by those variables in the present analysis, although residual confounding cannot be discarded in explaining some of our results, in particular for HT. Also, use of controls that may not be representative of the population from which the cases arose was an inherent limitation of some of the participating studies' design.
1. 05/2. 1. 00/03. 0101 ; Fondation de France  ( 1999 008471 ;  EpiLymph-France );  Italian Association for Cancer Research  ( AIRC, Investigator Grant   11855 );  Italian Ministry of Education, University and Research, PRIN programme  ( 2007WEJLZB ,  20092ZELR2 ); and the  German Federal Office for Radiation Protection  ( StSch4261  and  StSch4420 ;  Epilymph Germany ). Funding for the Utah study was, in part, from the  Leukemia and Lymphoma Society   6067-09  (to N. J. Camp) and the  NCI   CA152336  (to N. J. Camp). Data collection for the Utah resource was made possible by the  Utah Population Database (UPDB)  and the  Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB was provided by the  University of Utah Huntsman Cancer Institute (HCI)  and the  HCI Cancer Center   Support grant ,  P30 CA42014  from the  NCI.
Data set and patient population The ClinicAl research using Linked Bespoke studies and Electronic Records (CALIBER) e-health database was the data resource for this study. CALIBER links patient records from four different data sources: Clinical Practice Research Database (CPRD), Myocardial Ischaemia National Audit Project (MINAP) registry, Hospital Episodes Statistics (HES), and the Office for National Statistics. The data of CPRD were used to obtain heart rate measurements, demographic variables, and other risk factors. Primary care practices that provide valuable data to CPRD and cover 4% of UK population are representative in terms of demographic parameters such as gender, age, and ethnicity  12, 13  and overall mortality  14  and have been validated for epidemiological research. A description of the CALIBER approach has been presented elsewhere.
15 lassification algorithms combining Read, International Classification of Disease 10 (ICD-10), drug, and procedure codes to define risk factors and endpoints are available at http://www. caliberresearch. org/portal/. Eligible patients were those with a diagnosis of stable angina, patients with a diagnosis of ACS within the study period (unstable angina or AMI), or those with a diagnosis of CHD in which there is no further specification of whether it is angina or MI (other CHD). Study start date was calculated from the date of diagnosis of stable angina or other CHD or from 6 months after an ACS or coronary intervention. The period of 6 months was chosen to differentiate long-term prognosis from the high-risk period that typically follows an ACS or revascularization. Diagnoses were identified in CPRD, HES, or MINAP records according to definitions given in the CALIBER data manual.
Healthcare utilization Healthcare utilization extracted from the data set included primary care consultations, pharmaceutical prescriptions, inpatient stays, and diagnostic tests. Primary care consultations included all contacts between the patient and healthcare professionals captured in the CPRD data set. Prescription data were available from the CPRD data set and distinguished between drugs that were cardiovascular disease (CVD)-related and those that were not. Inpatient stays extracted from HES were based on Health Resource Group (HRG) codes and defined as CHD, CVD (including CHD and broader HRGs), or non-CVD related based on ICD-10 codes. Diagnostic tests as recorded in the primary care data set but not outpatient consultations were also extracted, the latter being due to the absence of outpatient HES data linkage.
Costs All costs were calculated from the perspective of the UK National Health Service (NHS) in pound sterling based on 2011/12 prices. Costs were calculated by combining healthcare utilization data from CALIBER with associated unit costs that were taken from published UK sources. 16 -18 For hospitalizations, costs are calculated based on finished consultant episodes in HES. Costs are presented in terms of total healthcare costs (all costs incurred), CHD costs (all CHD-related hospitalization costs, CVD-related drugs, and all primary care and diagnostic costs), and CVD costs (all CVD-related hospitalization costs, CVD-related drugs, and all primary care and diagnostic costs).
Analytical methods Estimates of healthcare utilization and costs were calculated for the first year in the SCAD cohort and the first year following a non-fatal event during the follow-up period (AMI, ischaemic or haemorrhagic stroke) with results reported as means and standard deviations, with medians and interquartile ranges reported in the appendices. Observations that were right censored for any reason other than mortality (i. e. those for which the data are incomplete for the year of interest, either first year with SCAD or first year following an event, but the reason for incompleteness was not death) were excluded from the analysis. A generalized linear model with a log link and gamma distribution was used to estimate the impact of baseline covariates on costs in the first year in the SCAD cohort to account for the non-linear impact of covariates and the right skewness in cost data.
Covariates were based on those used by Rapsomaniki et al. ,  8  which developed a prognostic model for SCAD patients, on the assumption that predictors of costs were likely linked to prognostic indicators. The covariates included the baseline diagnosis for entry to SCAD, co-morbidities, age, gender, smoking status, and biomarkers. Models were fitted on five multiply-imputed data sets and estimates combined using Rubin's rules. 19 The impact of covariates has been transformed back onto the natural scale to allow for ease of interpretation. Panel data methods with time invariant covariates were used to estimate patient costs over each 90-day period. Also estimated were the impact of events (non-fatal AMI, ischaemic and haemorrhagic stroke, CVD-and non-CVD-related death) on the costs in the period of the event and subsequent periods if the event was non-fatal.
Acknowledgements We acknowledge the help of the authors of the original prognostic model, namely,  Eleni Rapsomaniki ,  Pablo Perel ,  Spiros Denaxas ,  Julie George ,  Owen Nicholas ,  Ruzan Udumyan ,  Gene Feder ,  Aroon Hingorani , and  Liam Smeeth. Further we acknowledge those responsible for the development of the CALIBER data set including  Spiros Denaxas ,  Julie George ,  Emily Herrett ,  Dipak Kalra ,  Aroon Hingorani ,  Mike Kivimaki , and  Liam Smeeth.
Funding The study was funded by the  UK National Institute for Health Research (NIHR)  ( RP-PG-0407-10314 ) and the  Wellcome Trust  ( WT 086091/Z/ 08/Z ) and was supported by the  Farr Institute of Health Informatics Research , funded by  The Medical Research Council  ( K006584/1 ) in partnership with  Arthritis Research UK , the  British Heart Foundation ,  Cancer Research UK , the  Economic and Social Research Council , the  Engineering and Physical Sciences Research Council , the  NIHR , the  National Institute for Social Care and Health Research (Welsh Assembly Government) , the  Chief Scientist Office (Scottish Government Health Directorates) , and the  Wellcome Trust. The views and opinions expressed within the paper do not necessarily reflect those of the NIHR or the UK Department of Health.
A. D. S. is supported by a  Wellcome Trust  clinical research training fellowship ( 0938/30/Z/10/Z ). C. P. G. is funded by the  National Institute for Health Research  ( NIHR-CTF-2014-03-03 ) as Associate Professor and Honorary Consultant Cardiologist. This work made use of the facilities of N8  HPC  provided and funded by the  N8 consortium and EPSRC  (Grant No. EP/K000225/ 1 ). The Centre is co-ordinated by the  Universities of Leeds and Manchester. Funding  to pay the Open Access publication charges for this article was provided by  University College London.
3/100 PY) and PBO+MTX (3. 7/100 PY). Conclusions CZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX. Trial registration number NCT01519791. phase III study placebo-controlled randomised, double-blind, factors: 1-year results from C-EARLY, a rheumatoid arthritis with poor prognostic DMARD-naïve patients with early, active.
INTRODUCTION ] [6]  Certolizumab pegol (CZP) is a PEGylated, Fc-free anti-TNF. The efficacy of CZP in combination with methotrexate (MTX) has been proven in patients with established RA and insufficient response to MTX alone in the pivotal RAPID1 and RAPID2 studies (the mean disease duration was ∼6 years in both trials). 7 8 More recently, CZP +MTX was shown to be efficacious in MTX-naïve patients with early RA and poor prognostic factors (C-OPERA study, conducted in Japan; the mean disease duration was ∼4 months),  9  justifying the need for a more thorough examination of the efficacy and safety of CZP+MTX in patients with recently diagnosed RA. C-EARLY (NCT01519791) is the first randomised double-blind study to assess the efficacy and safety of CZP+MTX versus placebo (PBO)+MTX treatment over 52 weeks in inducing and sustaining clinical response, and inhibiting radiographic damage, in DMARD-naïve patients with moderate-to-severe, active RA with poor prognostic factors.
Study design C-EARLY was a multicentre, double-blind, PBO-controlled, randomised study conducted in Europe, Australia, North America and Latin America at 181 sites (see online supplementary figure  S1 ). Patients were randomised 3:1 to receive CZP (400 mg subcutaneously at Weeks 0, 2, 4, then 200 mg every 2 weeks to Week 52)+MTX or PBO+MTX. Randomisation at Week 0 was performed centrally using an interactive voice and web response system and was stratified by disease duration of >4 months or ≤4 months. 5 Following completion of this 52-week study, patients in sustained low disease activity (sLDA; DAS28(ESR) ≤3. 2 at both Weeks 40 and 52) were eligible to enter a randomised, double-blind, dose-withdrawal study (C-EARLY Period 2 (NCT01521923); to be completed in 2016). The 3:1 randomisation was used to increase the pool of CZP patients eligible for Period 2 of the study.
Statistical analysis Full details of all statistical analyses are described in the online supplementary materials. In brief, the sample size was calculated assuming an expected percentage of patients in sustained remission (sREM) at Week 52 of 50% in the CZP+MTX group and 30% in the PBO+MTX group. A minimum of 600 CZP patients and 200 PBO patients were required (for 3:1 randomisation). Hypothesis testing was performed on Week 52 data in a hierarchical manner starting with sREM, followed by the secondary endpoints in the following order: sLDA, ACR50, change from baseline (CFB) in the Health Assessment Questionnaire-Disability Index (HAQ-DI) and CFB in the van Figure  1  Patient disposition in the C-EARLY study. a 'Other' included some mandatory withdrawals at Weeks 24 and 36. In addition, two patients in the certolizumab pegol (CZP)+methotrexate (MTX) group were randomised in error, were not dosed and were withdrawn shortly afterwards as screen failures (these two subjects were included in the RS).
Patients completed Week 52 if they had a Week 52 visit. FAS, full analysis set; PBO, placebo; RAD, radiographic set; RS, randomised set; SS, safety set. der Heijde modified total Sharp score (mTSS). All other statistical analyses are descriptive only. The full analysis set (FAS) was used for all efficacy data, except radiographic data which used the radiographic set (RAD). A logistic regression model was used for the primary and secondary Week 52 analyses and other dichotomous outcomes. CFB in HAQ-DI was analysed using analysis of covariance (ANCOVA) and CFB in mTSS was analysed using ANCOVA on the ranks. Missing data were imputed using non-responder imputation for analyses on dichotomous outcomes and last observation carried forward for continuous outcomes.
DISCUSSION C-EARLY is the first report of a double-blind, randomised PBO-controlled study assessing the efficacy and safety of CZP +optimised MTX in DMARD-naïve patients with early RA with poor prognostic factors, using a stringent primary outcome of sREM. These data demonstrate that CZP+MTX combination therapy results in a significantly higher proportion of patients  achieving sREM than those treated with PBO+MTX, even when using a 'treat-to-tolerance' dosing strategy for MTX. Significant improvements in physical function and inhibition of structural damage were observed for CZP+MTX patients. Consequently, for patients with poor prognostic factors for severe disease progression, treating early and aggressively may represent a unique opportunity to achieve maximal clinical benefit. Advances in the treatment options for RA, including DMARDs and biologic DMARDs/anti-TNFs, have made clinical remission and radiographic non-progression an achievable target.
14 In the C-EARLY trial, despite receiving optimised MTX, a significant proportion of patients were not in remission at Week 52 and an even smaller proportion achieved the primary outcome of sREM. Although patients generally responded well to MTX, which is expected in a DMARD-naïve population of patients, they responded significantly better to CZP, confirming the clinical relevance of our findings. Treatment of patients very early in the pathogenesis of disease is associated with significantly reduced joint destruction and better clinical outcomes. 15 The analysis of radiographic data in C-EARLY demonstrates that CZP+MTX therapy can inhibit structural damage significantly more than MTX alone-the percentage of patients with radiographic non-progression was significantly higher in the CZP+MTX group compared with the PBO+MTX group.
Time perception is an essential function of the human brain, which is compromised in Alzheimer's disease (AD). Here, we review empirical findings on time distortions in AD and provide a theoretical framework that integrates time and memory distortions in AD and explains their bidirectional modulation. The review was based on a literature survey performed on the PubMed and PsycInfo databases. According to our theoretical framework, time distortions may induce decline in the ability to mentally project oneself in time (i. e. , mental time travel), and consequently may contribute to an episodic memory compromise in AD. Conversely, episodic memory compromise in AD may result in a loss of the ability to retrieve information about time and/or the ability to project oneself in subjective time. The relationship between time distortions and memory decline in AD can be jointly attributed to hippocampus involvement, as this brain area supports both time perception and memory and is preferentially targeted by the neuropathological processes of AD.