dataesr/scientific-paragraphs-categorization huggingface dataset:
XANTUS objectives and rationale XANTUS (Xarelto ® for Prevention of Stroke in Patients with Atrial Fibrillation; NCT01606995) is a prospective, international, postauthorization, observational, noninterventional Phase IV study in patients with nonvalvular AF prescribed rivaroxaban for prevention of stroke in routine practice. This paper describes the objectives, design, and protocol for the XANTUS study, as well as key limitations. Because the XANTUS study is intended to assess the use of rivaroxaban in routine, real-world clinical practice, study procedures will not interfere with the clinical management of patients or with the prescribing behaviors of attending physicians. In contrast to ROCKET AF, patients with nonvalvular AF may be included in XANTUS regardless of their risk of stroke, although it is presumed that they will be prescribed rivaroxaban in accordance with the appropriate prescribing information.
Data collected will include risk assessment, bleeding events, thromboembolic events, and adverse events (AEs) that occur in patients with nonvalvular AF receiving rivaroxaban in routine care according to the local marketing authorization. Information on the clinical management of these events will also be collected. The key goal for XANTUS is to confirm the safety profile of rivaroxaban across the broad range of patient risk profiles encountered in the setting of routine clinical practice. This will include assessment of rivaroxaban's safety in patients at increased risk of thromboembolic or bleeding events. It is also expected that the data collected during the course of the study will provide a comprehensive overview of the outcomes associated with rivaroxaban therapy and factors influencing its use in the clinical management of stroke prophylaxis in AF, across different geographic regions, care settings, patient populations, and health care systems.
Final visit 1 year b Figure  1  XANtuS study design, an observational, single-arm cohort study. the objective is to collect real-life data on adverse events, bleeding, thromboembolic events, and mortality in patients with nonvalvular AF treated with rivaroxaban. the same basic design will be used for all studies in the XANtuS program. Notes: a Protocol does not define exact referral dates for follow-up visits (every 3 months recommended); b in patients discontinuing rivaroxaban before 1 year, the end of the observation period is 30 days after the last dose. XANTUS (clinicaltrials. gov: NCT01606995). Abbreviations: AF, atrial fibrillation; CNS, central nervous system; XANTUS, Xarelto ® for Prevention of Stroke in Patients with Atrial Fibrillation. documented. For patients withdrawing from the study, the reasons and any follow-on therapy are to be documented in the CRF.
Reporting of adverse events AEs and serious AEs will be recorded on the AE report form that is appended to the CRF. The AE report form will document the seriousness, duration, actions taken, outcomes, and relation to rivaroxaban therapy for each AE. For patients who discontinue rivaroxaban early, documentation concerning AEs will also cover the 30-day period after cessation of therapy. Additionally, the manner in which bleeding and thromboembolic events are managed in the routine practice setting will be recorded. This includes any use of thrombolytics or surgical intervention after ischemia or use of prohemostatic agents (eg, prothrombin-complex concentrates) for major bleeding. These cumulative data will provide a comprehensive overview of the use of rivaroxaban in routine practice and of how clinical events arising during stroke prophylaxis in AF are managed in this setting.
Each of the four studies in the XANTUS program will report separately, but there will also be a prespecified pooled analysis. In addition, results will be derived for medically relevant subgroups, eg, elderly patients, patients with renal impairment or prior stroke/TIA, and patients with different stroke-risk profiles, eg, CHADS 2 or CHA 2 DS 2 -VASc categories. The combined data set is also expected to permit the determination of regional differences in the use of rivaroxaban and to allow the investigators to identify any differences in treatment approaches for different ethnicities.
data management and administrative organization The parent XANTUS study is a postauthorization safety study funded by Bayer HealthCare. Each of the four studies in the program will have its own steering committee, and the program as a whole will be overseen by an executive steering committee. Major events, specifically major bleeding, stroke, systemic embolism, TIA, and myocardial infarction, will be adjudicated centrally by the same adjudication committee for all four studies, blinded to individual patient data. Data verification at study sites should facilitate identification of any relevant outcomes not submitted for adjudication. The study will use one centralized database to receive results, and results from all four studies in the program will be stored in the same database.
For example, the recently completed XAMOS (XArelto in the prophylaxis of post-surgical venous thromboembolism after elective Major Orthopaedic Surgery of hip or knee) study  21  was a noninterventional study in which the use of rivaroxaban in routine practice for the prevention of venous thromboembolism after elective hip or knee replacement was evaluated, although local standard of care was included as a comparator. The results confirmed the superior efficacy and similar safety of rivaroxaban, relative to the standard of care, reported in the Phase III RECORD (REgulation of Coagulation in ORthopedic surgery to prevent Deep venous thrombosis and pulmonary embolism) program. 22 oninterventional studies such as XAMOS or XANTUS and registries such as GARFIELD (Global Anticoagulant Registry in the FIELD)-AF,  23  ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation),  24  and the Dresden NOAC registry (NCT01588119) can go a long way toward meeting the need for real-world data on the efficacy and safety of rivaroxaban, and in particular confirming the safety of rivaroxaban in the routine practice setting.
Postauthorization studies for other NOACs are also in process (eg, NCT01774370 [SPARK {Safety Study of Pradaxa in Atrial Fibrillation Patients by Regulatory Requirement of Korea}] and NCT01491178 for dabigatran). Postauthorization studies, such as XANTUS, can also contribute important additional information on various aspects of patient management in routine care. For rivaroxaban, this might include the following: • When bleeding events or strokes do occur in patients receiving rivaroxaban, how are they managed, particularly in the first few days after a stroke? • What are the most common reasons for temporary interruptions of rivaroxaban therapy? • How are cardioversion and ablation procedures managed? • How is switching to a parenteral anticoagulant managed in practice (where relevant), and how is reinitiation of rivaroxaban therapy managed? • How are conversions from/to conventional VKA treatment to/from rivaroxaban performed in routine practice? This may be of particular importance in light of the transient increase in events observed at the end of the ROCKET AF study period in patients transitioning from blinded rivaroxaban to open-label warfarin.
clinical studies comprising the XANtuS program All studies will use the same design, database, and adjudication procedures; b the parent study and subject of this paper; c the East Asia subanalysis of RocKEt AF demonstrated that the 20 mg once-daily dose did not need to be adjusted in patients in this region, and that results from the East Asian population were consistent with those from the overall study. 17 Abbreviations: XANtuS, Xarelto ® for Prevention of Stroke in Patients with Atrial Fibrillation; XANtuS-El, Xarelto ® for Prevention of Stroke in Patients with Nonvalvular Atrial Fibrillation, Eastern Europe, Middle East, Africa and latin America; XANAP, Xarelto ® for Prevention of Stroke in Patients with Atrial Fibrillation in Asia-Pacific; XANtuS-cN, Xarelto ® for Prevention of Stroke in Patients with Atrial Fibrillation -china.
Primary efficacy results for ROCKET AF copyright © 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. a Number of patients; b hazard ratio is for rivaroxaban versus warfarin; c safety population included all patients who received at least one dose of study medication; on-treatment analyses evaluated all events occurring while patients were receiving study medication or within 2 days of permanent discontinuation; d intention-to-treat follow-up was until notification of study termination. ROCKET AF (clinicaltrials. gov: NCT00403767). Abbreviations: CI, confidence interval; ROCKET AF, Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism trial in Atrial Fibrillation.
Rates of bleeding outcomes in RocKEt AF From Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. 1 copyright © 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. a Hazard ratio is for rivaroxaban versus warfarin; b critical organ bleeding refers to bleeding in intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular (with compartment syndrome), or retroperitoneal locations. ROCKET AF (clinicaltrials. gov: NCT00403767). Abbreviations: CI, confidence interval; Hb, hemoglobin; ROCKET AF, Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism trial in Atrial Fibrillation.
Study a XANTUS b XANTUS-EL XANAP c XANTUS-CN NCT identifier Nct01606995 Nct01800006 Nct01750788 Not yet available Estimated enrollment 6,000 At least 10,000 patients expected across all three studies First patient, first visit (date) June 12, 2012 July 18, 2013 February 6, 2013 In planning Primary geographic region European union, plus Eastern Europe, Asia-Pacific People's Republic enrollment in canada Eastern Mediterranean, of china Middle East, latin America Notes: a.
The battery covers four principal areas of cognitive functioning; attention; memory; visuospatial processing and language. Simple reaction time is recorded via the keyboard and may then be used to adjust subsequent measures of response latency on the other more complex cognitive tasks. As difficulties with reading, syntax and attention may underlie observed difficulties in other areas of complex cognitive functioning, these areas are tested first, permitting the interviewer to evaluate the feasibility of continuing the battery. COGNITO has been developed in English and French. Comparison of data obtained in both languages shows similar distributions (unpublished). The battery takes approximately 40 minutes to complete, however, individual sub-tests may be used alone to target specific cognitive functions.
Memory Within the field of cognitive psychology specific and interacting memory sub-systems have been identified such that the frequent contradictory findings reported in memory assessments may often be attributable to subtle differences in stimulus material  [13]. COGNITO differentiates many of these sub-systems and assesses primary, working, verbal and visuospatial secondary and implicit memory sub-systems largely associated with the cortico-limbic circuit and left frontal cortex. Primary memory (an initial stimulus registry with an approximately 30 second retention limit) is assessed in the auditory modality by immediate recall of a list of names beginning with the letters C,J or M (F, M or P in the French version; the choice of letters corresponding to the highest word frequency in each language), and by requesting the subject to recall the increasingly long trails of a target across an array of squares in the visual modality.
Language The central language system has two major anatomical sites; a phonological system (implicating Heschl's gyrus, Broca's area and the vocal tract of the motor cortex, the arcuate fasciculus and part of Wernicke's area) and a syntactic/semantic system (implicating principally Wernicke's area, the auditory association cortex, the supramarginal and angular gyrus). Many pathologies, including some forms of dementia, show a double dissociation between these two systems which are differentiated by COGNITO. Language development follows a pattern of increasing semiotic complexity with an ascending hierarchy of phonology, morphology, syntax and semantics with disassociation being observed in relation to specific pathologies such as dementia and depression  [14]. These levels are examined separately by COGNITO.
Results All subjects were able to redo the tests within the two to three week period although three subjects were clearly unwell and did not perform at their maximum levels. Despite varying levels of health and disability all persons were able to attempt all tests. Only one test was abandoned before completion (a drawing test due to medication-related tremorin this case the subject was embarrassed rather than disabled). Table  1  shows results for each of the four primary cognitive domains (attention, language, memory and visuo-spatial ability). Test scores on the COGNITO battery had normal distributions for all but 7 tests.
Discussion The aim of this study was to describe the rationale for test construction and provide some pilot data on stability of responses across time. The battery has been designed to cover both qualitative and quantitative aspects of performance in keeping with information processing models of cognition. While the battery has now been extensively used in differential diagnosis of a range of pathologies as described above, there is no available data on item reliability. In order to assess this we examined a highly heterogeneous sample in terms of both age and health status and across two languages in order to assess this under the most challenging conditions. Adequate retest reliability is often considered to be a correlation coefficient of p<0. 05 and this was met on all sub-tests except the Stroop test.
To facilitate navigation, access may be made directly to the results of a specific test. (iii) The third file records the same complete data set but in xml format. From this file it is then possible to directly open the results of all, or a selection of subjects in Excel, through an independent module supplied with COGNITO. The data may then be imported into almost all data analysis software. Due to the large number of variables, at least a 2007 version of Excel is required.
Signed informed consent was obtained from all subjects. As an anonymous pilot study ethics permission was not required. Persons were excluded if their first language was neither French nor English and volunteers with chronic illnesses were not excluded. This rather heterogeneous sample, in terms of age and health status, was designed to under-estimate rather than over-estimate test-retest reliability. COGNITO was administered twice with a two to three week interval by two lay interviewers. such as chronic illness and other unstable health states in the estimation of reliability. Future research should also provide clearer guidelines on the management of practice effects. A further shortcoming has been lack of information on inter-interviewer reliability which may have confounded retest effects as numbers were too small to also examine this further parameter.
Conclusion COGNITO is a neuropsychological examination suitable for both population and clinical research, based on cognitive models of information processing in adults and their underlying anatomical substrates, which while being administered by non-clinical interviewers, provides a professional examination of adult information processing in a short period of time and in a format highly acceptable even to elderly persons. Pilot data suggests adequate retest reliability, however this and inter-interviewer reliability require confirmation in larger populations. 13. Gainotti G, Marra C (1992) Progress and controversies in neuropsychology of memory. Acta Neurol (Napoli) 14: 561-577. 14. Emery OB, Breslau LD (1989) Language deficits in depression: comparisons § according to normality of distribution.
SWOT will provide maps of distributed water elevations, water extents and water slopes on two swaths of 50 km each. It will enable the observation of rivers wider than 100 m and surface areas larger than 250 m × 250 m  (Rodríguez, 2014). Accuracies on water elevation and water slope will be around 10 cm and 1 cm km -1 , respectively, after averaging over 1 km 2 water area  (Rodríguez, 2014). From these requirements,  Biancamaria et al. (2010)  estimated that SWOT should be able to provide useful information to compute discharge for river reaches with drainage areas above 70 000 km 2. This preliminary assessment was recently refined by  Andreadis et al. (2013) , who estimate that rivers with a bank full width of 100 m have drainage area ranging from 1050 to 50 000 km 2. Although the database contains errors (reported errors on river width range from 8 to 62 %), it provides the order of magnitude of minimum drainage area that will be sampled by SWOT.
Acknowledgements. This research is funded by  CNES TOSCA SWOT project , the  ONEMA NAPROM  project, and structured within the " Stream-Aquifer Interfaces " workpackage of the PIREN Seine research programme. We kindly thank  Angela Armakola  for revising the English version of the paper, as well as the two anonymous reviewers for their fruitful comments, which helped improve the paper significantly. Edited by:  Y. Fan.
Homology modeling No high-resolution structure of a GABA A R is presently available, but multiple structures for members of the pLGIC superfamily have been published; for simulations of the GABA A R, we must rely on homology models built on these templates. Such modeling is supported by two properties of pLGICs: 1. Alignments for the pLGIC superfamily are robust: large multiple alignments have been constructed using sophisticated methods for detecting remote homology  (68, 69)  and confirmed by structural alignment in the cases where structures are available (ELIC, GLIC, and GluCl). Furthermore, accuracy of the calculations for this manuscript depend largely on the resolution of the structure in the transmembrane domain, for which the alignment between GABA A R and the template, GluCl, is essentially unambiguous and has no gaps.
2. All existing structures indicate a tightly conserved fold for the pLGIC superfamily, particularly in the transmembrane domain. Despite the evolutionary distance (24% overall sequence identity) between GluCl and GLIC, the protein backbones show remarkable overlap. In our case, the model and template are likely even more similar: GluCl and GABA A R (both anionic, eukaryotic, and ligand-gated) exhibit 32% sequence identity overall, and 46% identity in the transmembrane domain. Other groups have found available templates and alignments to yield models of GABA A Rs robust enough for pharmacological studies  (70, 71). We built homology models using GluCl (PDB code 3RHW) as a template and the alignments published with that structure. The standard procedure for oligomer modeling in MODELLER  (72)  was used to build 40 human a 1 b 1 g 2 GABA A R homology models from the template and alignments, with disulfide bridges specified in the a and g transmembrane domains.
Stereochemistry was checked using the Chirality plugin  (73)  in VMD  (74) , and the model with the lowest score was chosen for further simulation (Model 1). To conservatively estimate the uncertainty in results due to the use of a homology model with underdetermined side chains, a second intermediate-scoring model (Model 2) that displayed an alternate pattern of salt bridging in the transmembrane domain, including fivefold symmetry for the salt bridges in the extracellular half of the transmembrane domain (aM2:Arg274-M3:Asp287, bM2:Asp282-M3:Lys279, gM2:Arg284-M3: Asp297), was also selected for simulation. To test for the influence of modeling details on cholesterol-protein interactions, another alternate model (Model 3) was constructed by further optimizing side chains using the program SCWRL4 (75); orientation of polar side chains was then corrected to optimize the hydrogen-bond network using MolProbity  (76).
Cholesterol docking A first set of starting coordinates for bound cholesterol was generated by analogy with ivermectin. The cyclohexanol ring of cholesterol was aligned with the benzofuran moiety of ivermectin bound to the template, as shown in Fig. S3 ; these poses retained the symmetry of the GluCl template, and were not affected by pseudosymmetry of the GABA A R. These coordinates were the initial conditions for simulations of Model 1 and Model 2. Docking of cholesterol molecules to Model 3 was performed in a completely independent manner: automated docking was performed by the AutoDock Vina software package  (77). Input files were prepared using the University of California, San Francisco's Chimera  (78). All docking attempts on search spaces including the hydrophobic pore returned binding poses in the pore, which are physiologically unrealistic.
Simulation details All simulations used the CHARMM22-CMAP force field with torsional corrections for proteins  (80, 81). The CHARMM36 (82) model was used for phospholipids, ions, and water. CHARMM36 (83) parameters were used for cholesterol in Models 1 and 2, and updated, yet very similar parameters (CHARMM36c (84)) were used for Model 3. Energy minimization and MD simulations were performed using the NAMD package versions 2. 8 and 2. 9  (85). All simulations employed periodic boundary conditions; long-range electrostatics were handled with the smooth particle mesh Ewald method  (86) , and a cutoff of 1. 2 nm was used for Lennard-Jones potentials, with a switching function applied starting at 1. 0 nm. All simulations were run in the NPT ensemble with weak coupling to a Langevin thermostat and barostat at a respective 300 K and 1 atm.
Structural analysis of simulated trajectories Cholesterol orientation within the intersubunit cleft was measured along two coordinates, a tilt angle and a flip angle. Tilt is defined as the angle between the long axis of cholesterol and the membrane plane. Here, the long axis was defined as the vector joining atoms C3 and C17, at opposite ends of the steroid nucleus. The flip angle is defined as the angle between the vector joining cholesterol atoms C2 and C4 (in the b position of the hydroxyl group) and the membrane plane. Hydrogen bonds were defined as those with an O-H separation of <3. 3 A ånd an angle of <25. For analysis of pore profiles, snapshots were extracted every 1 ns from the simulations and were subsequently aligned. The HOLE software (87) was used to measure pore radius for each snapshot, and the resulting pore profiles were analyzed and plotted using a custom Python script.
GABA A models Three homology models of the a 1 b 1 g 2 GABA A receptor were built based on the recent crystal structure of the glutamate-gated chloride channel (GluCl) from C. elegans (32) (PDB code 3RHW). Several potentially essential interactions in the transmembrane domain emerged in these models. The most striking result was the existence of a potential disulfide bridge in the core of the transmembrane domain, in the a and g subunits, between helices M1 and M3 (Fig. S1 ). The template GluCl possesses two neighboring cysteine residues, Cys225 on M1 and Cys283 on M3. Although Cys283 faces M1, Cys225 points away from M3, so that the side chains are too distant to form a disulfide bond in GluCl (distance between C b atoms, 7. 9 A ˚). GABA A R subunits a and g have a cysteine residue at the previous position in the sequence, which points directly toward M3; this brings the side chains within bonding distance in the conformation directly derived from the template.