XANTUS: rationale and design of a noninterventional study of rivaroxaban for the prevention of stroke in patients with atrial fibrillation.

Atrial fibrillation (AF) is associated with a fivefold increase in the risk of stroke. The Phase III 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) trial showed that rivaroxaban, an oral, direct Factor Xa inhibitor, was noninferior to warfarin for the reduction of stroke or systemic embolism in patients with AF. Compared with warfarin, rivaroxaban significantly reduced rates of intracranial and fatal hemorrhages, although not rates of bleeding overall. XANTUS (Xarelto(®) for Prevention of Stroke in Patients with Atrial Fibrillation) is a prospective, international, observational, postauthorization, noninterventional study designed to collect safety and efficacy data on the use of rivaroxaban for stroke prevention in AF in routine clinical practice. The key goal is to determine whether the safety profile of rivaroxaban established in ROCKET AF is also observed in routine clinical practice. XANTUS is designed as a single-arm cohort study to minimize selection bias, and will enroll approximately 6,000 patients (mostly from Europe) with nonvalvular AF prescribed rivaroxaban, irrespective of their level of stroke risk. Overall duration of follow-up will be 1 year; the first patient was enrolled in June 2012. Similar studies (XANTUS-EL [Xarelto(®) for Prevention of Stroke in Patients with Nonvalvular Atrial Fibrillation, Eastern Europe, Middle East, Africa and Latin America] and XANAP [Xarelto(®) for Prevention of Stroke in Patients with Atrial Fibrillation in Asia-Pacific]) are ongoing in Latin America and Asia-Pacific. Data from these studies will supplement those from ROCKET AF and provide practical information concerning the use of rivaroxaban for stroke prevention in AF

Impact of Modifiable Bleeding Risk Factors on Major Bleeding in Patients With Atrial Fibrillation Anticoagulated With Rivaroxaban.

Background Reducing major bleeding events is a challenge when managing anticoagulation in patients with atrial fibrillation. This study evaluated the impact of modifiable and nonmodifiable bleeding risk factors in patients with atrial fibrillation receiving rivaroxaban and estimated the impact of risk factor modification on major bleeding events. Methods and Results Modifiable and nonmodifiable risk factors associated with major bleeding events were identified from the XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation) prospective registry data set (6784 rivaroxaban-treated patients). Parameters showing univariate association with bleeding were used to construct a multivariable model identifying independent risk factors. Modeling was used to estimate attributed weights to risk factors. Heavy alcohol use (hazard ratio [HR]=2.37; 95% CI 1.24-4.53); uncontrolled hypertension (HR after parameter-wise shrinkage=1.79; 95% CI 1.05-3.05); and concomitant treatment with antiplatelets, nonsteroidal anti-inflammatory drugs, or paracetamol (HR=1.80; 95% CI 1.24-2.61) were identified as modifiable, independent bleeding risk factors. Increasing age (HR=1.25 [per 5-year increment]; 95% CI 1.12-1.38); heart failure (HR=1.97; 95% CI 1.36-2.86); and vascular disease (HR=1.91; 95% CI 1.32-2.77) were identified as nonmodifiable bleeding risk factors. Overall, 128 (1.9%) patients experienced major bleeding events; of these, 11% had no identified bleeding risk factors, 50% had nonmodifiable bleeding risk factors only, and 39% had modifiable bleeding risk factors (with or without nonmodifiable risk factors). The presence of 1 modifiable bleeding risk factor doubled the risk of major bleeding. Conclusions Elimination of modifiable bleeding risk factors is a potentially effective strategy to reduce bleeding risk in atrial fibrillation patients receiving rivaroxaban. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01606995

Time-motion characteristics and physiological responses of small-sided games in elite youth players: The influence of player number and rule changes

The aim of this study was to examine acute physiological responses and time-motion characteristics associated with 4 soccer-specific small-sided game (SSG) formats (3 vs. 4 players, 3 vs. 3 players + floater, 5 vs. 6 players, and 5 vs. 5 players + floater) and 4 rule changes in elite youth soccer players. Sixteen male youth soccer players (mean ± SD: age = 15.6 ± 0.8 years, stature = 170.8 ± 6.6 cm, body mass = 67.5 ± 6.2 kg, and 20-m shuttle run estimated V̇2 max = 57.4 ± 3.7 ml·kg-1-min-1) participated in the study, in which heart rate (HR), rating of perceived exertion (RPE), blood lactate (La -), and time-motion characteristics were recorded. The rule change requiring extra sprint running had a greater effect on the time-motion characteristics than all other rule modifications but no effect on acute %HRmax, La-, and RPE. Rule changes had no effect on RPE. Fixed underload teams (i.e., lower number of players compared with the opponent team) recorded a significantly higher RPE compared with the fixed overload teams, although there were no differences in %HRmax and La-. The major practical findings are that subtle changes in SSGs playing rules can influence the physiological, perceptual, and time-motion responses in young elite soccer players. Rules that are related to a team's chances of scoring may improve player motivation and thereby increase training intensity during SSGs. There were no differences between fixed and variable formats in terms of physiological and perceptual responses, although both may provide useful technical-tactical training. Coaches should take care in designing different soccer SSGs as each rule or game format change may influence exercise intensity independently. © 2010 National Strength and Conditioning Association

Outcomes Associated With Oral Anticoagulants Plus Antiplatelets in Patients With Newly Diagnosed Atrial Fibrillation.

Importance: Patients with nonvalvular atrial fibrillation at risk of stroke should receive oral anticoagulants (OAC). However, approximately 1 in 8 patients in the Global Anticoagulant Registry in the Field (GARFIELD-AF) registry are treated with antiplatelet (AP) drugs in addition to OAC, with or without documented vascular disease or other indications for AP therapy. Objective: To investigate baseline characteristics and outcomes of patients who were prescribed OAC plus AP therapy vs OAC alone. Design, Setting, and Participants: Prospective cohort study of the GARFIELD-AF registry, an international, multicenter, observational study of adults aged 18 years and older with recently diagnosed nonvalvular atrial fibrillation and at least 1 risk factor for stroke enrolled between March 2010 and August 2016. Data were extracted for analysis in October 2017 and analyzed from April 2018 to June 2019. Exposure: Participants received either OAC plus AP or OAC alone. Main Outcomes and Measures: Clinical outcomes were measured over 3 and 12 months. Outcomes were adjusted for 40 covariates, including baseline conditions and medications. Results: A total of 24 436 patients (13 438 [55.0%] male; median [interquartile range] age, 71 [64-78] years) were analyzed. Among eligible patients, those receiving OAC plus AP therapy had a greater prevalence of cardiovascular indications for AP, including acute coronary syndromes (22.0% vs 4.3%), coronary artery disease (39.1% vs 9.8%), and carotid occlusive disease (4.8% vs 2.0%). Over 1 year, patients treated with OAC plus AP had significantly higher incidence rates of stroke (adjusted hazard ratio [aHR], 1.49; 95% CI, 1.01-2.20) and any bleeding event (aHR, 1.41; 95% CI, 1.17-1.70) than those treated with OAC alone. These patients did not show evidence of reduced all-cause mortality (aHR, 1.22; 95% CI, 0.98-1.51). Risk of acute coronary syndrome was not reduced in patients taking OAC plus AP compared with OAC alone (aHR, 1.16; 95% CI, 0.70-1.94). Patients treated with OAC plus AP also had higher rates of all clinical outcomes than those treated with OAC alone over the short term (3 months). Conclusions and Relevance: This study challenges the practice of coprescribing OAC plus AP unless there is a clear indication for adding AP to OAC therapy in newly diagnosed atrial fibrillation

A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: towards the development of novel anti-inflammatory compounds

Complement factor C5a is one of the most powerful pro-inflammatory agents involved in recruitment of leukocytes, activation of phagocytes and other inflammatory responses. C5a triggers inflammatory responses by binding to its G-protein-coupled C5a-receptor (C5aR). Excessive or erroneous activation of the C5aR has been implicated in numerous inflammatory diseases. The C5aR is therefore a key target in the development of specific anti-inflammatory compounds. A very potent natural inhibitor of the C5aR is the 121-residue chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS). Although CHIPS effectively blocks C5aR activation by binding tightly to its extra-cellular N terminus, it is not suitable as a potential anti-inflammatory drug due to its immunogenic properties. As a first step in the development of an improved CHIPS mimic, we designed and synthesized a substantially shorter 50-residue adapted peptide, designated CHOPS. This peptide included all residues important for receptor binding as based on the recent structure of CHIPS in complex with the C5aR N terminus. Using isothermal titration calorimetry we demonstrate that CHOPS has micromolar affinity for a model peptide comprising residues 7–28 of the C5aR N terminus including two O-sulfated tyrosine residues at positions 11 and 14. CD and NMR spectroscopy showed that CHOPS is unstructured free in solution. Upon addition of the doubly sulfated model peptide, however, the NMR and CD spectra reveal the formation of structural elements in CHOPS reminiscent of native CHIPS

Impact of gender: Rivaroxaban for patients with atrial fibrillation in the XANTUS real-world prospective study.

BACKGROUND: The XANTUS study (NCT01606995) demonstrated low rates of stroke and major bleeding in patients with atrial fibrillation (AF) receiving rivaroxaban in clinical practice for the prevention of thromboembolic events (N = 6784). HYPOTHESIS: Because previous real-world studies have not reported gender-dependent responses to rivaroxaban treatment, this sub-analysis of the XANTUS study investigated the effect of gender on outcomes. METHODS: The centrally adjudicated outcomes were compared between genders. Primary outcomes were major bleeding and all-cause death. Secondary outcomes included symptomatic thromboembolic events. Multivariable Cox regression analysis was performed to assess the effect of risk factors on outcomes between genders. RESULTS: A total of 2765 female and 4016 male patients were included in the analysis. Baseline characteristics were generally similar. No nominally significant interaction between gender and risk factors for the study outcomes was observed. Rates of major bleeding, all-cause death and symptomatic thromboembolic events in patients with non-valvular AF receiving rivaroxaban for stroke prevention were similar in men and women; no significant differences in risk factors for these outcomes were observed between genders. CONCLUSIONS: Further research is needed to better characterize the relative importance of different risk factors on outcomes in men vs women and to determine whether gender differences exist in patients treated with non-vitamin K antagonist oral anticoagulants

Is Neolithic land use correlated with demography? An evaluation of pollen-derived land cover and radiocarbon-inferred demographic change from Central Europe

The transformation of natural landscapes in Middle Europe began in the Neolithic as a result of the introduction of food-producing economies. This paper examines the relation between land-cover and demographic change in a regionally restricted case study. The study area is the Western Lake Constance area which has very detailed palynological as well as archaeological records. We compare land-cover change derived from nine pollen records using a pseudo-biomisation approach with 14C date probability density functions from archaeological sites which serve as a demographic proxy. We chose the Lake Constance area as a regional example where the pollen signal integrates a larger spatial pattern. The land-cover reconstructions for this region show first notable impacts at the Middle to Young Neolithic transition. The beginning of the Bronze Age is characterised by increases of arable land and pasture/meadow, whereas the deciduous woodland decreases dramatically. Changes in the land-cover classes show a correlation with the 14C density curve: the correlation is best with secondary woodland in the Young Neolithic which reflects the lake shore settlement dynamics. In the Early Bronze Age, the radiocarbon density correlates with open land-cover classes, such as pasture, meadow and arable land, reflecting a change in the land-use strategy. The close overall correspondence between the two archives implies that population dynamics and land-cover change were intrinsically linked. We therefore see human impact as a key driver for vegetation change in the Neolithic. Climate might have an influence on vegetation development, but the changes caused by human land use are clearly detectable from Neolithic times, at least in these densely settled, mid-altitude landscapes

Dust-free quasars in the early Universe

The most distant quasars known, at redshifts z=6, generally have properties indistinguishable from those of lower-redshift quasars in the rest-frame ultraviolet/optical and X-ray bands. This puzzling result suggests that these distant quasars are evolved objects even though the Universe was only seven per cent of its current age at these redshifts. Recently one z=6 quasar was shown not to have any detectable emission from hot dust, but it was unclear whether that indicated different hot-dust properties at high redshift or if it is simply an outlier. Here we report the discovery of a second quasar without hot-dust emission in a sample of 21 z=6 quasars. Such apparently hot-dust-free quasars have no counterparts at low redshift. Moreover, we demonstrate that the hot-dust abundance in the 21 quasars builds up in tandem with the growth of the central black hole, whereas at low redshift it is almost independent of the black hole mass. Thus z=6 quasars are indeed at an early evolutionary stage, with rapid mass accretion and dust formation. The two hot-dust-free quasars are likely to be first-generation quasars born in dust-free environments and are too young to have formed a detectable amount of hot dust around them.Comment: To be published in Nature on the 18 March 2010

Damagnetization cooling of a gas

We demonstrate demagnetization cooling of a gas of ultracold $^{52}$Cr atoms. Demagnetization is driven by inelastic dipolar collisions which couple the motional degrees of freedom to the spin degree. By that kinetic energy is converted into magnetic work with a consequent temperature reduction of the gas. Optical pumping is used to magnetize the system and drive continuous demagnetization cooling. Applying this technique, we can increase the phase space density of our sample by one order of magnitude, with nearly no atom loss. This method can be in principle extended to every dipolar system and could be used to achieve quantum degeneracy via optical means.Comment: 10 pages, 5 figure

Changes in the midpalatal and pterygopalatine sutures induced by micro-implant-supported skeletal expander, analyzed with a novel 3D method based on CBCT imaging

Abstract Background Mini-implant-assisted rapid palatal expansion (MARPE) appliances have been developed with the aim to enhance the orthopedic effect induced by rapid maxillary expansion (RME). Maxillary Skeletal Expander (MSE) is a particular type of MARPE appliance characterized by the presence of four mini-implants positioned in the posterior part of the palate with bi-cortical engagement. The aim of the present study is to evaluate the MSE effects on the midpalatal and pterygopalatine sutures in late adolescents, using high-resolution CBCT. Specific aims are to define the magnitude and sagittal parallelism of midpalatal suture opening, to measure the extent of transverse asymmetry of split, and to illustrate the possibility of splitting the pterygopalatine suture. Methods Fifteen subjects (mean age of 17.2 years; range, 13.9–26.2 years) were treated with MSE. Pre- and post-treatment CBCT exams were taken and superimposed. A novel methodology based on three new reference planes was utilized to analyze the sutural changes. Parameters were compared from pre- to post-treatment and between genders non-parametrically using the Wilcoxon sign rank test. For the frequency of openings in the lower part of the pterygopalatine suture, the Fisher’s exact test was used. Results Regarding the magnitude of midpalatal suture opening, the split at anterior nasal spine (ANS) and at posterior nasal spine (PNS) was 4.8 and 4.3 mm, respectively. The amount of split at PNS was 90% of that at ANS, showing that the opening of the midpalatal suture was almost perfectly parallel antero-posteriorly. On average, one half of the anterior nasal spine (ANS) moved more than the contralateral one by 1.1 mm. Openings between the lateral and medial plates of the pterygoid process were detectable in 53% of the sutures (P < 0.05). No significant differences were found in the magnitude and frequency of suture opening between males and females. Correlation between age and suture opening was negligible (R 2 range, 0.3–4.2%). Conclusions Midpalatal suture was successfully split by MSE in late adolescents, and the opening was almost perfectly parallel in a sagittal direction. Regarding the extent of transverse asymmetry of the split, on average one half of ANS moved more than the contralateral one by 1.1 mm. Pterygopalatine suture was split in its lower region by MSE, as the pyramidal process was pulled out from the pterygoid process. Patient gender and age had a negligible influence on suture opening for the age group considered in the study