Disparities by sex in P2Y 12 inhibitor therapy duration, or differences in the balance of ischaemic-benefit and bleeding-risk clinical outcomes in older women versus comparable men following acute myocardial infarction? A P2Y 12 inhibitor new user retrospective cohort analysis of US Medicare claims data

Objectives To determine if comparable older women and men received different durations of P2Y 12 inhibitor therapy following acute myocardial infarction (AMI) and if therapy duration differences were justified by differences in ischaemic benefits and/or bleeding risks. Design Retrospective cohort. Setting 20% sample of 2007-2015 US Medicare fee-for-service administrative claims data. Participants ≥66-year-old P2Y 12 inhibitor new users following 2008-2013 AMI hospitalisation (N=30 613). Older women compared to older men with similar predicted risks of study outcomes. Primary and secondary outcome measures Primary outcome: P2Y 12 inhibitor duration (modelled as risk of therapy discontinuation). Secondary outcomes: clinical events while on P2Y 12 inhibitor therapy, including (1) death/hospice admission, (2) composite of ischaemic events (AMI/stroke/revascularisation) and (3) hospitalised bleeds. Cause-specific risks and relative risks (RRs) estimated using Aalen-Johansen cumulative incidence curves and bootstrapped 95% CIs. Results 10 486 women matched to 10 486 men with comparable predicted risks of all 4 study outcomes. No difference in treatment discontinuation was observed at 12 months (women 31.2% risk; men 30.9% risk; RR 1.01; 95% CI 0.97 to 1.05), but women were more likely than men to discontinue therapy at 24 months (54.4% and 52.9% risk, respectively; RR 1.03; 95% CI 1.00 to 1.05). Among patients who did not discontinue P2Y 12 inhibitor therapy, women had lower 24-month risks of ischaemic outcomes than men (13.1% and 14.7%, respectively; RR 0.90; 95% CI 0.84 to 0.96), potentially lower 24-month risks of death/hospice admission (5.0% and 5.5%, respectively; RR 0.91; 95% CI 0.82 to 1.02), but women and men both had 2.5% 24-month bleeding risks (RR 0.98; 95% CI 0.82 to 1.14). Conclusions Risks for death/hospice and ischaemic events were lower among women still taking a P2Y 12 inhibitor than comparable men, with no difference in bleeding risks. Shorter P2Y 12 inhibitor durations in older women than comparable men observed between 12 and 24 months post-AMI may reflect a disparity that is not justified by differences in clinical need

Função energia generalizada de controle para estabilização de sistemas não lineares

Neste trabalho, o conceito de função de Lyapunov de controle é estendido em duas direções principais. Na primeira direção, o conceito de função energia de controle (FEC) é proposto com o objetivo de não somente projetar leis de controle estabilizantes para sistemas não lineares mas também com o objetivo de fornecer uma estimativa da região de estabilidade do sistema em malha fechada. A FLC garante estabilidade local de um certo ponto de equilíbrio do sistema em malha fechada, mas usualmente não fornece estimativasótimas da região de estabilidade. O conceito de FEC é mais exigente que o conceito de FLC. Além de garantir estabilidade local do equilíbrio, a FEC fornece informações globais a respeito dos conjuntos limites e estimativas ótimas das regiões de estabilidade. A segunda direção está relacionada com o fato de que, em geral, é difícil encontrar FLC ou FEC para muitos sistemas não lineares. De forma a minimizar este problema e aplicar õ conceito de CEF em uma classe maior de sistemas, propõe-se neste artigo o conceito de função energia generalizada de controle (FEGC). A FEGC permite o projeto de controladores mesmo quando a derivada da função energia é positiva em algumas regiões limitadas do espaço de estados.extended in two main directions. In the first direction, the concept of control energy function (CEF) is proposed not only to design stabilizing feedback control laws but also to provide an estimate of the stability region of the closed-loopsystem. The CLF guarantees local stability of the closedloop- system but usually cannot provide optimal estimates of its stability region. The CEF concept is more restrict than the CLF concept. Beyond the guarantee of local stability, the CEF provides global information about limit sets and optimal estimates of stability region. The second direction is related to the fact that, in general, it is difficult to find a CLF or a CEF for many nonlinear systems. In order to overcome this problem and apply the concept of CEF for a larger class of systems, the concept of generalized control energy function (GCEF) is proposed in this paper. The GCEF allows the design of nonlinear controllers even when the derivative of the energy function is positive in some bounded regions of the state space

The phase relation between sunspot numbers and soft X-ray flares

To better understand long-term flare activity, we present a statistical study on soft X-ray flares from May 1976 to May 2008. It is found that the smoothed monthly peak fluxes of C-class, M-class, and X-class flares have a very noticeable time lag of 13, 8, and 8 months in cycle 21 respectively with respect to the smoothed monthly sunspot numbers. There is no time lag between the sunspot numbers and M-class flares in cycle 22. However, there is a one-month time lag for C-class flares and a one-month time lead for X-class flares with regard to sunspot numbers in cycle 22. For cycle 23, the smoothed monthly peak fluxes of C-class, M-class, and X-class flares have a very noticeable time lag of one month, 5 months, and 21 months respectively with respect to sunspot numbers. If we take the three types of flares together, the smoothed monthly peak fluxes of soft X-ray flares have a time lag of 9 months in cycle 21, no time lag in cycle 22 and a characteristic time lag of 5 months in cycle 23 with respect to the smoothed monthly sunspot numbers. Furthermore, the correlation coefficients of the smoothed monthly peak fluxes of M-class and X-class flares and the smoothed monthly sunspot numbers are higher in cycle 22 than those in cycles 21 and 23. The correlation coefficients between the three kinds of soft X-ray flares in cycle 22 are higher than those in cycles 21 and 23. These findings may be instructive in predicting C-class, M-class, and X-class flares regarding sunspot numbers in the next cycle and the physical processes of energy storage and dissipation in the corona.Comment: 8 pages, 3 figures, Accepted for publication in Astrophysics & Space Scienc

Depressive symptoms, cardiac structure and function, and risk of incident heart failure with preserved ejection fraction and heart failure with reduced ejection fraction in late life

BACKGROUND: Depressive symptoms are associated with heightened risk of heart failure (HF), but their association with cardiac function and with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) in late life is un-clear. We aimed to determine the prevalence of depression in HFpEF and in HFrEF in late life, and the association of depressive symptoms with cardiac function and incident HFpEF and HFrEF. METHODS AND RESULTS: We studied 6025 participants (age, 75.3±5.1 years; 59% women; 20% Black race) in the ARIC (Atherosclerosis Risk in Communities) study at visit 5 who underwent echocardiography and completed the Center for Epidemiologic Studies Depression Scale questionnaire. Among HF-free participants (n=5086), associations of Center for Epidemiologic Studies Depression Scale score with echocardiography and incident adjudicated HFpEF and HFrEF were assessed using multivariable linear and Cox proportional hazards regression. Prevalent HFpEF, but not HFrEF, was associated with a higher prevalence of depression compared with HF-free participants (P0.05). Over 5.5-year follow-up, higher Center for Epidemiologic Studies Depression Scale score was associated with heightened risk of incident HFpEF (hazard ratio [HR] [95% CI], 1.06 [1.04–1.12]; P=0.02), but not HFrEF (HR [95% CI], 1.02 [0.96–1.08]; P=0.54), independent of echocardiographic measures, NT-proBNP (N-terminal pro-B-type natriuretic peptide), troponin, and hs-CRP (high-sensitivity C-reactive protein) (HR [95% CI], 1.06 [1.00–1.12]; P=0.04). CONCLUSIONS: Worse depressive symptoms predict incident HFpEF in late life, independent of common comorbidities, cardiac structure and function, and prognostic biomarkers. Further studies are necessary to understand the mechanisms linking depression to risk of HFpEF

Relativistic Calculation of the Meson Spectrum: a Fully Covariant Treatment Versus Standard Treatments

A large number of treatments of the meson spectrum have been tried that consider mesons as quark - anti quark bound states. Recently, we used relativistic quantum "constraint" mechanics to introduce a fully covariant treatment defined by two coupled Dirac equations. For field-theoretic interactions, this procedure functions as a "quantum mechanical transform of Bethe-Salpeter equation". Here, we test its spectral fits against those provided by an assortment of models: Wisconsin model, Iowa State model, Brayshaw model, and the popular semi-relativistic treatment of Godfrey and Isgur. We find that the fit provided by the two-body Dirac model for the entire meson spectrum competes with the best fits to partial spectra provided by the others and does so with the smallest number of interaction functions without additional cutoff parameters necessary to make other approaches numerically tractable. We discuss the distinguishing features of our model that may account for the relative overall success of its fits. Note especially that in our approach for QCD, the resulting pion mass and associated Goldstone behavior depend sensitively on the preservation of relativistic couplings that are crucial for its success when solved nonperturbatively for the analogous two-body bound-states of QED.Comment: 75 pages, 6 figures, revised content

Association of a marker of N-acetylglucosamine with progressive multiple sclerosis and neurodegeneration

IMPORTANCE: N-glycan branching modulates cell surface receptor availability, and its deficiency in mice promotes inflammatory demyelination, reduced myelination, and neurodegeneration. N-acetylglucosamine (GlcNAc) is a rate-limiting substrate for N-glycan branching, but, to our knowledge, endogenous serum levels in patients with multiple sclerosis (MS) are unknown. OBJECTIVE: To investigate a marker of endogenous serum GlcNAc levels in patients with MS. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional discovery study and cross-sectional confirmatory study were conducted at 2 academic MS centers in the US and Germany. The discovery study recruited 54 patients with MS from an outpatient clinic as well as 66 healthy controls between April 20, 2010, and June 21, 2013. The confirmatory study recruited 180 patients with MS from screening visits at an academic MS study center between April 9, 2007, and February 29, 2016. Serum samples were analyzed from December 2, 2013, to March 2, 2015. Statistical analysis was performed from February 23, 2020, to March 18, 2021. MAIN OUTCOMES AND MEASURES: Serum levels of GlcNAc plus its stereoisomers, termed N-acetylhexosamine (HexNAc), were assessed using targeted tandem mass spectroscopy. Secondary outcomes (confirmatory study) comprised imaging and clinical disease markers. RESULTS: The discovery cohort included 66 healthy controls (38 women; mean [SD] age, 42 [20] years), 33 patients with relapsing-remitting MS (RRMS; 25 women; mean [SD] age, 50 [11] years), and 21 patients with progressive MS (PMS; 14 women; mean [SD] age, 55 [7] years). The confirmatory cohort included 125 patients with RRMS (83 women; mean [SD] age, 40 [9] years) and 55 patients with PMS (22 women; mean [SD] age, 49 [80] years). In the discovery cohort, the mean (SD) serum level of GlcNAc plus its stereoisomers (HexNAc) was 710 (174) nM in healthy controls and marginally reduced in patients with RRMS (mean [SD] level, 682 [173] nM; P = .04), whereas patients with PMS displayed markedly reduced levels compared with healthy controls (mean [SD] level, 548 [101] nM; P = 9.55 × 10(-9)) and patients with RRMS (P = 1.83 × 10(-4)). The difference between patients with RRMS (mean [SD] level, 709 [193] nM) and those with PMS (mean [SD] level, 405 [161] nM; P = 7.6 × 10(-18)) was confirmed in the independent confirmatory cohort. Lower HexNAc serum levels correlated with worse expanded disability status scale scores (ρ = -0.485; P = 4.73 × 10(-12)), lower thalamic volume (t = 1.7; P = .04), and thinner retinal nerve fiber layer (B = 0.012 [SE = 7.5 × 10(-11)]; P = .008). Low baseline serum HexNAc levels correlated with a greater percentage of brain volume loss at 18 months (t = 1.8; P = .04). CONCLUSIONS AND RELEVANCE: This study suggests that deficiency of GlcNAc plus its stereoisomers (HexNAc) may be a biomarker for PMS. Previous preclinical, human genetic, and ex vivo human mechanistic studies revealed that N-glycan branching and/or GlcNAc may reduce proinflammatory responses, promote myelin repair, and decrease neurodegeneration. Combined, the data suggest that GlcNAc deficiency may be associated with progressive disease and neurodegeneration in patients with MS

Atmospheric effects on extensive air showers observed with the Surface Detector of the Pierre Auger Observatory

Atmospheric parameters, such as pressure (P), temperature (T) and density, affect the development of extensive air showers initiated by energetic cosmic rays. We have studied the impact of atmospheric variations on extensive air showers by means of the surface detector of the Pierre Auger Observatory. The rate of events shows a ~10% seasonal modulation and ~2% diurnal one. We find that the observed behaviour is explained by a model including the effects associated with the variations of pressure and density. The former affects the longitudinal development of air showers while the latter influences the Moliere radius and hence the lateral distribution of the shower particles. The model is validated with full simulations of extensive air showers using atmospheric profiles measured at the site of the Pierre Auger Observatory.Comment: 24 pages, 9 figures, accepted for publication in Astroparticle Physic

Anisotropy studies around the galactic centre at EeV energies with the Auger Observatory

Data from the Pierre Auger Observatory are analyzed to search for anisotropies near the direction of the Galactic Centre at EeV energies. The exposure of the surface array in this part of the sky is already significantly larger than that of the fore-runner experiments. Our results do not support previous findings of localized excesses in the AGASA and SUGAR data. We set an upper bound on a point-like flux of cosmic rays arriving from the Galactic Centre which excludes several scenarios predicting sources of EeV neutrons from Sagittarius $A$. Also the events detected simultaneously by the surface and fluorescence detectors (the `hybrid' data set), which have better pointing accuracy but are less numerous than those of the surface array alone, do not show any significant localized excess from this direction.Comment: Matches published versio

Update on the correlation of the highest energy cosmic rays with nearby extragalactic matter

Data collected by the Pierre Auger Observatory through 31 August 2007 showed evidence for anisotropy in the arrival directions of cosmic rays above the Greisen-Zatsepin-Kuz'min energy threshold, \nobreak{$6\times 10^{19}$eV}. The anisotropy was measured by the fraction of arrival directions that are less than $3.1^\circ$ from the position of an active galactic nucleus within 75 Mpc (using the V\'eron-Cetty and V\'eron $12^{\rm th}$ catalog). An updated measurement of this fraction is reported here using the arrival directions of cosmic rays recorded above the same energy threshold through 31 December 2009. The number of arrival directions has increased from 27 to 69, allowing a more precise measurement. The correlating fraction is $(38^{+7}_{-6})$, compared with $21$ expected for isotropic cosmic rays. This is down from the early estimate of $(69^{+11}_{-13})$. The enlarged set of arrival directions is examined also in relation to other populations of nearby extragalactic objects: galaxies in the 2 Microns All Sky Survey and active galactic nuclei detected in hard X-rays by the Swift Burst Alert Telescope. A celestial region around the position of the radiogalaxy Cen A has the largest excess of arrival directions relative to isotropic expectations. The 2-point autocorrelation function is shown for the enlarged set of arrival directions and compared to the isotropic expectation.Comment: Accepted for publication in Astroparticle Physics on 31 August 201

The Fluorescence Detector of the Pierre Auger Observatory

The Pierre Auger Observatory is a hybrid detector for ultra-high energy cosmic rays. It combines a surface array to measure secondary particles at ground level together with a fluorescence detector to measure the development of air showers in the atmosphere above the array. The fluorescence detector comprises 24 large telescopes specialized for measuring the nitrogen fluorescence caused by charged particles of cosmic ray air showers. In this paper we describe the components of the fluorescence detector including its optical system, the design of the camera, the electronics, and the systems for relative and absolute calibration. We also discuss the operation and the monitoring of the detector. Finally, we evaluate the detector performance and precision of shower reconstructions.Comment: 53 pages. Submitted to Nuclear Instruments and Methods in Physics Research Section