Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events : The ODYSSEY OUTCOMES Trial

The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths. This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES. Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death. With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk. In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS

Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome

Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C). A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE). One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina. Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081). Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402

Strategies to reengage patients lost to follow up in HIV care in high income countries, a scoping review

Background: Despite remarkable achievements in antiretroviral therapy (ART), losses to follow-up (LTFU) might prevent the long-term success of HIV treatment and might delay the achievement of the 90-90-90 objectives. This scoping review is aimed at the description and analysis of the strategies used in high-income countries to reengage LTFU in HIV care, their implementation and impact. Methods: A scoping review was done following Arksey & O'Malley's methodological framework and recommendations from Joanna Briggs Institute. Peer reviewed articles were searched for in Pubmed, Scopus and Web of Science; and grey literature was searched for in Google and other sources of information. Documents were charted according to the information presented on LTFU, the reengagement procedures used in HIV units in high-income countries, published during the last 15 years. In addition, bibliographies of chosen articles were reviewed for additional articles. Results: Twenty-eight documents were finally included, over 80% of them published in the United States later than 2015. Database searches, phone calls and/or mail contacts were the most common strategies used to locate and track LTFU, while motivational interviews and strengths-based techniques were used most often during reengagement visits. Outcomes like tracing activities efficacy, rates of reengagement and viral load reduction were reported as outcome measures. Conclusions: This review shows a recent and growing trend in developing and implementing patient reengagement strategies in HIV care. However, most of these strategies have been implemented in the United States and little information is available for other high-income countries. The procedures used to trace and contact LTFU are similar across reviewed studies, but their impact and sustainability are widely different depending on the country studied

Joint analysis of the energy spectrum of ultra-high-energy cosmic rays measured at the Pierre Auger Observatory and the Telescope Array

The measurement of the energy spectrum of ultra-high-energy cosmic rays (UHECRs) is of crucial importance to clarify their origin and acceleration mechanisms. The Pierre Auger Observatory in Argentina and the Telescope Array (TA) in the US have reported their measurements of UHECR energy spectra observed in the southern and northern hemisphere, respectively. The region of the sky accessible to both Observatories ([−15,+24] degrees in declination) can be used to cross-calibrate the two spectra. The Auger-TA energy spectrum working group was organized in 2012 and has been working to understand the uncertainties in energy scale in both experiments, their systematic differences, and differences in the shape of the spectra. In previous works, we reported that there was an overall agreement of the energy spectra measured by the two observatories below 10 EeV while at higher energies, a remaining significant difference was observed in the common declination band. We revisit this issue to understand its origin by examining the systematic uncertainties, statistical effects, and other possibilities. We will also discuss the differences in the spectra in different declination bands and a new feature in the spectrum recently reported by the Auger Collaboration

The UHECR dipole and quadrupole in the latest data from the original Auger and TA surface detectors

The sources of ultra-high-energy cosmic rays are still unknown, but assuming standard physics, they are expected to lie within a few hundred megaparsecs from us. Indeed, over cosmological distances cosmic rays lose energy to interactions with background photons, at a rate depending on their mass number and energy and properties of photonuclear interactions and photon backgrounds. The universe is not homogeneous at such scales, hence the distribution of the arrival directions of cosmic rays is expected to reflect the inhomogeneities in the distribution of galaxies; the shorter the energy loss lengths, the stronger the expected anisotropies. Galactic and intergalactic magnetic fields can blur and distort the picture, but the magnitudes of the largest-scale anisotropies, namely the dipole and quadrupole moments, are the most robust to their effects. Measuring them with no bias regardless of any higher-order multipoles is not possible except with full-sky coverage. In this work, we achieve this in three energy ranges (approximately 8--16 EeV, 16--32 EeV, and 32--∞ EeV) by combining surface-detector data collected at the Pierre Auger Observatory until 2020 and at the Telescope Array (TA) until 2019, before the completion of the upgrades of the arrays with new scintillator detectors. We find that the full-sky coverage achieved by combining Auger and TA data reduces the uncertainties on the north-south components of the dipole and quadrupole in half compared to Auger-only results

UHECR arrival directions in the latest data from the original Auger and TA surface detectors and nearby galaxies

The distribution of ultra-high-energy cosmic-ray arrival directions appears to be nearly isotropic except for a dipole moment of order $6 \times (E/10~\mathrm{EeV})$ per cent. Nonetheless, at the highest energies, as the number of possible candidate sources within the propagation horizon and the magnetic deflections both shrink, smaller-scale anisotropies might be expected to emerge. On the other hand, the flux suppression reduces the statistics available for searching for such anisotropies. In this work, we consider two different lists of candidate sources: a sample of nearby starburst galaxies and the 2MRS catalog tracing stellar mass within 250 Mpc. We combine surface-detector data collected at the Pierre Auger Observatory until 2020 and the Telescope Array until 2019, and use them to test models in which UHECRs comprise an isotropic background and a foreground originating from the candidate sources and randomly deflected by magnetic fields. The free parameters of these models are the energy threshold, the signal fraction, and the search angular scale. We find a correlation between the arrival directions of $11.8\%_{-3.1\%}^{+5.0\%}$ of cosmic rays detected with $E \ge 38~\mathrm{EeV}$ by Auger or with $E \gtrsim 49~\mathrm{EeV}$ by TA and the position of nearby starburst galaxies on a ${15.5^\circ}_{-3.2^\circ}^{+5.3^\circ}$ angular scale, with a 4.2σ post-trial significance, as well as a weaker correlation with the overall galaxy distribution

The UHECR dipole and quadrupole in the latest data from the original Auger and TA surface detectors

The sources of ultra-high-energy cosmic rays are still unknown, but assuming standard physics, they are expected to lie within a few hundred megaparsecs from us. Indeed, over cosmological distances cosmic rays lose energy to interactions with background photons, at a rate depending on their mass number and energy and properties of photonuclear interactions and photon backgrounds. The universe is not homogeneous at such scales, hence the distribution of the arrival directions of cosmic rays is expected to reflect the inhomogeneities in the distribution of galaxies; the shorter the energy loss lengths, the stronger the expected anisotropies. Galactic and intergalactic magnetic fields can blur and distort the picture, but the magnitudes of the largest-scale anisotropies, namely the dipole and quadrupole moments, are the most robust to their effects. Measuring them with no bias regardless of any higher-order multipoles is not possible except with full-sky coverage. In this work, we achieve this in three energy ranges (approximately 8--16 EeV, 16--32 EeV, and 32--∞ EeV) by combining surface-detector data collected at the Pierre Auger Observatory until 2020 and at the Telescope Array (TA) until 2019, before the completion of the upgrades of the arrays with new scintillator detectors. We find that the full-sky coverage achieved by combining Auger and TA data reduces the uncertainties on the north-south components of the dipole and quadrupole in half compared to Auger-only results

The UHECR dipole and quadrupole in the latest data from the original Auger and TA surface detectors

The sources of ultra-high-energy cosmic rays are still unknown, but assuming standard physics, they are expected to lie within a few hundred megaparsecs from us. Indeed, over cosmological distances cosmic rays lose energy to interactions with background photons, at a rate depending on their mass number and energy and properties of photonuclear interactions and photon backgrounds. The universe is not homogeneous at such scales, hence the distribution of the arrival directions of cosmic rays is expected to reflect the inhomogeneities in the distribution of galaxies; the shorter the energy loss lengths, the stronger the expected anisotropies. Galactic and intergalactic magnetic fields can blur and distort the picture, but the magnitudes of the largest-scale anisotropies, namely the dipole and quadrupole moments, are the most robust to their effects. Measuring them with no bias regardless of any higher-order multipoles is not possible except with full-sky coverage. In this work, we achieve this in three energy ranges (approximately 8–16 EeV, 16–32 EeV, and 32–∞ EeV) by combining surface-detector data collected at the Pierre Auger Observatory until 2020 and at the Telescope Array (TA) until 2019, before the completion of the upgrades of the arrays with new scintillator detectors. We find that the full-sky coverage achieved by combining Auger and TA data reduces the uncertainties on the north-south components of the dipole and quadrupole in half compared to Auger-only results

UHECR arrival directions in the latest data from the original Auger and TA surface detectors and nearby galaxies

The distribution of ultra-high-energy cosmic-ray arrival directions appears to be nearly isotropic except for a dipole moment of order 6× (E/10 EeV) per cent. Nonetheless, at the highest energies, as the number of possible candidate sources within the propagation horizon and the magnetic deflections both shrink, smaller-scale anisotropies might be expected to emerge. On the other hand, the flux suppression reduces the statistics available for searching for such anisotropies. In this work, we consider two different lists of candidate sources: a sample of nearby starburst galaxies and the 2MRS catalog tracing stellar mass within 250 Mpc. We combine surface-detector data collected at the Pierre Auger Observatory until 2020 and the Telescope Array until 2019, and use them to test models in which UHECRs comprise an isotropic background and a foreground originating from the candidate sources and randomly deflected by magnetic fields. The free parameters of these models are the energy threshold, the signal fraction, and the search angular scale. We find a correlation between the arrival directions of 11.8%5.0%-3.1% of cosmic rays detected with E ≥ 38 EeV by Auger or with ≥ 49 EeV by TA and the position of nearby starburst galaxies on a 15.5°+5.3°-3.2° angular scale, with a 4.2f post-trial significance, as well as a weaker correlation with the overall galaxy distribution

UHECR arrival directions in the latest data from the original Auger and TA surface detectors and nearby galaxies

The distribution of ultra-high-energy cosmic-ray arrival directions appears to be nearly isotropic except for a dipole moment of order $6 \times (E/10~\mathrm{EeV})$ per cent. Nonetheless, at the highest energies, as the number of possible candidate sources within the propagation horizon and the magnetic deflections both shrink, smaller-scale anisotropies might be expected to emerge. On the other hand, the flux suppression reduces the statistics available for searching for such anisotropies. In this work, we consider two different lists of candidate sources: a sample of nearby starburst galaxies and the 2MRS catalog tracing stellar mass within 250 Mpc. We combine surface-detector data collected at the Pierre Auger Observatory until 2020 and the Telescope Array until 2019, and use them to test models in which UHECRs comprise an isotropic background and a foreground originating from the candidate sources and randomly deflected by magnetic fields. The free parameters of these models are the energy threshold, the signal fraction, and the search angular scale. We find a correlation between the arrival directions of $11.8\%_{-3.1\%}^{+5.0\%}$ of cosmic rays detected with $E \ge 38~\mathrm{EeV}$ by Auger or with $E \gtrsim 49~\mathrm{EeV}$ by TA and the position of nearby starburst galaxies on a ${15.5^\circ}_{-3.2^\circ}^{+5.3^\circ}$ angular scale, with a 4.2σ post-trial significance, as well as a weaker correlation with the overall galaxy distribution