Evolution of the X-ray Emission of Radio-Quiet Quasars

We report new Chandra observations of seven optically faint, z \sim 4 radio-quiet quasars. We have combined these new observations with previous Chandra observations of radio-quiet quasars to create a sample of 174 sources. These sources have 0.1 < z < 4.7, and 10^{44} ergs s^{-1} < nu L_{nu} (2500 \AA) < 10^{48} ergs s^{-1}. The X-ray detection fraction is 90%. We find that the X-ray loudness of radio-quiet quasars decreases with UV luminosity and increases with redshift. The model that is best supported by the data has a linear dependence of optical-to-X-ray ratio, alpha_{ox}, on cosmic time, and a quadratic dependence of alpha_{ox} on log L_{UV}, where alpha_{ox} becomes X-ray quiet more rapidly at higher log L_{UV}. We find no significant evidence for a relationship between the X-ray photon index, Gamma_X, and the UV luminosity, and we find marginally significant evidence that the X-ray continuum flattens with increasing z (2 sigma). The Gamma_X-z anti-correlation may be the result of X-ray spectral curvature, redshifting of a Compton reflection component into the observed Chandra band, and/or redshifting of a soft excess out of the observed Chandra band. Using the results for Gamma_X, we show that the alpha_{ox}-z relationship is unlikely to be a spurious result caused by redshifting of the observable X-ray spectral region. A correlation between alpha_{ox} and z implies evolution of the accretion process. We present a qualitative comparison of these new results with models for accretion disk emission.Comment: Accepted by ApJ, 48 pages, 10 figures, 5 table

Rationale and design of the Medical Research Council precision medicine with Zibotentan in microvascular angina (PRIZE) trial

Background: Microvascular angina is caused by cardiac small vessel disease and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. Methods: We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The Precision medicine with Zibotentan in microvascular angina (PRIZE) trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. Conclusion: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Rationale and design of the Medical Research Council Precision medicine with Zibotentan in microvascular angina (PRIZE) trial MRI sub-study

Introduction: Microvascular angina is caused by cardiac small vessel disease and dysregulation of the endothelin system is implicated. The chronic elevation of circulating ET-1 in microvascular angina may be influenced by genetic factors. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with microvascular angina. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. The Precision medicine with Zibotentan in microvascular angina (PRIZE) trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. After randomisation in PRIZE, subjects will be invited to participate in the cardiac MRI sub-study. Myocardial perfusion is generally impaired in patients with microvascular angina. The rationale for undertaking this MRI sub-study is to determine whether, compared with placebo, treatment with zibotentan improves myocardial blood flow. Methods: Patients will undergo multiparametric CMR at three points (baseline prior to therapy and after each 12 week treatment phase). At each scan they will have assessments of myocardial blood flow (both rest and stress using the Kellman quantitative perfusion method), left ventricular function and mass, aortic stiffness assessment and tissue characterisation (T1 mapping (MOLLI and ShMOLLI), T2 mapping and late gadolinium enhancement imaging). Conclusion: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicentre trial. The MRI sub-study contributes to this study by providing vital mechanistic and safety information