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

Expression quantitative trait locus fine mapping of the 17q12–21 asthma locus in African American children: a genetic association and gene expression study

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus. Methods: We first did a genetic association study and meta-analysis using 17q12–21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12–21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12–21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). Findings: 17q12–21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12–1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13–1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [β] 1·35 [95% CI 1·25–1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (β 1·15 [1·08–1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLβ 1·24 [1·15–1·32], p<0·0001; and for ORMDL3 (β 1·19 [1·12–1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (β 1·29 [1·15–1·44], p<0·0001). Interpretation: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12–21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus.6 month embargo; published: 01 May 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used

Improved measurement of CPCP violation parameters in Bs0→J/ψK+K−B_s^0\to J/\psi K^+K^- decays in the vicinity of the ϕ(1020)\phi(1020) resonance

The decay-time-dependent $CP$ asymmetry in $B_s^0\to J/\psi(\to \mu^+\mu^-) K^+ K^-$ decays is measured using proton-proton collision data, corresponding to an integrated luminosity of $6 {\rm fb}^{-1}$, collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 $B_s^0$ signal decays with an invariant $K^+ K^-$ mass in the vicinity of the $\phi(1020)$ resonance, the $CP$-violating phase $\phi_s$ is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the $B_s^0$-$\overline{B}_s^0$ system, $\Delta\Gamma_s$, and the difference of the average $B_s^0$ and $B^0$ meson decay widths, $\Gamma_s-\Gamma_d$. The values obtained are $\phi_s = -0.039 \pm 0.022 \pm 0.006$ rad, $\Delta\Gamma_s = 0.0845 \pm 0.0044 \pm 0.0024 ~{\rm ps}^{-1}$ and $\Gamma_s-\Gamma_d = -0.056^{\:+\:0.0013}_{\:-\:0.0015} \pm 0.0014 ~{\rm ps}^{-1}$, where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase $\phi_s$ is also measured independently for each polarization state of the $K^+K^-$ system and shows no evidence for polarization dependence.The decay-time-dependent $CP$ asymmetry in $B^0_s\to J/\psi(\to \mu^{+}\mu^{-}) K^{+}K^{-}$ decays is measured using proton-proton collision data, corresponding to an integrated luminosity of 6 $fb^{-1}$, collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 $B^{0}_{s}$ signal decays with an invariant $K^{+}K^{-}$ mass in the vicinity of the $\phi(1020)$ resonance, the $CP$-violating phase $\phi_s$ is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the $B^0_s$-$\bar{B}^0_s$ system, $\Delta\Gamma_s$, and the difference of the average $B^0_s$ and $B^0$ meson decay widths, $\Gamma_s-\Gamma_d$. The values obtained are $\phi_s = \ -0.039 \pm 0.022 \pm 0.006$ rad, $\Delta\Gamma_s = 0.0845 \pm 0.0044 \pm 0.0024$ ps$^{-1}$ and $\Gamma_s-\Gamma_d = -0.0056 ^{+ 0.0013}_{-0.0015} \pm 0.0014$ ps$^{-1}$, where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase $\phi_s$ is also measured independently for each polarization state of the $K^{+}K^{-}$ system and shows no evidence for polarization dependence

Improved measurement of CPCP violation parameters in Bs0→J/ψK+K−B^0_s\to J/\psi K^{+}K^{-} decays in the vicinity of the ϕ(1020)\phi(1020) resonance

International audienceThe decay-time-dependent $CP$ asymmetry in $B^0_s\to J/\psi(\to \mu^{+}\mu^{-}) K^{+}K^{-}$ decays is measured using proton-proton collision data, corresponding to an integrated luminosity of 6 $fb^{-1}$, collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 $B^{0}_{s}$ signal decays with an invariant $K^{+}K^{-}$ mass in the vicinity of the $\phi(1020)$ resonance, the $CP$-violating phase $\phi_s$ is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the $B^0_s$-$\bar{B}^0_s$ system, $\Delta\Gamma_s$, and the difference of the average $B^0_s$ and $B^0$ meson decay widths, $\Gamma_s-\Gamma_d$. The values obtained are $\phi_s = \ -0.039 \pm 0.022 \pm 0.006$ rad, $\Delta\Gamma_s = 0.0845 \pm 0.0044 \pm 0.0024$ ps$^{-1}$ and $\Gamma_s-\Gamma_d = -0.0056 ^{+ 0.0013}_{-0.0015} \pm 0.0014$ ps$^{-1}$, where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase $\phi_s$ is also measured independently for each polarization state of the $K^{+}K^{-}$ system and shows no evidence for polarization dependence

Improved measurement of CPCP violation parameters in Bs0→J/ψK+K−B^0_s\to J/\psi K^{+}K^{-} decays in the vicinity of the ϕ(1020)\phi(1020) resonance

International audienceThe decay-time-dependent $CP$ asymmetry in $B^0_s\to J/\psi(\to \mu^{+}\mu^{-}) K^{+}K^{-}$ decays is measured using proton-proton collision data, corresponding to an integrated luminosity of 6 $fb^{-1}$, collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 $B^{0}_{s}$ signal decays with an invariant $K^{+}K^{-}$ mass in the vicinity of the $\phi(1020)$ resonance, the $CP$-violating phase $\phi_s$ is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the $B^0_s$-$\bar{B}^0_s$ system, $\Delta\Gamma_s$, and the difference of the average $B^0_s$ and $B^0$ meson decay widths, $\Gamma_s-\Gamma_d$. The values obtained are $\phi_s = \ -0.039 \pm 0.022 \pm 0.006$ rad, $\Delta\Gamma_s = 0.0845 \pm 0.0044 \pm 0.0024$ ps$^{-1}$ and $\Gamma_s-\Gamma_d = -0.0056 ^{+ 0.0013}_{-0.0015} \pm 0.0014$ ps$^{-1}$, where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase $\phi_s$ is also measured independently for each polarization state of the $K^{+}K^{-}$ system and shows no evidence for polarization dependence

Measurement of CP violation in B0→ψ(→ℓ+ℓ−)KS0(→π+π−)B^0\to\psi(\to\ell^+\ell^-)K^0_S(\to\pi^+\pi^-) decays

International audienceA measurement of time-dependent CP violation in the decays of $B^0$ and $\overline{B}^0$ mesons to the final states $J/\psi(\to\mu^+\mu^-)K^0_S$, $\psi(2S)(\to\mu^+\mu^-)K^0_S$ and $J/\psi(\to e^+e^-)K^0_S$ with $K^0_S\to\pi^+\pi^-$ is presented. The data correspond to an integrated luminosity of 6 fb${}^{-1}$ collected at a centre-of-mass energy of $\sqrt{s}=13$ TeV with the LHCb detector. The CP-violation parameters are measured to be \begin{align*} S_{\psi K^0_S} &= 0.717 \pm 0.013 (\text{stat}) \pm 0.008 (\text{syst}), \\ C_{\psi K^0_S} &= 0.008 \pm 0.012 (\text{stat}) \pm 0.003 (\text{syst}). \end{align*} This measurement of $S_{\psi K^0_S}$ represents the most precise single measurement of the CKM angle $\beta$ to date and is more precise than the current world average. In addition, measurements of the CP-violation parameters of the individual channels are reported and a combination with the LHCb Run 1 measurements is performed

A measurement of ΔΓs\Delta \Gamma_{s}

International audienceUsing a dataset corresponding to $9~\mathrm{fb}^{-1}$ of integrated luminosity collected with the LHCb detector between 2011 and 2018 in proton-proton collisions, the decay-time distributions of the decay modes $B_s^0 \rightarrow J/\psi \eta'$ and $B_s^0 \rightarrow J/\psi \pi^{+} \pi^{-}$ are studied. The decay-width difference between the light and heavy mass eigenstates of the $B_s^0$ meson is measured to be $\Delta \Gamma_s = 0.087 \pm 0.012 \pm 0.009 \, \mathrm{ps}^{-1}$, where the first uncertainty is statistical and the second systematic