Abstract
Aims
Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40–49% should be managed similar to LVEF ≥ 50%. We investigated the effect of ...beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials.
Methods and results
Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21–33%), including 575 patients with LVEF 40–49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40–49%, death occurred in 21/292 7.2% randomized to beta-blockers compared to 35/283 12.4% with placebo; adjusted hazard ratio (HR) 0.59 95% confidence interval (CI) 0.34–1.03. Cardiovascular death occurred in 13/292 4.5% with beta-blockers and 26/283 9.2% with placebo; adjusted HR 0.48 (95% CI 0.24–0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis.
Conclusion
Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40–49%.
The relationship between mortality and heart rate remains unclear for patients with heart failure with reduced ejection fraction in either sinus rhythm or atrial fibrillation (AF).
This analysis ...explored the prognostic importance of heart rate in patients with heart failure with reduced ejection fraction in randomized controlled trials comparing beta-blockers and placebo.
The Beta-Blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual patient data from 11 double-blind randomized controlled trials. The primary outcome was all-cause mortality, analyzed with Cox proportional hazard ratios (HR) modeling heart rate measured at baseline and approximately 6 months post-randomization.
A higher heart rate at baseline was associated with greater all-cause mortality for patients in sinus rhythm (n = 14,166; adjusted HR: 1.11 per 10 beats/min; 95% confidence interval CI: 1.07 to 1.15; p < 0.0001) but not in AF (n = 3,034; HR: 1.03 per 10 beats/min; 95% CI: 0.97 to 1.08; p = 0.38). Beta-blockers reduced ventricular rate by 12 beats/min in both sinus rhythm and AF. Mortality was lower for patients in sinus rhythm randomized to beta-blockers (HR: 0.73 vs. placebo; 95% CI: 0.67 to 0.79; p < 0.001), regardless of baseline heart rate (interaction p = 0.35). Beta-blockers had no effect on mortality in patients with AF (HR: 0.96, 95% CI: 0.81 to 1.12; p = 0.58) at any heart rate (interaction p = 0.48). A lower achieved resting heart rate, irrespective of treatment, was associated with better prognosis only for patients in sinus rhythm (HR: 1.16 per 10 beats/min increase, 95% CI: 1.11 to 1.22; p < 0.0001).
Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with heart failure with reduced ejection fraction in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm.
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ABSTRACT
The formation of stellar clusters dictates the pace at which galaxies evolve, and solving the question of their formation will undoubtedly lead to a better understanding of the Universe as a ...whole. While it is well known that star clusters form within parsec-scale overdensities of interstellar molecular gas called clumps, it is, however, unclear whether these clumps represent the high-density tip of a continuous gaseous flow that gradually leads towards the formation of stars, or a transition within the gas physical properties. Here, we present a unique analysis of a sample of 27 infrared dark clouds embedded within 24 individual molecular clouds that combine a large set of observations, allowing us to compute the mass and velocity dispersion profiles of each, from the scale of tens of parsecs down to the scale of tenths of a parsec. These profiles reveal that the vast majority of the clouds, if not all, are consistent with being self-gravitating on all scales, and that the clumps, on parsec-scale, are often dynamically decoupled from their surrounding molecular clouds, exhibiting steeper density profiles (ρ∝r−2) and flat velocity dispersion profiles (σ∝r0), clearly departing from Larson’s relations. These findings suggest that the formation of star clusters correspond to a transition regime within the properties of the self-gravitating molecular gas. We propose that this transition regime is one that corresponds to the gravitational collapse of parsec-scale clumps within otherwise stable molecular clouds.
Summary Background Atrial fibrillation and heart failure often coexist, causing substantial cardiovascular morbidity and mortality. β blockers are indicated in patients with symptomatic heart failure ...with reduced ejection fraction; however, the efficacy of these drugs in patients with concomitant atrial fibrillation is uncertain. We therefore meta-analysed individual-patient data to assess the efficacy of β blockers in patients with heart failure and sinus rhythm compared with atrial fibrillation. Methods We extracted individual-patient data from ten randomised controlled trials of the comparison of β blockers versus placebo in heart failure. The presence of sinus rhythm or atrial fibrillation was ascertained from the baseline electrocardiograph. The primary outcome was all-cause mortality. Analysis was by intention to treat. Outcome data were meta-analysed with an adjusted Cox proportional hazards regression. The study is registered with Clinicaltrials.gov , number NCT0083244 , and PROSPERO, number CRD42014010012. Findings 18 254 patients were assessed, and of these 13 946 (76%) had sinus rhythm and 3066 (17%) had atrial fibrillation at baseline. Crude death rates over a mean follow-up of 1·5 years (SD 1·1) were 16% (2237 of 13 945) in patients with sinus rhythm and 21% (633 of 3064) in patients with atrial fibrillation. β-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm (hazard ratio 0·73, 0·67–0·80; p<0·001), but not in patients with atrial fibrillation (0·97, 0·83–1·14; p=0·73), with a significant p value for interaction of baseline rhythm (p=0·002). The lack of efficacy for the primary outcome was noted in all subgroups of atrial fibrillation, including age, sex, left ventricular ejection fraction, New York Heart Association class, heart rate, and baseline medical therapy. Interpretation Based on our findings, β blockers should not be used preferentially over other rate-control medications and not regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation. Funding Menarini Farmaceutica Internazionale (administrative support grant).
To compare arthroscopic hip surgery with physiotherapy and activity modification for improving patient reported outcome measures in patients with symptomatic femoroacetabular impingement (FAI).
Two ...group parallel, assessor blinded, pragmatic randomised controlled trial.
Secondary and tertiary care centres across seven NHS England sites.
222 participants aged 18 to 60 years with symptomatic FAI confirmed clinically and with imaging (radiography or magnetic resonance imaging) were randomised (1:1) to receive arthroscopic hip surgery (n=112) or a programme of physiotherapy and activity modification (n=110). Exclusion criteria included previous surgery, completion of a physiotherapy programme targeting FAI within the preceding 12 months, established osteoarthritis (Kellgren-Lawrence grade ≥2), and hip dysplasia (centre-edge angle <20 degrees).
Participants in the physiotherapy group received a goal based programme tailored to individual patient needs, with emphasis on improving core stability and movement control. A maximum of eight physiotherapy sessions were delivered over five months. Participants in the arthroscopic surgery group received surgery to excise the bone that impinged during hip movements, followed by routine postoperative care.
The primary outcome measure was the hip outcome score activities of daily living subscale (HOS ADL) at eight months post-randomisation, with a minimum clinically important difference between groups of 9 points. Secondary outcome measures included additional patient reported outcome measures and clinical assessment.
At eight months post-randomisation, data were available for 100 patients in the arthroscopic hip surgery group (89%) and 88 patients in the physiotherapy programme group (80%). Mean HOS ADL was 78.4 (95% confidence interval 74.4 to 82.3) for patients randomised to arthroscopic hip surgery and 69.2 (65.2 to 73.3) for patients randomised to the physiotherapy programme. After adjusting for baseline HOS ADL, age, sex, and study site, the mean HOS ADL was 10.0 points higher (6.4 to 13.6) in the arthroscopic hip surgery group compared with the physiotherapy programme group (P<0.001)). No serious adverse events were reported in either group.
Patients with symptomatic FAI referred to secondary or tertiary care achieve superior outcomes with arthroscopic hip surgery than with physiotherapy and activity modification.
ClinicalTrials.gov NCT01893034.
ABSTRACT
It is speculated that the high star formation efficiency observed in spiral-arm molecular clouds is linked to the prevalence of compressive (curl-free) turbulent modes, while the ...shear-driven solenoidal (divergence-free) modes appear to be the main cause of the low star formation efficiency that characterizes clouds in the Central Molecular Zone. Similarly, analysis of the Orion B molecular cloud has confirmed that, although turbulent modes vary locally and at different scales within the cloud, the dominant solenoidal turbulence is compatible with its low star formation rate. This evidence points to intercloud and intracloud fluctuations of the solenoidal modes being an agent for the variability of star formation efficiency. We present a quantitative estimation of the relative fractions of momentum density in the solenoidal modes of turbulence in a large sample of plane molecular clouds in the 13CO/C18O (J = 3 → 2) Heterodyne Inner Milky Way Plane Survey (CHIMPS). We find a negative correlation between the solenoidal fraction and star formation efficiency. This feature is consistent with the hypothesis that solenoidal modes prevent or slow down the collapse of dense cores. In addition, the relative power in the solenoidal modes of turbulence (solenoidal fraction) appears to be higher in the Inner Galaxy declining with a shallow gradient with increasing Galactocentric distance. Outside the Inner Galaxy, the slowly, monotonically declining values suggest that the solenoidal fraction is unaffected by the spiral arms.
Objectives To determine the efficacy and tolerability of β blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data ...from placebo controlled randomised trials.Design Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction <0.45.Participants 13 833 patients from 11 trials; median age 64; 24% women.Main outcome measures The primary outcome was all cause mortality; the major secondary outcome was admission to hospital for heart failure. Analysis was by intention to treat with an adjusted one stage Cox proportional hazards model.Results Compared with placebo, β blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by β blockers, although this effect was attenuated at older ages (interaction P=0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4% in those give β blockers, 15.6% in those receiving placebo).Conclusion Irrespective of age or sex, patients with HFrEF in sinus rhythm should receive β blockers to reduce the risk of death and admission to hospital.Registration PROSPERO CRD42014010012; Clinicaltrials.gov NCT00832442.
Background & Aims:
Dendritic cells (DCs) recognize and respond to microbial structures using pattern recognition receptors, including Toll-like receptors (TLRs). In the intestine, DCs are pivotal in ...tolerance induction and direct the differentiation of T cells. We aimed to identify changes in intestinal DCs that may underlie the dysregulated immune response to enteric bacteria that occurs in patients with inflammatory bowel disease (IBD).
Methods:
DCs were identified in freshly isolated lamina propria mononuclear cells by multicolor flow cytometry in patients with IBD and controls. Expression of TLR2, TLR4, and the activation/maturation marker CD40 was assessed by cell surface labeling. Production of cytokines (interleukin IL-12, IL-6, and IL-10) was assessed in the absence of exogenous stimulation by intracellular staining of permeabilized cells.
Results:
In healthy controls, few intestinal DCs expressed TLR2 or TLR4, in contrast to blood DCs. DC expression of both TLRs was significantly enhanced in Crohn’s disease and ulcerative colitis. DCs from inflamed tissue of patients with Crohn’s disease expressed significantly higher levels of the maturation/activation marker CD40. Elevated levels of CD40 on DCs were decreased after treating patients with anti-tumor necrosis factor α. In Crohn’s disease, but not ulcerative colitis, more colonic DCs produced IL-12 and IL-6. The number of IL-10-producing DCs did not differ significantly between patients with IBD and controls.
Conclusions:
In IBD, DCs are activated, their expression of microbial recognition receptors is up-regulated, and more DCs produce pathologically relevant cytokines. Intestinal DCs are likely to be key initiators or perpetuators of the inflammatory response that characterizes IBD.
ABSTRACT
The physical processes behind the transfer of mass from parsec-scale clumps to massive star-forming cores remain elusive. We investigate the relation between the clump morphology and the ...mass fraction that ends up in its most massive core (MMC) as a function of infrared brightness, i.e. a clump evolutionary tracer. Using Atacama Large Millimeter/submillimeter Array (ALMA) 12 m and Atacama Compact Array, we surveyed six infrared dark hubs in 2.9 mm continuum at ∼3 arcsec resolution. To put our sample into context, we also re-analysed published ALMA data from a sample of 29 high-mass surface density ATLASGAL sources. We characterize the size, mass, morphology, and infrared brightness of the clumps using Herschel and Spitzer data. Within the six newly observed hubs, we identify 67 cores, and find that the MMCs have masses between 15 and 911 M⊙ within a radius of 0.018–0.156 pc. The MMC of each hub contains 3–24 per cent of the clump mass (fMMC), becoming 5–36 per cent once core masses are normalized to the median core radius. Across the 35 clumps, we find no significant difference in the median fMMC values of hub and non-hub systems, likely the consequence of a sample bias. However, we find that fMMC is ∼7.9 times larger for infrared dark clumps compared to infrared bright ones. This factor increases up to ∼14.5 when comparing our sample of six infrared dark hubs to infrared bright clumps. We speculate that hub-filament systems efficiently concentrate mass within their MMC early on during its evolution. As clumps evolve, they grow in mass, but such growth does not lead to the formation of more massive MMCs.
Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of ...life-saving therapy.
This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR).
Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm.
Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m2; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m2, and 2,286 (13.7%) 30 to 44 ml/min/1.73 m2. Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m2 lower eGFR (95% confidence interval CI: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m2 (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m2 (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m2) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR.
Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction.
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