The implantable cardioverter-defibrillator (ICD) is highly effective in reducing mortality among patients at risk for fatal arrhythmias, but inappropriate ICD activations are frequent, with potential ...adverse effects.
We randomly assigned 1500 patients with a primary-prevention indication to receive an ICD with one of three programming configurations. The primary objective was to determine whether programmed high-rate therapy (with a 2.5-second delay before the initiation of therapy at a heart rate of ≥200 beats per minute) or delayed therapy (with a 60-second delay at 170 to 199 beats per minute, a 12-second delay at 200 to 249 beats per minute, and a 2.5-second delay at ≥250 beats per minute) was associated with a decrease in the number of patients with a first occurrence of inappropriate antitachycardia pacing or shocks, as compared with conventional programming (with a 2.5-second delay at 170 to 199 beats per minute and a 1.0-second delay at ≥200 beats per minute).
During an average follow-up of 1.4 years, high-rate therapy and delayed ICD therapy, as compared with conventional device programming, were associated with reductions in a first occurrence of inappropriate therapy (hazard ratio with high-rate therapy vs. conventional therapy, 0.21; 95% confidence interval CI, 0.13 to 0.34; P<0.001; hazard ratio with delayed therapy vs. conventional therapy, 0.24; 95% CI, 0.15 to 0.40; P<0.001) and reductions in all-cause mortality (hazard ratio with high-rate therapy vs. conventional therapy, 0.45; 95% CI, 0.24 to 0.85; P=0.01; hazard ratio with delayed therapy vs. conventional therapy, 0.56; 95% CI, 0.30 to 1.02; P=0.06). There were no significant differences in procedure-related adverse events among the three treatment groups.
Programming of ICD therapies for tachyarrhythmias of 200 beats per minute or higher or with a prolonged delay in therapy at 170 beats per minute or higher, as compared with conventional programming, was associated with reductions in inappropriate therapy and all-cause mortality during long-term follow-up. (Funded by Boston Scientific; MADIT-RIT ClinicalTrials.gov number, NCT00947310.).
Positron Emission Tomography (PET) is a widely-used imaging modality for medical research and clinical diagnosis. Imaging of the radiotracer is obtained from the detected hit positions of the two ...positron annihilation photons in a detector array. The image is degraded by backgrounds from random coincidences and in-patient scatter events which require correction. In addition to the geometric information, the two annihilation photons are predicted to be produced in a quantum-entangled state, resulting in enhanced correlations between their subsequent interaction processes. To explore this, the predicted entanglement in linear polarisation for the two photons was incorporated into a simulation and tested by comparison with experimental data from a cadmium zinc telluride (CZT) PET demonstrator apparatus. Adapted apparati also enabled correlation measurements where one of the photons had undergone a prior scatter process. We show that the entangled simulation describes the measured correlations and, through simulation of a larger preclinical PET scanner, illustrate a simple method to quantify and remove the unwanted backgrounds in PET using the quantum entanglement information alone.
The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) showed that early intervention with cardiac-resynchronization therapy with a ...defibrillator (CRT-D) in patients with an electrocardiographic pattern showing left bundle-branch block was associated with a significant reduction in heart-failure events over a median follow-up of 2.4 years, as compared with defibrillator therapy alone.
We evaluated the effect of CRT-D on long-term survival in the MADIT-CRT population. Post-trial follow-up over a median period of 5.6 years was assessed among all 1691 surviving patients (phase 1) and subsequently among 854 patients who were enrolled in post-trial registries (phase 2). All reported analyses were performed on an intention-to-treat basis.
At 7 years of follow-up after initial enrollment, the cumulative rate of death from any cause among patients with left bundle-branch block was 18% among patients randomly assigned to CRT-D, as compared with 29% among those randomly assigned to defibrillator therapy alone (adjusted hazard ratio in the CRT-D group, 0.59; 95% confidence interval CI, 0.43 to 0.80; P<0.001). The long-term survival benefit of CRT-D in patients with left bundle-branch block did not differ significantly according to sex, cause of cardiomyopathy, or QRS duration. In contrast, CRT-D was not associated with any clinical benefit and possibly with harm in patients without left bundle-branch block (adjusted hazard ratio for death from any cause, 1.57; 95% CI, 1.03 to 2.39; P=0.04; P<0.001 for interaction of treatment with QRS morphologic findings).
Our findings indicate that in patients with mild heart-failure symptoms, left ventricular dysfunction, and left bundle-branch block, early intervention with CRT-D was associated with a significant long-term survival benefit. (Funded by Boston Scientific; ClinicalTrials.gov numbers, NCT00180271, NCT01294449, and NCT02060110.).
A new version of the ERICA Tool (version 1.2) was released in November 2014; this constitutes the first major update of the Tool since release in 2007. The key features of the update are presented in ...this article. Of particular note are new transfer databases extracted from an international compilation of concentration ratios (CRwo-media) and the modification of ‘extrapolation’ approaches used to select transfer data in cases where information is not available. Bayesian updating approaches have been used in some cases to draw on relevant information that would otherwise have been excluded in the process of deriving CRwo-media statistics. All of these efforts have in turn led to the requirement to update Environmental Media Concentration Limits (EMCLs) used in Tier 1 assessments. Some of the significant changes with regard to EMCLs are highlighted.
•The ERICA Tool for performing environmental risk assessment has been updated.•The new version is underpinned by an internationally supported transfer database.•The Tool provides coverage for many organism groups and radioisotopes.•New calculations were required to derive environmental media concentration limits.•Modified approaches to deriving missing transfer parameters are elaborated.
Climate change is altering the productivity of natural resources with far-reaching implications for those who depend on them. Resource-dependent industries and communities need the capacity to adapt ...to a range of climate risks if they are to remain viable. In some instances, the scale and nature of the likely impacts means that transformations of function or structure will be required. Transformations represent a switch to a distinct new system where a different suite of factors become important in the design and implementation of response strategies. There is a critical gap in knowledge on understanding transformational capacity and its influences. On the basis of current knowledge on adaptive capacity we propose four foundations for measuring transformational capacity: (1) how risks and uncertainty are managed, (2) the extent of skills in planning, learning and reorganizing, (3) the level of financial and psychological flexibility to undertake change and (4) the willingness to undertake change. We test the influence of place attachment and occupational identity on transformational capacity using the Australian peanut industry, which is presently assessing significant structural change in response to predicted climatic changes. Survey data from 88% of peanut farmers in Queensland show a strong negative correlation between transformational capacity and both place attachment and occupational attachment, suggesting that whilst these factors may be important positive influences on the capacity to adapt to incremental change, they act as barriers to transformational change.
The Laser Interferometer Gravitational Wave Observatory (LIGO) has been directly detecting gravitational waves from compact binary mergers since 2015. We report on the first use of squeezed vacuum ...states in the direct measurement of gravitational waves with the Advanced LIGO H1 and L1 detectors. This achievement is the culmination of decades of research to implement squeezed states in gravitational-wave detectors. During the ongoing O3 observation run, squeezed states are improving the sensitivity of the LIGO interferometers to signals above 50 Hz by up to 3 dB, thereby increasing the expected detection rate by 40% (H1) and 50% (L1).
We present an improved analysis of the final data set from the QUaD experiment. Using an improved technique to remove ground contamination, we double the effective sky area and hence increase the ...precision of our cosmic microwave background (CMB) power spectrum measurements by ~30% versus that previously reported. In addition, we have improved our modeling of the instrument beams and have reduced our absolute calibration uncertainty from 5% to 3.5% in temperature. The robustness of our results is confirmed through extensive jackknife tests, and by way of the agreement that we find between our two fully independent analysis pipelines. For the standard six-parameter Delta *LCDM model, the addition of QUaD data marginally improves the constraints on a number of cosmological parameters over those obtained from the WMAP experiment alone. The impact of QUaD data is significantly greater for a model extended to include either a running in the scalar spectral index, or a possible tensor component, or both. Adding both the QUaD data and the results from the Arcminute Cosmology Bolometer Array Receiver experiment, the uncertainty in the spectral index running is reduced by ~25% compared to WMAP alone, while the upper limit on the tensor-to-scalar ratio is reduced from r < 0.48 to r < 0.33 (95% c.l.). This is the strongest limit on tensors to date from the CMB alone. We also use our polarization measurements to place constraints on parity-violating interactions to the surface of last scattering, constraining the energy scale of Lorentz violating interactions to <1.5 X 10-43 GeV (68% c.l.). Finally, we place a robust upper limit on the strength of the lensing B-mode signal. Assuming a single flat band power between = 200 and = 2000, we constrain the amplitude of B-modes to be <0.57 Delta *mK2 (95% c.l.).
Akt activation supports survival of cardiomyocytes against ischemia/reperfusion, which induces cell death through opening of the mitochondrial permeability transition pore (PT-pore). Mitochondrial ...depolarization induced by treatment of cardiomyocytes with H(2)O(2) is prevented by activation of Akt with leukemia inhibitory factor (LIF). This protective effect is observed even when cardiomyocytes treated with LIF are permeabilized and mitochondrial depolarization is elicited by elevating Ca(2+). Cell fractionation studies demonstrate that LIF treatment increases both total and phosphorylated Akt in the mitochondrial fraction. Furthermore, the association of Akt with HK-II is increased by LIF. HK-II contains consensus sequences for phosphorylation by Akt and LIF treatment induces PI3K- and Akt-dependent HK-II phosphorylation. Addition of recombinant kinase-active Akt to isolated adult mouse heart mitochondria stimulates phosphorylation of HK-II and concomitantly inhibits the ability of Ca(2+) to induce cytochrome c release. This protection is prevented when HK-II is dissociated from mitochondria by incubation with glucose 6-phosphate or HK-II-dissociating peptide. Finally LIF increases HK-II association with mitochondria and dissociation of HK-II from mitochondria attenuates the protective effect of LIF on H(2)O(2)-induced mitochondrial depolarization in cardiomyocytes. We conclude that Akt has a direct effect at the level of the mitochondrion, which is mediated via phosphorylation of HK-II and results in protection of mitochondria against oxidant or Ca(2+)-stimulated PT-pore opening.
The Ultraviolet/Optical Telescope (UVOT) is one of three instruments onboard the Swift observatory. The photometric calibration has been published, and this paper follows up with details on other ...aspects of the calibration including a measurement of the point spread function with an assessment of the orbital variation and the effect on photometry. A correction for large-scale variations in sensitivity over the field of view is described, as well as a model of the coincidence loss which is used to assess the coincidence correction in extended regions. We have provided a correction for the detector distortion and measured the resulting internal astrometric accuracy of the UVOT, also giving the absolute accuracy with respect to the International Celestial Reference System. We have compiled statistics on the background count rates, and discuss the sources of the background, including instrumental scattered light. In each case, we describe any impact on UVOT measurements, whether any correction is applied in the standard pipeline data processing or whether further steps are recommended.
Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains ...are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum β-lactamase producers.
To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae.
Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study.
Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician.
The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used.
Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% 1-sided 97.5% CI, -∞ to 14.5%; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group.
Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting.
anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.