Clinical trials often rely on echocardiographic measures of left ventricular size and function as surrogate end points. However, the quantitative impact of factors that affect the reproducibility of ...these measures is unknown. To address this issue, the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network designed a longitudinal observational study of children with known or suspected dilated cardiomyopathy aged 0 to 22 years from eight pediatric clinical centers.
Clinical data were collected together with 150 echocardiographic indices of left ventricular size and function. Separate observers performed duplicate echocardiographic imaging. Multiple observers performed measurements from three cardiac cycles to enable assessment of intraobserver and interobserver variability. The impacts of beat averaging (BA), observer type (local vs core), and variable type (areas, calculations, dimensions, slopes, time intervals, and velocities) on measurement reproducibility were studied. The outcome measure was percentage error (100 × difference/mean).
Of 173 enrolled subjects, 131 met criteria for dilated cardiomyopathy. BA, variable type and observer type all influenced percentage error (P < .0001). Core interobserver percentage error (medians, 11.4%, 10.2%, and 9.3% for BA using one, two, and three beats, respectively) was approximately twice the intraobserver percentage error (medians, 6.3%, 4.9%, and 4.2% for BA using one, two, and three beats, respectively). Slopes and calculated variables exhibited high percentage error despite BA. Chamber dimensions, areas, velocities, and time intervals exhibited low percentage error.
This comprehensive evaluation of quantitative echocardiographic methods will provide a valuable resource for the design of future pediatric studies. BA and a single core lab observer improve the reproducibility of echocardiographic measurements in children with dilated cardiomyopathy. Certain measurements are highly reproducible, while others, despite BA, are poorly reproducible.
The effect of quantum statistics in quantum gases and liquids results in observable collective properties among many-particle systems. One prime example is Bose-Einstein condensation, whose onset in ...a quantum liquid leads to phenomena such as superfluidity and superconductivity. A Bose-Einstein condensate is generally defined as a macroscopic occupation of a single-particle quantum state, a phenomenon technically referred to as off-diagonal long-range order due to non-vanishing off-diagonal components of the single-particle density matrix. The wavefunction of the condensate is an order parameter whose phase is essential in characterizing the coherence and superfluid phenomena. The long-range spatial coherence leads to the existence of phase-locked multiple condensates in an array of superfluid helium, superconducting Josephson junctions or atomic Bose-Einstein condensates. Under certain circumstances, a quantum phase difference of pi is predicted to develop among weakly coupled Josephson junctions. Such a meta-stable pi-state was discovered in a weak link of superfluid 3He, which is characterized by a 'p-wave' order parameter. The possible existence of such a pi-state in weakly coupled atomic Bose-Einstein condensates has also been proposed, but remains undiscovered. Here we report the observation of spontaneous build-up of in-phase ('zero-state') and antiphase ('pi-state') 'superfluid' states in a solid-state system; an array of exciton-polariton condensates connected by weak periodic potential barriers within a semiconductor microcavity. These in-phase and antiphase states reflect the band structure of the one-dimensional polariton array and the dynamic characteristics of metastable exciton-polariton condensates.
Controlling the rate of softening to extend shelf life was a key target for researchers engineering genetically modified (GM) tomatoes in the 1990s, but only modest improvements were achieved. ...Hybrids grown nowadays contain 'non-ripening mutations' that slow ripening and improve shelf life, but adversely affect flavor and color. We report substantial, targeted control of tomato softening, without affecting other aspects of ripening, by silencing a gene encoding a pectate lyase.
We present ultraviolet, optical and near-infrared data of the Type Ibn supernovae (SNe) 2010al and 2011hw. SN 2010al reaches an absolute magnitude at peak of M
R
= −18.86 ± 0.21. Its early light ...curve shows similarities with normal SNe Ib, with a rise to maximum slower than most SNe Ibn. The spectra are dominated by a blue continuum at early stages, with narrow P-Cygni He i lines indicating the presence of a slow-moving, He-rich circumstellar medium. At later epochs, the spectra well match those of the prototypical SN Ibn 2006jc, although the broader lines suggest that a significant amount of He was still present in the stellar envelope at the time of the explosion. SN 2011hw is somewhat different. It was discovered after the first maximum, but the light curve shows a double peak. The absolute magnitude at discovery is similar to that of the second peak (M
R
= −18.59 ± 0.25), and slightly fainter than the average of SNe Ibn. Though the spectra of SN 2011hw are similar to those of SN 2006jc, coronal lines and narrow Balmer lines are clearly detected. This indicates substantial interaction of the SN ejecta with He-rich, but not H-free, circumstellar material. The spectra of SN 2011hw suggest that it is a transitional SN Ibn/IIn event similar to SN 2005la. While for SN 2010al the spectrophotometric evolution favours a H-deprived Wolf–Rayet progenitor (of WN-type), we agree with the conclusion of Smith et al. that the precursor of SN 2011hw was likely in transition from a luminous blue variable to an early Wolf–Rayet (Ofpe/WN9) stage.
Objectives Neonates undergoing complex congenital heart surgery have a significant incidence of neurologic problems. Erythropoietin has antiapoptotic, antiexcitatory, and anti-inflammatory properties ...to prevent neuronal cell death in animal models, and improves neurodevelopmental outcomes in full-term neonates with hypoxic ischemic encephalopathy. We designed a prospective phase I/II trial of erythropoietin neuroprotection in neonatal cardiac surgery to assess safety and indicate efficacy. Methods Neonates undergoing surgery for D-transposition of the great vessels, hypoplastic left heart syndrome, or aortic arch reconstruction were randomized to 3 perioperative doses of erythropoietin or placebo. Neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development III was performed at age 12 months. Results Fifty-nine patients received the study drug. Safety profile, including magnetic resonance imaging brain injury, clinical events, and death, was not different between groups. Three patients in each group died. Forty-two patients (22 in the erythropoietin group and 20 in the placebo group; 79% of survivors) returned for 12-month follow-up. In the group receiving erythropoietin, mean Cognitive Scale scores were 101.1 ± 13.6, Language Scale scores were 88.5 ± 12.8, and Motor Scale scores were 89.9 ± 12.3. In the group receiving placebo, Cognitive Scale scores were 106.3 ± 10.8 ( P = .19), Language Scores were 92.4 ± 12.4 ( P = .33), and Motor Scale scores were 92.6 ± 14.1 ( P = .51). Conclusions Safety profile for erythropoietin administration was not different than placebo. Neurodevelopmental outcomes were not different between groups; however, this pilot study was not powered to definitively address this outcome. Lessons learned suggest optimized study design features for a larger prospective trial to definitively address the utility of erythropoietin for neuroprotection in this population.
Background Testing excised valves in surgically treated infective endocarditis (IE) patients provides an opportunity to identify the microbial etiology of IE. Microbial sequencing (universal ...bacterial, mycobacterial, or fungal polymerase chain reaction followed by DNA sequencing) of valves can identify microorganisms accurately, but the value it adds beyond information provided by blood and valve cultures has not been adequately explored. Methods Three hundred fifty-six patients who underwent surgery for active IE from January 1, 2010, to January 1, 2013, were identified from our cardiovascular information registry and outpatient parenteral antibiotic therapy registry. Their records were reviewed to identify 174 patients whose valves were sent for sequencing. The microbial etiology of IE was defined using comprehensive clinical, pathologic, and microbiological criteria. Blood culture, valve culture, and valve sequencing were examined to determine how frequently they identified the definitive cause of IE. Results Of the 174 patients, 162 (93%) had acute inflammation on histopathologic examination of their valves. Valve sequencing was significantly more sensitive than valve culture in identifying the causative pathogen (90% versus 31%, p < 0.001), and yielded fewer false positive results (3% versus 33%, p <0.001). The pathogen would not have been identified in 25 patients (15%) had it not been for valve sequencing. All the value provided by sequencing was attributable to bacterial DNA sequencing; mycobacterial and fungal sequencing provided no additional information beyond that provided by blood culture, histopathology, and valve culture. Conclusions Valve sequencing, not valve culture, should be considered the primary test for identifying bacteria in excised cardiac valves.
Background Ventricular septal defect (VSD) is the most commonly recognized congenital heart defect. With the development of device closure for intracardiac defects, we sought to evaluate current ...expectations for surgical closure of isolated VSD. Methods Between January 1, 2000, and December 31, 2006, 215 patients underwent isolated VSD repair at a median age of 10 months (range, 20 days to 18 years) and a median weight of 7 kg (range, 2 to 66 kg). The following VSD types were found: 172 perimembranous (80%), 28 supracristal (13%), 6 inlet (3%), and 9 muscular (4%). One hundred eight patients (50%) had evidence of congestive heart failure or failure to thrive preoperatively. Thirty-one patients (14%) had aortic valve cusp prolapse, and 63 (29%) had genetic abnormalities. Results Incidence of significant postoperative complications was extremely low. No patient underwent reoperation for a residual VSD. None had complete heart block. One operative mortality (0.5%) and 2 late deaths (0.9%) occurred. Median postoperative hospital length of stay was 5 days (range, 2 to 187 days). In the immediate postoperative period, 6 patients (2.8%) required reoperation. No patients were discharged on antiarrhythmic agents, had complete heart block, or required permanent pacing. At mean follow-up of 2.1 ± 2.0 years, 99.5% (211 of 212) of patients were asymptomatic from a cardiac standpoint. None exhibited greater than mild new-onset tricuspid valve regurgitation. No aortic valve injuries occurred. Conclusions Surgical closure of isolated VSD is a safe, effective therapy. Risk of death, complete heart block, and reoperation is minimal. As new technologies for VSD closure evolve, results such as these should be considered when evaluating patients, choosing therapeutic options, and counseling families.
Summary Background Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or ...refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. Methods The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m2 intravenously on days 2–3 in cycle 1, and days 1–2 in cycles 2–6; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2–6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov , number NCT01611090. Findings Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7–20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3–13·9) in the placebo group (hazard ratio HR 0·203, 95% CI 0·150–0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73–83) in the ibrutinib group and 24% (18–31) in the placebo group (HR 0·203, 95% CI 0·150–0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3–4 events; the most common grade 3–4 adverse events in both groups were neutropenia (154 54% in the ibrutinib group vs 145 51% in the placebo group) and thrombocytopenia (43 15% in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. Interpretation In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. Funding Janssen Research & Development.
A bosonic condensate of exciton polaritons in a semiconductor microcavity is a macroscopic quantum state subject to pumping and decay. The fundamental nature of this driven-dissipative condensate is ...still under debate. Here, we gain an insight into spontaneous condensation by imaging long-lifetime exciton polaritons in a high-quality inorganic microcavity in a single-shot optical excitation regime, without averaging over multiple condensate realisations. We demonstrate that condensation is strongly influenced by an incoherent reservoir and that the reservoir depletion, the so-called spatial hole burning, is critical for the transition to the ground state. Condensates of photon-like polaritons exhibit strong shot-to-shot fluctuations and density filamentation due to the effective self-focusing associated with the reservoir depletion. In contrast, condensates of exciton-like polaritons display smoother spatial density distributions and are second-order coherent. Our observations show that the single-shot measurements offer a unique opportunity to study fundamental properties of non-equilibrium condensation in the presence of a reservoir.
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