Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial

Background Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement. Methods Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36–43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155. Findings The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference −0·01, 95% CI −0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded. Interpretation Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia

Anomalous Self-Energy Effects of the B_1g Phonon in Y_{1-x}(Pr,Ca)_xBa_2Cu_3O_7 Films

In Raman spectra of cuprate superconductors the gap shows up both directly, via a redistribution of the electronic background, the so-called "2Delta peaks", and indirectly, e.g. via the renormalization of phononic excitations. We use a model that allows us to study the redistribution and the related phonon self-energy effects simultaneously. We apply this model to the B_1g phonon of Y_{1-x}(Pr,Ca)_xBa_2Cu_3O_7 films, where Pr or Ca substitution enables us to investigate under- and overdoped samples. While various self-energy effects can be explained by the strength and energy of the 2\Delta peaks, anomalies remain. We discuss possible origins of these anomalies.Comment: 6 pages including 4 figure

Electronic Raman scattering in YBCO and other superconducting cuprates

Superconductivity induced structures in the electronic Raman spectra of high-Tc superconductors are computed using the results of ab initio LDA-LMTO three-dimensional band structure calculations via numerical integrations of the mass fluctuations, either in the whole 3D Brillouin zone or limiting the integrations to the Fermi surface. The results of both calculations are rather similar, the Brillouin zone integration yielding additional weak structures related to the extended van Hove singularities. Similar calculations have been performed for the normal state of these high-Tc cuprates. Polarization configurations have been investigated and the results have been compared to experimental spectra. The assumption of a simple d_(x^2-y^2)-like gap function allows us to explain a number of experimental features but is hard to reconcile with the relative positions of the A1g and B1g peaks.Comment: 14 pages, LaTeX (RevTeX), 5 PostScript figures, uses multicol.sty, submitted to PR

MR-IMPACT II: Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary artery disease Trial: perfusion-cardiac magnetic resonance vs. single-photon emission computed tomography for the detection of coronary artery disease: a comparative multicentre, multivendor trial

Aims Perfusion-cardiac magnetic resonance (CMR) has emerged as a potential alternative to single-photon emission computed tomography (SPECT) to assess myocardial ischaemia non-invasively. The goal was to compare the diagnostic performance of perfusion-CMR and SPECT for the detection of coronary artery disease (CAD) using conventional X-ray coronary angiography (CXA) as the reference standard. Methods and results In this multivendor trial, 533 patients, eligible for CXA or SPECT, were enrolled in 33 centres (USA and Europe) with 515 patients receiving MR contrast medium. Single-photon emission computed tomography and CXA were performed within 4 weeks before or after CMR in all patients. The prevalence of CAD in the sample was 49%. Drop-out rates for CMR and SPECT were 5.6 and 3.7%, respectively (P = 0.21). The primary endpoint was non-inferiority of CMR vs. SPECT for both sensitivity and specificity for the detection of CAD. Readers were blinded vs. clinical data, CXA, and imaging results. As a secondary endpoint, the safety profile of the CMR examination was evaluated. For CMR and SPECT, the sensitivity scores were 0.67 and 0.59, respectively, with the lower confidence level for the difference of +0.02, indicating superiority of CMR over SPECT. The specificity scores for CMR and SPECT were 0.61 and 0.72, respectively (lower confidence level for the difference: −0.17), indicating inferiority of CMR vs. SPECT. No severe adverse events occurred in the 515 patients. Conclusion In this large multicentre, multivendor study, the sensitivity of perfusion-CMR to detect CAD was superior to SPECT, while its specificity was inferior to SPECT. Cardiac magnetic resonance is a safe alternative to SPECT to detect perfusion deficits in CA

Non-equlibrium effects in transport through quantum dots

The role of non-equilibrium effects in the conductance through quantum dots is investigated. Associated with single-electron tunneling are shake-up processes and the formation of excitonic-like resonances. They change qualitatively the low temperature properties of the system. We analyze by quantum Monte Carlo methods the renormalization of the effective capacitance and the gate-voltage dependent conductance. Experimental relevance is discussed.Comment: 10 pages, 8 postscript figure

High resolution 3D imaging of living cells with sub-optical wavelength phonons

Label-free imaging of living cells below the optical diffraction limit poses great challenges for optical microscopy. Biologically relevant structural information remains below the Rayleigh limit and beyond the reach of conventional microscopes. Super-resolution techniques are typically based on the nonlinear and stochastic response of fluorescent labels which can be toxic and interfere with cell function. In this paper we present, for the first time, imaging of live cells using sub-optical wavelength phonons. The axial imaging resolution of our system is determined by the acoustic wavelength (λa = λprobe/2n) and not on the NA of the optics allowing sub-optical wavelength acoustic sectioning of samples using the time of flight. The transverse resolution is currently limited to the optical spot size. The contrast mechanism is significantly determined by the mechanical properties of the cells and requires no additional contrast agent, stain or label to image the cell structure. The ability to breach the optical diffraction limit to image living cells acoustically promises to bring a new suite of imaging technologies to bear in answering exigent questions in cell biology and biomedicine

Hypothermia for perinatal asphyxia: trial-based quality of life at 6–7 years

Objective: To assess the impact of hypothermic neural rescue at birth on health-related quality of life (HRQL) in middle childhood. Design: Six-year to 7-year follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) Trial. Setting: Community study including a single parental questionnaire to collect information on children’s HRQL. Patients: 145 children (70 in the control group, 75 in the hypothermia group) whose parents consented and returned the questionnaire. Interventions: Intensive care with cooling of the body to 33.5°C for 72 hours or intensive care alone. Main outcome measures: HRQL attributes and utility scores using the Health Utilities Index (HUI). Results: At 6–7 years, speech appeared disproportionately affected when compared with other aspects of HRQL but levels of normal emotional functioning were similar in both groups. The mean (SE) HUI3 HRQL scores were 0.73 (0.05) in the hypothermia group and 0.62 (0.06) in the control group; mean difference (95% CI) 0.11 (−0.04 to 0.26). Conclusions: Findings of non-significant differences were not unexpected; the study used data from long-term survivors in a neonatal trial and was underpowered. However, results favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. The work provides further insight into the long-term HRQL impact of perinatal asphyxial encephalopathy and provides previously unavailable utility data with which to contemplate the longer term cost-effectiveness of hypothermic neural rescue

Cost-effectiveness of therapeutic hypothermia to treat neonatal encephalopathy.

OBJECTIVE: To estimate the cost-effectiveness (CE) of total body hypothermia plus intensive care versus intensive care alone to treat neonatal encephalopathy. METHODS: Decision analytic modeling was used to synthesize mortality and morbidity data from three randomized controlled trials, the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), National Institute of Child Health and Human Development (NICHD), and CoolCap trials. Cost data inputs were informed by TOBY, the sole source of prospectively collected resource utilization data for encephalopathic infants. CE was expressed in terms of incremental cost per disability-free life year (DFLY) gained. Probabilistic sensitivity analysis was performed to generate CE acceptability curves (CEACs). RESULTS: Cooling led to a cost increase of £3787 (95% confidence interval [CI]: -2516, 12,360) (€5115; 95% CI: -3398-16,694; US$5344; 95$28,124). The baseline CEAC showed that if decision-makers are willing to pay £30,000 for an additional DFLY, there is a 69% probability that cooling is cost-effective. The probability of CE exceeded 99% at this threshold when the throughput of infants was increased to reflect the national incidence of neonatal encephalopathy or when the time horizon of the economic evaluation was extended to 18 years after birth. CONCLUSIONS: The probability that cooling is a cost-effective treatment for neonatal encephalopathy is finely balanced over the first 18 months after birth but increases substantially when national incidence data or an extended time horizon are considered