Observation of inverse Compton emission from a long γ-ray burst.

Long-duration γ-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectronvolt-to-megaelectronvolt band, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission1,2. Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands1-6. The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock7-9. Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C10,11. Here we report multi-frequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 × 10-6 to 1012 electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs.

Signatures of a jet cocoon in early spectra of a supernova associated with a γ-ray burst.

Long γ-ray bursts are associated with energetic, broad-lined, stripped-envelope supernovae1,2 and as such mark the death of massive stars. The scarcity of such events nearby and the brightness of the γ-ray burst afterglow, which dominates the emission in the first few days after the burst, have so far prevented the study of the very early evolution of supernovae associated with γ-ray bursts3. In hydrogen-stripped supernovae that are not associated with γ-ray bursts, an excess of high-velocity (roughly 30,000 kilometres per second) material has been interpreted as a signature of a choked jet, which did not emerge from the progenitor star and instead deposited all of its energy in a thermal cocoon4. Here we report multi-epoch spectroscopic observations of the supernova SN 2017iuk, which is associated with the γ-ray burst GRB 171205A. Our spectra display features at extremely high expansion velocities (around 115,000 kilometres per second) within the first day after the burst5,6. Using spectral synthesis models developed for SN 2017iuk, we show that these features are characterized by chemical abundances that differ from those observed in the ejecta of SN 2017iuk at later times. We further show that the high-velocity features originate from the mildly relativistic hot cocoon that is generated by an ultra-relativistic jet within the γ-ray burst expanding and decelerating into the medium that surrounds the progenitor star7,8. This cocoon rapidly becomes transparent9 and is outshone by the supernova emission, which starts to dominate the emission three days after the burst.

Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study.

Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.

Current practice in patient selecting for long-term mechanical circulatory support.

With the advances of mechanical circulatory support, the selection of patients has undergone many changes over the last decade. Determining who is suitable for left ventricular assist device (LVAD) implantation is important to understanding the overall risk and outcomes. As devices improve, it is expected that changes will continue in this field. This review describes current state of patient selection, evaluation, and optimization prior to implantation of a long-term circulatory support device.

Circular polarization in the optical afterglow of GRB 121024A.

Gamma-ray bursts (GRBs) are most probably powered by collimated relativistic outflows (jets) from accreting black holes at cosmological distances. Bright afterglows are produced when the outflow collides with the ambient medium. Afterglow polarization directly probes the magnetic properties of the jet when measured minutes after the burst, and it probes the geometric properties of the jet and the ambient medium when measured hours to days after the burst. High values of optical polarization detected minutes after the burst of GRB 120308A indicate the presence of large-scale ordered magnetic fields originating from the central engine (the power source of the GRB). Theoretical models predict low degrees of linear polarization and no circular polarization at late times, when the energy in the original ejecta is quickly transferred to the ambient medium and propagates farther into the medium as a blast wave. Here we report the detection of circularly polarized light in the afterglow of GRB 121024A, measured 0.15 days after the burst. We show that the circular polarization is intrinsic to the afterglow and unlikely to be produced by dust scattering or plasma propagation effects. A possible explanation is to invoke anisotropic (rather than the commonly assumed isotropic) electron pitch-angle distributions, and we suggest that new models are required to produce the complex microphysics of realistic shocks in relativistic jets.

High-energy emission from transients.

Cosmic explosions dissipate energy into their surroundings on a very wide range of time scales: producing shock waves and associated particle acceleration. The historical culprits for the acceleration of the bulk of Galactic cosmic rays are supernova remnants: explosions on approximately 10(4) year time scales. Increasingly, however, time-variable emission points to rapid and efficient particle acceleration in a range of different astrophysical systems. Gamma-ray bursts have the shortest time scales, with inferred bulk Lorentz factors of approximately 1000 and photons emitted beyond 100 GeV, but active galaxies, pulsar wind nebulae and colliding stellar winds are all now associated with time-variable emission at approximately teraelectron volt energies. Cosmic photons and neutrinos at these energies offer a powerful probe of the underlying physical mechanisms of cosmic explosions, and a tool for exploring fundamental physics with these systems. Here, we discuss the motivations for high-energy observations of transients, the current experimental situation, and the prospects for the next decade, with particular reference to the major next-generation high-energy observatory, the Cherenkov Telescope Array.

Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial.

In an open-label, 24-month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced-dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard-dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12-month composite incidence of biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow-up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: -7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24-month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12-month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced-dose cyclosporine offers similar efficacy to MMF with standard-dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

The effect of recipient hepatitis C virus infection on outcomes following heart transplantation.

BACKGROUND: Insufficient data exist on the clinical course of hepatitis C virus (HCV) infection in heart transplant (HT) recipients. Our study reports the outcomes of heart transplantation in pretransplantation HCV-positive (HCV+) recipients. METHODS: A retrospective analysis of the heart transplantation database at our institution was performed to identify HT recipients who were HCV+ prior to transplantation. Chart reviews yielded demographic features, liver function tests, graft function, incidence of posttransplantation acute hepatitis and transplant coronary artery disease, and patient survival data. RESULTS: Between 1995 and 2006, 10 HCV+ patients underwent cardiac transplantation. The recipient mean age was 47 years (range, 23-69). Seven recipients were males and 3 were females. At listing 9 patients had no cirrhosis. One patient with Child-B cirrhosis was listed for combined heart-liver transplantation. Two of 10 donors were known to be HCV carriers. Posttransplantation in-hospital survival rate was 100%. At a mean follow-up of 58 months (range, 1.6-145), 3 deaths occurred, yielding an overall survival rate of 70%. Only 1 death (10%) was linked to accelerated acute hepatitis. Transplant coronary artery disease was detected in 2 patients (20%). Echocardiograms of survivors at last follow-up revealed normal ejection fractions. In addition, there were no cases of hepatocellular carcinoma; all survivors were without evidence of hepatic dysfunction. CONCLUSIONS: Transplanting recipients known to have HCV did not seem to affect overall posttransplantation survival or to increase the risk of liver dysfunction or graft-related complications.

A gamma-ray burst at a redshift of z approximately 8.2.

Long-duration gamma-ray bursts (GRBs) are thought to result from the explosions of certain massive stars, and some are bright enough that they should be observable out to redshifts of z > 20 using current technology. Hitherto, the highest redshift measured for any object was z = 6.96, for a Lyman-alpha emitting galaxy. Here we report that GRB 090423 lies at a redshift of z approximately 8.2, implying that massive stars were being produced and dying as GRBs approximately 630 Myr after the Big Bang. The burst also pinpoints the location of its host galaxy.

Correlation of donor-specific antibodies, complement and its regulators with graft dysfunction in cardiac antibody-mediated rejection.

Antibody-mediated rejection (AMR) is an immunopathologic process in which activation of complement often results in allograft injury. This study correlates C4d and C3d with HLA serology and graft function as diagnostic criteria for AMR. Immunofluorescence staining for C4d and C3d was performed on 1511 biopsies from 330 patients as part of routine diagnostic work-up of rejection. Donor-specific antibodies were detected in 95% of those with C4d+C3d+ biopsies versus 35% in the C4d+C3d- group (p = 0.002). Allograft dysfunction was present in 84% in the C4d+ C3d+ group versus 5% in the C4d+C3d- group (p < 0.0001). Combined C4d and C3d positivity had a sensitivity of 100% and specificity of 99% for the pathologic diagnosis of AMR and a mortality of 37%. Since activation of complement does not always result in allograft dysfunction, we correlated the expression pattern of the complement regulators CD55 and CD59 in patients with and without complement deposition. The proportion of patients with CD55 and/or CD59 staining was highest in C4d+C3d- patients without allograft dysfunction (p = 0.03). We conclude that a panel of C4d and C3d is diagnostically more useful than C4d alone in the evaluation of AMR. CD55 and CD59 may play a protective role in patients with evidence of complement activation.

Broadband observations of the naked-eye gamma-ray burst GRB 080319B.

Long-duration gamma-ray bursts (GRBs) release copious amounts of energy across the entire electromagnetic spectrum, and so provide a window into the process of black hole formation from the collapse of massive stars. Previous early optical observations of even the most exceptional GRBs (990123 and 030329) lacked both the temporal resolution to probe the optical flash in detail and the accuracy needed to trace the transition from the prompt emission within the outflow to external shocks caused by interaction with the progenitor environment. Here we report observations of the extraordinarily bright prompt optical and gamma-ray emission of GRB 080319B that provide diagnostics within seconds of its formation, followed by broadband observations of the afterglow decay that continued for weeks. We show that the prompt emission stems from a single physical region, implying an extremely relativistic outflow that propagates within the narrow inner core of a two-component jet.

Post-transplant ischemic injury is associated with up-regulated AlloMap gene expression.

BACKGROUND: The AlloMap gene expression test is used for the non-invasive detection of rejection. However, the impact of early post-transplant ischemic injury on subsequent AlloMap gene expression analysis has not been evaluated before. METHODS: Sixty seven heart transplant recipients, mean age 53 years, were evaluated at a mean 34 months post-transplant. AlloMap score was determined on the same day of heart biopsies. Nineteen patients had evidence of early post-transplant ischemic injury (Injury group). These were compared with the remaining 48 patients, Control group. RESULTS: Using multiple regression model with a backward selection method, post-transplant ischemic injury was found to be associated with significant increased AlloMap score compared with controls (31.5 +/- 4.6 vs. 26 +/- 6.2, p < 0.001). The Injury group had increased transplant vasculopathy (KM 5-year freedom from vasculopathy: 34% vs. 52%, p = 0.015), than Controls. CONCLUSIONS: Post-transplant ischemic injury is associated with up-regulated AlloMap gene expression, and hence, may provide another explanation for a high score in the absence of rejection.

Attrition from heart transplant waiting list for patients on ventricular assist devices is not affected by desensitization strategies.

BACKGROUND: Ventricular assist device (VAD) patients, who are commonly sensitized, can be successfully transplanted using strategies aimed at diminishing antibody burden. However, the impact of these therapies on outcomes for VAD patients on the waiting list is ill-defined. The following study was conducted to ascertain the relationship between desensitization therapies and attrition rate from the waiting list for VAD patients. METHODS: The VAD patients listed between July 1996 and June 2002 were used for this report. Transplant and inpatient pharmacy databases were queried for demographics, date of transplantation, degree of allosensitization, use of desensitization therapy, immunosuppressive strategies, and specific causes of death. RESULTS: Among 232 patients listed for heart transplantation who required bridging to transplantation with a VAD, 79 (34%) died while on the waiting list. Common causes of death included multisystem organ failure in 32 (40.5%), sepsis in 19 (24.0%), and stroke in 10 (12.6%) patients. While nearly 50% of these patients were sensitized at listing, only 5 (6.3%) patients received desensitization therapy following VAD implantation. Therapies included mycophenolate mofetil in 3 (3.7%) and IVIG in 2 (2.5%) patients. Not a single patient underwent plasmapheresis or OKT3 therapy. CONCLUSION: For patients bridged to heart transplantation with a VAD, attrition from the waiting list was associated with factors other than desensitization or induction regimens.

Utility of long-term surveillance endomyocardial biopsy: a multi-institutional analysis.

BACKGROUND: The utility of long-term endomyocardial biopsy surveillance in heart transplant recipients has been questioned. This study was undertaken to identify risk factors for late rejection and to examine the impact of different biopsy surveillance protocols on outcomes using the registry of the Cardiac Transplant Research Database. METHODS: The study group consisted of all adult patients who underwent heart transplantation at the 33 centers participating in this investigation between January 1, 1993 and January 1, 2002, survived past the second post-transplant year, and were followed-up by a defined surveillance biopsy protocol. RESULTS: During a follow-up that consisted of 24,137 patient-years, 1,626 late rejections occurred. Shorter time since transplant, history of rejection, younger age and African-American ethnicity of the recipient were strong risk factors for late rejection. The practice of surveillance biopsy varied among institutions. Continued surveillance increased the rate of diagnosis of late rejection (RR = 1.3, p = 0.002). There was no reduction in the incidence of hemodynamically compromising rejection and no increase in survival in patients with long-term vs intermediate-term surveillance. Short-term surveillance was associated with an increased incidence of hemodynamically compromising rejection, particularly among high-risk patients, and increased mortality in African-American patients. CONCLUSIONS: There are no apparent benefits from surveillance biopsy beyond 5 years post-transplant. Surveillance biopsy between 2 and 5 years post-transplant was found to reduce mortality in African-American recipients. Non-African-American recipients at high risk for late rejection will likely benefit from surveillance up to 5 years post-transplant.

An optical supernova associated with the X-ray flash XRF 060218.

Long-duration gamma-ray bursts (GRBs) are associated with type Ic supernovae that are more luminous than average and that eject material at very high velocities. Less-luminous supernovae were not hitherto known to be associated with GRBs, and therefore GRB-supernovae were thought to be rare events. Whether X-ray flashes--analogues of GRBs, but with lower luminosities and fewer gamma-rays--can also be associated with supernovae, and whether they are intrinsically 'weak' events or typical GRBs viewed off the axis of the burst, is unclear. Here we report the optical discovery and follow-up observations of the type Ic supernova SN 2006aj associated with X-ray flash XRF 060218. Supernova 2006aj is intrinsically less luminous than the GRB-supernovae, but more luminous than many supernovae not accompanied by a GRB. The ejecta velocities derived from our spectra are intermediate between these two groups, which is consistent with the weakness of both the GRB output and the supernova radio flux. Our data, combined with radio and X-ray observations, suggest that XRF 060218 is an intrinsically weak and soft event, rather than a classical GRB observed off-axis. This extends the GRB-supernova connection to X-ray flashes and fainter supernovae, implying a common origin. Events such as XRF 060218 are probably more numerous than GRB-supernovae.

Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling.

Rejection diagnosis by endomyocardial biopsy (EMB) is invasive, expensive and variable. We investigated gene expression profiling of peripheral blood mononuclear cells (PBMC) to discriminate ISHLT grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT > or = 3A). Patients were followed prospectively with blood sampling at post-transplant visits. Biopsies were graded by ISHLT criteria locally and by three independent pathologists blinded to clinical data. Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real-time PCR assays were developed. An 11 gene real-time PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis (LDA), converted into a score (0-40), and validated prospectively in an independent set (n = 63 samples, 63 patients). The test distinguished biopsy-defined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84% (95% CI 66% C94%) with grade ISHLT > or = 3A rejection. Patients >1 year post-transplant with scores below 30 (approximately 68% of the study population) are very unlikely to have grade > or = 3A rejection (NPV = 99.6%). Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings. Additional clinical experience is needed to establish the role of molecular testing for clinical event prediction and immunosuppression management.

Preimplantation B-type natriuretic peptide concentration is an independent predictor of future appropriate implantable defibrillator therapies.

OBJECTIVE: To assess prospectively whether preimplantation B-type natriuretic peptide (BNP) and C reactive protein (CRP) concentrations predict future appropriate therapies from an implantable cardioverter-defibrillator (ICD). DESIGN AND SETTING: Prospective cohort study conducted in a tertiary cardiac care centre. METHODS: 345 consecutive patients undergoing first time ICD implantation were prospectively studied. Serum BNP and CRP concentrations were obtained the day before ICD implantation. Patients were followed up with device interrogation to assess for appropriate shocks or antitachycardia pacing. Inappropriate therapies were excluded. Mean (SD) follow up was 13 (5) months. RESULTS: Patients had ischaemic (71%), primary dilated (17%), and valvar or other cardiomyopathies (12%). About half (52%) had ICDs implanted for primary prevention. Sixty three (18%) received appropriate ICD therapies. Serum creatinine, beta blocker, statin, and angiotensin converting enzyme inhibitor usage did not differ between therapy and no therapy groups. By univariate comparison, ejection fraction (p = 0.048), not taking amiodarone (p = 0.033), and BNP concentration (p = 0.0003) were risk factors for ICD therapy. However, by Cox regression multivariate analysis, only BNP above the 50th centile was a significant predictor (hazard ratio 2.19, 95% confidence interval 1.07 to 4.71, p = 0.040). Median BNP was 573 ng/l versus 243 ng/l in therapy and no therapy patients, respectively (p = 0.0003). More patients with BNP above the 50th centile (27% v 10%, p = 0.006) received ICD therapies. CONCLUSIONS: A single preimplantation BNP concentration determination is independently predictive of ICD therapies in patients with cardiomyopathies undergoing first time ICD implantation. CRP was not independently predictive of ICD therapies when compared with BNP.

Early and late rejection and HLA sensitization at the time of heart transplantation in patients bridged with left ventricular assist devices.

Over the years, the frequency of heart transplant candidates with HLA sensitization has increased as a result of the number of patients bridged to transplant using left ventricular assist devices (LVAD). Here we have examined 119 patients who were bridged to transplant with LVAD for a relationship between HLA antibodies and early (30 days) and late (2 years or more) rejection, as evidenced by endomyocardial biopsies. Both cytotoxic panel-reactive antibody reactions against a panel of T lymphocytes (T-PRA) and the percentage of transplants that occurred across a positive class I flow cross-match were examined. Biopsies were scored using ISHLT criteria. At 30 days, patients who had a biopsy grade of 0 had a mean T-PRA at transplant of 2.2%, while the mean PRAs of the other biopsy grades were significantly higher (P < .001). A similar pattern was seen with the highest biopsy results at 2 years or later (P < .001). None of the patients who had a grade 0 biopsy at 30 days posttransplant had a positive flow cytometry class I cross-match (P = .02), although the same pattern did not occur later due to a small number of patients (n = 3) who had negative biopsies. Thus, when biopsy results were examined early or late posttransplant, patients with negative biopsy results tended to have less HLA sensitization. While the methods of HLA sensitization involve humoral responses, more aggressive immunosuppression might be warranted to attempt to reduce cellular rejection posttransplant if HLA class I antibodies are present at the time of transplant.