B-type natriuretic peptide trumps other prognostic markers in patients assessed for coronary disease

Background: Risk prediction for patients with suspected coronary artery disease is complex due to the common occurrence of prior cardiovascular disease and extensive risk modification in primary care. Numerous markers have the potential to predict prognosis and guide management, but we currently lack robust 'real-world' evidence for their use. Methods: Prospective, multicentre observational study of consecutive patients referred for elective coronary angiography. Clinicians were blinded to all risk assessments, consisting of conventional factors, radial artery pulse wave analysis, 5-minute heart rate variability, high-sensitivity C-reactive protein and B-type natriuretic peptide (BNP). Blinded, independent adjudication was performed for all-cause mortality and the composite of death, myocardial infarction or stroke, analysed with Cox proportional hazards regression. Results: Five hundred twenty-two patients were assessed with median age 66 years and 21% prior revascularization. Median baseline left ventricular ejection fraction was 64%, and 62% had ≥ 50% stenosis on angiography. During 5.0 years median follow-up, 30% underwent percutaneous and 16% surgical revascularization. In multivariate analysis, only age and BNP were independently associated with outcomes. The adjusted hazard ratio per log unit increase in BNP was 2.15 for mortality (95% CI 1.45-3.19; p = 0.0001) and 1.27 for composite events (1.04-1.54; p = 0.018). Patients with baseline BNP > 100 pg/mL had substantially higher mortality and composite events (20.9% and 32.2%) than those with BNP ≤ 100 pg/mL (5.6% and 15.5%). BNP improved both classification and discrimination of outcomes (p ≤ 0.003), regardless of left ventricular systolic function. Conversely, high-sensitivity C-reactive protein, pulse wave analysis and heart rate variability were unrelated to prognosis at 5 years after risk modification and treatment of coronary disease. Conclusions: Conventional risk factors and other markers of arterial compliance, inflammation and autonomic function have limited value for prediction of outcomes in risk-modified patients assessed for coronary disease. BNP can independently identify patients with subtle impairment of cardiac function that might benefit from more intensive management. Trial registration: Clinicaltrials.gov, NCT00403351 Registered on 22 November 200

CD8+ T-cell recognition of a synthetic epitope formed by t-butyl modification

We set out to clone Bax-specific CD8+ T cells from peripheral blood sam- ples of patients with primary chronic lymphocytic leukaemia. A number of clones were generated using a Bax peptide pool and their T-cell epitope was mapped to two peptides sharing a common 9-amino-acid sequence (LLSYFGTPT), restricted by HLA-A*0201. However, when these T-cell clones were tested against highly purified syntheses (> 95%) of the same peptide sequence, there was no functional response. Subsequent mass spectrometric analysis and HPLC fractionation suggested that the active component in the original crude peptide preparations (77% pure) was a peptide with a tert-butyl (tBu) modification of the tyrosine residue. This was confirmed by modification of the inactive wild-type sequence to gen- erate functionally active peptides. Computer modelling of peptide:HLA- A*0201 structures predicted that the tBu modification would not affect interactions between peptide residues and the HLA binding site. However, these models did predict that the tBu modification of tyrosine would result in an extension of the side chain out of the peptide-binding groove up towards the T-cell receptor. This modified product formed < 1% of the original P603 crude peptide preparation and < 0.05% of the origi- nal 23-peptide mixture used for T-cell stimulation. The data presented here, illustrate the potential for chemical modifications to change the immunogenicity of synthetic peptides, and highlight the exquisite capacity of T-cell receptors to discriminate between structurally similar peptide sequences. Furthermore, this study highlights potential pitfalls associated with the use of synthetic peptides for the monitoring and modulating of human immune responses

Neutrophil gelatinase-associated lipocalin prior to cardiac surgery predicts acute kidney injury and mortality.

OBJECTIVE: We aimed to investigate whether preoperative serum neutrophil gelatinase-associated lipocalin (sNGALpre-op) predicted postoperative acute kidney injury (AKI) during hospitalisation and 1-year cardiovascular and all-cause mortality following adult cardiac surgery. METHODS: This study was a post hoc analysis of the Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patient Undergoing Coronary Artery Bypass Graft Surgery trial involving adult patients undergoing coronary artery bypass graft. Postoperative AKI within 72 hours was defined using the International Kidney Disease: Improving Global Outcomes classification. RESULTS: 1371 out of 1612 patients had data on sNGALpre-op. The overall 1-year cardiovascular and all-cause mortality was 5.2% (71/1371) and 7.7% (105/1371), respectively. There was an observed increase in the incidence of AKI from the first to the third tertile of sNGALpre-op (30.5%, 41.5% and 45.9%, respectively, p220 ng/L) had an estimated twofold increase risk of cardiovascular and all-cause mortality at 1 year. CLINICAL TRIAL REGISTRATION: NCT101247545; Post-results

Effect of Remote Ischaemic preconditioning on Clinical outcomes in patients undergoing Coronary Artery bypass graft surgery (ERICCA study): a multicentre double-blind randomised controlled clinical trial

BackgroundNovel cardioprotective strategies are required to improve clinical outcomes in higher-risk patients undergoing coronary artery bypass graft (CABG) with or without valve surgery. Remote ischaemic preconditioning (RIPC) in which brief episodes of non-lethal ischaemia and reperfusion are applied to the arm or leg has been demonstrated to reduce perioperative myocardial injury (PMI) following CABG with or without valve surgery.ObjectiveTo investigate whether or not RIPC can improve clinical outcomes in this setting in the Effect of Remote Ischaemic preconditioning on Clinical outcomes in patients undergoing Coronary Artery bypass graft surgery (ERICCA) study in patients undergoing CABG surgery.DesignMulticentre, double-blind, randomised sham controlled trial.SettingThe study was conducted across 30 cardiothoracic centres in the UK between March 2010 and March 2015.ParticipantsEligible patients were higher-risk adult patients (aged &gt; 18 years of age; additive European System for Cardiac Operative Risk of ≥ 5) undergoing on-pump CABG with or without valve surgery with blood cardioplegia.InterventionsPatients were randomised to receive either RIPC (four 5-minute inflations/deflations of a standard blood pressure cuff placed on the upper arm) or the sham control procedure (simulated RIPC protocol) following anaesthetic induction and prior to surgical incision. Anaesthetic management and perioperative care were not standardised.Main outcome measuresThe combined primary end point was the rate of major adverse cardiac and cerebral events comprising cardiovascular death, myocardial infarction, coronary revascularisation and stroke within 12 months of randomisation. Secondary end points included perioperative myocardial and acute kidney injury (AKI), intensive care unit and hospital stay, inotrope score, left ventricular ejection fraction, changes in quality of life and exercise tolerance.ResultsIn total, 1612 patients (sham control group,n = 811; RIPC group,n = 801) were randomised in 30 cardiac surgery centres in the UK. There was no difference in the primary end point at 12 months between the RIPC group and the sham control group (26.5% vs. 27.7%; hazard ratio 0.95, 95% confidence interval 0.79 to 1.15;p = 0.58). Furthermore, there was no evidence for any differences in either adverse events or the secondary end points of PMI (72-hour area under the curve for serum high-sensitivity troponin T), inotrope score, AKI, intensive therapy unit and hospital stay, 6-minute walk test and quality of life.ConclusionsIn patients undergoing elective on-pump CABG with or without valve surgery, without standardisation of the anaesthetic regimen, RIPC using transient arm ischaemia–reperfusion did not improve clinical outcomes. It is important that studies continue to investigate the potential mechanisms underlying RIPC, as this may facilitate the translation of this simple, non-invasive, low-cost intervention into patient benefit. The limitations of the study include the lack of standardised pre-/perioperative anaesthesia and medication, the level of missing and incomplete data for some of the secondary end points and the incompleteness of the data for the echocardiography substudy.Trial registrationClinicalTrials.gov NCT01247545.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a MRC and NIHR partnership, and the British Heart Foundation.</jats:sec

Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery.

BACKGROUND: Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. METHODS: We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. RESULTS: We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. CONCLUSIONS: Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program [a Medical Research Council and National Institute of Health Research partnership] and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.)

KELT-11b: A Highly Inflated Sub-Saturn Exoplanet Transiting the V=8 Subgiant HD 93396

We report the discovery of a transiting exoplanet, KELT-11b, orbiting the bright ($V=8.0$) subgiant HD 93396. A global analysis of the system shows that the host star is an evolved subgiant star with $T_{\rm eff} = 5370\pm51$ K, $M_{*} = 1.438_{-0.052}^{+0.061} M_{\odot}$, $R_{*} = 2.72_{-0.17}^{+0.21} R_{\odot}$, log $g_*= 3.727_{-0.046}^{+0.040}$, and [Fe/H]$= 0.180\pm0.075$. The planet is a low-mass gas giant in a $P = 4.736529\pm0.00006$ day orbit, with $M_{P} = 0.195\pm0.018 M_J$, $R_{P}= 1.37_{-0.12}^{+0.15} R_J$, $\rho_{P} = 0.093_{-0.024}^{+0.028}$ g cm$^{-3}$, surface gravity log ${g_{P}} = 2.407_{-0.086}^{+0.080}$, and equilibrium temperature $T_{eq} = 1712_{-46}^{+51}$ K. KELT-11 is the brightest known transiting exoplanet host in the southern hemisphere by more than a magnitude, and is the 6th brightest transit host to date. The planet is one of the most inflated planets known, with an exceptionally large atmospheric scale height (2763 km), and an associated size of the expected atmospheric transmission signal of 5.6%. These attributes make the KELT-11 system a valuable target for follow-up and atmospheric characterization, and it promises to become one of the benchmark systems for the study of inflated exoplanets.Comment: 15 pages, Submitted to AAS Journal

The Astropy Problem

The Astropy Project (http://astropy.org) is, in its own words, "a community effort to develop a single core package for Astronomy in Python and foster interoperability between Python astronomy packages." For five years this project has been managed, written, and operated as a grassroots, self-organized, almost entirely volunteer effort while the software is used by the majority of the astronomical community. Despite this, the project has always been and remains to this day effectively unfunded. Further, contributors receive little or no formal recognition for creating and supporting what is now critical software. This paper explores the problem in detail, outlines possible solutions to correct this, and presents a few suggestions on how to address the sustainability of general purpose astronomical software

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Dynamic Imaging of CD8+ T Cells and Dendritic Cells during Infection with Toxoplasma gondii

To better understand the initiation of CD8+ T cell responses during infection, the primary response to the intracellular parasite Toxoplasma gondii was characterized using 2-photon microscopy combined with an experimental system that allowed visualization of dendritic cells (DCs) and parasite specific CD8+ T cells. Infection with T. gondii induced localization of both these populations to the sub-capsular/interfollicular region of the draining lymph node and DCs were required for the expansion of the T cells. Consistent with current models, in the presence of cognate antigen, the average velocity of CD8+ T cells decreased. Unexpectedly, infection also resulted in modulation of the behavior of non-parasite specific T cells. This TCR-independent process correlated with the re-modeling of the lymph node micro-architecture and changes in expression of CCL21 and CCL3. Infection also resulted in sustained interactions between the DCs and CD8+ T cells that were visualized only in the presence of cognate antigen and were limited to an early phase in the response. Infected DCs were rare within the lymph node during this time frame; however, DCs presenting the cognate antigen were detected. Together, these data provide novel insights into the earliest interaction between DCs and CD8+ T cells and suggest that cross presentation by bystander DCs rather than infected DCs is an important route of antigen presentation during toxoplasmosis