Relation of microvascular dysfunction to exercise capacity and symptoms in patients with severe aortic stenosis

Objective: The aim of this study was to assess the impact of left ventricular hypertrophy, myocardial fibrosis, myocardial perfusion reserve (MPR) and diastolic dysfunction on objectively measured aerobic exercise capacity (peak VO$_{2}$) in severe aortic stenosis (AS). Background: The management of asymptomatic patients with severe AS remains controversial and clinical practice varies. Echocardiographic measures of severity do not discriminate between symptomatic status or predict exercise capacity. The purpose of this study was to investigate the mechanisms contributing to symptom generation and exercise intolerance. This needs to be fully understood to optimise the management of asymptomatic AS. Methods: Patients were prospectively enrolled from a single cardiac surgical centre. Inclusion criteria: age 18-85, isolated severe AS referred for valve replacement. Exclusion criteria: syncope; other moderate/severe valve disease, previous valve surgery, obstructive coronary artery disease (>50% luminal stenosis on invasive angiography), chronic obstructive pulmonary disease, atrial fibrillation, estimated glomerular filtration rate <30mL/min. Investigations and primary outcome measures; cardiac magnetic resonance (CMR) - left ventricular mass index (LVMI), MPR (calculated from absolute myocardial blood flow during adenosine hyperaemia and rest determined by model-independent deconvolution of signal intensity curves with an arterial input function), late gadolinium enhancement (LGE); echocardiography - AS severity, tissue Doppler-derived diastolic function; symptom-limited bicycle ergometer cardiopulmonary exercise testing (CPEX) - peak VO$_{2}$. Linear regression investigated possible predictors of continuous outcome measures. Stepwise selection methods were used to determine the most important predictors of outcome. Results: Four patients with variable LVMI, LGE and MPR are shown, Figure 1. Univariate analyses and results from the stepwise model selection for peak VO$_{2}$ are summarised in Table 1. Only MPR was of independent significance in predicting age and sex corrected peak VO$_{2}$. The relationship between peak VO$_{2}$ and MPR is shown, Figure 2. Patients with higher NYHA Class had lower MPR (p=0.001). Examining predictors of MPR the best stepwise model contained LVMI and LGE category as independent predictors, Table 2. Conclusions: MPR is a novel independent predictor of peak VO$_{2}$ and is inversely related to NYHA functional class in severe AS. Microvascular dysfunction is determined by a combination of factors including AS severity, LVMI, diastolic perfusion time, myocardial fibrosis and LV filling pressure. Further work is required to determine the clinical significance of microvascular dysfunction in AS

A genetically encoded reporter of synaptic activity in vivo

To image synaptic activity within neural circuits, we tethered the genetically encoded calcium indicator (GECI) GCaMP2 to synaptic vesicles by fusion to synaptophysin. The resulting reporter, SyGCaMP2, detected the electrical activity of neurons with two advantages over existing cytoplasmic GECIs: it identified the locations of synapses and had a linear response over a wider range of spike frequencies. Simulations and experimental measurements indicated that linearity arises because SyGCaMP2 samples the brief calcium transient passing through the presynaptic compartment close to voltage-sensitive calcium channels rather than changes in bulk calcium concentration. In vivo imaging in zebrafish demonstrated that SyGCaMP2 can assess electrical activity in conventional synapses of spiking neurons in the optic tectum and graded voltage signals transmitted by ribbon synapses of retinal bipolar cells. Localizing a GECI to synaptic terminals provides a strategy for monitoring activity across large groups of neurons at the level of individual synapses

All-sky convolution for polarimetry experiments

We discuss all-sky convolution of the instrument beam with the sky signal in polarimetry experiments, such as the Planck mission which will map the temperature anisotropy and polarization of the cosmic microwave background (CMB). To account properly for stray light (from e.g. the galaxy, sun, and planets) in the far side-lobes of such an experiment, it is necessary to perform the beam convolution over the full sky. We discuss this process in multipole space for an arbitrary beam response, fully including the effects of beam asymmetry and cross-polarization. The form of the convolution in multipole space is such that the Wandelt-Gorski fast technique for all-sky convolution of scalar signals (e.g. temperature) can be applied with little modification. We further show that for the special case of a pure co-polarized, axisymmetric beam the effect of the convolution can be described by spin-weighted window functions. In the limits of a small angle beam and large Legendre multipoles, the spin-weight 2 window function for the linear polarization reduces to the usual scalar window function used in previous analyses of beam effects in CMB polarimetry experiments. While we focus on the example of polarimetry experiments in the context of CMB studies, we emphasise that the formalism we develop is applicable to anisotropic filtering of arbitrary tensor fields on the sphere.Comment: 8 pages, 1 figure; Minor changes to match version accepted by Phys. Rev.

Fabry-Perot Absorption Line Spectroscopy of the Galactic Bar. I. Kinematics

We use Fabry-Perot absorption line imaging spectroscopy to measure radial velocities using the Ca II 8542 line in 3360 stars towards three lines of sight in the Milky Way's bar: Baade's Window and offset position at (l,b) ~ (+-5.0, -3.5). This sample includes 2488 bar red clump giants, 339 bar M/K-giants, and 318 disk main sequence stars. We measure the first four moments of the stellar velocity distribution of the red clump giants, and find it to be symmetric and flat-topped. We also measure the line-of-sight average velocity and dispersion of the red clump giants as a function of distance in the bar. We detect stellar streams at the near and far side of the bar with velocity difference > 30 km/s at l = +-5, but we do not detect two separate streams in Baade's Window. Our M-giants kinematics agree well with previous studies, but have dispersions systematically lower than those of the red clump giants by ~ 10 km/s. For the disk main sequence stars we measure a velocity dispersion of ~ 45 km/s for all three lines-of-sight, placing a majority of them in the thin disk within 3.5 kpc of the Sun, associated with the Sagittarius spiral arm. We measure the equivalent widths of the Ca II 8542 line that can be used to infer metallicities. We find indications of a metallicity gradient with Galactic longitude, with greater metallicity in Baade's Window. We find the bulge to be metal-rich, consistent with some previous studies.Comment: Accepted for publication in the Astrophysical Journal,16 pages, 12 figure

British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease

Sjögren disease (SD) is a chronic, autoimmune disease of unknown aetiology with significant impact on quality of life. Although dryness (sicca) of the eyes and mouth are the classically described features, dryness of other mucosal surfaces and systemic manifestations are common. The key management aim should be to empower the individual to manage their condition-conserving, replacing and stimulating secretions; and preventing damage and suppressing systemic disease activity. This guideline builds on and widens the recommendations developed for the first guideline published in 2017. We have included advice on the management of children and adolescents where appropriate to provide a comprehensive guideline for UK-based rheumatology teams.</p

Severity of Psoriasis Associates With Aortic Vascular Inflammation Detected by FDG PET/CT and Neutrophil Activation in a Prospective Observational Study.

This is the author accepted manuscript. The final version is available from the American Heart Association via http://dx.doi.org/10.1161/ATVBAHA.115.306460OBJECTIVE: To understand whether directly measured psoriasis severity is associated with vascular inflammation assessed by (18)F-fluorodeoxyglucose positron emission tomography computed tomography. APPROACH: In-depth cardiovascular and metabolic phenotyping was performed in adult psoriasis patients (n=60) and controls (n=20). Psoriasis severity was measured using psoriasis area severity index. Vascular inflammation was measured using average aortic target-to-background ratio using (18)F-fluorodeoxyglucose positron emission tomography computed tomography. RESULTS: Both the psoriasis patients (28 men and 32 women, mean age 47 years) and controls (13 men and 7 women, mean age 41 years) were young with low cardiovascular risk. Psoriasis area severity index scores (median 5.4; interquartile range 2.8-8.3) were consistent with mild-to-moderate skin disease severity. Increasing psoriasis area severity index score was associated with an increase in aortic target-to-background ratio (β=0.41, P=0.001), an association that changed little after adjustment for age, sex, and Framingham risk score. We observed evidence of increased neutrophil frequency (mean psoriasis, 3.7±1.2 versus 2.9±1.2; P=0.02) and activation by lower neutrophil surface CD16 and CD62L in blood. Serum levels of S100A8/A9 (745.1±53.3 versus 195.4±157.8 ng/mL; P<0.01) and neutrophil elastase-1 (43.0±2.4 versus 30.8±6.7 ng/mL; P<0.001) were elevated in psoriasis. Finally, S100A8/A9 protein was related to both psoriasis skin disease severity (β=0.53; P=0.02) and vascular inflammation (β=0.48; P=0.02). CONCLUSIONS: Psoriasis severity is associated with vascular inflammation beyond cardiovascular risk factors. Psoriasis increased neutrophil activation and neutrophil markers, and S100A8/A9 was related to both skin disease severity and vascular inflammation.JMT is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z) and the NIHR Cambridge Biomedical Research Centre. JHFR is part-supported by the HEFCE, the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trus

Testing for an Unusual Distribution of Rare Variants

Technological advances make it possible to use high-throughput sequencing as a primary discovery tool of medical genetics, specifically for assaying rare variation. Still this approach faces the analytic challenge that the influence of very rare variants can only be evaluated effectively as a group. A further complication is that any given rare variant could have no effect, could increase risk, or could be protective. We propose here the C-alpha test statistic as a novel approach for testing for the presence of this mixture of effects across a set of rare variants. Unlike existing burden tests, C-alpha, by testing the variance rather than the mean, maintains consistent power when the target set contains both risk and protective variants. Through simulations and analysis of case/control data, we demonstrate good power relative to existing methods that assess the burden of rare variants in individuals

Packed Ultra-wideband Mapping Array (PUMA): A Radio Telescope for Cosmology and Transients

PUMA is a proposal for an ultra-wideband, low-resolution and transit interferometric radio telescope operating at $200-1100\,\mathrm{MHz}$. Its design is driven by six science goals which span three science themes: the physics of dark energy (measuring the expansion history and growth of the universe up to $z=6$), the physics of inflation (constraining primordial non-Gaussianity and primordial features) and the transient radio sky (detecting one million fast radio bursts and following up SKA-discovered pulsars). We propose two array configurations composed of hexagonally close-packed 6m dish arrangements with 50% fill factor. The initial 5,000 element 'petite array' is scientifically compelling, and can act as a demonstrator and a stepping stone to the full 32,000 element 'full array'. Viewed as a 21cm intensity mapping telescope, the program has the noise equivalent of a traditional spectroscopic galaxy survey comprised of 0.6 and 2.5 billion galaxies at a comoving wavenumber of $k=0.5\,h\mathrm{Mpc}^{-1}$ spanning the redshift range $z = 0.3 - 6$ for the petite and full configurations, respectively. At redshifts beyond $z=2$, the 21cm technique is a uniquely powerful way of mapping the universe, while the low-redshift range will allow for numerous cross-correlations with existing and upcoming surveys. This program is enabled by the development of ultra-wideband radio feeds, cost-effective dish construction methods, commodity radio-frequency electronics driven by the telecommunication industry and the emergence of sufficient computing power to facilitate real-time signal processing that exploits the full potential of massive radio arrays. The project has an estimated construction cost of 55 and 330 million FY19 USD for the petite and full array configurations. Including R&D, design, operations and science analysis, the cost rises to 125 and 600 million FY19 USD, respectively.Comment: 10 pages + references, 3 figures, 3 tables; project white paper submitted to the Astro2020 decadal survey; further details in updated arXiv:1810.0957