Cepheid Mass-loss and the Pulsation -- Evolutionary Mass Discrepancy

I investigate the discrepancy between the evolution and pulsation masses for Cepheid variables. A number of recent works have proposed that non-canonical mass-loss can account for the mass discrepancy. This mass-loss would be such that a 5Mo star loses approximately 20% of its mass by arriving at the Cepheid instability strip; a 14Mo star, none. Such findings would pose a serious challenge to our understanding of mass-loss. I revisit these results in light of the Padova stellar evolutionary models and find evolutionary masses are ($17\pm5$)% greater than pulsation masses for Cepheids between 5<M/Mo<14. I find that mild internal mixing in the main-sequence progenitor of the Cepheid are able to account for this mass discrepancy.Comment: 15 pages, 3 figures, ApJ accepte

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m−2) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m−2) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m−2 in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m−2 in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug–drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m−2 and 420 mg pertuzumab following a loading dose of 840 mg

Timing of cardiac resynchronization therapy implantation

Aims The optimum timing of cardiac resynchronization therapy (CRT) implantation is unknown. We explored long-term outcomes after CRT in relation to the time interval from a first heart failure hospitalization (HFH) to device implantation. .Methods A database covering the population of England (56.3 million in 2019) was used to quantify clinical outcomes after CRT im- and results plantation in relation to first HFHs. From 2010 to 2019, 64 968 patients [age: 71.4 ± 11.7 years; 48 606 (74.8%) male] underwent CRT implantation, 57% in the absence of a previous HFH, 12.9% during the first HFH, and 30.1% after ≥1 HFH. Over 4.54 (2.80–6.71) years [median (interquartile range); 272 989 person-years], the time in years from the first HFH to CRT implantation was associated with a higher risk of total mortality [hazard ratio (HR); 95% confidence intervals (95% CI)] (1.15; 95% CI 1.14–1.16, HFH (HR: 1.26; 95% CI 1.24–1.28), and the combined endpoint of total mortality or HFH (HR: 1.19; 95% CI 1.27–1.20) than CRT in patients with no previous HFHs, after co-variate adjustment. Total mortality (HR: 1.67), HFH (HR: 2.63), and total mortality or HFH (HR: 1.92) (all P &lt; 0.001) were highest in patients undergoing CRT ≥2 years after the first HFH. Conclusion In this study of a healthcare system covering an entire nation, delays from a first HFH to CRT implantation were associated with progressively worse long-term clinical outcomes. The best clinical outcomes were observed in patients with no previous HFH and in those undergoing CRT implantation during the first HFH. Condensed The optimum timing of CRT implantation is unknown. In this study of 64 968 consecutive patients, delays from a first heart abstract failure hospitalization (HFH) to CRT implantation were associated with progressively worse long-term clinical outcomes. Each year from a first HFH to CRT implantation was associated with a 21% higher risk of total mortality and a 34% higher risk of HFH. The best outcomes after CRT were observed in patients with no previous HFHs and in those undergoing implantation during their first HFH. The left upper panel shows the timing (y-axis) and numbers (x-axis) of cardiac resynchronization therapy (CRT) implantations in relation to the timing of first heart failure hospitalizations (HFHs); the right upper panel shows CRT implantations undertaken during a first HFH as a percentage of all implantations, according to year. Patients were regarded as not having had a HFH if this had not occurred within 5 years prior to CRT implantation. The left lower panel shows the Kaplan–Meier survival curve for total mortality. Event rates (per 100 person-years) for the three endpoints according to the timing of CRT implantation in relation to a first HFH are shown in the right lower panel

Constraints on the Formation of the Globular Cluster IC 4499 from Multi-Wavelength Photometry

We present new multiband photometry for the Galactic globular cluster IC 4499 extending well past the main sequence turn-off in the U, B, V, R, I, and DDO51 bands. This photometry is used to determine that IC4499 has an age of 12 pm 1 Gyr and a cluster reddening of E(B-V) = 0.22 pm 0.02. Hence, IC 4499 is coeval with the majority of Galactic GCs, in contrast to suggestions of a younger age. The density profile of the cluster is observed to not flatten out to at least r~800 arcsec, implying that either the tidal radius of this cluster is larger than previously estimated, or that IC 4499 is surrounded by a halo. Unlike the situation in some other, more massive, globular clusters, no anomalous color spreads in the UV are detected among the red giant branch stars. The small uncertainties in our photometry should allow the detection of such signatures apparently associated with variations of light elements within the cluster, suggesting that IC 4499 consists of a single stellar population.Comment: accepted to MNRA

Systematic review of the incidence and clinical risk predictors of atrial fibrillation and permanent pacemaker implantation for bradycardia in Fabry disease

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by enzyme deficiency, leading to glycosphingolipid accumulation. Cardiac accumulation triggers local tissue injury, electrical instability and arrhythmia. Bradyarrhythmia and atrial fibrillation (AF) incidence are reported in up to 16% and 13%, respectively. OBJECTIVE: We conducted a systematic review evaluating AF burden and bradycardia requiring permanent pacemaker (PPM) implantation and report any predictive risk factors identified. METHODS: We conducted a literature search on studies in adults with FD published from inception to July 2019. Study outcomes included AF or bradycardia requiring therapy. Databases included Embase, Medline, PubMed, Web of Science, CINAHL and Cochrane. The Risk of Bias Agreement tool for Non-Randomised Studies (RoBANS) was utilised to assess bias across key areas. RESULTS: 11 studies were included, eight providing data on AF incidence or PPM implantation. Weighted estimate of event rates for AF were 12.2% and 10% for PPM. Age was associated with AF (OR 1.05–1.20 per 1-year increase in age) and a risk factor for PPM implantation (composite OR 1.03). Left ventricular hypertrophy (LVH) was associated with AF and PPM implantation. CONCLUSION: Evidence supporting AF and bradycardia requiring pacemaker implantation is limited to single-centre studies. Incidence is variable and choice of diagnostic modality plays a role in detection rate. Predictors for AF (age, LVH and atrial dilatation) and PPM (age, LVH and PR/QRS interval) were identified but strength of association was low. Incidence of AF and PPM implantation in FD are variably reported with arrhythmia burden likely much higher than previously thought

Investigating the effects of particle shape on normal compression and overconsolidation using DEM

Discrete element modelling of normal compression has been simulated on a sample of breakable two-ball clumps and compared to that of spheres. In both cases the size effect on strength is assumed to be that of real silica sand. The slopes of the normal compression lines are compared and found to be consistent with the proposed equation of the normal compression line. The values of the coefficient of earth pressure at rest K0,nc are also compared and related to the critical state fiction angles for the two materials. The breakable samples have then been unloaded to establish the stress ratios on unloading. At low overconsolidation ratios the values of K0 follow a well-established empirical relationship and realistic Poisson ratios are observed. On progressive unloading both samples head towards passive failure, and the values of the critical state lines in extension in q–p' space are found to be consistent with the critical state angles deduced from the values of K0 during normal compression. The paper highlights the important role of particle shape in governing the stress ratio during both normal compression and subsequent overconsolidation

On the metallicity gradient of the Galactic disk

Aims: The iron abundance gradient in the Galactic stellar disk provides fundamental constraints on the chemical evolution of this important Galaxy component. However the spread around the mean slope is, at fixed Galactocentric distance, larger than estimated uncertainties. Methods: To provide quantitative constraints on these trends we adopted iron abundances for 265 classical Cepheids (more than 50% of the currently known sample) based either on high-resolution spectra or on photometric metallicity indices. Homogeneous distances were estimated using near-infrared Period-Luminosity relations. The sample covers the four disk quadrants and their Galactocentric distances range from ~5 to ~17 kpc. Results: A linear regression over the entire sample provides an iron gradient of -0.051+/-0.004 dex/kpc. The above slope agrees quite well, within the errors, with previous estimates based either on Cepheids or on open clusters covering similar Galactocentric distances. However, once we split the sample in inner (Rg < 8 kpc) and outer disk Cepheids we found that the slope (-0.130+/-0.015 dex/kpc) in the former region is ~3 times steeper than the slope in the latter one (-0.042+/-0.004 dex/kpc). We found that in the outer disk the radial distribution of metal-poor (MP, [Fe/H]<-0.02 dex) and metal-rich (MR) Cepheids across the four disk quadrants does not show a clear trend when moving from the innermost to the external disk regions. We also found that the relative fractions of MP and MR Cepheids in the 1st and in the 3rd quadrant differ at 8 sigma (MP) and 15 sigma (MR) level.Comment: 6 pages, 6 figures, A&A accepte