Clinical outcomes of patients with low-flow, low-gradient, severe aortic stenosis and either preserved or reduced ejection fraction undergoing transcatheter aortic valve implantation

AIMS Our aim was to evaluate the invasive haemodynamic indices of high-risk symptomatic patients presenting with 'paradoxical' low-flow, low-gradient, severe aortic stenosis (AS) (PLF-LG) and low-flow, low-gradient severe AS (LEF-LG) and to compare clinical outcomes following transcatheter aortic valve implantation (TAVI) among these challenging AS subgroups. METHODS AND RESULTS Of 534 symptomatic patients undergoing TAVI, 385 had a full pre-procedural right and left heart catheterization. A total of 208 patients had high-gradient severe AS [HGAS; mean gradient (MG) ≥40 mmHg], 85 had PLF-LG [MG ≤ 40 mmHg, indexed aortic valve area [iAVA] ≤0.6 cm(2) m(-2), stroke volume index ≤35 mL/m(2), ejection fraction (EF) ≥50%], and 61 had LEF-LG (MG ≤ 40 mmHg, iAVA ≤0.6 cm(2) m(-2), EF ≤40%). Compared with HGAS, PLF-LG and LEF-LG had higher systemic vascular resistances (HGAS: 1912 ± 654 vs. PLF-LG 2006 ± 586 vs. LEF-LG 2216 ± 765 dyne s m(-5), P = 0.007) but lower valvulo-arterial impedances (HGAS: 7.8 ± 2.7 vs. PLF-LG 6.9 ± 1.9 vs. LEF-LG 7.7 ± 2.5 mmHg mL(-1) m(-2), P = 0.027). At 30 days, no differences in cardiac death (6.5 vs. 4.9 vs. 6.6%, P = 0.90) or death (8.4 vs. 6.1 vs. 6.6%, P = 0.88) were observed among HGAS, PLF-LG, and LEF-LG groups, respectively. At 1 year, New York Heart Association functional improvement occurred in most surviving patients (HGAS: 69.2% vs. PLF-LG 71.7% vs. LEF-LG 89.3%, P = 0.09) and no significant differences in overall mortality were observed (17.6 vs. 20.5 vs. 24.5%, P = 0.67). Compared with HGAS, LEF-LG had a higher 1 year cardiac mortality (adjusted hazard ratio 2.45, 95% confidence interval 1.04-5.75, P = 0.04). CONCLUSION TAVI in PLF-LG or LEF-LG patients is associated with overall mortality rates comparable with HGAS patients and all groups profit symptomatically to a similar extent.

Computational and experimental methodology for site-matched investigations of the influence of mineral mass fraction and collagen orientation on the axial indentation modulus of lamellar bone

Relationships between mineralization, collagen orientation and indentation modulus were investigated in bone structural units from the mid-shaft of human femora using a site-matched design. Mineral mass fraction, collagen fibril angle and indentation moduli were measured in registered anatomical sites using backscattered electron imaging, polarized light microscopy and nano-indentation, respectively. Theoretical indentation moduli were calculated with a homogenization model from the quantified mineral densities and mean collagen fibril orientations. The average indentation moduli predicted based on local mineralization and collagen fibers arrangement were not significantly different from the average measured experimentally with nanoindentation (p=0.9). Surprisingly, no substantial correlation of the measured indentation moduli with tissue mineralization and/or collagen fiber arrangement was found. Nano-porosity, micro-damage, collagen cross-links, non-collagenous proteins or other parameters affect the indentation measurements. Additional testing/simulation methods need to be considered to properly understand the variability of indentation moduli, beyond the mineralization and collagen arrangement in bone structural units.

Effects of inspiratory muscle training in patients with heart failure with preserved ejection fraction

BACKGROUND Heart failure with preserved ejection fraction (HFpEF) is remarkably common in elderly people with highly prevalent comorbid conditions. Despite its increasing in prevalence, there is no evidence-based effective therapy for HFpEF. We sought to evaluate whether inspiratory muscle training (IMT) improves exercise capacity, as well as left ventricular diastolic function, biomarker profile and quality of life (QoL) in patients with advanced HFpEF and nonreduced maximal inspiratory pressure (MIP). DESIGN AND METHODS A total of 26 patients with HFpEF (median (interquartile range) age, peak exercise oxygen uptake (peak VO2) and left ventricular ejection fraction of 73 years (66-76), 10 ml/min/kg (7.6-10.5) and 72% (65-77), respectively) were randomized to receive a 12-week programme of IMT plus standard care vs. standard care alone. The primary endpoint of the study was evaluated by positive changes in cardiopulmonary exercise parameters and distance walked in 6 minutes (6MWT). Secondary endpoints were changes in QoL, echocardiogram parameters of diastolic function, and prognostic biomarkers. RESULTS The IMT group improved significantly their MIP (p < 0.001), peak VO2 (p < 0.001), exercise oxygen uptake at anaerobic threshold (p = 0.001), ventilatory efficiency (p = 0.007), metabolic equivalents (p < 0,001), 6MWT (p < 0.001), and QoL (p = 0.037) as compared to the control group. No changes on diastolic function parameters or biomarkers levels were observed between both groups. CONCLUSIONS In HFpEF patients with low aerobic capacity and non-reduced MIP, IMT was associated with marked improvement in exercise capacity and QoL.

Development of automated image analysis tools for verification of radiotherapy field accuracy with an electronic portal imaging device

The successful management of cancer with radiation relies on the accurate deposition of a prescribed dose to a prescribed anatomical volume within the patient. Treatment set-up errors are inevitable because the alignment of field shaping devices with the patient must be repeated daily up to eighty times during the course of a fractionated radiotherapy treatment. With the invention of electronic portal imaging devices (EPIDs), patient's portal images can be visualized daily in real-time after only a small fraction of the radiation dose has been delivered to each treatment field. However, the accuracy of human visual evaluation of low-contrast portal images has been found to be inadequate. The goal of this research is to develop automated image analysis tools to detect both treatment field shape errors and patient anatomy placement errors with an EPID. A moments method has been developed to align treatment field images to compensate for lack of repositioning precision of the image detector. A figure of merit has also been established to verify the shape and rotation of the treatment fields. Following proper alignment of treatment field boundaries, a cross-correlation method has been developed to detect shifts of the patient's anatomy relative to the treatment field boundary. Phantom studies showed that the moments method aligned the radiation fields to within 0.5mm of translation and 0.5$\sp\circ$ of rotation and that the cross-correlation method aligned anatomical structures inside the radiation field to within 1 mm of translation and 1$\sp\circ$ of rotation. A new procedure of generating and using digitally reconstructed radiographs (DRRs) at megavoltage energies as reference images was also investigated. The procedure allowed a direct comparison between a designed treatment portal and the actual patient setup positions detected by an EPID. Phantom studies confirmed the feasibility of the methodology. Both the moments method and the cross-correlation technique were implemented within an experimental radiotherapy picture archival and communication system (RT-PACS) and were used clinically to evaluate the setup variability of two groups of cancer patients treated with and without an alpha-cradle immobilization aid. The tools developed in this project have proven to be very effective and have played an important role in detecting patient alignment errors and field-shape errors in treatment fields formed by a multileaf collimator (MLC). ^

Clathrin heavy chain plays multiple roles in polarizing the Drosophila oocyte downstream of Bic-D

Bicaudal-D (Bic-D), Egalitarian (Egl), microtubules and their motors form a transport machinery that localizes a remarkable diversity of mRNAs to specific cellular regions during oogenesis and embryogenesis. Bic-D family proteins also promote dynein-dependent transport of Golgi vesicles, lipid droplets, synaptic vesicles and nuclei. However, the transport of these different cargoes is still poorly understood. We searched for novel proteins that either mediate Bic-Ddependent transport processes or are transported by them. Clathrin heavy chain (Chc) co-immunopurifies with Bic-D in embryos and ovaries, and a fraction of Chc colocalizes with Bic-D. Both proteins control posterior patterning of the Drosophila oocyte and endocytosis. Although the role of Chc in endocytosis is well established, our results show that Bic-D is also needed for the elevated endocytic activity at the posterior of the oocyte. Apart fromaffecting endocytosis indirectly by its role in osk mRNA localization, Bic-D is also required to transport Chc mRNA into the oocyte and for transport and proper localization of Chc protein to the oocyte cortex, pointing to an additional,more direct role of Bic-D in the endocytic pathway. Furthermore, similar to Bic-D, Chc also contributes to proper localization of osk mRNA and to oocyte growth. However, in contrast to other endocytic components and factors of the endocytic recycling pathway, such as Rabenosyn-5 (Rbsn-5) and Rab11, Chc is needed during early stages of oogenesis (from stage 6 onwards) to localize oskmRNA correctly.Moreover,we also uncovered a novel, presumably endocytosis-independent, role of Chc in the establishment of microtubule polarity in stage 6 oocytes.

Scaling relations between trabecular bone volume fraction and microstructure at different skeletal sites

In this study, we investigated the scaling relations between trabecular bone volume fraction (BV/TV) and parameters of the trabecular microstructure at different skeletal sites. Cylindrical bone samples with a diameter of 8mm were harvested from different skeletal sites of 154 human donors in vitro: 87 from the distal radius, 59/69 from the thoracic/lumbar spine, 51 from the femoral neck, and 83 from the greater trochanter. μCT images were obtained with an isotropic spatial resolution of 26μm. BV/TV and trabecular microstructure parameters (TbN, TbTh, TbSp, scaling indices (< > and σ of α and αz), and Minkowski Functionals (Surface, Curvature, Euler)) were computed for each sample. The regression coefficient β was determined for each skeletal site as the slope of a linear fit in the double-logarithmic representations of the correlations of BV/TV versus the respective microstructure parameter. Statistically significant correlation coefficients ranging from r=0.36 to r=0.97 were observed for BV/TV versus microstructure parameters, except for Curvature and Euler. The regression coefficients β were 0.19 to 0.23 (TbN), 0.21 to 0.30 (TbTh), −0.28 to −0.24 (TbSp), 0.58 to 0.71 (Surface) and 0.12 to 0.16 (<α>), 0.07 to 0.11 (<αz>), −0.44 to −0.30 (σ(α)), and −0.39 to −0.14 (σ(αz)) at the different skeletal sites. The 95% confidence intervals of β overlapped for almost all microstructure parameters at the different skeletal sites. The scaling relations were independent of vertebral fracture status and similar for subjects aged 60–69, 70–79, and >79years. In conclusion, the bone volume fraction–microstructure scaling relations showed a rather universal character.

C-reactive protein predicts mortality in patients referred for coronary angiography and symptoms of heart failure with preserved ejection fraction

AIMS Heart failure with preserved ejection fraction (HFpEF) has a different pathophysiological background compared to heart failure with reduced ejection fraction (HFrEF). Tailored risk prediction in this separate heart failure group with a high mortality rate is of major importance. Inflammation may play an important role in the pathogenesis of HFpEF because of its significant contribution to myocardial fibrosis. We therefore aimed to assess the predictive value of C-reactive protein (CRP) in patients with HFpEF. METHODS AND RESULTS Plasma levels of CRP were determined in 459 patients with HFpEF in the LUdwigshafen Risk and Cardiovascular Health (LURIC) study using a high-sensitivity assay. During a median follow-up of 9.7 years 40% of these patients died. CRP predicted all-cause mortality with an adjusted hazard ratio (HR) of 1.20 [95% confidence interval (CI) 1.02-1.40, P = 0.018] and cardiovascular mortality with a HR of 1.32 (95% CI 1.08-1.62, P = 0.005) per increase of one standard deviation. CRP was a significantly stronger mortality predictor in HFpEF patients than in a control group of 522 HFrEF patients (for interaction, P = 0.015). Furthermore, CRP added prognostic value to N-terminal pro B-type natriuretic peptide (Nt-proBNP): the lowest 5-year mortality rate of 6.8% was observed for patients in the lowest tertile of Nt-proBNP as well as CRP. The mortality risk peaked in the group combining the highest values of Nt-proBNP and CRP with a 5-year rate of 36.5%. CONCLUSION It was found that CRP was an independent and strong predictor of mortality in HFpEF. This observation may reflect immunological processes with an adverse impact on the course of HFpEF.

Benefaction proper and surrogation

The semantic role of beneficiary is usually conceptualized in very general terms, typically without an intensive definition of what can constitute a benefit in the particular construction under study. Among those accounts that have proposed to discuss benefaction as related to the notion(s) of surrogation, substituting, and/or deputing, Kittilä (2005) proposes a distinction between recipients, beneficiaries, and recipient-beneficiaries based on the binary features [reception] and [substitutive benefaction]; the recipient includes only reception (and the beneficiary only substitutive benefaction), whereas both features are relevant with recipient-beneficiaries. This paper proposes an alternative account (i) by defining benefaction proper in terms of a prototype related to possession (and thereby to reception) and a periphery, and (ii) by defining surrogation as a separate notion that can, but need not, coalesce with benefaction proper. Thus, the beneficiaries’ condition improves because they are relieved from having to carry out a given action themselves.

Bone Volume Fraction and Fabric Anisotropy Are Better Determinants of Trabecular Bone Stiffness than Other Morphological Variables

As our population ages, more individuals suffer from osteoporosis. This disease leads to impaired trabecular architecture and increased fracture risk. It is essential to understand how morphological and mechanical properties of the cancellous bone are related. Morphologyelasticity relationships based on bone volume fraction (BV/TV) and fabric anisotropy explain up to 98% of the variation in elastic properties. Yet, other morphological variables such as individual trabeculae segmentation (ITS) and trabecular bone score (TBS) could improve the stiffness predictions. A total of 743 micro-computed tomography reconstructions of cubic trabecular bone samples extracted from femur, radius, vertebrae and iliac crest were analysed. Their morphology was assessed via 25 variables and their stiffness tensor (inline image) was computed from six independent load cases using micro finite element analyses. Variance inflation factors were calculated to evaluate collinearity between morphological variables and decide upon their inclusion in morphology-elasticity relationships. The statistically admissible morphological variables were included in a multi-linear regression modelling the dependent variable inline image. The contribution of each independent variable was evaluated (ANOVA). Our results show that BV/TV is the best determinant of inline image (inline image=0.889), especially in combination with fabric (inline image=0.968). Including the other independent predictors hardly affected the amount of variance explained by the model (inline image=0.975). Across all anatomical sites, BV/TV explained 87% of the variance of the bone elastic properties. Fabric further described 10% of the bone stiffness, but the improvement in variance explanation by adding other independent factors was marginal (<1%). These findings confirm that BV/TV and fabric are the best determinants of trabecular bone stiffness and show, against common belief, that other morphological variables do not bring any further contribution. These overall conclusions remain to be confirmed for specific bone diseases and post-elastic properties.

Proper paraffin slide storage is crucial for translational research projects involving immunohistochemistry stains.

The use of paraffin slides and tissue microarrays (TMA) is indispensable for translational research. However, storage of paraffin slides over time has a substantial detrimental effect on the quality and reliability of immunohistochemistry stains. Particularly affected by this issue may be any collaborative efforts where paraffin slides or TMAs are shipped to central laboratories and then 'biobanked' for some time until use. This article summarizes some of the key issues affecting loss of antigenicity on paraffin slides and some simple storage solutions to help maintain high quality immunohistochemistry results when paraffin slides must be stored for a certain time prior to use.

Von Willebrand Factor Improves Risk Prediction in Addition to N-Terminal Pro-B-type Natriuretic Peptide in Patients Referred to Coronary Angiography and Signs and Symptoms of Heart Failure and Preserved Ejection Fraction.

BACKGROUND Heart failure with preserved ejection fraction (HFpEF) represents a growing health burden associated with substantial mortality and morbidity. Consequently, risk prediction is of highest importance. Endothelial dysfunction has been recently shown to play an important role in the complex pathophysiology of HFpEF. We therefore aimed to assess von Willebrand factor (vWF), a marker of endothelial damage, as potential biomarker for risk assessment in patients with HFpEF. METHODS AND RESULTS Concentrations of vWF were assessed in 457 patients with HFpEF enrolled as part of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. All-cause mortality was observed in 40% of patients during a median follow-up time of 9.7 years. vWF significantly predicted mortality with a hazard ratio (HR) per increase of 1 SD of 1.45 (95% confidence interval, 1.26-1.68; P<0.001) and remained a significant predictor after adjustment for age, sex, body mass index, N-terminal pro-B-type natriuretic peptide (NT-proBNP), renal function, and frequent HFpEF-related comorbidities (adjusted HR per 1 SD, 1.22; 95% confidence interval, 1.05-1.42; P=0.001). Most notably, vWF showed additional prognostic value beyond that achievable with NT-proBNP indicated by improvements in C-Statistic (vWF×NT-proBNP: 0.65 versus NT-proBNP: 0.63; P for comparison, 0.004) and category-free net reclassification index (37.6%; P<0.001). CONCLUSIONS vWF is an independent predictor of long-term outcome in patients with HFpEF, which is in line with endothelial dysfunction as potential mediator in the pathophysiology of HFpEF. In particular, combined assessment of vWF and NT-proBNP improved risk prediction in this vulnerable group of patients.

Impact of mitral regurgitation on clinical outcomes of patients with low-ejection fraction, low-gradient severe aortic stenosis undergoing transcatheter aortic valve implantation.

BACKGROUND Up to 1 in 6 patients undergoing transcatheter aortic valve implantation (TAVI) present with low-ejection fraction, low-gradient (LEF-LG) severe aortic stenosis and concomitant relevant mitral regurgitation (MR) is present in 30% to 55% of these patients. The effect of MR on clinical outcomes of LEF-LG patients undergoing TAVI is unknown. METHODS AND RESULTS Of 606 consecutive patients undergoing TAVI, 113 (18.7%) patients with LEF-LG severe aortic stenosis (mean gradient ≤40 mm Hg, aortic valve area <1.0 cm(2), left ventricular ejection fraction <50%) were analyzed. LEF-LG patients were dichotomized into ≤mild MR (n=52) and ≥moderate MR (n=61). Primary end point was all-cause mortality at 1 year. No differences in mortality were observed at 30 days (P=0.76). At 1 year, LEF-LG patients with ≥moderate MR had an adjusted 3-fold higher rate of all-cause mortality (11.5% versus 38.1%; adjusted hazard ratio, 3.27 [95% confidence interval, 1.31-8.15]; P=0.011), as compared with LEF-LG patients with ≤mild MR. Mortality was mainly driven by cardiac death (adjusted hazard ratio, 4.62; P=0.005). As compared with LEF-LG patients with ≥moderate MR assigned to medical therapy, LEF-LG patients with ≥moderate MR undergoing TAVI had significantly lower all-cause mortality (hazard ratio, 0.38; 95% confidence interval, 0.019-0.75) at 1 year. CONCLUSIONS Moderate or severe MR is a strong independent predictor of late mortality in LEF-LG patients undergoing TAVI. However, LEF-LG patients assigned to medical therapy have a dismal prognosis independent of MR severity suggesting that TAVI should not be withheld from symptomatic patients with LEF-LG severe aortic stenosis even in the presence of moderate or severe MR.

Midrash milim : an English and Hebrew lexicon to which is added a selection of proper names occuring in scripture and in the Rabbinical writings

by Michael Josephs

The calculation of Afρ and mass loss rate for comets

Ab initio calculations of Afρ are presented using Mie scattering theory and a Direct Simulation Monte Carlo (DSMC) dust outflow model in support of the Rosetta mission and its target 67P/Churyumov-Gerasimenko (CG). These calculations are performed for particle sizes ranging from 0.010 μm to 1.0 cm. The present status of our knowledge of various differential particle size distributions is reviewed and a variety of particle size distributions is used to explore their effect on Afρ , and the dust mass production View the MathML sourcem˙. A new simple two parameter particle size distribution that curtails the effect of particles below 1 μm is developed. The contributions of all particle sizes are summed to get a resulting overall Afρ. The resultant Afρ could not easily be predicted a priori and turned out to be considerably more constraining regarding the mass loss rate than expected. It is found that a proper calculation of Afρ combined with a good Afρ measurement can constrain the dust/gas ratio in the coma of comets as well as other methods presently available. Phase curves of Afρ versus scattering angle are calculated and produce good agreement with observational data. The major conclusions of our calculations are: – The original definition of A in Afρ is problematical and Afρ should be: qsca(n,λ)×p(g)×f×ρqsca(n,λ)×p(g)×f×ρ. Nevertheless, we keep the present nomenclature of Afρ as a measured quantity for an ensemble of coma particles.– The ratio between Afρ and the dust mass loss rate View the MathML sourcem˙ is dominated by the particle size distribution. – For most particle size distributions presently in use, small particles in the range from 0.10 to 1.0 μm contribute a large fraction to Afρ. – Simplifying the calculation of Afρ by considering only large particles and approximating qsca does not represent a realistic model. Mie scattering theory or if necessary, more complex scattering calculations must be used. – For the commonly used particle size distribution, dn/da ∼ a−3.5 to a−4, there is a natural cut off in Afρ contribution for both small and large particles. – The scattering phase function must be taken into account for each particle size; otherwise the contribution of large particles can be over-estimated by a factor of 10. – Using an imaginary index of refraction of i = 0.10 does not produce sufficient backscattering to match observational data. – A mixture of dark particles with i ⩾ 0.10 and brighter silicate particles with i ⩽ 0.04 matches the observed phase curves quite well. – Using current observational constraints, we find the dust/gas mass-production ratio of CG at 1.3 AU is confined to a range of 0.03–0.5 with a reasonably likely value around 0.1.