Can cartilage loss be detected in knee osteoarthritis (OA) patients with 3–6 months' observation using advanced image analysis of 3T MRI?

SummaryPurposePrior investigations of magnetic resonance imaging (MRI) biomarkers of cartilage loss in knee osteoarthritis (OA) suggest that trials of interventions which affect this biomarker with adequate statistical power would require large clinical studies of 1–2 years duration. We hypothesized that smaller, shorter duration, “Proof of Concept” (PoC) studies might be achievable by: (1) selecting a population at high risk of rapid medial tibio-femoral (TF) progression, in conjunction with; (2) high-field MRI (3T), and; (3) using advanced image analysis. The primary outcome was the cartilage thickness in the central medial femur.MethodsMulti-centre, non-randomized, observational cohort study at four sites in the US. Eligible participants were females with knee pain, a body mass index (BMI)≥25kg/m2, symptomatic radiographic evidence of medial TF OA, and varus mal-alignment. The 29 participants had a mean age of 62 years, mean BMI of 36kg/m2, with eight index knees graded as Kellgren–Lawrence (K&L)=2 and 21 as K&L=3. Eligible participants had four MRI scans of one knee: two MRIs (1 week apart) were acquired as a baseline with follow-up MRI at 3 and 6 months. A trained operator, blind to time-point but not subject, manually segmented the cartilage from the Dual Echo Steady State water excitation MR images. Anatomically corresponding regions of interest were identified on each image by using a three-dimensional statistical shape model of the endosteal bone surface, and the cartilage thickness (with areas denuded of cartilage included as having zero thickness – ThCtAB) within each region was calculated. The percentage change from baseline at 3 and 6 months was assessed using a log-scale analysis of variance (ANOVA) model including baseline as a covariate. The primary outcome was the change in cartilage thickness within the aspect of central medial femoral condyle exposed within the meniscal window (w) during articulation, neglecting cartilage edges [nuclear (n)] (nwcMF·ThCtAB), with changes in other regions considered as secondary endpoints.ResultsAnatomical mal-alignment ranged from −1.9° to 6.3°, with mean 0.9°. With one exception, no changes in ThCtAB were detected at the 5% level for any of the regions of interest on the TF joint at 3 or 6 months of follow-up. The change in the primary variable (nwcMF·ThCtAB) from (mean) baseline at 3 months from the log-scale ANOVA model was −2.1% [95% confidence interval (CI) (−4.4%, +0.2%)]. The change over 6 months was 0.0% [95% CI (−2.7%, +2.8%)]. The 95% CI for the change from baseline did not include zero for the cartilage thickness within the meniscal window of the lateral tibia (wLT·ThCtAB) at 6 month follow-up (−1.5%, 95% CI [−2.9, −0.2]), but was not significant at the 5% level after correction for multiple comparisons.ConclusionsThe small inconsistent compartment changes, and the relatively high variabilities in cartilage thickness changes seen over time in this study, provide no additional confidence for a 3- or 6-month PoC study using a patient population selected on the basis of risk for rapid progression with the MRI acquisition and analyses employed

Plausibility functions and exact frequentist inference

In the frequentist program, inferential methods with exact control on error rates are a primary focus. The standard approach, however, is to rely on asymptotic approximations, which may not be suitable. This paper presents a general framework for the construction of exact frequentist procedures based on plausibility functions. It is shown that the plausibility function-based tests and confidence regions have the desired frequentist properties in finite samples---no large-sample justification needed. An extension of the proposed method is also given for problems involving nuisance parameters. Examples demonstrate that the plausibility function-based method is both exact and efficient in a wide variety of problems.Comment: 21 pages, 5 figures, 3 table

Bounds for graph regularity and removal lemmas

We show, for any positive integer k, that there exists a graph in which any equitable partition of its vertices into k parts has at least ck^2/\log^* k pairs of parts which are not \epsilon-regular, where c,\epsilon>0 are absolute constants. This bound is tight up to the constant c and addresses a question of Gowers on the number of irregular pairs in Szemer\'edi's regularity lemma. In order to gain some control over irregular pairs, another regularity lemma, known as the strong regularity lemma, was developed by Alon, Fischer, Krivelevich, and Szegedy. For this lemma, we prove a lower bound of wowzer-type, which is one level higher in the Ackermann hierarchy than the tower function, on the number of parts in the strong regularity lemma, essentially matching the upper bound. On the other hand, for the induced graph removal lemma, the standard application of the strong regularity lemma, we find a different proof which yields a tower-type bound. We also discuss bounds on several related regularity lemmas, including the weak regularity lemma of Frieze and Kannan and the recently established regular approximation theorem. In particular, we show that a weak partition with approximation parameter \epsilon may require as many as 2^{\Omega(\epsilon^{-2})} parts. This is tight up to the implied constant and solves a problem studied by Lov\'asz and Szegedy.Comment: 62 page

The clustering instability of inertial particles spatial distribution in turbulent flows

A theory of clustering of inertial particles advected by a turbulent velocity field caused by an instability of their spatial distribution is suggested. The reason for the clustering instability is a combined effect of the particles inertia and a finite correlation time of the velocity field. The crucial parameter for the clustering instability is a size of the particles. The critical size is estimated for a strong clustering (with a finite fraction of particles in clusters) associated with the growth of the mean absolute value of the particles number density and for a weak clustering associated with the growth of the second and higher moments. A new concept of compressibility of the turbulent diffusion tensor caused by a finite correlation time of an incompressible velocity field is introduced. In this model of the velocity field, the field of Lagrangian trajectories is not divergence-free. A mechanism of saturation of the clustering instability associated with the particles collisions in the clusters is suggested. Applications of the analyzed effects to the dynamics of droplets in the turbulent atmosphere are discussed. An estimated nonlinear level of the saturation of the droplets number density in clouds exceeds by the orders of magnitude their mean number density. The critical size of cloud droplets required for clusters formation is more than $20 \mu$m.Comment: REVTeX 4, 15 pages, 2 figures(included), PRE submitte

Effects of Impurity Content on the Sintering Characteristics of Plasma-Sprayed Zirconia

Yttria-stabilized zirconia powders, containing different levels of SiO2 and Al2O3, have been plasma sprayed onto metallic substrates. The coatings were detached from their substrates and a dilatometer was used to monitor the dimensional changes they exhibited during prolonged heat treatments. It was found that specimens containing higher levels of silica and alumina exhibited higher rates of linear contraction, in both in-plane and through-thickness directions. The in-plane stiffness and the through-thickness thermal conductivity were also measured after different heat treatments and these were found to increase at a greater rate for specimens with higher impurity (silica and alumina) levels. Changes in the pore architecture during heat treatments were studied using Mercury Intrusion Porosimetry (MIP). Fine scale porosity (<_50 nm) was found to be sharply reduced even by relatively short heat treatments. This is correlated with improvements in inter-splat bonding and partial healing of intra-splat microcracks, which are responsible for the observed changes in stiffness and conductivity, as well as the dimensional changes

Data visualization in yield component analysis: an expert study

Even though data visualization is a common analytical tool in numerous disciplines, it has rarely been used in agricultural sciences, particularly in agronomy. In this paper, we discuss a study on employing data visualization to analyze a multiplicative model. This model is often used by agronomists, for example in the so-called yield component analysis. The multiplicative model in agronomy is normally analyzed by statistical or related methods. In practice, unfortunately, usefulness of these methods is limited since they help to answer only a few questions, not allowing for a complex view of the phenomena studied. We believe that data visualization could be used for such complex analysis and presentation of the multiplicative model. To that end, we conducted an expert survey. It showed that visualization methods could indeed be useful for analysis and presentation of the multiplicative model

Atmospheric Heating and Wind Acceleration: Results for Cool Evolved Stars based on Proposed Processes

A chromosphere is a universal attribute of stars of spectral type later than ~F5. Evolved (K and M) giants and supergiants (including the zeta Aurigae binaries) show extended and highly turbulent chromospheres, which develop into slow massive winds. The associated continuous mass loss has a significant impact on stellar evolution, and thence on the chemical evolution of galaxies. Yet despite the fundamental importance of those winds in astrophysics, the question of their origin(s) remains unsolved. What sources heat a chromosphere? What is the role of the chromosphere in the formation of stellar winds? This chapter provides a review of the observational requirements and theoretical approaches for modeling chromospheric heating and the acceleration of winds in single cool, evolved stars and in eclipsing binary stars, including physical models that have recently been proposed. It describes the successes that have been achieved so far by invoking acoustic and MHD waves to provide a physical description of plasma heating and wind acceleration, and discusses the challenges that still remain.Comment: 46 pages, 9 figures, 1 table; modified and unedited manuscript; accepted version to appear in: Giants of Eclipse, eds. E. Griffin and T. Ake (Berlin: Springer

Shopping externalities and retail concentration:Evidence from dutch shopping streets

Why do shops cluster in shopping streets? We argue that retail firms benefit from shopping externalities. We identify these externalities for the main Dutch shopping streets by estimating the effect of footfall – the number of pedestrians that pass by – and the number of shops in the vicinity on store owners’ rental income. We address endogeneity issues by exploiting spatial variation within shopping streets combined with historic long-lagged instruments. Our estimates imply an elasticity of rental income with respect to footfall as well as number of shops in the vicinity of (at least) 0.25. We show that these shopping externalities are unlikely to be internalised. It follows that substantial subsidies to shop owners are welfare improving, seemingly justifying current policies. Finally, we find limited evidence for heterogeneity between retail firms located in shopping streets in their willingness to pay for shopping externalities