Application of Heterogeneity of Treatment-Effects Methods: Exploratory Analyses of a Trial of Exercise-Based Interventions for Knee Osteoarthritis

Objective: To evaluate heterogeneity of treatment effects in a trial of exercise-based interventions for knee osteoarthritis (OA). Methods: Participants (n = 350) were randomized to standard physical therapy (PT; n = 140), internet-based exercise training (IBET; n = 142), or wait list (WL; n = 68) control. We applied qualitative interaction trees (QUINT), a sequential partitioning method, and generalized unbiased interaction detection and estimation (GUIDE), a regression tree approach, to identify subgroups with greater improvements in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 4 months. Predictors included 24 demographic, clinical, and psychosocial characteristics. We conducted internal validation to estimate optimism (bias) in the range of mean outcome differences among arms. Results: Both QUINT and GUIDE indicated that for participants with lower body mass index (BMI), IBET was better than PT (improvements of WOMAC ranged from 6.3 to 9.1 points lower), and for those with higher BMI and a longer duration of knee OA, PT was better than IBET (WOMAC improvement was 6.3 points). In GUIDE analyses comparing PT or IBET to WL, participants not employed had improvements in WOMAC ranging from 1.8 to 6.8 points lower with PT or IBT versus WL. From internal validation, there were large corrections to the mean outcome differences among arms; however, after correction, some differences remained in the clinically meaningful range. Conclusion: Results suggest there may be subgroups who experience greater improvement in symptoms from PT or IBET, and this finding could guide referrals and future trials. However, uncertainty persists for specific treatment-effects size estimates and how they apply beyond this study sample

Solar Intranetwork Magnetic Elements: bipolar flux appearance

The current study aims to quantify characteristic features of bipolar flux appearance of solar intranetwork (IN) magnetic elements. To attack such a problem, we use the Narrow-band Filter Imager (NFI) magnetograms from the Solar Optical Telescope (SOT) on board \emph{Hinode}; these data are from quiet and an enhanced network areas. Cluster emergence of mixed polarities and IN ephemeral regions (ERs) are the most conspicuous forms of bipolar flux appearance within the network. Each of the clusters is characterized by a few well-developed ERs that are partially or fully co-aligned in magnetic axis orientation. On average, the sampled IN ERs have total maximum unsigned flux of several 10^{17} Mx, separation of 3-4 arcsec, and a lifetime of 10-15 minutes. The smallest IN ERs have a maximum unsigned flux of several 10^{16} Mx, separations less than 1 arcsec, and lifetimes as short as 5 minutes. Most IN ERs exhibit a rotation of their magnetic axis of more than 10 degrees during flux emergence. Peculiar flux appearance, e.g., bipole shrinkage followed by growth or the reverse, is not unusual. A few examples show repeated shrinkage-growth or growth-shrinkage, like magnetic floats in the dynamic photosphere. The observed bipolar behavior seems to carry rich information on magneto-convection in the sub-photospheric layer.Comment: 26 pages, 14 figure

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Sample vial inserts: A better approach for sampling heterogeneous slurry samples in the SRS Defense Waste Processing Facility

A convenient and effective new approach for analyzing DWPF samples involves the use of inserts with volumes of 1.5--3 ml placed in the neck of 14 ml sample vials. The inserts have rims that conform to the rim of the vials so that they sit straight and stable in the vial. The DWPF tank sampling system fills the pre-weighed insert rather than the entire vial, so the vial functions only as the insert holder. The shielded cell operator then removes the vial cap and decants the insert containing the sample into a plastic bottle, crucible, etc., for analysis. Inert materials such as Teflon, plastic, and zirconium are used for the insert so it is unnecessary to separate the insert from the sample for most analyses. The key technique advantage of using inserts to take DWPF samples versus filling sample vials is that it provides a convenient and almost foolproof way of obtaining and handling small volumes of slurry samples in a shielded cell without corrupting the sample. Since the insert allows the entire sample to be analyzed, this approach eliminates the errors inherent with subsampling heterogeneous slurries that comprise DWPF samples. Slurry samples can then be analyzed with confidence. Analysis times are dramatically reduced by eliminating the drying and vitrification steps normally used to produce a homogeneous solid sample. Direct dissolution and elemental analysis of slurry samples are achieved in 8 hours or less compared with 40 hours for analysis of vitrified slurry samples. Comparison of samples taken in inserts versus full vials indicate that the insert does not significantly affect sample composition