The backwards comparability of wrist worn GENEActiv and waist worn ActiGraph accelerometer estimates of sedentary time in children

Objectives: To examine the backward comparability of a range of wrist-worn accelerometer estimates of sedentary time (ST) with ActiGraph 100 count∙min-1 waist ST estimates. Design: Cross-sectional, secondary data analysis Method: One hundred and eight 10-11-year-old children (65 girls) wore an ActiGraph GT3X+ accelerometer (AG) on their waist and a GENEActiv accelerometer (GA) on their non-dominant wrist for seven days. GA ST data were classified using a range of thresholds from 23-56 mg. ST estimates were compared to AG ST 100 count∙min-1 data. Agreement between the AG and GA thresholds was examined using Cronbach’s alpha, intraclass correlation coefficients (ICC), limits of agreement (LOA), Kappa values, percent agreement, mean absolute percent error (MAPE) and equivalency analysis. Results: Mean AG total ST was 492.4 minutes over the measurement period. Kappa values ranged from 0.31-0.39. Percent agreement ranged from 68-69.9%. Cronbach’s alpha values ranged from 0.88-0.93. ICCs ranged from 0.59-0.86. LOA were wide for all comparisons. Only the 34 mg threshold produced estimates that were equivalent at the group level to the AG ST 100 count∙min-1 data though sensitivity and specificity values of ~64% and ~74% respectively were observed. Conclusions: Wrist-based estimates of ST generated using the 34 mg threshold are comparable with those derived from the AG waist mounted 100 count∙min-1 threshold at the group level. The 34 mg threshold could be applied to allow group-level comparisons of ST with evidence generated using the ActiGraph 100 count∙min-1 method though it is important to consider the observed sensitivity and specificity results when interpreting findings

Global and mitosis-specific interobserver variation in mitotic count scoring and implications for malignant melanoma staging

AIMS Staging is the gold standard for predicting malignant melanoma outcome but changes in its criteria over time indicate ongoing evolution. One notable recent change from the 8 edition of the AJCC staging manual was removal of mitotic count. We explore the extent that this feature is limited by interobserver error in order to find ways to improve its fitness for use should it be revisited in future staging versions. METHODS AND RESULTS In a cohort of 476 patients with melanoma ≤ 1.0 mm, a mitotic count of 0 vs 1 was significant for metastasis-free survival, but not melanoma-specific or overall survival. In 10 melanomas that were 0.9 to 1.0 mm thick, the mitotic count intra-class correlation coefficient for histopathologists was 0.58 (moderate agreement). Uniquely, we also assessed agreement for specific putative mitotic figures, identifying precise reasons why specific mitotic figures qualified for scoring or elimination. A kappa score was 0.54 (moderate agreement). We also gathered data on other staging features. Breslow thickness had an intraclass correlation coefficient of 0.41 (moderate agreement) and there was a systematic difference between histopathologists across cases (p = 0.04). Every case had a range that crossed the AJCC8 0.8 mm pT1a/pT1b staging boundary. Ulceration was only identified in 2 out the 10 cases. For ulceration, kappa agreement score was 0.31 (fair). CONCLUSION This study supports the removal of mitotic count from staging but shows that its scoring is substantially affected by interobserver variation, suggesting that more prescriptive guidelines might have a beneficial impact on its prognostic value

QSAR studies on Withanolide analogs for anticancer activity

Withanolides are a group of pharmacologically active compounds present in most prodigal amounts in roots and leaves of Withania somnifera (Indian ginseng), one of the most important medicinal plants of Indian systems of medicine. Withanolides are basically steroidal lactones (highly oxygenated C-28 phytochemicals) and similar to ginsenosides activity. Some of the withanolides that have been reported possess immunomodulatory, and anticancer activities. In the present investigation, a quantitative structure activity relationship (QSAR) model based on forward stepwise multiple linear regression (MLR) has been developed against the MCF7, MCF7/BUS, and SK-Br-3 human solid tumor breast cancer cell lines. Relationship correlation coefficient (r2) and cross validation correlation coefficient (r2CV) of QSAR model were 0.77 and 0.73 for MCF7, 0.91 and 0.85 for MCF7/BUS, 0.93 and 0.90 for SK-Br-3 respectively. Developed QSAR model was also evaluated for prediction accuracy through internal, external and randomization validation methods. The QSAR study indicates that chemical descriptors viz., atom count (all atoms), connectivity index (order 2, standard), for MCF7, Connectivity Index (order 0, standard), Dipole Vector X (debye), Molar Refractivity, Shape Index (basic kappa, order 2) for SK-Br-3 and Atom Count (all atoms), Dielectric Energy (kcal/mole), Total Energy (Hartree), Heat of Formation (kcal/mole) for MCF7/BUS are correlate well with the breast cancer activity, Moreover, on the basis of screening for oral bioavailability, in silico ADME and toxicity risk assessment, we concluded that compounds W3, W4, W8 have markedly higher anticancer activity compared to control. These results can offer useful references for directing the molecular design of lead compound(s) based on withanolide or analogous template with improved activity

Comparison of Varying Tissue Freezing Methods on Murine Colonic Tissue

Histology often requires a tissue specimen to be embedded so that it may be sectioned, stained, and mounted on a microscope slide for viewing. One common method of tissue embedding for rapid histology is freezing, since freezing allows tissue to be stored without the need for fixing. Frozen tissue is often embedded in a medium such as Optimal Cutting Temperature (OCT) compound so that it can be sectioned using a cryostat. However, factors such as ice-crystal formation during the freezing process can cause damage to the tissue. As such, the protocol used to freeze the tissue can affect the quality of the slides. The purpose of this project is to compare different freezing methods and examine their strengths and weaknesses when applied to murine colonic tissue. Murine colonic tissue was frozen using two snap-freezing methods, piezoelectric freezing, and two different cold storage methods, each with their own three to four variations. Transverse sections were made in a cryostat, which were mounted on slides and stained using a hematoxylin and eosin (H&E) staining protocol. The sections were then imaged using a light microscope. A blind test was conducted to rate the image quality and inter-rater agreement was calculated using Fleiss’s Kappa. Paraffin embedding obtained the highest score, while OCT embedding inside a -80°C freezer received the second highest score

Inferring source properties of monoenergetic electron precipitation from kappa and Maxwellian moment-voltage relationships

We present two case studies of FAST electrostatic analyzer measurements of both highly nonthermal ($\kappa \lesssim$~2.5) and weakly nonthermal/thermal monoenergetic electron precipitation at $\sim$4000~km, from which we infer the properties of the magnetospheric source distributions via comparison of experimentally determined number density--, current density--, and energy flux--voltage relationships with corresponding theoretical relationships. We also discuss the properties of the two new theoretical number density--voltage relationships that we employ. Moment uncertainties, which are calculated analytically via application of the \citet{Gershman2015} moment uncertainty framework, are used in Monte Carlo simulations to infer ranges of magnetospheric source population densities, temperatures, $\kappa$ values, and altitudes. We identify the most likely ranges of source parameters by requiring that the range of $\kappa$ values inferred from fitting experimental moment-voltage relationships correspond to the range of $\kappa$ values inferred from directly fitting observed electron distributions with two-dimensional kappa distribution functions. Observations in the first case study, which are made over $\sim$78--79$^\circ$ invariant latitude (ILAT) in the Northern Hemisphere and 4.5--5.5 magnetic local time (MLT), are consistent with a magnetospheric source population density $n_m =$~0.7--0.8~cm$^{-3}$, source temperature $T_m \approx$~70~eV, source altitude $h =$~6.4--7.7~$R_E$, and $\kappa =$~2.2--2.8. Observations in the second case study, which are made over 76--79$^\circ$~ILAT in the Southern Hemisphere and $\sim$21~MLT, are consistent with a magnetospheric source population density $n_m =$~0.07--0.09~cm$^{-3}$, source temperature $T_m \approx$~95~eV, source altitude $h \gtrsim$~6~$R_E$, and $\kappa =$~2--6

Increased plasma viscosity as a reason for inappropriate erythropoietin formation

The aim of this study was to examine whether altered plasma viscosity could contribute to the inappropriately low production rate of erythropoietin (EPO) observed in patients suffering from hypergammaglobulinemias associated with multiple myeloma or Waldenström's disease. We found that the EPO formation in response to anemia in these patients was inversely related to plasma viscosity. A similar inverse relationship between plasma viscosity and EPO production was seen in rats in which EPO formation had been stimulated by exchange transfusion and the plasma viscosity of which was thereby altered by using exchange solutions of different composition to alter plasma viscosity and thus whole blood viscosity independently from hematocrit. Raising the gammaglobulin concentration to approximately 40 mg/ml plasma in the rats almost totally blunted the rise in serum EPO levels despite a fall of the hematocrit to 20%. Determination of renal EPO mRNA levels by RNase protection revealed that the reductions in serum EPO levels at higher plasma viscosities were paralleled by reductions in renal EPO mRNA levels. Taken together, our findings suggest that plasma viscosity may be a significant inhibitory modulator of anemia-induced EPO formation. The increased plasma viscosity in patients with hypergammaglobulinemias may therefore contribute to the inappropriate EPO production, which is a major reason for the anemia developing in these patients