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Background: Challenges in predicting risk of recurrence for individual patients with meningioma limits appropriate selection of patients who may benefit from adjuvant radiation therapy to delay recurrence. Here, we aimed to develop and validate a combined clinicomolecular predictor of early recurrence for individual patients with meningiomas. Methods: A methylation-based predictor of 5-year recurrence-free-survival (RFS) was developed using DNA-methylation profiles from a training cohort of 228 patients. Model performance was compared to a standard-of-care histological-based model using three independent cohorts (N=54 ;N=140; N=64 patients). Subsequently, a nomogram that integrated the methylome-based predictor with prognostic clinical factors was developed and validated. Results: The methylome-based predictor of 5-year RFS performed favorably compared to a grade-based predictor when tested using the three validation cohorts (ΔAUC=0.10, 95%CI 0.03 – 0.018) and was independently associated with RFS on multivariable Cox regression analysis (HR=3.6, 95%CI 1.8–7.2, P<0.001). A nomogram combining the methylome-predictor with clinical factors demonstrated greater discrimination for recurrence than a nomogram using clinical factors alone (ΔAUC=0.25, 95%CI 0.22–0.27) and resulted in two risk groups with distinct recurrence patterns (HR=7.7, 95%CI 5.3–11.1, P<0.001) and clinical implications. Conclusions: Our validated models provide important novel prognostic information that could be used to individualize decisions regarding post-operative therapeutic interventions in meningioma.
Background: Molecular signatures are being increasing used to classify central nervous system (CNS) tumors with incorporation into World Health Organization (WHO) classifications. A recently published genome-wide DNA methylation-based CNS tumor classifier assisted in diagnostically challenging cases. However its impact on patient care has not been reported, limiting translation to other centres. Methods: All 55 challenging CNS tumour diagnoses over three years underwent DNA methylation profiling. Tumor classification along with copy number variant (CNV) plot results were integrated with histopathological findings to determine final diagnoses and corresponding clinical impact was assessed. Results: After methylation profiling 46/55 (84%) received clinically relevant diagnostic changes, 30 (55%) with a new diagnosis or resolved differential diagnosis and 16 (29%) with clinically important molecular diagnostic or subtyping changes. WHO grade changed in 15 (27%), with two-thirds upgraded. Nine new IDH mutations in gliomas, four new molecular subtypes in medulloblastomas/ependymomas, and three false positive 1p/19q codeletions were identified. Patient care was directly changed by methylation profiling in 7/47 (15%) followed-up cases to avoid unnecessary treatment in three, insufficient treatment in three, and medically assisted death in one. Conclusions: This real-world use of methylation-based CNS tumor classification substantially impacts patient care for diagnostically challenging tumors and also avoids misdiagnosis-related uncessary resource use.
Carbohydrate-rich diets may increase urinary excretion of chromium (Cr) and increase its requirements. This study was conducted to investigate the effect of grain type (barley v. corn) and Cr supplementation on feed intake, feeding behavior and weight gain in dairy calves. Forty-eight neonatal Holstein female calves were assigned randomly to four experimental diets in a 2×2 factorial arrangement. Experimental diets were either barley-based diet (BBD) or corn-based diet (CBD) supplemented with (+Cr) or without (−Cr) Cr as Cr-methionine (0.05 mg/kg of BW0.75). Chromium was provided in milk (from days 3 to 73 of life) during the pre-weaning period and then in pre-warmed water (from day 74 until day 94 of life) after weaning. Meal length tended to increase in calves fed the BBD v. CBD during the pre-weaning period. During the post-weaning period, meal size, inter-meal interval, and eating rate increased concurrently but meal frequency and eating time decreased in the BBD v. CBD. During the pre-weaning period, feed efficiency, BW at weaning, and heart girth increased and non-nutritive oral behaviors tended to decrease with Cr supplementation. Due to increased meal frequency, the starter feed intake but not eating time increased by Cr supplementation during the post-weaning period. Supplementing Cr increased starter feed intake, final BW, average daily gain and heart girth during the overall period. Rumination time increased in BBD+Cr calves due to increases in the frequency and duration of rumination, or decreased rumination bout interval. Overall, the type of grain had no effect on feed intake and growth performance; however, Cr supplementation decreased non-nutritive oral behaviors and increased starter feed intake via increasing the meal frequency and thereby improved growth performance.
Stressful situations may result in serum chromium (Cr) depletion with increased urinary excretion of the mineral and increased Cr requirements. The objective of this study was to investigate the effects of Cr supplementation on growth performance, feeding behavior, blood metabolites and hormones, indicators of oxidative stress and glucose-insulin kinetics of summer-exposed weaned dairy calves. In total, 48 Holstein female calves (63 days of age; 77.0±1.45 kg of BW) were assigned randomly to one of two treatments: (1) a control group with no supplemental Cr (Cr−), and (2) a supplemental Cr group (Cr+) to supply 0.05 mg Cr as Cr-methionine/kg of BW0.75. Chromium was provided in the starter feed and adjusted weekly based on BW over the experimental period. All calves were on experiment for 4 weeks after weaning. The average maximum temperature–humidity index was 76.1 units during the study period, indicating a mild degree of environmental heat load. Results indicated that in summer-exposed dairy calves, increased dietary Cr provision tended to decrease fecal score, tended to change rumination pattern, increased antioxidant capacity by increasing serum concentration of catalase, but had no effects on growth performance, metabolic status or peripheral glucose and insulin metabolism.
Traditionally goats are indeed important in Iran especially for milk and fibers. This country has nearly 5000000 cashmere producing goat, which produce approximately 1500 metric ton of raw cashmere. So research on environmental factors which have effect on cashmere production, is very vital to economy of the country. Raeini breed is the most productive Cashmere goat in Iran. However, There are no detailed descriptions of the effects of nutrition on cashmere characteristics in Raeini goat. There is some debate on the effects of nutrition on cashmere growth. In some studies cashmere growth does not respond to increased feed intake above maintenance. While some reviewers have concluded that nutrition does influence cashmere growth (McGregor, 1998). The objective of this study was to describe the effects of feeding level on the cashmere growth of Raeini female goats at two different ages.
The date palm hopper, Ommatissus lybicus, is a key pest of the date palm, which is expected to be comprised of many allopatric populations. The current study was carried out to determine bacterial endosymbiont diversity in the different populations of this pest. Ten date palm hopper populations were collected from the main date palm growing regions in Iran and an additional four samples from Pakistan, Oman, Egypt and Tunisia for detection of primary and secondary endosymbionts using polymerase chain reaction (PCR) assay with their specific primers. The PCR products were directly sequenced and edited using SeqMan software. The consensus sequences were subjected to a BLAST similarity search. The results revealed the presence of ‘Candidatus Sulcia muelleri’ (primary endosymbiont) and Wolbachia, Arsenophonus and Enterobacter (secondary endosymbionts) in all populations. This assay failed to detect ‘Candidatus Nasuia deltocephalinicola’ and Serratia in these populations. ‘Ca. S. muelleri’ exhibited a 100% infection frequency in populations and Wolbachia, Arsenophonus and Enterobacter demonstrated 100, 93.04 and 97.39% infection frequencies, respectively. The infection rate of Arsenophonus and Enterobacter ranged from 75 to 100% and 62.5 to 100%, respectively, in different populations of the insect. The results demonstrated multiple infections by ‘Ca. Sulcia muelleri’, Wolbachia, Arsenophonus and Enterobacter in the populations and may suggest significant roles for these endosymbionts on date palm hopper population fitness. This study provides an insight to endosymbiont variation in the date palm hopper populations; however, further investigation is needed to examine how these endosymbionts may affect host fitness.
Small perturbation evolution in compressible Poiseuille flow is contrasted against the incompressible case using direct simulations and non-modal linear analysis. The onset of compressibility effects leads to a profound change in the behaviour of pressure and its interaction with the velocity field. Linear analysis shows that the most significant compressibility outcome is the harmonic coupling between pressure and wall-normal velocity perturbations. Oscillations in normal perturbations can lead to periods of negative production causing suppression of perturbation growth. The extent of the influence of compressibility can be characterized in terms of an effective gradient Mach number (
). Analysis shows that
diminishes as the angle of the perturbation increases with respect to the shear plane. Direct numerical simulations show that streamwise perturbations, which would lead to Tollmien–Schlichting instability in the incompressible case, are completely suppressed in the compressible case and experience the highest
. At the other extreme, computations reveal that spanwise perturbations, which experience negligible
, are entirely unaltered from the incompressible case. Perturbation behaviour at intermediate obliqueness angles is established. Moreover, the underlying pressure–velocity interactions are explicated.
Factors which might influence outcome in patients with meningioma are not well-understood. Previous studies have examined associations of laboratory blood values including hemoglobin levels with patient outcomes in cancer. We hypothesized those changes in CBC before tumor resection can be used as one of the prognostic factors for tumor recurrence/progression in meningioma. To address this, we gathered the clinical and pre-operative CBC results for final analysis from 226 patients (64 males and 162 females) who underwent craniotomy for primary meningioma (grades: 157 WHO GI, 59 GII, 10 GIII) at our institution between 2001 and 2015.Individual parameters were analyzed for correlation with progression-free survival. The median recurrence free survival (RFS) was not reached and follow-up ranged 0.3-14 years. Fifty-six patients (25%) had anemia and 30% of the patients showed leukocytosis using standard cut-offs. On univariate analyses, low hemoglobin (Hb) level, as well as high leukocytes (Lkc), neutrophil (Neutro) and monocyte counts correlated with worse RFS. As expected, tumor grade was correlated with RFS. Low Hb level, high Lkc and Neutro counts were all significantly associated with RFS after adjusting for grade. Strikingly, 32% of patients with pre-operative anemia experienced a recurrence at 5 years, compared with only 11% of non-anemic patients. Conclusion: In this exploratory study, we find that pre-operative CBC data, which is readily available, may contain prognostic information relevant to subsequent risk of recurrence or progression in meningioma. While the biological mechanism for these associations is not clear, they represent hypotheses for further investigation.
The Lattice Boltzmann Method (LBM) has established itself as a popular numerical method in computational fluid dynamics. Several advancements have been recently made in LBM, which include multiple-relaxation-time LBM to simulate anisotropic advection-diffusion processes. Because of the importance of LBM simulations for transport problems in subsurface and reactive flows, one needs to study the accuracy and structure preserving properties of numerical solutions under the LBM. The solutions to advective-diffusive systems are known to satisfy maximum principles, comparison principles, the non-negative constraint, and the decay property. In this paper, using several numerical experiments, it will be shown that current single- and multiple-relaxation-time lattice Boltzmann methods fail to preserve these mathematical properties for transient diffusion-type equations. We will also show that these violations may not be removed by simply refining the discretization parameters. More importantly, it will be shown that meeting stability conditions alone does not guarantee the preservation of the aforementioned mathematical principles and physical constraints in the discrete setting. A discussion on the source of these violations and possible approaches to avoid them is included. A condition to guarantee the non-negativity of concentration under LBM in the case of isotropic diffusion is also derived. The impact of this research is twofold. First, the study poses several outstanding research problems, which should guide researchers to develop LBM-based formulations for transport problems that respect important mathematical properties and physical constraints in the discrete setting. This paper can also serve as a good source of benchmark problems for such future research endeavors. Second, this study cautions the practitioners of the LBM for transport problems with the associated numerical deficiencies of the LBM, and provides guidelines for performing predictive simulations of advective-diffusive processes using the LBM.
Atherosclerosis is the underlying cause of cardiovascular disease and stroke. Endothelial cell dysfunctions are early events in atherosclerosis, resulting in the recruitment of circulating monocytes. The immune system can elicit an inflammatory response toward the atherosclerotic lesion, thereby accelerating lesion growth. Risk factors for atherosclerosis include hypertension, smoking, stress perception or low birth weight. As prenatal stress challenge decreases the birth weight and affects the offspring's postnatal immune response, we aimed to investigate whether prenatal stress contributes to the development of atherosclerosis in mice. Syngenic pregnant apolipoprotein E-deficient (apoE−/−) dams were exposed to sound stress on gestation days 12.5 and 14.5. The presence and size of atherosclerotic plaques in the offspring at the age of 15 weeks was evaluated by histomorphology, accompanied by flow cytometric analysis of the frequency and phenotype of monocytes/macrophages and regulatory T (Treg) cells in the blood. Further, cytokine secretion of peripheral blood lymphocytes was analyzed. In response to prenatal stress challenge, an increased frequency of large atherosclerotic plaques was detectable in apoE−/− offspring, which was particularly profound in females. Prenatal stress also resulted in alterations of the offspring's immune response, such as a decreased frequency of Treg cells in blood, alterations of macrophage populations in blood and an increased secretion of inflammatory cytokines. We provide novel evidence that prenatally stressed adult offspring show an increased severity of atherosclerosis. As Treg cells are key players in dampening inflammation, the observed increase in atherosclerosis may be due to the lack of Treg cell frequency. Future interdisciplinary research is urgently required to understand the developmental origin of prenatal stress-induced atherosclerosis. The availability of our model may facilitate and foster such research endeavors.
Calculations are presented of the effective doses
per unit neutron fluence according to the ICRP publications 60 and 103.
Monte Carlo N-Particle (MCNPX) code was used for six geometrical
conditions of irradiation (Anterior-Posterior, Posterior-Anterior,
Left-Lateral, Right-Lateral, Rotation and Isotropic) on Oak Ridge
National Laboratory (ORNL) modified mathematical adult phantoms
for monoenergetic neutrons from 10-9 MeV to 20 MeV. The conversion
coefficients were compared with the results of an analytical phantom
(Medical Internal Radiation Dose (MIRD-5)) and some voxel model
(ICRP/ICRU Reference Voxel Phantom (ICRP/ICRU RVP), HANAKO, TARO
and Visible Human Project (VIPMAN)). From these comparisons, one can
conclude that large discrepancies between data sets appear when
wR and different sizes of the phantoms have been used for calculations.
Furthermore, the differences in applied Monte Carlo codes or simulated
body models could make some discrepancies less than 15%.
An atomistic simulation of H-Pd(100) provided a phase diagram for the c2×2 H overlayer phase. The Embedded Atom Method (EAM) calculated energy of each configuration of atoms and the Metropolis Monte Carlo algorithm equilibrated the structure and generated configurations from which to sample the structure factor for the H overlayer. The procedure provided the expectation of the square of the structure factor modulus, < |S2| >, as a function of temperature at three coverages. The inflection point of the < |S2| > versus T curve estimated the critical temperature for disordering, Tc,, for one value of coverage, θ. The plot of Tc versus θ, the phase boundary for the c2×2 phase, lay about 125 K below the experimentally determined boundary. A comparison of the energies of ordered and disordered phases showed ΔE = 0.016 eV per hydrogen atom. Equating this unrealistically small energy difference to thermal kinetic energy (3/2)kBTc at the critical temperature implies Tc ≈ 100 K. Obtaining – |S2| > values relatively free of noise at such low temperatures required large numbers of Monte Carlo steps. The c2×2 phase is the experimentally determined stable low temperature phase, and was assumed to be the lowest-energy phase possible in this simulation. The very small ΔE indicates that some other ordered phase may be more stable than c2×2 in the EAM model.
We have derived the embedding energy functional and two body potential of the Embedded Atom Method (EAM) using decreasing exponentials for both the electron density and the two body potential. The embedding function was obtained from the equation of state given by Rose et al. Because of the form of the embedding function, the equilibrium lattice constant, cohesive energy, and bulk modulus are automatically satisfied. The two parameters Φe and γ of the two body potential were determined by fitting to shear modulus and the single vacancy formation energy. Contributions of up to the third nearest neighbors were included in the evaluation of the charge density ρ and the two body potential Φ. The stability and anisotropy of each structure were estimated and compared with the available experimental data.
The magnetomechanical damping capacity of cast and thermally sprayed Fe-Cr based alloys has been investigated using free and forced vibration techniques. The coatings were deposited using a vacuum plasma spraying method and the cast alloys were prepared in a high frequency furnace under an argon atmosphere. Three laboratory devices including a torsion pendulum, a resonant bar and a cantilever were used to cover a wide range of frequencies and amplitudes varying between f = 1Hz to 10 kHz, and ε = 10−6 to 10−3. The damping capacity of the plasma sprayed coatings was found to be comparable to that of cast alloys. Appropriate heat treatments improved the damping capacity of both coatings and cast alloys by several times. The variation of the loss factor as function of the vibration amplitude showed a maximum, but versus frequency exhibited a slightly monotonous character. The magnetic domains were observed using the magneto-optical Kerr effect and their modification under heat treatments was associated with different values of the damping capacities.
Crack formation in hard thin films and the influence of nanostructuring on nucleation and propagation of different crack types were studied using TiAlSiN-based multicomponent nitrides. Thin films of about 2 μm thickness were deposited onto tungsten carbide-cobalt substrates using cathodic arc PVD method. By rotation of samples and changing deposition parameters and chemical composition of target materials, various nanostructured thin films were obtained including: nanocomposite films made of nanocrystallites about 10–30 nm, chemically modulated layers with the bilayer thickness at the range of 10 nm, iso-structured TiAlN/TiAlSiN multilayers with variable bilayer thickness, and finally monolithic single layer with columnar structures of different size. Depth sensing nanoindentation was used to measure hardness and modulus of thin films and to activate several failure modes in order to provide an estimation of the fracture toughness and interfacial fracture energies. Morphology of cracks mainly consist of successive microcracks nucleated at the contact edge periodically under stretching tensile stress upon displacement of indenter. These cracks are almost straight, parallel to each other, regularly distributed at the contact site in fine structure films. They appear discontinuous and irregular in coarse columnar monolithic and in multilyers with larger bilayer periods. The annular cracks appear at greater loads due to tensile peaks caused by bending stresses generated from the substrate depression and coating deflection. These can be accompanied by the interface fracture and delamination. The radial cracks emanating from the corner of indenter appear in high stress films and extend to the neighbouring zones of the contact area. In addition to geometrical cracks, nanoscale cracks frequently appear around the contact area leading to the formation of small discontinuities on the load-displacement curves.