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1
Bamieh, B., M. A. Dahleh, and J. B. Pearson. "Minimization of the L/sup infinity /-induced norm for sampled-data systems." IEEE Transactions on Automatic Control 38, no. 5 (May 1993): 23. http://dx.doi.org/10.1109/9.277236.
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Sychev, M. A. "Characterization of homogeneous scalar variational problems solvable for all boundary data." Proceedings of the Royal Society of Edinburgh: Section A Mathematics 130, no. 3 (June 2000): 611–31. http://dx.doi.org/10.1017/s0308210500000330.
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It is known that the condition ‘either ∂L (F) ≠ Ø or there exist υ1,…,υq ∈ Rnsuch thatF ∈ int co {υ1,…,υq} characterizes solvability of the problem with f(·) = 〈F,·〉.We extend this result to the case of lower semicontinuous integrands L : Rn → R.We also show that validity of this condition for all F ∈ Rn is both a necessary and sufficient requirement for solvability of all minimization problems with sufficiently regular Ω and f. Moreover, the assumptions on Ω and f can be completely dropped if L has sufficiently fast growth at infinity.
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Karpińska, M., M. Wlazło, D. Ramjugernath, P. Naidoo, and U. Domańska. "Assessment of certain ionic liquids for separation of binary mixtures based on gamma infinity data measurements." RSC Advances 7, no. 12 (2017): 7092–107. http://dx.doi.org/10.1039/c6ra25208g.
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Limiting activity coefficients for 64 solutes in [BzMIM][NTf2] and [BzMIM][DCA], the gas–liquid partition coefficients, KL, thermodynamic functions and selectivity for hexane/hex-1-ene, cyclohexane/cyclohexene and ethylbenzene/styrene separation were presented.
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Gajic, Dejan, and Claude Warnick. "Quasinormal Modes in Extremal Reissner–Nordström Spacetimes." Communications in Mathematical Physics 385, no. 3 (June 27, 2021): 1395–498. http://dx.doi.org/10.1007/s00220-021-04137-4.
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AbstractWe present a new framework for characterizing quasinormal modes (QNMs) or resonant states for the wave equation on asymptotically flat spacetimes, applied to the setting of extremal Reissner–Nordström black holes. We show that QNMs can be interpreted as honest eigenfunctions of generators of time translations acting on Hilbert spaces of initial data, corresponding to a suitable time slicing. The main difficulty that is present in the asymptotically flat setting, but is absent in the previously studied asymptotically de Sitter or anti de Sitter sub-extremal black hole spacetimes, is that $$L^2$$ L 2 -based Sobolev spaces are not suitable Hilbert space choices. Instead, we consider Hilbert spaces of functions that are additionally Gevrey regular at infinity and at the event horizon. We introduce $$L^2$$ L 2 -based Gevrey estimates for the wave equation that are intimately connected to the existence of conserved quantities along null infinity and the event horizon. We relate this new framework to the traditional interpretation of quasinormal frequencies as poles of the meromorphic continuation of a resolvent operator and obtain new quantitative results in this setting.
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Arifin, Ajib Setyo, and Tomoaki Ohtsuki. "Capacity of Data Collection in Wireless Sensor Networks Based on Mutual Information and MMSE Estimation." ISRN Sensor Networks 2014 (February 17, 2014): 1–9. http://dx.doi.org/10.1155/2014/389451.
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We investigate the properties of data collection in wireless sensor networks, in terms of both capacity and power allocation strategy. We consider a scenario in which a number of sensors observe a target being estimated at fusion center (FC) using minimum mean-square error (MMSE) estimator. Based on the relationship between mutual information and MMSE (I-MMSE), the capacity of data collection in coherent and orthogonal multiple access channel (MAC) models is derived. Considering power constraint, the capacity is derived under two scenarios: equal power allocation and optimal power allocation of both models. We provide the upper bound of capacity as a benchmark. In particular, we show that the capacity of data collection scales as Θ((1/2)log(1+L)) when the number of sensors L grows to infinity. We show through simulation results that for both coherent and orthogonal MAC models, the capacity of the optimal power is larger than that of the equal power. We also show that the capacity of coherent MAC is larger than that of orthogonal MAC, particularly when the number of sensors L is large and the total power P is fixed.
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Jamali, A., and F. A. Castro. "TOPOLOGICAL 3D ELEVATION DATA INTERPOLATION OF ASTER GDEM BASED ON CONTINUOUS DEFORMATION." ISPRS - International Archives of the Photogrammetry, Remote Sensing and Spatial Information Sciences XLII-4/W10 (September 12, 2018): 71–77. http://dx.doi.org/10.5194/isprs-archives-xlii-4-w10-71-2018.
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<p><strong>Abstract.</strong> In Geographic Information Science, polynomial methods such as linear estimation and non-polynomial methods including Inverse Distance Weighting and Kriging have been used for elevation data interpolation. In this paper, 3D data interpolation using linear and non-linear homotopy continuation as well as advanced polynomial interpolation methods are researched. Continuous deformations that reconstruct straight lines or algebraic curves between any pair of 3D data are presented. The implemented topological mathematical algorithm for 3D elevation data interpolation is compared to Inverse Distance Weighting and Triangulated Irregular Network (TIN) methods. The presented linear and non-linear mathematical algorithms show better results compared to Inverse Distance Weighting and TIN in terms of Root Mean Square Error and L-infinity.</p>
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LI, DONG, TONG LI, and KUN ZHAO. "ON A HYPERBOLIC–PARABOLIC SYSTEM MODELING CHEMOTAXIS." Mathematical Models and Methods in Applied Sciences 21, no. 08 (August 2011): 1631–50. http://dx.doi.org/10.1142/s0218202511005519.
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We investigate local/global existence, blowup criterion and long-time behavior of classical solutions for a hyperbolic–parabolic system derived from the Keller–Segel model describing chemotaxis. It is shown that local smooth solution blows up if and only if the accumulation of the L∞ norm of the solution reaches infinity within the lifespan. Our blowup criteria are consistent with the chemotaxis phenomenon that the movement of cells (bacteria) is driven by the gradient of the chemical concentration. Furthermore, we study the long-time dynamics when the initial data is sufficiently close to a constant positive steady state. By using a new Fourier method adapted to the linear flow, it is shown that the smooth solution exists for all time and converges exponentially to the constant steady state with a frequency-dependent decay rate as time goes to infinity.
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Chiarello, Felisia Angela, and Paola Goatin. "Global entropy weak solutions for general non-local traffic flow models with anisotropic kernel." ESAIM: Mathematical Modelling and Numerical Analysis 52, no. 1 (January 2018): 163–80. http://dx.doi.org/10.1051/m2an/2017066.
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We prove the well-posedness of entropy weak solutions for a class of scalar conservation laws with non-local flux arising in traffic modeling. We approximate the problem by a Lax-Friedrichs scheme and we provide L∞ and BV estimates for the sequence of approximate solutions. Stability with respect to the initial data is obtained from the entropy condition through the doubling of variable technique. The limit model as the kernel support tends to infinity is also studied.
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Hoang, Luan T., and Thinh T. Kieu. "Interior Estimates for Generalized Forchheimer Flows of Slightly Compressible Fluids." Advanced Nonlinear Studies 17, no. 4 (October 1, 2017): 739–67. http://dx.doi.org/10.1515/ans-2016-6027.
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AbstractThe generalized Forchheimer flows are studied for slightly compressible fluids in porous media with time-dependent Dirichlet boundary data for the pressure. No restrictions are imposed on the degree of the Forchheimer polynomial. We derive, for all time, the interior {L^{\infty}}-estimates for the pressure, its gradient and time derivative, and the interior {L^{2}}-estimates for its Hessian. The De Giorgi and Ladyzhenskaya–Uraltseva iteration techniques are used taking into account the special structures of the equations for both pressure and its gradient. These are combined with the uniform Gronwall-type bounds in establishing the asymptotic estimates when time tends to infinity.
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Sulttan, Mohammed. "Impact of using Infinity-Norm with Initial Radius on Performance and Complexity of SD Algorithm in MIMO systems." INTERNATIONAL JOURNAL OF COMPUTERS & TECHNOLOGY 15, no. 6 (April 20, 2016): 6857–64. http://dx.doi.org/10.24297/ijct.v15i6.1614.
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 In recent years, the iterative decoding techniques have played a role in improving the performance (e.g., bit error rate) and reducing the complexity of various digital communication systems. Techniques of Multiple-Input Multiple-Output (MIMO) are the main technology to enhance and achieve high-speed, high data rates, improved reliability and coverage in wireless communications. The modern wireless communications require a low complexity system for detection, since a high CPU processing involves more energy consumption and thus less flexibility in mobility terms. The sphere decoding (SD) technique proposed to solve this problem, such as an efficient algorithm. The norm-2 or l^2-norm (Euclidean metric) considered as a traditional norm that is used to achieve the tree traversal stage in SD algorithm. This work is divided into two parts; Firstly, we propose to using Infinity-Norm or l^∞-norm instead l^2-norm to decreases the hardware complexity of SD with a loss of performance is negligible, the simulation results show that the proposed l^∞-norm SD needs 14.5% to 5.9% fewer complexities than l^2-norm SD. Secondly, we are investigating the impact of choosing initial radius on the performance and complexity of SD algorithm, we can conclude from the simulation results, that gain a better performance requires increasing in the initial radius of an SD algorithm from d1 (γ =2) to d3 (γ =8), and this mean addition more complexity due to the tradeoff  between performance and complexity.    In recent years, the iterative decoding techniques have played a role in improving the performance (e.g., bit error rate) and reducing the complexity of various digital communication systems. Techniques of Multiple-Input Multiple-Output (MIMO) are the main technology to enhance and achieve high-speed, high data rates, improved reliability and coverage in wireless communications. The modern wireless communications require a low complexity system for detection, since a high CPU processing involves more energy consumption and thus less flexibility in mobility terms. The sphere decoding (SD) technique proposed to solve this problem, such as an efficient algorithm. The norm-2 or -norm (Euclidean metric) considered as a traditional norm that is used to achieve the tree traversal stage in SD algorithm. This work is divided into two parts; Firstly, we propose to using Infinity-Norm or -norm instead -norm to decreases the hardware complexity of SD with a loss of performance is negligible, the simulation results show that the proposed -norm SD needs 14.5% to 5.9% fewer complexities than -norm SD. Secondly, we are investigating the impact of choosing initial radius on the performance and complexity of SD algorithm, we can conclude from the simulation results, that gain a better performance require increasing in the initial radius of an SD algorithm from d1 ( =2) to d3 ( =8), and this mean addition more complexity due to the tradeoff between performance and complexity.
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Pfiffner, M., V. Gotta, E. Berger-Olah, M. Pfister, and P. Vonbach. "P78 Pharmacokinetics of intravenous and intranasal nalbuphine in infants." Archives of Disease in Childhood 104, no. 6 (May 17, 2019): e49.2-e49. http://dx.doi.org/10.1136/archdischild-2019-esdppp.116.
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BackgroundNalbuphine is a mixed agonist-antagonist opioid analgesic agent frequently used in paediatrics, and licensed for parenteral use only. Intranasal delivery could be a safe, effective and non-invasive alternative, especially in infants in the acute setting. However, pharmacokinetic (PK) data for this route of administration is completely lacking. The aim of this study was to assess PK of nalbuphine in infants 1–3 months after single intravenous (0.05 mg/kg) and intranasal (0.1 mg/kg) application, respectively.MethodsWe conducted a prospective, single centre, open-label pharmacokinetic study in infants 1–3 months undergoing sepsis workup in the emergency unit. Included infants received alternating nalbuphine as 0.05 mg/kg intravenous bolus or as 0.1 mg/kg intranasal spray. PK samples were taken at 3 pre-defined time points (15, 30 and max. 240 min post-dose before discharge). Area under the concentration-time curve (AUC0-Tlast, and AUC0-infinity for i.v.) was calculated using noncompartmental analysis and was compared between groups using Wilcoxon test. Further parameters derived included maximum concentration (Cmax), time of maximum concentration (Tmax for i.n.) and terminal half-life (t1/2).ResultsA total of 31 patients were included in the analysis. Median age was 55 days [interquartile range 38–63] in the intranasal (N=20) and 42 [37–76] days in the iv group (N=11). Median AUC0-Tlast was 7.6 (5.4–10.4) mcg*h/L following intranasal versus 7.9 (6.0–14.7) mcg*h/L for iv administration (p=0.46). AUC0-Tlast (i.v.) covered 80 [68–83]% of AUC0-infinity. Median Cmax was 4.5 [3.5–5.6] mcg/L (i.n.) versus 6.5 [5.3–15.9] mcg/L (i.v.) (p=0.014), t1/22.4 [1.3–2.8] h (i.n.) versus 1.3 [1.1–1.5] h (i.v.) (p=0.021). Tmax occurred 37 [32–65] min after intranasal administration.ConclusionThis first PK study of intranasal nalbuphine in infants suggests that 0.1 mg/kg i.n. dosing provides similar exposure as 0.05 mg/kg i.v. in infants in terms of AUC, and hence intranasal bioavailability close to 50%.Disclosure(s)Nothing to disclose
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Sychev, Mikhail A., Giulia Treu, and Giovanni Colombo. "Stable minimizers of functionals of the gradient." Proceedings of the Royal Society of Edinburgh: Section A Mathematics 150, no. 5 (July 5, 2019): 2642–55. http://dx.doi.org/10.1017/prm.2019.38.
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AbstractLet Ω ⊂ ℝn be a bounded Lipschitz domain. Let $L: {\mathbb R}^n\rightarrow \bar {\mathbb R}= {\mathbb R}\cup \{+\infty \}$ be a continuous function with superlinear growth at infinity, and consider the functional $\mathcal {I}(u)=\int \nolimits _\Omega L(Du)$, u ∈ W1,1(Ω). We provide necessary and sufficient conditions on L under which, for all f ∈ W1,1(Ω) such that $\mathcal {I}(f) < +\infty $, the problem of minimizing $\mathcal {I}(u)$ with the boundary condition u|∂Ω = f has a solution which is stable, or – alternatively – is such that all of its solutions are stable. By stability of $\mathcal {I}$ at u we mean that $u_k\rightharpoonup u$ weakly in W1,1(Ω) together with $\mathcal {I}(u_k)\to \mathcal {I}(u)$ imply uk → u strongly in W1,1(Ω). This extends to general boundary data some results obtained by Cellina and Cellina and Zagatti. Furthermore, with respect to the preceding literature on existence results for scalar variational problems, we drop the assumption that the relaxed functional admits a continuous minimizer.
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Tiganov, George, Magda-Ioana Nenciu, Cristian Sorin Danilov, and Victor Nicolae Nita. "Estimates of the Population Parameters and Exploitation Rate of Pontic Shad (Alosa Immaculata Bennett, 1835) in the Romanian Black Sea Coast." “Agriculture for Life, Life for Agriculture” Conference Proceedings 1, no. 1 (July 1, 2018): 162–67. http://dx.doi.org/10.2478/alife-2018-0024.
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Abstract Sex ratio, morphometric characteristics, age and growth for Pontic shad from Romanian Black Sea Coast were examined. A total of 2.133 individuals were caught between March 2012 and September 2013. Female : male sex ratio was 0.62. According to the age reading, distribution varied form II to V year. The von Bertalanffy equation and growth performance index were determined by ESP software in Pontic shad. The asymptotic length (L∞ = L infinity) of Pontic shad generated by the ELEFAN I method, after introducing total length data for the two years of study, was 41.5. The natural mortality instantaneous coefficient (M) of the entire Pontic shad population, calculated according to Pauly’s empirical equation, using the growth parameters of the Von Bertalanffy formula and the mean annual temperature of the two study years of 13°C, recorded the following values: M = 0.585 in 2012 and M = 0.639 in 2013. According with the resultants, it is recommended to perform a sustainable fishing which allows the capture of legal-sized of fish.
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Wang, L. H., M. Schultz, S. Weller, M. L. Smiley, and M. R. Blum. "Pharmacokinetics and safety of multiple-dose valaciclovir in geriatric volunteers with and without concomitant diuretic therapy." Antimicrobial Agents and Chemotherapy 40, no. 1 (January 1996): 80–85. http://dx.doi.org/10.1128/aac.40.1.80.
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A randomized, double-blind study was conducted to evaluate the safety and pharmacokinetics of acyclovir following multiple-dose oral administration of valaciclovir (three times a day for 8 days) in geriatric volunteers (65 to 83 years of age). Pharmacokinetic evaluation was performed for three groups: normotensive subjects given 500-mg doses of valaciclovir (n = 11), normotensive subjects given, 1,000-mg doses of valaciclovir (n = 9), and thiazide diuretic-treated hypertensive subjects given 500-mg doses of valaciclovir (n = 9). Valaciclovir, the l-valyl ester of acylclovir, was rapidly absorbed and converted to acyclovir, with plasma valaciclovir concentrations generally undetectable or < or = 0.4 microgram/ml. The peak concentration of drug in plasma (Cmax) for acyclovir occurred at 1 to 2 h, and the half-life of acyclovir was 3 to 4 h in all three elderly groups. The Cmax and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) values of acyclovir obtained on days 1 and 8 indicated no unexpected accumulation at steady state. The steady-state acyclovir Cmax (4.30 and 5.98 micrograms/ml) and daily AUC0-infinity (44 and 74 h.micrograms/ml) following dosing of valaciclovir (500 and 1,000 mg) three times a day were two to three times greater than those expected after high-dose oral acyclovir treatment (800 mg, five times daily). There were no valaciclovir-related changes or abnormalities in safety parameters and no reports of serious adverse experiences in these elderly volunteers. The plasma acyclovir concentration-time curves for the hypertensive and normotensive (500-mg valaciclovir treatment) elderly groups were almost superimposable, and acyclovir pharmacokinetic parameters for the two groups were not significantly different, indicating that concomitant thiazide diuretics do not alter acyclovir pharmacokinetics following valaciclovir dosing in the elderly. Compared with historical data for younger volunteers (creatinine clearance [CLCR] > 75 ml/min/1.73 m2), the elderly subjects (CLCR = 40 to 65 ml/min/1.73 m2) showed higher (approximately 15 to 20%) mean Cmaxs and higher (approximately 30 to 50%) mean AUC(0-infinity)s of acyclovir (P < 0.01), which were consistent with age-related decreases in CLCR. The increased acyclovir exposure from valaciclovir dosing will permit reduced dosing frequency and may result in improved efficacy in the management of herpesvirus diseases.
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Elsheikh Abdelrahman, Abubaker, Fatima Abbas, and Selma Elsheikh Abdelrahman. "Crystallites Dimensions and Electrical Conductivity of Solid Carbon Pellets (SCPs) from Date Palm Leaves (Phoenix dactylifera L.)." Academic Journal of Research and Scientific Publishing 4, no. 45 (January 5, 2023): 05–21. http://dx.doi.org/10.52132/ajrsp.en.2023.45.1.
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Solid carbon pellets (SCPs) were prepared from self-adhesive properties of date palm leaves (Phoenix dactylifera L.), primary pre-carbonized at low temperature, milled to fine grain, powdered, and pelletized as a grain pellet by applying of (5-21) metric tons of compression load, to carbonization at 1000 ºC. The SCPs produced were analyzed in terms of the volume shrinkage, carbon yield, crystallites dimensions and electrical conductivity of the solid carbon pellets as a function of compression load. The values of the electrical conductivity were further analyzed in terms of percolation theory to estimate the critical density of the SCPs produced. The results show that the volume shrinkage and carbon yield after carbonization were in a range of 54.0-64.8% and 26.98-32.4%, respectively, indicating that the body is physically shrinking to maintain its structural integrity. X-ray diffraction intensity shows that the structures of the SCPs are non-graphitic, and their crystallite dimensions are improved by increasing the compressive load. The d002, Lc and La data were found to obey the linear relation of d002 versus 1/ Lc and 1/ La, as Lc and La approach infinity. The electrical conductivity was varied with the compression load and 19 metric tons is a higher value than the others. The critical density of the SCP obtained from the percolation theory was 0.025 g/cm3.
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Sawetri, Sevi, Subagdja Subagdja, and Dina Muthmainnah. "POPULATION DYNAMICS OF MALAYAN LEAF FISH (Pristolepisgrooti Blkr.) IN RANAU LAKE, SOUTH SUMATRA." Indonesian Fisheries Research Journal 24, no. 2 (December 26, 2018): 125. http://dx.doi.org/10.15578/ifrj.24.2.2018.125-131.
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The Malayan leaf fish or locally named as kepor (Pristolepis grooti) is one of important biotic components in Ranau Lake ecosystems. This study aimed to estimate population dynamic and exploitation rate of kepor in Ranau Lake, South Sumatera. The population parameters are estimated based on length frequency data which were collected in March to October 2013. Growth parameters and fishing mortality rates were calculated using FiSAT software package. The results showed that kepor’s growth was negative allometric, which tended to gain length faster than weight. Kepor population was dominated (42%) by individual length of 10.0 to 11.0 cm. Predicted length infinity (L) was 17.28 cm with high value of growth rates (K) of 1.4 year-1. The natural mortality rate (M) is 2.57 year-1, the fishing mortality rate (F) is 5.36 year-1 and total mortality rate (Z) is 7.93 year-1. The exploitation rate of Malayan leaf fish in Ranau Lake (E = 0.68 year-1) has passed the optimum score.
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Davison, Andrew S., Brendan P. Norman, Hazel Sutherland, Anna M. Milan, James A. Gallagher, Jonathan C. Jarvis, and Lakshminarayan R. Ranganath. "Impact of Nitisinone on the Cerebrospinal Fluid Metabolome of a Murine Model of Alkaptonuria." Metabolites 12, no. 6 (May 25, 2022): 477. http://dx.doi.org/10.3390/metabo12060477.
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Background: Nitisinone-induced hypertyrosinaemia is well documented in Alkaptonuria (AKU), and there is uncertainty over whether it may contribute to a decline in cognitive function and/or mood by altering neurotransmitter metabolism. The aim of this work was to evaluate the impact of nitisinone on the cerebrospinal fluid (CSF) metabolome in a murine model of AKU, with a view to providing additional insight into metabolic changes that occur following treatment with nitisinone. Methods: 17 CSF samples were collected from BALB/c Hgd−/− mice (n = 8, treated with nitisinone—4 mg/L and n = 9, no treatment). Samples were diluted 1:1 with deionised water and analysed using a 1290 Infinity II liquid chromatography system coupled to a 6550 quadrupole time-of-flight mass spectrometry (Agilent, Cheadle, UK). Raw data were processed using a targeted feature extraction algorithm and an established in-house accurate mass retention time database. Matched entities (±10 ppm theoretical accurate mass and ±0.3 min retention time window) were filtered based on their frequency and variability. Experimental groups were compared using a moderated t-test with Benjamini–Hochberg false-discovery rate adjustment. Results: L-Tyrosine, N-acetyl-L-tyrosine, γ-glutamyl-L-tyrosine, p-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)lactic acid were shown to increase in abundance (log2 fold change 2.6–6.9, 3/5 were significant p < 0.05) in the mice that received nitisinone. Several other metabolites of interest were matched, but no significant differences were observed, including the aromatic amino acids phenylalanine and tryptophan, and monoamine metabolites adrenaline, 3-methoxy-4-hydroxyphenylglycol, and octopamine. Conclusions: Evaluation of the CSF metabolome of a murine model of AKU revealed a significant increase in the abundance of a limited number of metabolites following treatment with nitisinone. Further work is required to understand the significance of these findings and the mechanisms by which the altered metabolite abundances occur.
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Charão, Ruy Coimbra, Alessandra Piske, and Ryo Ikehata. "A dissipative logarithmic-Laplacian type of plate equation: Asymptotic profile and decay rates." Discrete & Continuous Dynamical Systems 42, no. 5 (2022): 2215. http://dx.doi.org/10.3934/dcds.2021189.
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<p style='text-indent:20px;'>We introduce a new model of the logarithmic type of wave like plate equation with a nonlocal logarithmic damping mechanism. We consider the Cauchy problem for this new model in <inline-formula><tex-math id="M1">\begin{document}$ {{\bf R}}^{n} $\end{document}</tex-math></inline-formula>, and study the asymptotic profile and optimal decay rates of solutions as <inline-formula><tex-math id="M2">\begin{document}$ t \to \infty $\end{document}</tex-math></inline-formula> in <inline-formula><tex-math id="M3">\begin{document}$ L^{2} $\end{document}</tex-math></inline-formula>-sense. The operator <inline-formula><tex-math id="M4">\begin{document}$ L $\end{document}</tex-math></inline-formula> considered in this paper was first introduced to dissipate the solutions of the wave equation in the paper studied by Charão-Ikehata [<xref ref-type="bibr" rid="b7">7</xref>]. We will discuss the asymptotic property of the solution as time goes to infinity to our Cauchy problem, and in particular, we classify the property of the solutions into three parts from the viewpoint of regularity of the initial data, that is, diffusion-like, wave-like, and both of them.</p>
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Madan, Mina, Tasnim Vira, Emmanouil Rampakakis, Anup Gupta, Anil Khithani, Lyn Balleza, Julie Vaillancourt, Stella Boukas, John Sampalis, and Emidio de Carolis. "A Randomized Trial Assessing the Effectiveness of Ezetimibe in South Asian Canadians with Coronary Artery Disease or Diabetes: The INFINITY Study." Advances in Preventive Medicine 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/103728.
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Background. There is a paucity of data regarding the effectiveness and safety of lipid-lowering treatments among South-Asian patients.Methods. Sixty-four South-Asian Canadians with coronary artery disease or diabetes and persistent hypercholesterolemia on statin therapy, were randomized to ezetimibe 10 mg/day co-administered with statin therapy (EZE + Statin) or doubling their current statin dose (STAT2). Primary outcome was the proportion of patients achieving target LDL-C (<2.0 mmol/L) after 6 weeks. Secondary outcomes included the change in lipid profile and the incidence of treatment-emergent adverse events through 12 weeks. Exploratory markers for vascular inflammation were assessed at baseline and 12 weeks.Results. At 6 weeks, the primary outcome was significantly higher among the EZE + Statin patients (68% versus 36%;P=0.031) with an OR (95% CI) of 3.97 (1.19, 13.18) upon accounting for baseline LDL-C and adjusting for age. At 12 weeks, 76% of EZE + Statin patients achieved target LDL-C compared to 48% (P=0.047) of the STAT2patients (adjusted OR (95% CI) = 3.31 (1.01,10.89)). No significant between-group differences in exploratory markers were observed with the exception of CRP.Conclusions. Patients receiving ezetimibe and statin were more likely to achieve target LDL-C after 6 and 12 weeks compared to patients doubling their statin dose. Ezetimibe/statin combination therapy was well tolerated among this cohort of South-Asian Canadians, without safety concerns.
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Dunbar, Joi, Jylle Nevejans, Charlotte McKee, Kerrie Faia, Jan Jaap van Lier, Peter Pruim, Janet Stegehuis, et al. "Pharmacokinetics and Pharmacodynamics of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, Following Single- and Multiple-Dose Administration in Healthy Subjects and Patients with Advanced Hematologic Malignancies." Blood 120, no. 21 (November 16, 2012): 4853. http://dx.doi.org/10.1182/blood.v120.21.4853.4853.
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Abstract Abstract 4853 Introduction: Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions. PI3K-δ and PI3K-γ isoforms are necessary for adaptive and innate immunity and contribute to the development and maintenance of inflammatory and autoimmune diseases and hematologic malignancies. IPI-145 is a potent inhibitor of PI3K- δ,γ isoforms (Ki = 23 pM and 243 pM, respectively) in clinical development for patients with advanced hematologic malignancies and inflammatory/autoimmune disorders. The pharmacokinetics (PK) and pharmacodynamics (PD) of IPI-145 were evaluated in a Phase 1 clinical study in healthy subjects and are being characterized in patients with advanced hematologic malignancies. Methods: In a healthy subject study, IPI-145 was administered orally as a single dose and as multiple doses once daily (QD) or twice daily (BID) for 14 days. In a Phase 1 oncology study, IPI-145 was administered orally starting at a dose of 8 mg BID. PK and PD markers were evaluated after the first dose and at steady state. PD activity (PI3K inhibition) in whole blood was evaluated using a basophil activation assay which measured reduction in CD63 expression on the surface of basophils following ex vivo stimulation. Results: IPI-145 was well tolerated in healthy subjects at single doses up to 30 mg (highest dose tested) and up to 10 mg total daily dose (highest dose tested; 5 mg BID or 10 mg QD) for 14 days. In healthy subjects, the PK profile of IPI-145 is characterized by rapid absorption (peak plasma concentrations reached within 0.5–1 hour), moderately rapid elimination (half-life 3.5 to 9.5 hours following a single dose and 6.5 to 11.7 hours following repeat dosing) and dose proportional increases in systemic exposure (Cmax and AUC). Minimal accumulation was observed after multiple dose administration (accumulation ratio 1.65–1.83 for BID dosing and 1.54 for QD dosing). Following single oral dose administration, clearance ranged from 6.7 L/h to 11.1 L/h and the volume of distribution ranged from 38.8 L to 147 L. Excretion of unchanged IPI-145 in urine was <2% of the administered dose, indicating minimal renal elimination of parent drug. CD63 expression on the surface of activated CCR3+ basophils was reduced in a dose-dependent manner at all single and multiple dose levels, with a maximum reduction at 1 hour post dose, corresponding to the time of maximum IPI-145 plasma concentrations. Inhibition of basophil activation mirrored the IPI-145 concentration-time profile, with CD63 expression returning to baseline levels as plasma concentrations declined. Administration of 5 mg BID maintained PI3K-δ inhibition (EC50 = 48 ng/mL) throughout the 12 hour dosing interval. Concomitant administration of a high-fat, high-calorie meal decreased Cmax approximately 10%, shifted median Tmaxfrom 1 to 3 hours, and increased overall exposure (AUC) approximately 8–9%. These data suggest IPI-145 may be administered without regard to meals. Emerging data from a Phase 1, dose escalation study in subjects with hematologic malignancies demonstrate rapid drug absorption and dose-proportional PK. As in healthy subjects, maximum inhibition of basophil activation was observed 1 hour post dose. Prior to dose administration at the beginning of Cycle 2 (i.e. after 28 days of BID dosing), CD63 expression was reduced 45% or more relative to the start of treatment. Mean steady-state trough concentrations were maintained above levels sufficient for PI3K-δ inhibition following doses ≥15 mg BID. Early signs of clinical response have been observed. Conclusions: Across both Phase 1 studies, IPI-145 drug absorption was rapid and exposure was proportional to dose. CD63 expression on the surface of activated basophils was reduced in the presence of IPI-145 in both healthy and oncology subjects, an observation consistent with PI3K-δ inhibition. An exposure-response relationship was evident, suggesting a concentration-dependent pharmacological response to IPI-145. Preliminary PK/PD data from the oncology study demonstrate inhibition of PI3K-δ activity and suggest higher doses may increasingly suppress PI3K-γ activity. Dose escalation and PK/PD monitoring are ongoing. Collectively, the data available support the clinical development of IPI-145 as a potential therapeutic in hematologic malignancies and inflammatory diseases. Disclosures: Dunbar: Infinity Pharmaceuticals, Inc.: Employment. Nevejans:Infinity Pharmaceuticals, Inc.: Employment. McKee:Infinity Pharmaceuticals, Inc.: Employment. Faia:Infinity Pharmaceuticals, Inc.: Employment. Zhao:ApoCell: Employment. Kahl:Infinity Pharmaceuticals, Inc.: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding. Patel:Infinity Pharmaceuticals, Inc.: Research Funding. Younes:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; MIllenium: Honoraria; Incyte: Honoraria; Genentech: Research Funding; Infinity Pharmaceuticals, Inc.: Research Funding; Gilead: Research Funding. Flinn:Infinity Pharmaceuticals, Inc.: Research Funding.
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Ben Abdallah, N., F. Méhats, and N. Vauchelet. "DIFFUSIVE TRANSPORT OF PARTIALLY QUANTIZED PARTICLES: EXISTENCE, UNIQUENESS AND LONG-TIME BEHAVIOUR." Proceedings of the Edinburgh Mathematical Society 49, no. 3 (October 2006): 513–49. http://dx.doi.org/10.1017/s0013091504000987.
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AbstractA self-consistent model for charged particles, accounting for quantum confinement, diffusive transport and electrostatic interaction is considered. The electrostatic potential is a solution of a three-dimensional Poisson equation with the particle density as the source term. This density is the product of a two-dimensional surface density and that of a one-dimensional mixed quantum state. The surface density is the solution of a drift–diffusion equation with an effective surface potential deduced from the fully three-dimensional one and which involves the diagonalization of a one-dimensional Schrödinger operator. The overall problem is viewed as a two-dimensional drift–diffusion equation coupled to a Schrödinger–Poisson system. The latter is proven to be well posed by a convex minimization technique. A relative entropy and an a priori $L^2$ estimate provide sufficient bounds to prove existence and uniqueness of a global-in-time solution. In the case of thermodynamic equilibrium boundary data, a unique stationary solution is proven to exist. The relative entropy allows us to prove the convergence of the transient solution towards it as time grows to infinity. Finally, the low-order approximation of the relative entropy is used to prove that this convergence is exponential in time.
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Smith, E. B., F. M. Williams, and C. R. Fisher. "Effects of intrapopulation variability on von Bertalanffy growth parameter estimates from equal mark–recapture intervals." Canadian Journal of Fisheries and Aquatic Sciences 54, no. 9 (September 1, 1997): 2025–32. http://dx.doi.org/10.1139/f97-110.
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The effects of intrapopulation variability on the parameter estimates of the von Bertalanffy growth equation have received discussion in the literature. Here we evaluated the effects of intrapopulation variability, using computer simulations, on four commonly used methods for estimating the von Bertalanffy growth parameters: the Ford-Walford plot, Ricker's method, Bayley's method, and Fabens' method. Intrapopulation variability in growth rates (k) and maximum sizes ( L infinity ) plus initial size distributions and measurement error, were tested for their effects on the accuracy of the parameter estimates using simulated mark-recapture data with equal recapture intervals. Fabens' method and a modified Ford-Walford plot provided the most accurate estimates in all cases, but when intrapopulation variability was large, they performed poorly. With moderate intrapopulation variability, the bias in estimates was small although between-sample variance was quite large. Biased initial size distributions without either small or large size classes cause a magnification of the estimation errors. Without knowledge of the degree of intrapopulation variability in a natural population, large errors of unknown magnitude in parameter estimation can result, and care should be taken when interpreting these estimates. However, if this variability can be quantified, then approximate parameter estimate errors can be obtained.
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DIAS, KEALEY. "Enumerating combinatorial classes of the complex polynomial vector fields in ℂ." Ergodic Theory and Dynamical Systems 33, no. 2 (February 20, 2012): 416–40. http://dx.doi.org/10.1017/s0143385711000952.
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AbstractIn order to understand the parameter space Ξd of monic and centered complex polynomial vector fields in ℂ of degree d, decomposed by the combinatorial classes of the vector fields, it is interesting to know the number of loci in parameter space consisting of vector fields with the same combinatorial data (corresponding to topological classification with fixed separatrices at infinity). This paper answers questions posed by Adam L. Epstein and Tan Lei about the total number of combinatorial classes and the number of combinatorial classes corresponding to loci of a specific (real) dimension q in parameter space, for fixed degree d; these numbers are denoted by cd and cd,q, respectively. These results are extensions of a result by Douady, Estrada, and Sentenac, which shows that the number of combinatorial classes of the structurally stable complex polynomial vector fields in ℂ of degree d is the Catalan number Cd−1. We show that enumerating the combinatorial classes is equivalent to a so-called bracketing problem. Then we analyze the generating functions and find closed-form expressions for cd and cd,q, and we furthermore make an asymptotic analysis of these sequences for d tending to ∞. These results are also applicable to special classes of quadratic and Abelian differentials and singular holomorphic foliations of the plane.
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Stewart, C. F., S. D. Baker, R. L. Heideman, D. Jones, W. R. Crom, and C. B. Pratt. "Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity." Journal of Clinical Oncology 12, no. 9 (September 1994): 1946–54. http://dx.doi.org/10.1200/jco.1994.12.9.1946.
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PURPOSE Topotecan pharmacokinetics and pharmacodynamics were studied following a 72-hour continuous infusion in 20 children with cancer (median age, 8 years; range, 3.5 to 18). METHODS Serial plasma and urine samples were collected during the infusion and for up to 6 hours following the end of infusion. Topotecan (lactone) and total (lactone plus hydroxy acid) concentrations were determined by a sensitive and specific high-performance liquid chromatography (HPLC) assay with fluorescence detection. Using maximum a posteriori-Bayesian modeling, lactone and total plasma concentrations were described separately by a two-compartment model. Hematologic toxicity was expressed as the percent decrease in absolute neutrophil count (ANC) and platelet count. The relation between systemic exposure (SE) and hematologic toxicity was modeled using a sigmoid maximum-effect model. RESULTS Systemic clearance rates for lactone and total topotecan were (mean +/- SD) 18.5 +/- 7.0 and 6.5 +/- 2.4 L/h/m2, respectively. Urinary recovery of total topotecan was (mean +/- SD) 67.5% +/- 25.2% (n = 12 patients). SE (area under the concentration-time curve from zero to infinity [AUC] or steady-state plasma concentration [Cpss]) to either topotecan lactone or total topotecan was significantly correlated to hematologic toxicity (P < .05). Overall, patients with a higher SE to topotecan experienced greater hematologic toxicity. CONCLUSION These data demonstrate a relation between systemic exposure to topotecan and clinical effect (myelosuppression). Moreover, these data provide the basis for development of individualized topotecan administration schedules.
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Gonçalves, Sílvia. "THE MOVING BLOCKS BOOTSTRAP FOR PANEL LINEAR REGRESSION MODELS WITH INDIVIDUAL FIXED EFFECTS." Econometric Theory 27, no. 5 (March 25, 2011): 1048–82. http://dx.doi.org/10.1017/s0266466610000630.
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In this paper we propose a bootstrap method for panel data linear regression models with individual fixed effects. The method consists of applying the standard moving blocks bootstrap of Künsch (1989, Annals of Statistics 17, 1217–1241) and Liu and Singh (1992, in R. LePage & L. Billiard (eds.), Exploring the Limits of the Bootstrap) to the vector containing all the individual observations at each point in time. We show that this bootstrap is robust to serial and cross-sectional dependence of unknown form under the assumption that n (the cross-sectional dimension) is an arbitrary nondecreasing function of T (the time series dimension), where T → ∞, thus allowing for the possibility that both n and T diverge to infinity. The time series dependence is assumed to be weak (of the mixing type), but we allow the cross-sectional dependence to be either strong or weak (including the case where it is absent). Under appropriate conditions, we show that the fixed effects estimator (and also its bootstrap analogue) has a convergence rate that depends on the degree of cross-section dependence in the panel. Despite this, the same studentized test statistics can be computed without reference to the degree of cross-section dependence. Our simulation results show that the moving blocks bootstrap percentile-t intervals have very good coverage properties even when the degree of serial and cross-sectional correlation is large, provided the block size is appropriately chosen.
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Ashton, A. C. L., and A. S. Fokas. "A novel method of solution for the fluid-loaded plate." Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences 465, no. 2112 (September 4, 2009): 3667–85. http://dx.doi.org/10.1098/rspa.2009.0170.
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We study the equations governing a fluid-loaded plate. We first reformulate these equations as a system of two equations, one of which is an explicit non-local equation for the wave height and the velocity potential on the free surface. We then concentrate on the linearized equations and show that the problems formulated either on the full or the half-line can be solved by employing the unified approach to boundary value problems introduced by one of the authors in the late 1990s. The problem on the full line was analysed by Crighton & Oswell (Crighton & Oswell 1991 Phil. Trans. R. Soc. Lond. A 335 , 557–592 (doi:10.1098/rsta.1991.0060)) using a combination of Laplace and Fourier transforms. The new approach avoids the technical difficulty of the a priori assumption that the amplitude of the plate is in L d t 1 ( R + ) and furthermore yields a simpler solution representation that immediately implies that the problem is well-posed. For the problem on the half-line, a similar analysis yields a solution representation, which, however, involves two unknown functions. The main difficulty with the half-line problem is the characterization of these two functions. By employing the so-called global relation, we show that the two functions can be obtained via the solution of a complex-valued integral equation of the convolution type. This equation can be solved in a closed form using the Laplace transform. By prescribing the initial data η 0 to be in H 〈5〉 5 ( R + ), or equivalently four times continuously differentiable with sufficient decay at infinity, we show that the solution depends continuously on the initial data, and, hence, the problem is well-posed.
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Kaul, S., L. N. Igwemezie, D. J. Stewart, S. Z. Fields, M. Kosty, N. Levithan, R. Bukowski, D. Gandara, G. Goss, and P. O'Dwyer. "Pharmacokinetics and bioequivalence of etoposide following intravenous administration of etoposide phosphate and etoposide in patients with solid tumors." Journal of Clinical Oncology 13, no. 11 (November 1995): 2835–41. http://dx.doi.org/10.1200/jco.1995.13.11.2835.
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PURPOSE To assess the pharmacokinetics and bioequivalence of etoposide following intravenous (i.v.) administration of etoposide phosphate (Etopophos; Bristol-Myers Squibb, Princeton, NJ), a prodrug of etoposide, and VePesid (Bristol-Myers Squibb). PATIENTS AND METHODS Forty-nine solid tumor patients were randomized to receive Etopophos or VePesid on day 1 of a day-1,3,5 schedule of treatment. The alternate drug was given on day 3 and repeated on day 5. The dose, 150 mg/m2 of etoposide equivalent, was administered by constant rate infusion over 3.5 hours. The plasma concentrations of etoposide phosphate and etoposide were determined using validated high-performance liquid chromatography (HPLC) assays. Pharmacokinetic parameters were calculated by a noncompartmental method. Etopophos was considered to be bioequivalent to VePesid if the 90% confidence limits for the differences in mean maximum concentration (Cmax) and AUCinf of etoposide were contained within 80% to 125% for the long-transformed data. RESULTS Forty-one patients were assessable for pharmacokinetics and bioequivalence assessment. Following i.v. administration, etoposide phosphate was rapidly and extensively converted to etoposide in systemic circulation, resulting in insufficient data to estimate its pharmacokinetics. The mean bioavailability of etoposide from Etopophos, relative to VePesid, was 103% (90% confidence interval, 99% to 106%) based on Cmax, and 107% (90 confidence interval, 105% to 110%) based on area under the concentration versus time curve from zero to infinity (AUCinf) values. Mean terminal elimination half-life (t1/2), steady-state volume of distribution (Vss), and total systemic clearance (CL) values of etoposide were approximately 7 hours, 7 L/m2, and 17 mL/min/m2 after Etopophos and VePesid treatments, respectively. The main toxicity observed was myelosuppression, characterized by leukopenia and neutropenia. CONCLUSION With respect to plasma levels of etoposide, i.v. Etopophos is bioequivalent to i.v. VePesid.
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Fu, Yingjia, and Ruth J. Williams. "Stability of a Subcritical Fluid Model for Fair Bandwidth Sharing with General File Size Distributions." Stochastic Systems 10, no. 3 (September 2020): 251–73. http://dx.doi.org/10.1287/stsy.2019.0058.
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This work concerns the asymptotic behavior of solutions to a (strictly) subcritical fluid model for a data communication network, where file sizes are generally distributed and the network operates under a fair bandwidth-sharing policy. Here we consider fair bandwidth-sharing policies that are a slight generalization of the [Formula: see text]-fair policies introduced by Mo and Walrand [Mo J, Walrand J (2000) Fair end-to-end window-based congestion control. IEEE/ACM Trans. Networks 8(5):556–567.]. Since the year 2000, it has been a standing problem to prove stability of the data communications network model of Massoulié and Roberts [Massoulié L, Roberts J (2000) Bandwidth sharing and admission control for elastic traffic. Telecommunication Systems 15(1):185–201.], with general file sizes and operating under fair bandwidth sharing policies, when the offered load is less than capacity (subcritical conditions). A crucial step in an approach to this problem is to prove stability of subcritical fluid model solutions. In 2012, Paganini et al. [Paganini F, Tang A, Ferragut A, Andrew LLH (2012) Network stability under alpha fair bandwidth allocation with general file size distribution. IEEE Trans. Automatic Control 57(3):579–591.] introduced a Lyapunov function for this purpose and gave an argument, assuming that fluid model solutions are sufficiently smooth in time and space that they are strong solutions of a partial differential equation and assuming that no fluid level on any route touches zero before all route levels reach zero. The aim of the current paper is to prove stability of the subcritical fluid model without these strong assumptions. Starting with a slight generalization of the Lyapunov function proposed by Paganini et al., assuming that each component of the initial state of a measure-valued fluid model solution, as well as the file size distributions, have no atoms and have finite first moments, we prove absolute continuity in time of the composition of the Lyapunov function with any subcritical fluid model solution and describe the associated density. We use this to prove that the Lyapunov function composed with such a subcritical fluid model solution converges to zero as time goes to infinity. This implies that each component of the measure-valued fluid model solution converges vaguely on [Formula: see text] to the zero measure as time goes to infinity. Under the further assumption that the file size distributions have finite pth moments for some p > 1 and that each component of the initial state of the fluid model solution has finite pth moment, it is proved that the fluid model solution reaches the measure with all components equal to the zero measure in finite time and that the time to reach this zero state has a uniform bound for all fluid model solutions having a uniform bound on the initial total mass and the pth moment of each component of the initial state. In contrast to the analysis of Paganini et al., we do not need their strong smoothness assumptions on fluid model solutions and we rigorously treat the realistic, but singular situation, where the fluid level on some routes becomes zero, whereas other route levels remain positive.
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Aida, Siti Nurul, and Agus Djoko Utomo. "STRIPED CATFISH (Pangasianodon hypophthalmus) (SAUVAGE, 1878) MOVEMENT AND GROWTH IN GAJAH MUNGKUR RESERVOIR, CENTRAL JAVA." Indonesian Fisheries Research Journal 21, no. 1 (June 1, 2015): 27. http://dx.doi.org/10.15578/ifrj.21.1.2015.27-38.
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Movement is an essential mechanism by which mobile animals acquire the resources necessary for the successful completion of their life-cycles. Striped catfish (<em>Pangasianodon hypophthalmus</em>) contributed about 384 tonnes or approximately 40,04% to the total fish production in Gajah Mungkur reservoir. Diversion of Keduang River, one of Gajah Mungkur important inlets, could affect the the movement of this fish. The objective of this research were to analyze data related to the movement patterns and growth of <em>Pangasianodon hypophthalmus</em>. Field works were conducted from March to December 2011 by tagging experiment of large fish with the PDS-Tags and the T Bar-Tags for the small ones. Fish samples used for the experiment were collected from fisherment catch in Gajah Mungkur reservoir. The tag numbers, the release time, and the fish size were noted before releasing the tagged fish were released. Fishermen who caught the tagged fish were advised to report the fish tag number, time of catching, and fish size. The results showed that the <em>Pangasianodon hypophthalmus</em> could moved as far as 200 m to 15 km in 3- 176 days. In the rainy season most of the catfish moved far into the inlet wiroko and Keduang, and some to the inlet Wuryantoro. <em>Pangasianodon hypophthalmusin</em> Gajah Mungkur Reservoir had growth equation of Lt= 99(1-e 0.762(t-0.15)), with the growth coeficient (K)= 0.762/year, t0=0.15 year, infinity length (L”)= 99 cm. Water diversion of Keduang river, one of Gajah Mungkur inlets, did not fully dried the River during dry season and affected striped catfish movement and growth.
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Liu, Qingxia, Huiping Huang, Baohua Xu, Dandan Li, Maobai Liu, Imam H. Shaik, and Xuemei Wu. "Two Innovative Approaches to Optimize Vancomycin Dosing Using Estimated AUC after First Dose: Validation Using Data Generated from Population PK Model Coupled with Monte-Carlo Simulation and Comparison with the First-Order PK Equation Approach." Pharmaceutics 14, no. 5 (May 7, 2022): 1004. http://dx.doi.org/10.3390/pharmaceutics14051004.
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The revised consensus guidelines for optimizing vancomycin doses suggest that maintaining the area under the concentration-time curve to minimal inhibitory concentration ratio (AUC/MIC) of 400–600 mg·h/L is the target pharmacokinetic/pharmacodynamic (PK/PD) index for efficacy. AUC-guided dosing approach uses a first-order pharmacokinetics (PK) equation to estimate AUC using two samples obtained at steady state and one-compartment model, which can cause inaccurate AUC estimation and fail to achieve the effective PK/PD target early in therapy (days 1 and 2). To achieve an efficacy target from the third or fourth dose, two innovative approaches (Method 1 and Method 2) to estimate vancomycin AUC at steady state (AUCSS) using two-compartment model and three or four levels after the first dose are proposed. The feasibility of the proposed methods was evaluated and compared with another published dosing algorithm (Method 3), which uses two samples and a one-compartment approach. Monte Carlo simulation was performed using a well-established population PK model, and concentration-time profiles for virtual patients with various degrees of renal function were generated, with 1000 subjects per group. AUC extrapolated to infinity (AUC0–∞) after the first dose was estimated using the three methods, whereas reference AUC (AUCref) was calculated using the linear-trapezoidal method at steady state after repeated doses. The ratio of AUC0–∞: AUCref and % bias were selected as the indicators to evaluate the accuracy of three methods. Sensitivity analysis was performed to examine the influence of change in each sampling time on the estimated AUC0–∞ using the two proposed approaches. For simulated patients with various creatinine clearance, the mean of AUC0–∞: AUCref obtained from Method 1, Method 2 and Method 3 ranged between 0.98 to 1, 0.96 to 0.99, and 0.44 to 0.69, respectively. The mean bias observed with the three methods was −0.10% to −2.09%, −1.30% to −3.59% and −30.75% to −55.53%, respectively. The largest mean bias observed by changing sampling time while using Method 1 and Method 2 were −4.30% and −10.50%, respectively. Three user-friendly and easy-to-use excel calculators were built based on the two proposed methods. The results showed that our approaches ensured sufficient accuracy and achieved target PK/PD index early and were superior to the published methodologies. Our methodology has the potential to be used for vancomycin dose optimization and can be easily implemented in clinical practice.
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Moreno, Carol, Julio Delgado, John C. Byrd, William L. Zvagelsky, Samuel Suzuki, Emily Hsu, Danelle F. James, and Emili Montserrat. "Changes in Clinical Stage Identify Different Response Categories Among Patients in Iwcll PR: Analysis of CLL Patients on the Resonate Study." Blood 128, no. 22 (December 2, 2016): 4384. http://dx.doi.org/10.1182/blood.v128.22.4384.4384.
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Abstract Background: In CLL/SLL, the iwCLL PR category is heterogeneous and complex to evaluate. Changes in clinical staging (Binet, Rai) have been proposed as a method to evaluate response in CLL (Montserrat, Cancer 1985; iwCLL, Ann Intern Med 1989). Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is indicated by the FDA for the treatment of pts with CLL/SLL and allows for treatment without chemotherapy. Robust improvements in progression-free survival (PFS) and overall survival (OS) among ibr-treated pts in the phase 3 RESONATE trial demonstrated superiority of ibr over ofatumumab (ofa) in heavily pretreated CLL, regardless of prognostic features. As the majority of ibr pts achieved iwCLL PR or PR-L manifested by improved hematologic function and/or disease burden, we analyzed RESONATE pts with PR or PR-L by Binet stage to determine if clinical downstaging captures different, clinically meaningful subgroups among patients in iwCLL PR/PR-L. Methods: Among 391 previously treated CLL pts randomized to receive oral ibr (n=195) or intravenous ofa (n=196), those who achieved a best overall response of PR or PR-L were assessed for Binet Stage at time of first response. Stage A was defined as no anemia or thrombocytopenia and <3/5 sites of involvement (unilateral or bilateral cervical, axillary, and inguinal lymph nodes, liver, spleen); Stage B as no anemia or thrombocytopenia and ≥3/5 involved sites; and Stage C as anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (platelets <100,000/µL) regardless of lymph node/organ site involvement. Binet stage data were considered missing if any one component of the staging criteria was not available. Kaplan-Meier analyses were performed based on Binet Stage at time of first response. Data were analyzed as of the interim analysis (Byrd, N Engl J Med 2014), and p-values are descriptive. Results: A total of 162 (83%) ibr pts and 45 (23%) ofa pts achieved PR/PR-L as best overall response as assessed by investigator; 53% of ibr responders were PR and 46% were PR-L at first response. Baseline characteristics (age, prior therapy, marrow infiltration, unmutated IGHV) were balanced between arms. A majority of PR/PR-L ibr pts were downstaged to Stage A reflecting improvement in lymphadenopathy/organomegaly and/or cytopenias with treatment. At time of first PR/PR-L, the proportion of Stage C pts decreased from 44% (n=72) at baseline to 27% (n=44) for the ibr arm and from 42% (n=19) to 33% (n=15) for the ofa arm. While maintaining PR/PR-L, 48% of ibr-treated and 40% of ofa-treated pts shifted from Stage C to A (or to B/A). The efficacy of ibr over ofa in PR/PR-L pts was similar to that observed in the intent-to-treat population for median PFS (not reached [NR] for ibr vs. 8.48 mo for ofa, P<0.0001). A treatment effect between ibr vs. ofa was also observed for duration of response (DOR) in PR/PR-L pts (NR for ibr vs. 5.52 mo for ofa, P<0.0001). Responders with PR/Stage A showed a longer PFS outcome than responders with PR/Stage C at time of first response to ibr (P=0.0314, Figure). The estimated median PFS for Stage C should be interpreted with caution as it occurred at the tail end of the curve with 2 pts at risk. Within the ofa arm, no difference in PFS between PR/Stage A vs. PR/Stage C was observed, although a limited sample size of responders prohibits robust analysis of this arm. For the ibr arm, both OS (P=0.0281) and DOR (P=0.0431) suggest a trend for improved outcome for PR/Stage A vs. PR/Stage C. Subset analysis (e.g., pts with del17p; PR vs PR-L outcomes) were not feasible because of the small number of pts in these categories. Conclusions: This ad-hoc analysis shows that changes in clinical stage break down the PR/PR-L (iwCLL) category into different, clinically meaningful subgroups, and reinforces the notion that improving cytopenias is a desirable goal of CLL therapy with ibrutinib (Barrientos, ASH 2014). Altogether, this study demonstrates that changes in clinical stage could be a useful and non-costly method to evaluate treatment response at different time points over the course of the disease, a concept with potential clinical implications that requires validation in prospective clinical trials. Disclosures Delgado: Janssen: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Suzuki:AbbVie: Equity Ownership; Pharmacyclics, LLC, an Abbie Company: Employment, Other: Leadership, travel, accommodations, expenses. Hsu:AbbVie: Equity Ownership; Pharmacyclics, LLC, an Abbie Company: Employment. James:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Montserrat:Vivia Biotech: Equity Ownership; Pharmacyclics: Consultancy; Janssen: Honoraria, Other: travel, accommodations, expenses; Morphosys: Other: Expert Testimony; Gilead: Consultancy, Other: Expert Testimony.
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Broutin, Sophie, Francois Lemonnier, Aurélie Dupuy, Julia Delahousse, Virginie Fataccioli, Vincent Ribrag, Violaine Safar, et al. "Serum 2-Hydroxyglutarate in Angioimmunoblastic T Cell Lymphomas: A New Marker for IDH2 Mutation Detection and Monitoring." Blood 132, Supplement 1 (November 29, 2018): 2898. http://dx.doi.org/10.1182/blood-2018-99-115893.
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Abstract Background: Angioimmunoblastic T cell lymphoma (AITL) is one of the most frequent peripheral T cell lymphoma, and has a poor prognosis. Neoplastic T cells originate from T follicular helper cells, and are admixed among a prominent microenvironment, making their identification sometimes difficult. IDH2 mutations are present in 20-30% AITL patients, where they often co-exist with TET2, DNMT3A and RHOA mutations. They affect almost exclusively the codon R172 of IDH2, providing to the IDH2 enzyme a neo-activity that converts α ketoglutarate (αKG) to D 2-hydroxyglutarate (2HG). D-2HG, the dextrogyre form of 2HG, is an oncometabolite present at very low level under physiological condition, which inhibits many αKG dependent dioxygenases, including TET proteins and is involved in oncogenesis of various cancers such as gliomas or acute myeloid leukemias (AML). Preliminary data, based on small series, showed that increased level of 2HG was detectable in tumor and in serum of IDH2 mutated AITL. However, 2HG level, as well as D/L ratio, has not been evaluated as a surrogate marker of IDH2 mutation in AITL, at diagnosis or during the follow-up. Patients and Methods: Serum from 69 AITL patients, collected in REVAIL trial (NCT00169156) (N=48), RAIL trial (NCT01553786) (N=9) or TENOMIC collection (N=12) were included in this study. IDH2 mutations were assessed in formalin fixed paraffin embedded tumor tissue by deep next generation sequencing of exon 4, using PGM technology (N=63) or allele specific PCR (N=6). For the purpose of the study the cohort was enriched in mutated patients. Serum was collected at diagnosis and at the end of the frontline treatment in 6 patients, 5 of them being IDH2 mutated. D and L 2HG was measured in serum using a liquid tandem mass spectrometry method as previously described (Poinsignon et al. J Chromatogr B 2016) to determine total (D+L) 2HG and D/L 2HG ratio. Results: Twenty-four patients (35%) were IDH2 mutated. Median IDH2 variant allele frequency (VAF) was 7% (IQR, 4%-12.5%). Median total 2HG was 3.63 µM (IQR, 1.6-6.1) in mutated patients versus 1.17 µM (IQR, 0.85-1.68) in wild type patients (p<0.001) (figure). D/L was also found significantly higher in mutated [4.7 (IQR 3.52-7.74)] than in WT patients [1.5 (IQR 0.94-2.23)] (p<0.001). IDH2 mutations included 11 IDH2R172K mutations, 5 IDH2R172G mutations, 4 IDH2R172S, 2 IDH2R172T, 1 IDH2R172M and 1 IDH2R140Q, all showing similar level of 2HG, without variation of 2HG level depending on the mutation. 2HG level correlated with IDH2 mutation VAF (Spearman r=0.4590, p=0.024) likely paralleling the tumor cells mass. Using the cut off established in AML, 2µM and 2.5 for respectively total 2HG and D/L ratio, we found that 17/24 (71%) mutated patients versus 7/45 (15%) had a total 2HG ≥ 2, and that 21/24 (87.5%) mutated versus 8/45 (18%) WT patients had D/L 2HG ratio ≥2.5, leading to a sensibility of 71% and 84%, and a specificity of 87% and 82%, respectively for total 2HG and D/L ratio to detect IDH2 mutations. End of treatment 2HG dosage was available in 5 IDH2 mutated patients with elevated 2HG at diagnosis. All patients had a total 2HG decreased below 2µM. Three patients normalized their D/L ratio, 2 of them being in complete response and one being not evaluable. In contrary, two patients kept a D/L 2HG ratio >2.5, one having progressive disease while the other remains in complete response 6 months after the end of treatment. Conclusion: Serum total 2HG and D/L 2HG ratio can reliably predict the presence of IDH2 mutation in AITL patients. Most patients in complete remission normalize their dosage and ratio, suggesting that serum 2HG could be a marker of residual disease that could be used to monitor patients. Specific cut-off values of 2HG and D/L 2HG ratio for AITL are under investigation. Figure. Figure. Disclosures Ribrag: Servier: Consultancy, Honoraria; pharmamar: Other: travel; Gilead: Consultancy, Honoraria; Amgen: Research Funding; epizyme: Consultancy, Honoraria; Roche: Honoraria, Other: travel; argenX: Research Funding; NanoString Technologies: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; Incyte Corporation: Consultancy; MSD: Honoraria; Infinity: Consultancy, Honoraria. Tilly:Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Haioun:Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Gaulard:Roche: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Research Funding.
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Hampel, Paul J., Kari G. Chaffee, Simonetto A. Douglas, Timothy G. Call, Wei Ding, Saad S. Kenderian, Jose F. Leis, et al. "Liver Dysfunction in Previously Untreated Chronic Lymphocytic Leukemia: Prevalence and Outcomes in a Large Cohort." Blood 128, no. 22 (December 2, 2016): 5585. http://dx.doi.org/10.1182/blood.v128.22.5585.5585.
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Abstract INTRODUCTION: The prevalence of liver dysfunction in patients with previously untreated chronic lymphocytic leukemia (CLL) is unknown; knowledge of which may provide important context for emerging therapeutic options with possible hepatotoxicity. The impact of liver dysfunction on outcomes of CLL patients is not well described. METHODS: Between 09/1993 and 04/2016, previously untreated CLL patients seen in the Division of Hematology at Mayo Clinic at diagnosis (<12 months) and who had baseline assessment of at least one of the following liver function tests (LFTs): alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin were included in this analysis. Baseline lab values were defined as the closest value to CLL diagnosis for each lab within 12 months prior to diagnosis up through 6 months after CLL diagnosis. Patients with at least one abnormal LFT (defined as greater than 1.5 x the upper limit of normal) were classified as having liver dysfunction at diagnosis. Analysis for factors related to baseline liver function was performed using age- and sex-adjusted logistic regression models. Kaplan-Meier methods and multivariable Cox regression analysis was used to evaluate time to first treatment (TTFT) and overall survival (OS). RESULTS: Of 2336 previously untreated CLL patients who met the inclusion criteria, 123 (5%) patients had at least one abnormal LFT value at time of diagnosis. Thirty five patients had abnormal AST (median value 106 U/L, range 72-745 U/L, reference range 8-48 U/L), 25 patients had abnormal ALT (median 112 U/L, range 82-313 U/L, reference 7-55 U/L), and 54 patients had abnormal total bilirubin (median 2.10 mg/dL, range 1.8-26.5 mg/dL, reference range ≤ 1.2 mg/dL). Forty five patients had abnormal alkaline phosphatase; 35 patients in the year 2003 or later (median 198 U/L, range 172-2269 U/L, reference range 45-115 U/L) and 10 patients in 2002 or earlier (median 471.5 U/L, range 394-706 U/L, reference range 98-260 U/L). Abnormal LFTs were more common among those with advanced Rai stage disease (Rai 0-II=4.7% vs. Rai III-IV=13.4%; p<0.001) and among patients with lower hemoglobin (median 13.1 g/dL vs. 13.9 g/dL; p<0.001) at diagnosis. No difference in the rate of abnormal LFTs was observed based on cytogenetic abnormalities detected by FISH or CD38, CD49d, ZAP-70 or IGHV gene mutation status. There was no significant difference in prior alcohol abuse history between patients with liver dysfunction at diagnosis (6%) and those without (5%) (p=0.63). Similarly, there was no significant difference in body mass index between groups (median 27.8 vs. 27.8; p=0.12). After 12 years of follow-up, an estimated 69% of the cases with abnormal LFTs were treated. The most common type of treatments included anti-CD20 monoclonal antibody therapy only, followed by purine nucleoside based chemoimmunotherapy, and an alkylating agent with a monoclonal antibody. The median time to treatment was 4.3 years for cases with abnormal LFTs compared to 6.3 years for cases without abnormal LFTs (p=0.02). However, after adjusting for age, sex and Rai stage, there was no difference in TTFT among patients with abnormal LFTs at baseline compared to those with normal LFTs (hazard ratio [HR] = 1.2 (95% CI, 0.9-1.6); p=0.23). The median survival of CLL patients with abnormal LFTs at diagnosis was significantly shorter than those with normal LFTs (8.6 vs. 11.6 years, p<0.001, Figure 1). After adjusting for age, sex and Rai stage, multivariable cox regression analysis showed that abnormal LFTs retained independent prognostic significance for OS with a HR of 1.4 (95% CI, 1.1-1.8; p=0.012). CONCLUSION: At the time of CLL diagnosis, ~1 out of every 20 patients with previously untreated CLL has abnormal LFTs. These data provide context to the recent reports of hepatotoxicity with the use of signal inhibitors in untreated CLL. Although the presence of liver dysfunction at diagnosis does not seem to predict a shorter TTFT, the OS of these patients is significantly shorter compared to patients who have normal LFTs. Figure 1 Figure 1. Disclosures Ding: Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding. Kay:Pharmacyclics: Research Funding; Tolero Pharmaceuticals: Research Funding; Acerta: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Morpho-Sys: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Shanafelt:Janssen: Research Funding; Pharmacyclics: Research Funding; GlaxoSmithkKine: Research Funding; Genentech: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; Hospira: Research Funding. Parikh:Pharmacyclics: Honoraria, Research Funding.
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Sharman, Jeff, Matthew Davids, Charles Michael Farber, David L. Grinblatt, Neil E. Kay, Nicole Lamanna, Anthony R. Mato, et al. "Characteristics of Patients (Pts) with Chronic Lymphocytic Leukemia (CLL) Receiving Rituximab Monotherapy in the Connect® CLL Registry." Blood 128, no. 22 (December 2, 2016): 5941. http://dx.doi.org/10.1182/blood.v128.22.5941.5941.
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Abstract Introduction: Rituximab (R) improves survival in CLL when added to intensive chemotherapy (such as fludarabine and cyclophosphamide [FCR]), and has been shown to improve progression-free survival when given as maintenance therapy following first- or second-line chemoimmunotherapy. However, early phase 2 studies demonstrated only modest activity of R monotherapy (R mono), particularly at standard dose, and its use as a single agent for pts with CLL has remained controversial. Here we describe the characteristics and outcomes of pts with CLL receiving R mono in a real-world setting. Methods: The Connect CLL registry (NCT01081015), a multicenter, prospective observational cohort study, enrolled 1,494 pts with CLL between 2010-2014 from 179 community, 17 academic, and 3 government sites throughout the USA. Pts were ≥ 18 years and were enrolled ≤ 2 months after initiating any line of therapy (LOT). Pts were treated according to individual physician/patient decision making, and adherence to IWCLL standards cannot be determined. Bone marrow biopsy and CT scans were at the physician's discretion; responses were physician assessed and not centrally reviewed. For this analysis, pts were stratified by first (LOT1) or subsequent LOT (LOT≥2), and by treatment with R mono or other treatments (Tx). Kaplan-Meier methods were used to estimate event-free survival (EFS; event defined as death, progression/relapse, or transformation). A log-rank test was used to evaluate differences in EFS. A multivariate analysis of EFS in LOT1 pts was performed using the Cox regression model. Results: Of the pts enrolled, 105 (11.8%) pts in LOT1 and 81 (13.4%) pts in LOT≥2 received R mono. Of the pts receiving other Tx, 620/784 pts (79%) in LOT1 and 333/524 pts (64%) in LOT≥2 received R in combination. In LOT1, pts receiving R mono were older than pts receiving other Tx (74 vs 67 years; P < 0.0001); in LOT≥2 median ages were comparable (71 vs 70 years). Pts receiving R mono were more likely to have Rai stage 0-1 CLL than pts receiving other Tx, both in LOT1 (63.9% vs 51.8%; P = 0.05) and LOT≥2 (70.4% vs 49.9%; P = 0.005). The proportion of pts receiving R mono vs other Tx with a CCI score of ≥ 4 was similar in LOT1 (25.7% vs 22.8%) and LOT≥2 (32.1% vs 28.4%). Median absolute lymphocyte count at enrollment was lower in pts on R mono vs other Tx in LOT1 (27.7 vs 46.1 x 109/L) but similar in LOT≥2 (35.6 vs 30.2 x 109/L). A lower proportion of pts receiving R mono had FISH/cytogenetics performed at enrollment than pts receiving other Tx in LOT1 (48.6% vs 67.0%; P = 0.0002) and LOT≥2 (30.9% vs 49.6%; P = 0.002). The most common Tx regimens in LOT1 were FCR (25.9%), bendamustine plus R ([BR] 21.0%), R mono (11.8%), fludarabine plus R ([FR] 6.3%), and chlorambucil (4.6%); and in LOT≥2, BR (27.6%), R mono (13.4%), FCR (8.6%), bendamustine (7.4%), FR (4.1%), and ofatumumab (4.0%). The most common reason to initiate treatment in any LOT was bone marrow failure (LOT1, 44.8% vs 39.3%; LOT≥2, 37.0% vs 31.5%; R mono vs other Tx). Duration of therapy was shorter for pts receiving R mono vs other Tx in LOT1 (1.4 vs 4.1 months) and LOT≥2 (1.6 vs 3.3 months). In LOT1, responses were lower in pts on R mono vs other Tx: overall response rate (ORR) was 38.1% vs 64.2% (complete response [CR], 16.2% vs 41.2%; P < 0.0001). In LOT≥2, ORR was 25.9% vs 24.6% for pts on R mono vs other Tx (CR, 9.9% vs 11.5%; P = 0.68). Partial response did not differ significantly between pts receiving R mono vs other Tx in LOT1 and LOT≥2. Pts receiving R mono in LOT1 had inferior median EFS vs other Tx (34 vs 50 months; log-rank P = 0.04); however, after adjusting for factors such as ECOG status and del(17p) status, there was no difference in EFS (HR 0.932; P = 0.79). In pts in LOT≥2, median EFS was similar for R mono and other Tx (15 months for both groups; P = 0.93). Conclusions: Pts receiving R mono as frontline CLL therapy were older than pts receiving other Tx. They also had lower stage disease and lower lymphocyte counts, a shorter duration of treatment, and inferior response rates. Pts receiving R mono in relapsed CLL, more closely approximated pts receiving other Tx in terms of age. Despite the shorter duration of therapy for pts receiving R mono in LOT1 and LOT≥2, both groups had similar ORR and EFS in LOT≥2. These data reinforce the idea that R mono is inadequate as frontline therapy in progressive CLL, and demonstrate the opportunity for improvement in relapsed/refractory disease with novel agents relative to traditional chemoimmunotherapy approaches. Disclosures Sharman: Celgene: Research Funding; Gilead: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding; Seattle Genetics: Research Funding. Davids:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Janssen, Gilead: Consultancy; Celgene Corporation: Consultancy. Farber:Seattle Genetics: Research Funding. Grinblatt:Celgene Corporation: Consultancy, Speakers Bureau. Lamanna:Gilead: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Pronai: Research Funding; Celgene Corporation: Research Funding. Mato:TG Therapeutics: Consultancy; Abbvie: Research Funding; Acerta Pharma: Research Funding; Gilead Sciences: Research Funding; ProNAi: Research Funding; TG Therapeutics: Research Funding; Theradex: Research Funding; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy. Nabhan:Astellas: Research Funding; Seattle Genetics: Research Funding; Cardinal Health: Consultancy; Infinity: Consultancy; Abbvie: Consultancy; Genentech: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding. Sullivan:Celgene Corporation: Employment, Equity Ownership. Flick:Celgene Corporation: Employment, Equity Ownership. Kiselev:Celgene Corporation: Employment, Equity Ownership. Bhushan:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene: Employment, Equity Ownership. Flowers:Seattle Genetics: Research Funding; Optum Rx, Seattle Genetics, Genentech/Roche: Consultancy; Celgene Corporation: Consultancy, Honoraria; Spectrum, Janssen, Infinity, AbbVie, Acerta, Pharmacyclics, TG Therapeutics: Research Funding; Millennium: Consultancy, Research Funding; Gilead: Consultancy, Research Funding.
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Hidayat, Thomas, Helman Nur Yusuf, Nurulludin Nurulludin, and Andina Ramadhani Putri Pane. "PARAMETER POPULASI KEPITING BAKAU (Scylla serrata) DI PERAIRAN PASAMAN BARAT." BAWAL Widya Riset Perikanan Tangkap 9, no. 3 (January 30, 2018): 207. http://dx.doi.org/10.15578/bawal.9.3.2017.207-213.
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Pemanfaatan sumber daya kepiting bakau (Scylla serrata) di perairan Pasaman Barat sudah lama dilakukan oleh nelayan kecil dengan menggunakan bubu (tangkul) yang bersifat tidak selektif. Sebagai komoditi perikanan yang mempunyai nilai ekonomis penting di Indonesia, perlu dilakukan pengelolaan yang tepat agar ketersediaannya tetap berkelanjutan. Penelitian dilaksanakan bulan Januari - November 2016, dengan tujuan mengkaji beberapa parameter populasi sebagai bahan kebijakan pengelolaan kepiting bakau di perairan Pasaman Barat agar tetap lestari. Pengumpulan sampel dilakukan secara acak dari hasil tangkapan nelayan oleh enumerator. Metode analisis parameter populasi menggunakan distribusi frekwensi lebar karapas dengan bantuan program FiSAT (FAO-ICLARM Stock Assessement Tools)-II. Hasil analisis diperoleh laju pertumbuhan (K) sebesar 0,63 pertahun, (CW)= 178,5 mm, kematian alami (M) 1,06 pertahun, kematian karena penangkapan (F)= 1,03 per tahun, dan kematian total (Z)=2,09 pertahun. Tingkat eksploitasi (E) =0,49. Tingkat pemanfaatan kepiting bakau di perairan Pasaman Barat sudah pada tahapan yang jenuh (fully exploited). Pembatasan alat tangkap merupakan opsi yang paling memungkinkan.Mud crab (Scylla serrata) is one of fisheries commodity that has an important economic value in Indonesia. Utilization of mud crabs in West Pasaman had been exploited for years long time with traps fishing gear. The research was conducted in January - November 2016 in the waters of West Pasaman. Sampling were conducted randomly. This paper aims to determine some population parameters of mud crab to used as a guidance guidance in the management of mud crab. in the waters of West Pasaman. Population parameter data analysis using software FiSAT (FAO-ICLARM Stock assessement Tools) II. The results of population dynamic parameters of mud crab showed that growth rate (K) was 0.63 per year, Length infinity (L) was 178.5 mm, natural mortality (M) was 1.06 per year, fishing mortality (F) was 1.03 per year, and total mortality (Z) 2.09 per year. Exploitation rate (E) was 0.49. The exploitation rate of mud crabs in the waters of West Pasaman were (fully exploited), the fishing need to be managed carefully, limitation of fishing gear is the most likely option to be enforced.
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Wagiyo, Karsono, Tirtadanu Tirtadanu, and Tri Ernawati. "PERIKANAN DAN DINAMIKA POPULASI RAJUNGAN (Portunus pelagicus Linnaeus, 1758) DI TELUK JAKARTA." Jurnal Penelitian Perikanan Indonesia 25, no. 2 (October 11, 2019): 79. http://dx.doi.org/10.15578/jppi.25.2.2019.79-92.
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Teluk Jakarta merupakan salah satu daerah penangkapan dan habitat rajungan (Portunus pelagicus) di Indonesia. Permintaan pasar yang terus meningkat dan bersamaan dengan penurunan kualitas perairan mengakibatkan stok rajungan mengalami tekanan eksploitasi dan degradasi habitat. Agar pengelolaan sumberdaya rajungan di Teluk Jakarta tetap lestari, maka diperlukan penelitian mengenai perikanan dan dinamika populasi. Tujuan penelitian memperoleh data dan informasi mengenai daerah tangkapan, alat dan musim penangkapan, indeks kelimpahan, produksi dan komposisi, struktur ukuran, nisbah kelamin, kematangan gonad, musim pemijahan, ukuran panjang pertama tertangkap, ukuran panjang pertama matang gonad, laju pertumbuhan, laju kematian dan laju eksploitasi. Data dan informasi diperoleh dengan eksplorasi, observasi, enumerasi, wawancara dan perunutan pada tempat pendaratan ikan dan instansi lain yang terkait dengan perikanan, selama tahun 2016. Hasil penelitian didapatkan karakteritik daerah penangkapan rajungan; substrat lumpur berpasir dengan perairan dasar yang mempunyai salinitas 30,5-32 ppt, oksigen 6,5-6,9 ml/l, pH 7,5-8,01, kecepatan arus 0,08-0,24 m/dt. Alat tangkap utama berupa jaring insang dasar bermata 3-3,5 inchi, musim penangkapan Mei-Agustus dan paceklik November-Januari. CPUE rajungan tahun 2016 sebesar 7,2 kg/tarik/trip/hari dan mengalami penurunan 55,22 % tahun 2007. Rajungan berkontribusi 69,11 % terhadap hasil tangkapan jaring insang dasar, sumberdaya ikan lainnya 30,89 %. Modus lebar karapas 85-90 mmCW, lebar karapas pada perairan dekat pantai 84,3 mm dan kearah lepas pantai 99,4 mm. Rajungan di Teluk Jakarta mempunyai tipe pertumbuhan alometrik negatif. Nisbah kelamin jantan : betina = 1 : 0,83, betina dominan pada perairan kearah lepas pantai dan jantan dominan kearah pantai (salinitas rendah). Musim pemijahan rajungan di Teluk Jakarta sepanjang tahun, mempunyai dua puncak pada bulan Maret dan September dengan pusat sebaran gonad ovigerous di sekitar perairan P. Damar. Rata-rata ukuran pertama tertangkap (Lc) = 93,87 mmCW lebih besar dari rata-rata ukuran pertama matang gonad (Lm) = 68,8 mmCW. Laju pertumbuhan (K) = 1,08 mmCW/tahun dengan lebar karapas maksimal (L”) = 142,5 mmCW. Laju kematian total (Z)= 4,87/tahun, penangkapan (F) = 3,63/tahun, alami (M) = 1,24/tahun dan laju pengusahaan (E) = 0,75/tahun. Jakarta Bay is one of the fishing areas and habitat of blue swimmer crabs (Portunus pelagicus) in Indonesia. Market demand that continues to increase and along with the decline in water quality results in crab stocks experiencing pressure from exploitation and habitat degradation. So that the management of crab resources in the Jakarta Bay remains sustainable, research on fisheries and population dynamics is needed. The purpose of the study was to obtain data and information; fishing ground, fishing season and main gears, abundance index, production and composition of catch, size structure, sex ratio, gonad maturity, spawning season, first length of catch, length of first gonad maturity, growth rate, mortality rate and exploitation rate. Data and information were obtained by exploration, observation, enumeration, interviews and tracing at fish landing sites and other institutions related to fisheries, during 2016. The results of the study obtained the characteristics of the crab fishing ground; sandy mud substrate with bottom waters which have a salinity of 30.5-32 ppt, oxygen 6.5-6.9 ml / l, pH 7.5-8.01, flow velocity 0.08-0.24 m / sec. The main gears are bottom gill nets with mesh size 3-3.5-inch, the fishing season in May-August and famine in the November-January. CPUE of blue swimmer crabs in the 2016 was 7.2 kg / pull / trip / day decreased 55.22% in 2007. The blue swimmer crabs contributed 69.11% to the catch of bottom gill nets, other fish resources 30.89%. Carapace width frequency have mode is 85-90 mmCW, carapace width in waters near the coast is 84.3 mm and offshore is 99.4 mm. The blue swimmer crabs in Jakarta Bay has a negative allometric growth type. Sex ratio male: female = 1: 0.83, female dominant in offshore and male dominant direction towards in shore and (low salinity). The spawning season of blue swimmer crabs in Jakarta Bay has two peaks in March and September with an ovigerous gonad distribution center around the waters of P. Damar. The average size of the length first catch (Lc) = 93.87 mmCW is greater than the average size of the length first gonad maturity (Lm) = 68.8 mmCW. Growth rate (K) = 1.08 mmCW / year with length infinity of carapace width (L”) = 142.5 mmCW. Maturity rate are total (Z) = 4.87/year, capture (F) = 3.63/year, natural (M) = 1.24/year and explotation rate (E) = 0.75/year.
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Mato, Anthony R., Brian T. Hill, Nicole Lamanna, Paul Barr, Chaitra S. Ujjani, Danielle M. Brander, Christina Howlett, et al. "Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in CLL: Results from a Large Multi-Center Study of 683 US-Patients." Blood 128, no. 22 (December 2, 2016): 4400. http://dx.doi.org/10.1182/blood.v128.22.4400.4400.
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Abstract Introduction: Ibrutinib (Ibr), idelalisib (Ide), andvenetoclax (Ven), are all now approved for treating CLL patients in the US. However, in the absence of head-to-head comparator trials, there is limited guidance as to the optimal sequence of these therapies and to the best choice upon failure of first selected agent. To address these gaps in current literature, 9 large US cancer centers and the Connect CLL Registry collaborated to capture the experience of 683 CLLpts treated with kinase inhibitors (KIs) - focusing on optimal sequencing and patterns of failure. Patients and Methods: We conducted a multicenter, retrospective analysis of CLLpts treated withIbr-, Ide- orVen-based therapy. We examined demographics, discontinuation rates, reasons for discontinuation, overall response rates (ORR), survival, and post kinase inhibitor (KI) salvage strategies. Primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death, or last follow-up) as determined by the Kaplan Meier (KM) method. Comparisons were made using the log rank (LR) test and COX regression analyses. Results: A total of 683 pts treated with KI therapy (Ibr=621/Ide=62) were identified (Table 1). Baseline characteristics were similar in theIbr and Ide-based groups. ORR toIbr as first KI was 69% [complete response (CR) 11%, partial response (PR) 45%, and PR-L 13%] and Ide was 81% (CR 5%, PR 71%,PR-L 5%). With a median follow-up from start of first KI of 17 months (range 1-60), median PFS and OS for the entire cohort from first KI was 35 months (216 events) and not reached respectively (107 events). Interestingly,pts treated withIbr (vs. Ide) as first KI had a significantly better PFS in all settings; front-line (figure a, HR 2.8, CI 1.3-6.3 p=.01), relapsed-refractory (figure b, HR 2.8, CI 1.9-4.1 p<.001), clinical trials (HR 3.3, CI 1.8-5.9 p<.001), commercial use (HR 2.5, CI 1.5-4.0 p<.001), del17p (HR 2.0, CI 1.2-3.4 p=.008), or complex karyotype (HR 2.5, CI 1.2-5.2 p=.02). Moreover, at the time of initial KI failure, the use of either an alternate KI orVen was associated with superior PFS as compared tochemoimmunotherapy (CIT) combinations (figure c). When treated with an alternate KI (Ibr followed by Ide or Ide followed byIbr),pts intolerant of a KI therapy due to toxicity had a superior PFS compared with those taken off a KI therapy due to CLL progression (p=0.03, LR test). Furthermore,Ibr-failurepts had a marginally better PFS if treated withVen (ORR 79%) vs. Ide (ORR 46%) (figure d, HR .6, CI.3-1.0 p=.06). Conclusions: In the largest experience of novel agents published to date in CLL,Ibr appears superior to Ide in all settings as first choice KI. Further, in the setting of KI failure, an alternate KI orVen therapy appear superior to CIT combinations. Alternate KI appear particularly effective in the setting of intolerance to a prior KI. The use ofVen uponIbr failure might be superior to the use of Ide. These data provide guidance for sequencing of novel agents and support the need for trials directly comparing novel agents and sequencing strategies in CLL. Table 1 Table 1. Figure Figure. Disclosures Mato: Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy; Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding. Lamanna:Roche-Genentech: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Pharmacyclics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Infinity: Research Funding; Acerta: Research Funding; TGR Therapeutics: Research Funding. Barr:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Ujjani:Genentech: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy. Brander:Gilead: Honoraria; TG Therapeutics: Research Funding. Cheson:Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiselev:Celgene: Employment, Equity Ownership. Svoboda:Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Schuster:Genentech: Consultancy, Honoraria; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Hoffman-LaRoche: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen Research & Development: Research Funding. Nabhan:Celgene Corporation: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy; Infinity: Consultancy; Cardinal Health: Consultancy; Seattle Genetics: Research Funding; Astellas: Research Funding.
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Tadjuddah, Muslim, Budy Wiryawan, Ari Purbayanto, and Eko Sri Wiyono. "Parameter Biologi Ikan Kerapu (Epinephelus sp.) Hasil Tangkapan di Perairan Taman Nasional Wakatobi, Sulawesi Tenggara Indonesia (Biological Parameters of Grouper (Epinephelus sp.) Caught in Wakatobi National Park, Southeast Sulawesi, Indonesia)." Marine Fisheries : Journal of Marine Fisheries Technology and Management 4, no. 1 (October 19, 2013): 11. http://dx.doi.org/10.29244/jmf.4.1.11-21.
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<p> </p><p class="MsoNormal" style="text-align: justify; text-indent: 1cm;"><span style="font-size: 10pt;" lang="sv" xml:lang="sv">Studi ini mengidentifikasi parameter ikan kerapu yang terdiri dari hubungan panjang-berat, tingkat kematangan gonad dan indeks kematangan gonad yang tertangkap dengan pancing hekaulu, bubu dan panah. Penelitian ini bertujuan </span><span style="font-size: 10pt;" lang="in" xml:lang="in">menganalisis karakteristik </span><span style="font-size: 10pt;" lang="sv" xml:lang="sv">parameter </span><span style="font-size: 10pt;" lang="in" xml:lang="in">biologi ikan kerapu berdasarkan pendekatan beberapa parameter populasi ikan</span><span style="font-size: 10pt;">. </span><span style="font-size: 10pt;" lang="it" xml:lang="it">Penelitian ini dilaksanakan di perairan Taman Nasional Wakatobi dari bulan Oktober sampai dengan Desember 2010. Pengambilan data biologi ikan kerapu ini dilaksanakan di perairan P. Wangi-wangi, P. Kaledupa dan P. Tomia.<span> </span>Pengambilan data pata panjang dan berat ikan langsung dilakukan di lapangan sedangkan data TKG dan <em>IKG</em> dilaksanakan pada lokasi yang telah ditentukan sesuai dengan metodologi. Hasil penelitian menunjukkan </span><span style="font-size: 10pt;" lang="fi" xml:lang="fi">pertumbuhan ikan kerapu dengan panjang infinity (L<sub>∞</sub>) sebesar, 59,43 cm, koefisien pertumbuhan<span> </span>(K) sebesar 0,460 dan umur teoritis (t<sub>0</sub>) sebesar 0,2540.</span><span style="font-size: 10pt;" lang="it" xml:lang="it"> Pola pertumbuhan ikan kerapu yang tertangkap pada <em>fishing ground</em> pancing hekaulu dan bubu bersifat <em>allometrik negatif</em><span> </span>sedangkan yang tertangkap dengan panah bersifat<span> </span><em>isometrik</em>. Pada <em>fishing ground</em> alat tangkap bubu menangkap ikan kerapu dalam kondisi tidak matang gonad sebesar 62,5% dengan nilai indeks gonad berkisar 0,3680-0,8996 dan hanya 37,5% saja yang dalam kondisi matang gonad dengan nilai indeks gonad berkisar 1,0059–1,1058.</span></p><p class="MsoNormal" style="text-align: justify; text-indent: 1cm;"><br /><span style="font-size: 10pt;" lang="it" xml:lang="it"><strong>Kata kunci: </strong>parameter biologi, kerapu, pancing hekaulu, bubu, panah, Taman Nasional Wakatobi <br /></span></p>
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Bendahmane, Mostafa, Moussa Chrif, and Said El Manouni. "Elliptic equations in weighted Sobolev spaces of infinite order with L 1 data." Mathematical Methods in the Applied Sciences 33, no. 1 (June 19, 2009): 49–56. http://dx.doi.org/10.1002/mma.1149.
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SANTRA, S. B. "STUDY OF FINITE SIZE EFFECTS ON DIRECTED SPIRAL PERCOLATION." International Journal of Modern Physics B 17, no. 29 (November 20, 2003): 5555–64. http://dx.doi.org/10.1142/s0217979203023252.
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Percolation under both directional and rotational constraints is studied numerically on the square lattice of different finite sizes L. The critical percolation threshold pc≈0.655 of the infinite network is determined by extrapolating the finite size data. The fractal dimension df of the infinite percolation clusters is found df≈1.72 from the finite size scaling, S∞~Ldf where S∞ is the mass of the infinite cluster. The critical exponents are estimated as a function of the system size L. It is seen that the results of smaller systems converge to that of the large systems. The results are then extrapolated to the infinite network. The extrapolated results for the infinite network are compared with Monte Carlo results on a single large lattice. A good agreement is found.
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Corcho, Adán J., and Lucas C. F. Ferreira. "Global existence for Schrödinger–Debye system for initial data with infinite ${L}^{2}$-norm." Quarterly of Applied Mathematics 73, no. 2 (March 16, 2015): 253–64. http://dx.doi.org/10.1090/s0033-569x-2015-01371-4.
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Stamatovic, Biljana, and Goran Kilibarda. "Algorithm for Identification of Infinite Clusters Based on Minimal Finite Automaton." Mathematical Problems in Engineering 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/8251305.
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We propose a finite automaton based algorithm for identification of infinite clusters in a 2D rectangular lattice with L=X×Y cells. The algorithm counts infinite clusters and finds one path per infinite cluster in a single pass of the finite automaton. The finite automaton is minimal according to the number of states among all the automata that perform such task. The correctness and efficiency of the algorithm are demonstrated on a planar percolation problem. The algorithm has a computational complexity of O(L) and could be appropriate for efficient data flow implementation.
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O'Brien, Susan, Jeffrey A. Jones, Steven Coutre, Anthony R. Mato, Peter Hillmen, Constantine Tam, Anders Osterborg, et al. "Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial." Blood 124, no. 21 (December 6, 2014): 327. http://dx.doi.org/10.1182/blood.v124.21.327.327.
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Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.
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D'Auria, Bernardo, and Sidney I. Resnick. "The influence of dependence on data network models." Advances in Applied Probability 40, no. 1 (March 2008): 60–94. http://dx.doi.org/10.1239/aap/1208358887.
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Consider an infinite-source marked Poisson process to model end user inputs to a data network. At Poisson times, connections are initated. The connection is characterized by a triple (F, L, R) denoting the total quantity of transmitted data in a connection, the length or duration of the connection, and the transmission rate; the three quantities are related by F = LR. How critical is the dependence structure of the mark for network characteristics such as burstiness, distribution tails of cumulative input, and long-range dependence properties of traffic measured in consecutive time slots? In a previous publication (D'Auria and Resnick (2006)) we assumed that F and R were independent. Here we assume that L and R are independent. The change in dependence assumptions means that the model properties change dramatically: tails of cumulative input per time slot are dramatically heavier, traffic cannot be approximated by a Gaussian distribution, and the decay of dependence cannot be measured in the traditional way using correlation functions. Different network applications are likely to have different mark dependence structure. We argue that the present independence assumption on L and R is likely to be appropriate for network applications such as streaming media or peer-to-peer networks. Our conclusion is that it is desirable to separate network traffic by application and to model each application with its own appropriate dependence structure.
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D'Auria, Bernardo, and Sidney I. Resnick. "The influence of dependence on data network models." Advances in Applied Probability 40, no. 01 (March 2008): 60–94. http://dx.doi.org/10.1017/s000186780000238x.
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Consider an infinite-source marked Poisson process to model end user inputs to a data network. At Poisson times, connections are initated. The connection is characterized by a triple (F, L, R) denoting the total quantity of transmitted data in a connection, the length or duration of the connection, and the transmission rate; the three quantities are related by F = LR. How critical is the dependence structure of the mark for network characteristics such as burstiness, distribution tails of cumulative input, and long-range dependence properties of traffic measured in consecutive time slots? In a previous publication (D'Auria and Resnick (2006)) we assumed that F and R were independent. Here we assume that L and R are independent. The change in dependence assumptions means that the model properties change dramatically: tails of cumulative input per time slot are dramatically heavier, traffic cannot be approximated by a Gaussian distribution, and the decay of dependence cannot be measured in the traditional way using correlation functions. Different network applications are likely to have different mark dependence structure. We argue that the present independence assumption on L and R is likely to be appropriate for network applications such as streaming media or peer-to-peer networks. Our conclusion is that it is desirable to separate network traffic by application and to model each application with its own appropriate dependence structure.
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Brault, Marion, Maxime Annereau, Alina Danu, Julien Lazarovici, Claude Chahine, Andrea Varga, Capucine Baldini, et al. "Outcomes of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Included in Phase I Clinical Trials." Blood 132, Supplement 1 (November 29, 2018): 2992. http://dx.doi.org/10.1182/blood-2018-99-112919.
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Abstract INTRODUCTION The phase 1 selection for clinical trials of patients with relapsed or refractory Diffuse Large-B cell lymphoma (R/R DLBCL) with a potentially rapid tumor growth is a challenge. Prognostics' factors identification could help to better orient patients in appropriate clinical trials. This study is focused on DLBCL to evaluate their outcomes in phase I clinical trials. Our main objectives were to identify prognostic factors, attest the investigational drugs' safety and perform a preliminary assessment of drugs' efficacy. METHOD All consecutive patients with R/R DLBCL included in phase I clinical trial at a single cancer center in France between 2008 and 2017. If a given patient had participated in several phase I clinical trial, only the data from his first trial were examined. The patients' and DLBCL characteristics, the safety data and the efficacy outcomes were recorded. Reponses were assessed according to the International Harmonization Project in Lymphoma Cheson 2007 criteria. Overall responses rates (ORR) included partial responses (PR) and complete response (CR) and tumor control rates included overall responses and stable disease (SD). RESULTS A total of 101 patients (males: 63,4%) with R/R DLBCL were included in a panel of 21 clinical trials. The median age was 64 (range 21-86). Before their inclusion in a phase I trial, patients had received a median of 3 (1-7) lines of treatment and 25,7% of patients had undergone an autologous stem cell transplantation. At the cute-off date, 5 of the 101 patients (4,95%) were still taking the investigational drug. The median progression-free survival and overall survival (OS) were 1,8 and 9,7 months. High-grade toxicity (grade 3 or higher) occurred in 47 of the 101 patients (46,5%), and was related to the investigational drug in 29 of these cases (61,7%). The most important drugs-related toxicity was a hematological toxicity (neutropenia and thrombocytopenia) for 79,3% of patients, other toxicities were digestive toxicity (5,9%), cutaneous toxicity (2,9%), hepatotoxicity (2,9%) and pneumopathy (2,9%). Dose-limiting toxicity (DLT) was experienced by 7 (6,9%) of the 101 patients. The time from D1C1 (day 1, cycle 1) to the occurrence of high-grade toxicity was 1,2 months (range 0,2-9,5). High-grade toxicity occurred during the DLT period (< 6 weeks) for 27 of the 46 patients (58,7%) and after the DLT period in the remaining 19 (41,3%) patients. Factors associated with poor overall survival (overall survival inferior to the median OS) were Ann Arbor staging (73.6% of poor OS patients (< 9.7 months) with a performance status at 4), serum albumin (30.2% of poor OS patients with a low rate of serum albumin ≤ 35 g/L), serum LDH (79.2% of poor OS patients with a high rate of serum LDH > 250 U/L) and progressive disease (90.6% of poor OS patients had a trial withdrawal because of progression). The overall objective response and disease control rates were 25% and 43%. The median trial duration was 1.9 months and were respectively 12,1 and 5,5 months for responders (PR and CR) and controlled patients (PR and CR and SD). 36.6% of patients were prematurely withdrawing of study (before weeks 6). Factors associated with premature withdrew were performance status at baseline (67.6% of early withdrawal patients at performance status 1); Ann Arbor staging (67.6% of early withdrawal patients at Ann Arbor stage 4); serum LDH (73% of early withdrawal patients with a high rate of serum LDH > 250 U/L) and serum albumin (35,1% of early withdrawal patients with a low rate of serum albumin ≤ 35 g/L). CONCLUSION High-grade toxicity occurred after the DLT period in 41.3% of patients with R/R DLBCL, suggesting that the conventional concept of dose-limiting toxicity should be redefined in the era of modern cancer therapies. Besides, even if the phase 1 selection for clinical trials is very selective, it's necessary to better orient patients in hematology. In fact, 36.6% of patients were prematurely withdrawing of study which could be anticipated thanks to the identification of prognostics' factors. Although the objective response is only a secondary endpoint in phase I clinical trials, the median duration of participation in trials (almost one year for responders and 5.5 months for controlled patients) are relevant for some new possibilities of therapeutics in the field of early drugs clinical trials. Disclosures Ribrag: NanoString Technologies: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; Incyte Corporation: Consultancy; MSD: Honoraria; Roche: Honoraria, Other: travel; Infinity: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; Amgen: Research Funding; Servier: Consultancy, Honoraria; pharmamar: Other: travel; Gilead: Consultancy, Honoraria; argenX: Research Funding.
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Horvei, Paulina, Reona Sakemura, Michelle J. Cox, Michael W. Ruff, Mehrdad Hefazi, Erin E. Tapper, Kendall J. Schick, et al. "Targeting of CD19 By Tafasitamab Does Not Impair CD19 Directed Chimeric Antigen Receptor T Cell Activity in Vitro." Blood 134, Supplement_1 (November 13, 2019): 2859. http://dx.doi.org/10.1182/blood-2019-130506.
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CD19 directed chimeric antigen receptor T cell (CART) therapy has shown remarkable activity in B cell lymphoma and acute lymphoblastic leukemia leading to the approval of two CART therapies. With the emergence of therapeutic anti-CD19 antibodies for the treatment of B cell malignancies, it remains to be elucidated whether such antibodies would interfere with the ability of CD19 targeting CARTs to exert their anti-tumor effect in a subsequent therapy. To address a part of this question, we investigated the potential for functional interference between the monoclonal anti-CD19 antibody tafasitamab (MOR208) and CD19 directed CART cells (CART19). CART19 cells were generated through lentiviral transduction of healthy donor T cells with a second generation CD19 CAR construct (FMC63-CD8h-CD8TM-41BBζ) which is similar to the construct used for the FDA-approved CART tisagenlecleucel. Tafasitamab, is an Fc-enhanced humanized monoclonal antibody which mediates antibody-dependent cellular toxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and direct cytotoxicity. It is currently being studied in phase 2 and 3 clinical trials in diffuse large B-cell lymphoma (DLBCL) in combination with the immunomodulatory agent lenalidomide (L-MIND) and the chemotherapeutic drug bendamustine (B-MIND). As a first step we confirmed the relevance of the tested CD19-positive target cell lines, JEKO (mantel cell lymphoma), Ly7 (DLBCL) and NALM-6 (ALL) based on functional activity of tafasitamab and CART19. In a 24 hours ADCC (tafasitamab titration plus natural killer (NK) cells; Figure 1A) and T cell cytotoxicity assays (CART19, E:T titrations; data not shown) distinct activity was observed for both therapies on all tested cell lines. Secondly, we studied whether the observed CART19 activity may be influenced by tafasitamab in case of a direct CD19 binding competition between tafasitamab and the CAR. To test for such binding competition we incubated the CD19+ cell lines NALM6 or JEKO with up to 100 µg/ml tafasitamab, to saturate the receptors. Subsequent flow cytometry analysis using the FMC63 antibody (carrying the same CD19 binding domain as contained in CART19) failed to detect CD19 expression, indicating a direct binding competition between FMC63 and tafasitamab (Figure 1B). Next, to investigate the potential impact of such binding competition on CART19 cell effector functions, we co-cultured tafasitamab CD19+ JEKO cell line at increasing concentrations of up to 100µg/ml, and then added CART19 cells at different effector to target ratios to the cell culture. The presence of tafasitamab, binding to the CD19 antigen, did not affect important CART cell effector functions such as antigen specific killing (Figure 1C), degranulation (Figure 1D), cytokine production or proliferation of CART19 (Figure 1E). In summary, our studies indicate that CART19 continue to exhibit potent antigen specific effector functions despite presence of tafasitamab and the related competition for CD19 binding. Besides the presented in vitro work the questions of therapeutic sequencing of tafasitamab and CART19 is being studied in xenograft models and will be presented at the meeting. Disclosures Sakemura: Humanigen: Patents & Royalties. Cox:Humanigen: Patents & Royalties. Schanzer:MorphoSys AG: Employment. Endell:MorphoSys AG: Employment, Patents & Royalties. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding.
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Archibald, William J., Timothy G. Call, Sara J. Achenbach, Kari G. Rabe, Curtis A. Hanson, Wei Ding, Amber Koehler, et al. "The Role of Imaging in Predicting Time to First Treatment and Overall Survival in Individuals with CLL-like High Count Monoclonal B-Cell Lymphocytosis." Blood 134, Supplement_1 (November 13, 2019): 3037. http://dx.doi.org/10.1182/blood-2019-131154.
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Background: The 2008 International Working Group for CLL (IWCLL) criteria define MBL as a clonal B-cell disorder with a peripheral blood B-cell count of <5 x 109/L, in the absence of cytopenias(s), lymphadenopathy and/or organomegaly on physical examination, and no other concomitant lymphoproliferative disorder. In the presence of palpable lymphadenopathy and/or organomegaly, and a B-cell count of < 5 x 109/L, a diagnosis of small lymphocytic lymphoma (SLL) is established. A study by Gentile et al (Am J Hematol. 2013) reported that 29 out of 62 individuals with clinically identified MBL (42%) had lymphadenopathy identified on CT imaging. Notably, however, after a median follow-up of 35 months, the rate of progression among cases of MBL with lymphadenopathy identified on CT imaging was only 6.9% (2/29 patients), which was no different than in cases of MBL without lymphadenopathy on CT imaging (rate of progression, 9%; 3/33 patients). Our study sought to 1) determine if lymphadenopathy and/or organomegaly detected by imaging studies performed for unrelated reasons in individuals with MBL can identify a subset with shorter time to first CLL therapy (TFT) and overall survival (OS); and 2) compare outcomes of individuals with MBL who have incidentally detected lymphadenopathy/splenomegaly and SLL patients. Methods: We used the Mayo Clinic CLL Database to identify individuals with high-count MBL (absolute B-cell count: 0.5 - 4.9 x 109/L) and divided them into the following three cohorts: a) Cohort A: no imaging studies available at MBL diagnosis; b) Cohort B: imaging studies done within one year of MBL with no evidence of lymphadenopathy and/or organomegaly; and c) Cohort C: imaging studies done within one year of MBL with lymphadenopathy and/or organomegaly, attributable to MBL. All individuals with MBL were first seen at Mayo Clinic after 1/1/2002; those with a concomitant lymphoproliferative disorder within 3 months of diagnosis were excluded. Patients with SLL seen during the same time interval were identified as a comparison cohort. We compared the baseline characteristics (Kruskal Wallis for continuous and Chi-square for categorical variables) and TFT and OS across the three MBL cohorts, and patients with SLL. Cumulative incidence of TFT was adjusted for the competing risk of death. Age- and sex-adjusted OS was analyzed using inverse weights methods. Results: 657 individuals with high-count MBL with a median follow-up of 6.7 years were identified: 415 (63%) individuals were in Cohort A, 142 (22%) in Cohort B, and 100 in (15%) Cohort C. Compared to Cohort B, individuals in Cohort C were more likely to have unmutated IGHV, high expression of CD38, and higher beta-2 microglobulin level (Table 1). SLL patients were younger, had higher rate of unmutated IGHV, and had high expression of CD49d compared to MBL individuals in Cohort C (Table 1). There was suggestive evidence of a difference in TFT between Cohorts B and C (estimated 10-year treatment rate 28.3% vs. 41.6%; p=0.16; HR 1.62 95% CI 0.84-3.15). TFT was significantly shorter in SLL patients compared to those with Cohort C (estimated 10-year treatment rate 71% vs. 41.6%, respectively, P<0.001; Figure 1A). There was a trend toward shorter OS in Cohort C compared to Cohort B (estimated 10-year OS rate 53.7% vs. 64.2%, respectively, P=0.09; Figure 1B). In contrast, there was no difference in OS among MBL individuals in Cohort C compared to those with SLL (estimated 10-year OS rate 56.9% vs. 62.6%, P=0.72). Summary/Conclusion: Our findings demonstrate that individuals with MBL who have incidentally identified lymphadenopathy/splenomegaly at diagnosis are more likely to have an unfavorable risk profile, shorter TFT and OS compared to patients who did not have lymphadenopathy/splenomegaly at MBL diagnosis. Additionally, these individuals have a longer TFT but similar OS compared to SLL patients seen during the same time interval. If externally validated, these findings have significant implications for individuals with newly diagnosed MBL. Disclosures Ding: Merck: Research Funding; DTRM Biopharma: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Parikh:AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding.
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Ju, Hee Young, Ji Won Lee, Che Ry Hong, Hyery Kim, Kyung Duk Park, Hee Young Shin, Seokuee Kim, et al. "Pharmacokinetics of Fludarabine in Pediatric Hematopoietic Stem Cell Transplantation." Blood 124, no. 21 (December 6, 2014): 2466. http://dx.doi.org/10.1182/blood.v124.21.2466.2466.
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Abstract Introduction: Fludarabine is a purine-analog which is effective for leukemic cells with lower toxicity. Thus it has been preferred for preparative regimens of hematopoietic stem cell transplantation (HSCT) recently. However, the pharmacokinetics of fludarabine in pediatric HSCT has not been studied before. This prospective study investigated the pharmacokinetics of fludarabine in children undergoing allogeneic HSCT, and attempted to establish the fludarabine administration in pediatric patients. Patients and Methods: Forty-three pediatric patients undergoing HSCT were enrolled to the study. The median age was 11.8 years old (range 1.3–17.3), and there were 31 male and 12 female patients. Among the 43 patients, there were 15 acute lymphoblastic leukemia (34.9%), 12 acute myeloid leukemia (27.9%), 3 severe aplastic anemia (7.0%), 3 chronic granulomatous disease (7.0%), and 10 other diseases (23.3%). The preparative regimens included cyclophosphamide with fludarabine, busulfan with fludarabine, busulfan with fludarabine and etoposide, which was selected according to the disease and risk group. Fludarabine was administered as 40 mg/m2/day i.v. over 30 minutes for 5 to 6 days, and the pharmacokinetic study was carried out at the first and last dose. Blood samplings were taken before administration and 0.5, 1, 3, 5, 8hr after the end of infusion. Fludarabine concentration was analyzed by high performance liquid chromatography-tandem mass spectrometry. Results: Median (min-max) fludarabine area under the drug concentration-time curve extrapolated to infinity (AUC0-∞) of the first day of infusion was 4.64 (2.71-9.52) μg*h/mL, apparent clearance 10.9 (3.28-26.49) L/h, and Cmax 1,222 (668-1,732) ng/mL. The AUC0-∞ was lower than previously reported AUC0-∞ of the adult study, but the median Cmax was higher than the result of adult study. In this study, the range of AUC and Cmax were narrower than those of adult data. When the AUC0-8hr of day 1 and the steady state (day 5 or day 6) was compared, the fludarabine exposure at steady state was 1.21 fold higher than the first day. In this study, the overall survival was 75.8%, and event-free survival was 60.9%. When grouped by median fludarabine AUC level, the high AUC group and low AUC group showed no significant difference in overall survival or relapse-free survival. Also, there was no significant difference in cumulative incidence of relapse or treatment-related mortality (TRM) between two groups. Neurotoxicity was observed in 5 patients (11.6%) and pulmonary toxicity was observed in 19 patients (44%). These toxicities were not significantly related to the level of fludarabine AUC. Conclusion: In this study, the fludarabine AUC(0-∞) and Cmax was similar with adults, and the range was narrower. Thus fludarabine exposure is considered to be similar with adult, and the recommended dosing for adults can be applied to children. This is the first study to investigate the pharmacokinetics of fludarabine in pediatric HSCT. As fludarabine is being more widely adopted for the pediatric HSCT, this study could provide useful data for the treatment in pediatric patients. Acknowledgment: This research was supported by a grant (11172MFDS288) from Ministry of Food and Drug safety in 2011. Disclosures No relevant conflicts of interest to declare.
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Sharma, Ravinder, and Harsh Kumar. "Volumetric and Acoustic Studies of Interactions between L-Phenylalanine and 1-Hexyl-3-Methylimidazolium Bromide in Aqueous Solution." ECS Transactions 107, no. 1 (April 24, 2022): 5227–33. http://dx.doi.org/10.1149/10701.5227ecst.
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Experimental density (ρ) and ultrasonic velocity (c) for phenylglycine in ( 0.01, 0.03, 0.05 and 0.05) mol.kg−1 aqueous solutions of 1-hexyl-3-methylimidazolium bromide at T = (313.15 and 318.15) K. Collected values for density and ultrasonic velocity were used to compute the apparent molar volumes (V f ), the apparent molar volumes at infinite dilution (), partial molar isentropic compression (K f ,s ) and partial molar isentropic compression at infinite dilution (). Also recorded data of these mixtures were utilized to calculate pair and triplet interaction coefficients. Such thermodynamic characteristics can be used to investigate the solvation behaviour, structure formation, and many sorts of interactions in (phenylglycine + water + 1-hexyl-3-methylimidazolium bromide) ternary solutions.