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There are few data on outcomes for patients with metastatic urothelial carcinoma (MUC) who receive chemotherapy (CT) after progression on immune checkpoint inhibitors (ICIs). We carried out a retrospective single-centre analysis of MUC patients who progressed after ICI and then received CT. Patients fell into two groups: CT-naive (no prior-CT) and CT-pretreated (platinum-based CT followed by ICI on progression). The response rate (RR), progression-free survival (PFS), and duration of response (DOR) were assessed. A total of 29 patients received CT following progression on ICI. The median follow-up was 17.0mo (interquartile range 9.1–20.5mo). In the CT-naive group (n=17), 53% had a partial response, 18% had stable disease, and 29% had progressive disease. In the CT-pretreated group (n=12) 17% had a partial response, 67% had stable disease, and 16% had progressive disease. The median PFS was 6.4mo (95% confidence interval [CI] 3.8–9.1) in the CT-naive and 4.4mo (95% CI 1.5–7.3) in the CT-pretreated group. The median DOR was 8.1mo (range 5.1–11.1) among the ten patients with a response to CT after ICI in both groups. Some 38% of patients in the CT-naive and 17% in the CT-pretreated group had dose reductions on post-ICI CT. CT and ICI can be sequenced after previous chemotherapy exposure, although this does not induce long-term durable remissions in most patients.

•MIR155HGΔexon3T cells provide protection against lethal acute GVHD in a xenogeneic mouse model of disease.•MIR155HGΔexon3T cells maintain beneficial graft-versus-leukemia response in vivo.

Background:Biomechanical analysis of foot loading characteristics may provide insights into the injury mechanisms and guide orthotic prescription for basketball players. This study aimed to quantify in-shoe plantar pressure profiles in amateur players when executing typical basketball movements.Methods:Twenty male university basketball players performed four basketball-specific movement tasks—running, maximal forward sprinting, maximal 45° cutting, and layup—in a pair of standardized basketball shoes fitted with an in-shoe plantar pressure measurement system. Peak pressure (PP) and pressure-time integral (PTI) data were extracted from ten plantar regions. One-way repeated-measures analysis of variance was performed across the tasks, with significance set at P< .05.Results:Distinct plantar pressure distribution patterns were observed among the four movements. Compared with running, significantly higher (P< .05) PP and PTI of up to approximately 55 were found in sprinting and layup, particularly at the forefoot region. Similarly, significantly higher (P< .05) PPs and PTIs, ranging from approximately 23 to 90, were observed in 45° cutting compared with running at most foot regions.Conclusions:Compared with running, sprinting and layup demonstrated higher plantar loading in the forefoot region, and 45° cutting yielded increased plantar loading in most regions of the foot. Understanding the plantar pressure characteristics of different movements may be useful in optimizing footwear designs, orthosis use, or training strategies to minimize regional plantar loading during amateur basketball play.

AimsPatients with diabetes are at increased risk of wound complications after open reduction and internal fixation of unstable ankle fractures. A fibular nail avoids large surgical incisions and allows anatomical reduction of the mortise.Patients and MethodsWe retrospectively reviewed the results of fluoroscopy-guided reduction and percutaneous fibular nail fixation for unstable Weber type B or C fractures in 24 adult patients with type 1 or type 2 diabetes. The re-operation rate for wound dehiscence or other indications such as amputation, mortality and functional outcomes was determined.ResultsTwo patients developed lateral side wound infection, one of whom underwent wound debridement. Three other patients required re-operation for removal of symptomatic hardware. No patient required a below-knee amputation. Six patients died during the study period for unrelated reasons. At a median follow-up of 12 months (7 to 38) the mean Short Form-36 Mental Component Score and Physical Component Score were 53.2 (95% confidence intervals (CI) 48.1 to 58.4) and 39.3 (95% CI 32.1 to 46.4), respectively. The mean Visual Analogue Score for pain was 3.1 (95% 1.4 to 4.9). The mean Ankle Osteoarthritis Scale total score was 32.9 (95% CI 16.0 to 49.7).ConclusionFluoroscopy-guided reduction and fibular nail fixation of unstable ankle fractures in patients with diabetes was associated with a low incidence of wound and overall complications, while providing effective surgical fixation.Cite this article: Bone Joint J2016;98-B:1197–1201.

This paper investigates the design and fabrication of an energy-harvesting device for converting the kinetic energy of heavy haul railcar vibrations into electrical energy. The inertial-based electromagnetic generator is a two-degree-of-freedom (2-DoF) coupled oscillating system that can efficiently operate at the two dominant frequencies corresponding to unloaded and loaded railcar conditions. Vibration measurements from the field indicate the dominant frequency of the railcar at a sprung location shifts between 14.6 and 5.8 Hz for the unloaded and loaded conditions, respectively. Design and optimization was investigated using multi-physics finite element analysis (COMSOL) with sinusoidal vibration input. A prototype was developed to demonstrate that a practical amount of power can be generated using the 2-DoF coupled system. Experimental results favourably agree with model predictions, and show that more than 200 mW of output power can be generated at each dominant frequency from a 0.4 gpeak sinusoidal host acceleration (where g= 9.8 m/s2). In addition measured railcar vibration was replicated using a power spectral density approach, allowing prediction to be made about the performance of the generator in the field.

This study investigates the heat transport mechanism in semiconductor elements within a homogeneous thermoelectric cooling system using the dual-phase-lag (DPL) model. The thermal lagging behavior is analyzed and explored during the energy transport process. The coupled energy and constitutive partial differential equations are solved simultaneously to reduce the complexity of the high-order spatial and time derivatives. This approach simplifies the mathematical solution process and reduces numerical instabilities when compared to the conventional methodology in which either the temperature or heat flux is solved individually with a single equation. The effect of the thermal lagging behavior on energy transport is examined and compared to results by using the Cattaneo–Vernotte model. Furthermore, the phase-lag behavior on the temperature and heat flux profiles is investigated in detail. This study provides perceptive information for engineering applications in which the microscale heat transport phenomenon plays a significant role during the design process. Adding the dual-phase-lag model to the traditional heat diffusion model is a complementary option for engineers in the thermoelectric industry.

Information and Communication Technology (ICT) integration has been a topic of discussion among scholars for over thirty years. Since it was first introduced, ICT has been increasingly being integrated at every level of educational system. As a subject that emphasizes creativity, innovation and critical thinking, Visual Art Education (VAE) teachers were urged to taking full advantage of ICT. The potential of ICT in promoting real world experiences through simulation, manipulation and creative expression should be applied, as these valuable approaches of teaching and learning arts have never been highlighted before in conventional arts classrooms. However, the success of ICT integration depends largely on factors that will eventually increase teachers’ intention to continue using it. Based on that understanding, this study synthesized the Technology Adoption Model (TAM), the Unified Theory of Acceptance and Use of Technology (UTAUT) and the Expectation- Confirmation Model (ECM) in explaining and predicting the VAE teachers’ intentions to continue using ICT in arts classrooms. A sample of 296 VAE teachers in Selangor, a state in Malaysia, took part in this study. Structural Equation Modelling (SEM) is used in testing the research hypotheses and validating the proposed model of the study. Results from the study demonstrate that teachers’ perceived ease of use has the most significant direct effect on their continuance intention. A significant effect was also found in the relationship between teachers’ perceived usefulness and social influences. Overall, these main factors explained 21.3 percent of VAE teachers’ continuance intention to integrate ICT in arts classrooms. On the basis of these findings, the implications for theory development, practices and policymaking are discussed in this paper.

The field of nanoionics is of great importance for the development of superior materials for devices that rely on the transport of charged ions, like fuel cells, batteries, and sensors. Often nanostructuring leads to enhanced ionic mobilities due to the induced space‐charge effects. Here these large space‐charge effects occurring in composites of the proton‐donating solid acid CsHSO4and the proton‐accepting TiO2or SiO2are studied. CsHSO4is chosen for this study because it can operate effectively as a fuel‐cell electrolyte at elevated temperature while its low‐temperature conductivity is increased upon nano­structuring. The composites have a negative enthalpy of formation for defects involving the transfer of protons from the acid to the acceptor. Very high defect densities of up to 10% of the available sites are observed by neutron diffraction. The effect on the mobility of the protons is observed directly using quasielastic neutron scattering and nuclear magnetic resonance spectroscopy. Surprisingly large fractions of up to 25% of the hydrogen ions show orders‐of‐magnitude enhanced mobility in the nanostructured composites of TiO2or SiO2, both in crystalline CsHSO4and an amorphous fraction.

Decreasing the dimensions of heterogeneous mixtures of ionic conductors towards the nanoscale results in ionic conduction enhancements, caused by the increased influence of the interfacial space‐charge regions. For a composite of TiO2anatase and solid acid CsHSO4, the strong enhancement of the ionic conductivity at the nanoscale also can be assigned to this space‐charge effect. Surprisingly high hydrogen concentrations in the order of 1021cm−3in TiO2are measured, which means that about 10% of the available sites for H+ions are filled on average. Such high concentrations require a specific elaboration of the space‐charge model that is explicitly performed here, by taking account of the large occupation numbers on the exhaustible sites. It is shown that ionic defects with negative formation enthalpy reach extremely high concentrations near the interfaces and throughout the material. By performing first‐principles density functional theory calculations, it is found that proton insertion from CsHSO4into the TiO2particles is preferred compared to neutral hydrogen atom insertion and indeed that the formation enthalpy is negative. Moreover, the average proton fractions in TiO2, estimated by the theoretical ionic density profiles, are in good agreement with the experimental observations.

Generally, any chemical or physical change in a material may cause variation in its permittivity and permeability. The propagation of microwave through the material can be affected by these variation in properties. The analysis of microwave propagation through materials may therefore provide a means for condition monitoring. This paper utilizes a one-dimensional scenario, demonstrating the feasibility to link measurable reflection and transmission coefficients of microwave to concrete permittivity and permeability, which are essentially associated with water content in concrete. As a result, water content can then be monitored through the measurement of these coefficients. The study also demonstrates the feasibility of using the same technique to estimate the thickness of the concrete that microwave propagates through.

Abstract This paper considers the statistical evaluation of DNA mixtures in the following situations: (1) two unknown contributors are related respectively to two typed persons, (2) two of the unknown or untyped contributors are related and the third unknown contributor is related to a typed person, or (3) there are two pairs of related unknown contributors to the DNA mixture. The corresponding formulas for evaluating the likelihood ratios on the strength of DNA evidence are derived and the kinship coefficients for the related persons are incorporated into the calculations. Two examples are analyzed for illustration.

This study describes a pharmacokinetic (PK) model to account for serum recombinant human erythropoietin (rHuEpo) concentrations in healthy volunteers following intravenous (IV) and subcutaneous (SC) dosing; it also characterizes the pharmacodynamics (PD) of SC rHuEpo effects on reticulocytes, red blood cells (RBC), and hemoglobin (Hb) in blood. Data were obtained from 4 clinical studies carried out in healthy volunteers. Epoetin alfa (rHuEpo) was administered as 5 single IV doses ranging from 10 to 500 IU/kg, as 8 single SC doses ranging from 300 to 2400 IU/kg, and as 2 multiple SC dosage regimens (150 IU/kg/3 times a week [tiw] and 600 IU/kg/wk). A dual‐absorption rate model (fast zero‐order and slow first‐order inputs) with nonlinear disposition characterized the PK of SC rHuEpo. A high Kmvalue was obtained indicating that clearance was mildly nonlinear. Absorption was slow (tmax∼24 hours), and the bioavailability of SC rHuEpo increased with dose (ranging from 46%‐100%). A catenary cell production and loss model with a feedback down regulation component was used to fit the reticulocyte data yielding estimates of the stimulatory capacity (Smax), sensitivity (SC50), and life span parameters. These parameters were used for simulations of RBC and Hb profiles. An SC50of 27 to 61 IU/L was estimated indicating that low physiological plasma rHuEpo concentrations were sufficient to produce pharmacological effects. No marked sex‐dependent differences in clinical responses to rHuEpo therapy were found despite baseline differences. Realistic pharmacokinetic and physiological models accounted for clinical responses from a wide array of dosing conditions with rHuEpo. The rationale for greater efficacy of SC administration of rHuEpo compared to IV was ascertained.

The anticoagulant warfarin exemplifies a type of drug that exhibits high affinity to pharmacologic target sites of limited capacity, resulting in unusual concentration-dependent distribution and elimination properties. The time course of warfarin concentrations in the serum, liver, kidneys, muscle, and abdominal fat of male Sprague-Dawley rats was determined by high-performance liquid chromatography after IV injection of a 0.25 or 1.0mg/kg dose. The rats were preclassified on the basis of their serum free fraction of warfarin; animals with free fraction values of approximately 0.004 and 0.01 and corresponding differences in elimination half-life were selected for study, yielding four experimental groups. Several rats of each group were sacrificed periodically over approximately 80–240h for determination of drug concentrations. S-warfarin concentrations in serum declined apparently exponentially over at least one order of magnitude. During this time, concentrations in all other assayed tissues declined much more slowly. In another experiment, S-warfarin concentrations in serum and liver were followed for approximately 50 days after IV injection of a 1mg/kg dose. This revealed a terminal, very slow elimination phase in serum nearly parallel to the decline in liver drug concentrations. Simultaneous physiologic modeling of all data (30 equations) using ADAPT II (Biomedical Simulations Resource, Los Angeles, CA), with intrinsic clearance, the dissociation constant of the warfarin-high affinity binding site complex, and two binding parameters for the (unassayed) remainder tissue compartment as parameters of unknown value, yielded very good fittings and parameter estimates with relatively small standard deviations. The unusual dose-dependent accumulation characteristics of this type of drug during continuous infusion are demonstrated by computer simulation of published results of warfarin infusions in rats. Utilization of a model premised on similar target-mediated drug disposition also allowed characterization of data from the literature for racemic warfarin pharmacokinetics in man.

The anticoagulant warfarin exemplifies a type of drug that exhibits high affinity to pharmacologic target sites of limited capacity, resulting in unusual concentration-dependent distribution and elimination properties. The time course of warfarin concentrations in the serum, liver, kidneys, muscle, and abdominal fat of male Sprague-Dawley rats was determined by high-performance liquid chromatography after IV injection of a 0.25 or 1.0 mg/kg dose. The rats were preclassified on the basis of their serum free fraction of warfarin; animals with free fraction values of approximately 0.004 and 0.01 and corresponding differences in elimination half-life were selected for study, yielding four experimental groups. Several rats of each group were sacrificed periodically over approximately 80–240 h for determination of drug concentrations. S-warfarin concentrations in serum declined apparently exponentially over at least one order of magnitude. During this time, concentrations in all other assayed tissues declined much more slowly. In another experiment, S-warfarin concentrations in serum and liver were followed for approximately 50 days after IV injection of a 1 mg/kg dose. This revealed a terminal, very slow elimination phase in serum nearly parallel to the decline in liver drug concentrations. Simultaneous physiologic modeling of all data (30 equations) using ADAPT II (Biomedical Simulations Resource, Los Angeles, CA), with intrinsic clearance, the dissociation constant of the warfarin-high affinity binding site complex, and two binding parameters for the (unassayed) remainder tissue compartment as parameters of unknown value, yielded very good fittings and parameter estimates with relatively small standard deviations. The unusual dose-dependent accumulation characteristics of this type of drug during continuous infusion are demonstrated by computer simulation of published results of warfarin infusions in rats. Utilization of a model premised on similar target-mediated drug disposition also allowed characterization of data from the literature for racemic warfarin pharmacokinetics in man. © 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:985–994, 2003

Length of stay (LOS) is an important measure of hospital activity and health care utilization, but its empirical distribution is often positively skewed.

Abstract. The assessment of DNA mixtures with the presence of relatives is discussed in this paper. The kinship coefficients are incorporated into the evaluation of the likelihood ratio and we first derive a unified expression of joint genotypic probabilities. A general formula and seven types of detailed expressions for calculating likelihood ratios are then developed for the case that a relative of the tested suspect is an unknown contributor to the mixed stain. These results can also be applied to the case of a non-tested suspect with one tested relative. Moreover, the formula for calculating the likelihood ratio when there are two related unknown contributors is given. Data for a real situation are given for illustration, and the effect of kinship on the likelihood ratio is shown therein. Some interesting findings are obtained.

In countries with multiple racial or ethnic groups, it is not uncommon that contributors to a mixed stain or a DNA mixture belong to different ethnic origins. This paper derives a general formula for evaluating the likelihood ratio in such situations based on the commonly adopted Recommendation 4.1 of the U.S. Second National Research Council Report on the evaluation of DNA evidence. The restrictive Hardy–Weinberg assumption is not taken in this paper. Our formula generalizes the results of Fung and Hu for a single ethnic group, and of Weir et al.under the Hardy–Weinberg law for a single, and Fukshansky and Bär for multiple ethnic groups. The effect of different ethnic groups of contributors to the interpretation of mixtures is illustrated through the analysis of the Simpson case. Copyright © 2002 John Wiley & Sons, Ltd.

The effect of a structured population on the evaluation of forensic mixed stains has been considered by the authors and others. However, in countries with multiple racial or ethnic groups, it is not uncommon that contributors to a DNA mixture are of different ethnic groups. A famous example is the OJ Simpson case in which the suspect was an African-American, the victims were Caucasian Americans and the true perpetrator(s) could be from any ethnic group(s). In this paper six common mixture cases are considered and the formulae for likelihood ratios are derived. These formulae can help forensic DNA scientists acquire a better understanding of the problem. The effect of different ethnic groups is illustrated using a case in Hong Kong.

In parentage testing using DNA markers, the formulae for calculating the probability of exclusion generally overstate the power of a test battery by considering its ability to exclude a random man. It is know that in many cases, in particular immigration applications, the false father is more likely to be a relative, e.g. brother, of the true father than an unrelated man. This work presents formulae that take this consideration into account. A practical example using Hong Kong data is provided to illustrate the effect of the modification. Also discussed is how the expected efficacy of a test battery will be affected when possible mutations and null alleles or genetic inconsistencies are taken into consideration.

In principal components analysis, the influence function and local influence approaches have been well established as important diagnostic tools. In this article, we first review the generalized local influence approach in the restricted likelihood framework. We then apply the restricted likelihood local influence diagnostic in the common principal components analysis. One special part of this local influence result is an elliptical norm of the empirical influence function, which is comparable to the deletion diagnostic scaled by the same matrix which requires iterative solutions for parameter estimates with every case deleted. Local influence diagnostics are constructed by some basic building blocks that are obtained directly from the maximum likelihood estimates of the parameters, and which are based on the original data and thus require less computation. A numerical example illustrates the technique and some joint influence effects are identified by the proposed method.

This report summarizes the results of two double‐blind, single‐center, randomized studies that used a two‐period crossover design. The objective of these two studies was to compare the safety, tolerability, pharmacokinetics, and pain score at the subcutaneous (sc) injection site of a phosphate‐buffered recombinant human erythropoietin (EPREX®, epoetin alfa, r‐HuEPO) formulated with a new stabilizer (glycine and Polysorbate 80) with the commercially available EPREX® formulations, which uses human serum albumin (HSA) as the stabilizer. Twenty‐four healthy male volunteers were enrolled in each of the two studies. In the first study, subjects received a single 150 IU/kg sc dose of r‐HuEPO using the 2000 IU/mL (2K) phosphate‐buffered formulation with or without the new stabilizer (12 subjects/group). In the second study, subjects received a single 750 IU/kg sc dose of r‐HuEPO using the 40 000 IU/mL (40K) phosphate‐buffered formulation with or without the new stabilizer (12 subjects/group). In each study, r‐HuEPO was administered over two separate dosing periods, each separated with a 28‐day washout period. There were no significant differences in AUC and Cmaxfor either strength of r‐HuEPO formulated with or without the new stabilizer, indicating that the absorption and disposition characteristics of the two formulations were similar after sc administration. Both r‐HuEPO strengths with and without the new stabilizer were safe and well tolerated; the safety and tolerability profiles of both formulations for each r‐HuEPO concentration were comparable. There were no statistically significant differences in pain score for either strength of r‐HuEPO with and without the new stabilizer. It was concluded that the two phosphate‐buffered r‐HuEPO concentrations formulated with and without the new stabilizer are pharmacokinetically equivalent. Copyright © 2000 John Wiley & Sons, Ltd.

This report summarizes the results of two double-blind, single-center, randomized studies that used a two-period crossover design. The objective of these two studies was to compare the safety, tolerability, pharmacokinetics, and pain score at the subcutaneous (sc) injection site of a phosphate-buffered recombinant human erythropoietin (EPREX®, epoetin alfa, r-HuEPO) formulated with a new stabilizer (glycine and Polysorbate 80) with the commercially available EPREX® formulations, which uses human serum albumin (HSA) as the stabilizer. Twenty-four healthy male volunteers were enrolled in each of the two studies. In the first study, subjects received a single 150 IU/kg sc dose of r-HuEPO using the 2000 IU/mL (2K) phosphate-buffered formulation with or without the new stabilizer (12 subjects/group). In the second study, subjects received a single 750 IU/kg sc dose of r-HuEPO using the 40 000 IU/mL (40K) phosphate-buffered formulation with or without the new stabilizer (12 subjects/group). In each study, r-HuEPO was administered over two separate dosing periods, each separated with a 28-day washout period. There were no significant differences in AUC and Cmax for either strength of r-HuEPO formulated with or without the new stabilizer, indicating that the absorption and disposition characteristics of the two formulations were similar after sc administration. Both r-HuEPO strengths with and without the new stabilizer were safe and well tolerated; the safety and tolerability profiles of both formulations for each r-HuEPO concentration were comparable. There were no statistically significant differences in pain score for either strength of r-HuEPO with and without the new stabilizer. It was concluded that the two phosphate-buffered r-HuEPO concentrations formulated with and without the new stabilizer are pharmacokinetically equivalent. Copyright © 2000 John Wiley & Sons, Ltd.

We consider S-estimators of multivariate location and common dispersion matrix in multiple populations. Instead of averaging the robust estimates of the individual covariance matrices, as used by Todorov, Neykov and Neytchev (1990), the observations are pooled for estimating the common covariance more efficiently. Two such proposals are evaluated by a breakdown point analysis and Monte Carlo simulations. Their applications to the discriminant analysis are also considered.

The Weibull family of distributions is frequently used in failure time models. The maximum likelihood estimator is very sensitive to occurrence of upper and lower outliers, especially when the hazard function is increasing. We consider the method of medians estimator for the two-parameter Weibull model. As an M-estimator, it has a bounded influence function and is highly robust against outliers. It is easy to compute as it requires solving only one equation instead of a pair of equations as for most other M-estimators. Furthermore, no assumptions or adjustments are needed for the estimator when there are some possibly censored observations at either end of the sample. About 16 per cent of the largest observations and 34 per cent of the smallest observations may be censored without affecting the calculations. We also present a simple criterion to choose between the maximum likelihood estimator and the method of medians estimator to improve on the finite-sample efficiency of the Weibull model. Robust inference on the shape parameter is also considered. The usefulness with contaminated or censored samples is illustrated by examples on three lifetime data sets. A simulation study was carried out to assess the performance of the proposed estimator and the confidence intervals of a variety of contaminated Weibull models. Copyright © 1999 John Wiley & Sons, Ltd.

The Weibull family of distributions is frequently used in failure time models. The maximum likelihood estimator is very sensitive to occurrence of upper and lower outliers, especially when the hazard function is increasing. We consider the method of medians estimator for the two‐parameter Weibull model. As an M‐estimator, it has a bounded influence function and is highly robust against outliers. It is easy to compute as it requires solving only one equation instead of a pair of equations as for most other M‐estimators. Furthermore, no assumptions or adjustments are needed for the estimator when there are some possibly censored observations at either end of the sample. About 16 per cent of the largest observations and 34 per cent of the smallest observations may be censored without affecting the calculations. We also present a simple criterion to choose between the maximum likelihood estimator and the method of medians estimator to improve on the finite‐sample efficiency of the Weibull model. Robust inference on the shape parameter is also considered. The usefulness with contaminated or censored samples is illustrated by examples on three lifetime data sets. A simulation study was carried out to assess the performance of the proposed estimator and the confidence intervals of a variety of contaminated Weibull models. Copyright © 1999 John Wiley & Sons, Ltd.

Object functions other than the likelihood displacement, such as a parameter estimate or a test statistic, can also be used in local influence analysis. The normal curvatures of these object functions have been studied in situations where the slopes were non-zero. In these situations, we show that the normal curvature is not scale invariant and thus ambiguous conclusions will be drawn. Comments on the application of the general normal curvature formula are presented.

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The potential advantages and disadvantages of incorporating an immediate-release (IR) component in sustained-release formulations with zero-order release characteristics (SR) are discussed. The dose of the IR component for SR doses other than the first one (DIS) should be less than that for the first SR dose (DI). Multiple dosing of an SR formulation with an IR component of dose DImay lead to unnecessary accumulation and fluctuation of plasma drug concentrations. An innovative and practical method for estimating the DIand DISdoses of this IR component is also presented.

Different schemes of perturbation can be adopted in the method of local influence on multiple regression analysis such as perturbation in case-weights, explanatory variables and response variables. These are generalized to multivariate regression analysis. Sometimes a subset of parameters is also of interest in local influence analysis. Kim (1995) has considered only the case-weights perturbation with full parameters of interest in multivariate regression, but his formulation is complicated. The proof of the equivalence of his result and one of our formulae is given. In this paper, all results derived are comparable to those obtained for multiple regression. An illustrative example is shown for the application of local influence in multivariate regression.

A study was conducted to investigate the effects of learning Logo programming on the transfer of problem solving skills. Sixty children (of 8 to 12 years) were divided into three groups (Logo Process-Oriented Group, Logo Content-Oriented Group, and Typing Control Group). All children were assessed on a variety of problem solving tasks before and after training. All groups were given twenty-five hours of small-group instruction in either Logo programming or typing lessons with a computer. Significant group × prepost interaction was observed in one of the problem solving tasks used in measuring the transfer of problem solving skills from the Logo context to a noncomputing context, leading to the conclusion that learning Logo with a Process-oriented approach might enhance general problem solving skills. However, much more empirical work will be required before it can be established what conditions will foster the transfer of problem solving skills.

Autopsy material comprising a total of 58 specimes of the temporal bone and the proximal part of the mandible was investigated tomographically and by microtome in comparative layers. Microradiographs and histologic sections were used as the main sources of information to determine the length dimensions of the different parts of the external auditory canal. The morphology and its developmental variations are compared and described. The diagnostic implications are discussed. In the authors' opinion, tomography is the method of choice to illustrate the morphologic properties of the external auditory canal. It is suggested that when the tomographic image reveals morphologic developmental or pathologic defects which give rise to problematic diagnosis, a control examination of the contralateral side should be performed.

Nilvadipine was administered as an oral solution formulation to 12 normotensive subjects in a three‐way randomized crossover study at at dose of 16 mg as three different dosing regimens: 1) as a single 16 mg dose, 2) as a 1.6 mg dose given hourly for 10 doses, and 3) as an initial dose of 4.8 mg, followed by 1.6 mg doses given every hour for seven additional doses. After each dose, clinical effects, hemodynamic changes and the pharmacokinetic profile of the drug were determined. The mean maximum changes in diastolic (DBP) and systolic (SBP) blood pressure and heart rate (HR) after dosing regimens 1, 2, and 3 were: −33, −13 and +46%; −17, −14 and +38%; and −24, −14 and +36%, respectively. There was a relationship between the changes in DBP and HR and plasma concentrations of nilvadipine only after dosing regimen 1. The effect‐concentration relationships were fit to a modified Emaxmodel. There was no relationship between the change in SBP and plasma concentration after any of the dosing regimens. While there were no significant differences in the mean area under the plasma concentration‐time curve (AUC0→∞) between dosing regimens 2 (38.7 ng ṁ hr/mL) and 3 (42.1 ng ṁ hr/mL) (P > 0.05), the mean AUC0→∞after regimen 1 (76.3 ng ṁ hr/mL) was significantly greater than after dosing regimens 2 or 3 (P < 0.05). The mean maximal plasma concentrations (Cmax) were 31.6, 1.3 and 6.3 ng/mL after dosing regimens 1, 2 and 3, respectively. Overall the results showed that nilvadipine caused changes in blood pressure and HR and that the largest changes were seen with dosing regimen 1, where peak plasma concentrations were greater than about 10 ng/mL.

The purpose of this study was to determine the prevalence of coprophagy in rats with differing iron status and its effect on the measurement of iron absorption from test meals with and without bran. Two experiments were performed using radioisotope-labelled microspheres added as a non-digestible marker for the ingested faeces and the diet and 59Fe added as a marker for the non-haem iron in the test meal.In this study, coprophagy occurred at group mean rates of between 5 and 22% and was independent of the iron status of the rats or the presence or absence of bran in the diet. The relative absorption of iron, measured as the retention of 59Fe from a single meal, was affected to the same extent in groups with the same iron status, if it was affected at all. Thus comparisons of iron absorption from diets with and without bran should not be affected by coprophagy.

A simple and concise finite-difference algorithm is presented for the solution of non-Fourier one-dimensional heat conduction. The numerical algorithm is developed by applying the Godunov scheme on the characteristic equations that govern thermal waves within the medium. A vigorous investigation of the order of accuracy and stability of the procedure is presented. Several heat conduction problems are tested with the scheme, and the predicted temperature field is verified by comparing with results available in the literature. The accuracy of the solution is limited only by the selection of the mesh width in the space and time directions. The solution is free of oscillation, while the dissipation error associated with the numerical scheme in the wave front is controlled by specifying the proper Courant-Fredrichs-Lewy (CFL) condition. The algorithm provides a convenient, accurate, and efficient approximation to the hyperbolic heat conduction equation. It is evident that the procedure is beneficial for the study of propagation and reflection of thermal waves in solids.

The 1H nuclear magnetic resonance spectra of ethylbenzene-β-13C in CS2/C6D12and acetone-d6solutions yield long-range 1H,1H and 1H,13C coupling constants. The 13C {1H} NMR spectra yield 13C, 13C couplings. The conformational dependence of some of these coupling constants is compatible with two values of the barrier to internal rotation about the exocyclic Csp2—Csp3bond. If the fourfold component of the internal rotational potential is not larger than about 20% of the twofold component and the perpendicular conformer is most stable, then the barrier height is probably less than 6 kJ/mol. However, if the stable conformer has a torsion angle of 60° for the exocyclic C—C bond, then the coupling constants are consistent with a twofold barrier of about 23 kJ/mol. Experimental values of and , where ψ and θ are the torsion angles for the exocyclic C—C and C—H bonds, respectively, are compared to those obtained from INDO MO FPT computations of the angular dependence of nJ(H,C), and nJ(H,H), nJ(C,C) for n ≥ 3. For example, the computations very likely give the correct qualitative ψ dependence of 5J(C,C), yet overestimate its extremum by about a factor of two, either because of an overestimate of the σ–π exchange integrals or because of too large a valence orbital density at the carbon nucleus. Other nJ values are discussed in a similar manner and, because optimized geometries are used in the computations, a somewhat more reliable treatment arises for some coupling constants; an example is 3J(C,C) at small torsion angles.

To understand the pharmacokinetic and pharmacodynamic properties of recombinant human erythropoietin (epoetin alfa) and to continue to optimize dosing regimens by determining whether administration of single high doses of epoetin alfa is as effective as repeated administration. Epoetin alfa was administered as single subcutaneous doses of 300, 450, 600, 900, 1200, 1350, 1800, and 2400 IU/kg and in multiple subcutaneous dose regimens: 150 IU/kg 3 times a week for 4 weeks and 600 IU/kg once per week for 4 weeks in 2 open‐label, randomized placebo‐controlled studies in healthy volunteers. The absorption rate of epoetin alfa after subcutaneous administration was independent of dose, whereas clearance was dose‐dependent in that it decreased with increasing dose. There was a linear relationship between response measured as percentage of reticulocytes area under the curve (AUC) and erythropoietin AUC for single doses up to 1800 IU/kg. Beyond the 1800 IU/kg dose, there was a saturation of response. The mean percentage of reticulocytes after single‐dose regimens began to increase by days 3 to 4, reached their maximum at days 8 to 11, and returned to baseline values by day 22. In contrast, the mean percentage of reticulocytes after both multiple‐dose regimens were maintained above baseline values through day 22 as both regimens stimulated modest but sustained increases in percentage of reticulocytes (1% to 2%). The mean percentage of reticulocytes AUC for 600 IU/kg epoetin alfa given once a week for 4 weeks was apparently greater than the mean percentage of reticulocytes AUC for 150 IU/kg 3 times a week for 4 weeks. Although daily oral iron supplementation was given, mean serum ferritin levels declined by approximately 75% through day 22 in subjects treated with multiple doses of epoetin alfa. These findings show that the pharmacologic response to epoetin alfa is a function of dose and dosing regimen. Repeated administration of epoetin alfa was more effective in stimulating a reticulocyte response than single‐dose administration of the same total amount of epoetin alfa. Clinical Pharmacology & Therapeutics(1998) 64, 412–423; doi:

Histamine release is part of the general inflammatory response and occurs during surgery and cardiopulmonary bypass (CPB) in adults. Few data are available for children. Histamine release was studied in 23 children undergoing CPB with standard anaesthetic and CPB techniques. Blood sampling was performed in relation to specific anaesthetic and surgical events, e.g., start of CPB, removal of aortic clamps, reventilation of the lungs. Plasma histamine was determined by a single isotope radioenzymatic technique. There was no consistent histamine release in the study population although there was an increase in plasma histamine concentration in some subjects after initiation of CPB (P<0.05) and on removal of the aortic cross-clamp (P<0.05). No correlation was demonstrated between histamine concentration and systolic arterial pressure, temperature, duration of CPB or cross-clamp time. Histamine concentration was positively correlated with heart rate.

A rare case of mandibular odontogenic fibroma is presented which transformed to a stage 1A odontogenic fibrosarcoma with a local recurrence after surgical resection and unusually delayed pulmonary metastases eight years later. Prolonged follow‐up of these patients after complete surgical resection, including regular chest X‐rays, is recommended.

A new class of anti-juvenile hormone agents is described. Active anti-juvenile hormone compounds were either diazine thiosemicarbazones or aryl substituted pyridyl thiosemicarbazones, synthesized from substituted benzaldehydes. While many analogs in these classes showed feeding and growth inhibition in a variety of insects, a select group caused formation of precocious pupal characteristics inAgrotis ipsilon(black cutworm) andHeliothis virescens(tobacco budworm) and black cuticle and precocious pupae inManduca sexta(tobacco hornworm). They were active only by diet incorporation. The symptoms of precocious development could be reversed by co-administration of a juvenoid. One of the active compounds was shown to inhibit juvenile hormone biosynthesis in vitro by corpora allata of the cockroachDiploptera punctata. However, none of the compounds were active inhibitors of purified chicken liver prenyl transferase.

A method is shown for estimating the reliability of structural components subject to fatigue crack growth. The method is general in that it can be used in conjunction with any crack‐growth law and either first‐ or second‐order reliability techniques. The initial crack length, final crack length, and crack‐growth parameters are taken as uncertain with known probability distributions, and the reliability is calculated by determining the probability that the component will survive to some desired service life. The method accounts for the effect of structural configuration on crack growth and can be adapted to take advantage of finite element methodologies. Two examples demonstrate the method. In the first example, the component is inspected and taken out of service when the crack length reaches a predetermined value. In the second example, the component is kept in service until the fracture toughness of the material is exceeded. In both examples the Wei‐bull distribution is used to show the relation between the method and standard time‐dependent reliability techniques.