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Improving IMRT dose accuracy via deliverable Monte Carlo optimization for the treatment of head and neck cancer patients.

The purpose of this work is to investigate the effect of dose-calculation accuracy on head and neck (H&N) intensity modulated radiation therapy (IMRT) plans by determining the systematic dose-prediction and optimization-convergence errors (DPEs and OCEs), using a superposition/convolution (SC) algorithm. Ten patients with locally advanced H&N squamous cell carcinoma who were treated with simultaneous integrated boost IMRT were selected for this study. The targets consisted of gross target volume (GTV), clinical target volume (CTV), and nodal target volumes (CTV nodes). The critical structures included spinal cord, parotid glands, and brainstem. For all patients, three IMRT plans were created: A: an SC optimized plan (SCopt), B: an SCopt plan recalculated with Monte Carlo [MC(SCopt)], and C: an MC optimized plan (MCopt). For each structure, DPEs and OCEs were estimated as DPE(SC)=D(B)-D(A) and OCE(SC)=D(C)-D(B) where A, B, and C stand for the three different optimized plans as defined above. Deliverable optimization was used for all plans, that is, a leaf-sequencing step was incorporated into the optimization loop at each iteration. The range of DPE(SC) in the GTV D98 varied from -1.9% to -4.9%, while the OCE(SC) ranged from 0.9% to 7.0%. The DPE(SC) in the contralateral parotid D50 reached 8.2%, while the OCE(SC) in the contralateral parotid D50 varied from 0.91% to 6.99%. The DPE(SC) in cord D2 reached -3.0%, while the OCE(SC) reached to -7.0%. The magnitude of the DPE(SC) and OCE(SC) differences demonstrate the importance of using the most accurate available algorithm in the deliverable IMRT optimization process, especially for the estimation of normal structure doses.

Algorithms↗

A versatile method for planning stereotactic brain implants.

Our approach to planning stereotactic 125I brachytherapy of brain tumors has involved least-squares optimization of individual seed positions within the target contour, followed by repeated combining of seeds from nearest-neighbor catheters in order to achieve an acceptably low number of catheters and an acceptable-separation of entry points. In one option, the catheters diverge from an extra-cranial point that can be close to the skull if all catheters are to be placed through a small craniectomy to treat a larger-diameter target. In another option, catheters converge toward a point beyond the target, to facilitate perpendicularity at the skull surface if a separate opening is to be drilled for each catheter. In either case, the fact that seed orientations are known, permits including anisotropy in dose calculations. Trial seed locations are constrained to a target region defined on a 1-mm mesh, both in the initial optimization of single-seed catheters and in subsequent combinations followed by tune-up optimizations. In the optimization process, sum-of-squares contributions are weighted more heavily when the dose rate is lower than the target dose rate; the weighting imbalance falls short of keeping all target points above the target dose rate and requires targeting on a dose rate about 25% higher than the desired minimum dose rate.

Biophysical Phenomena↗

A multiresolution restoration method for cardiac SPECT imaging.

In this study we present a multiresolution based method for restoring cardiac SPECT projections. Original projections were decomposed into a set of sub-band frequency images by using analyzing functions localized in both the space and frequency domain. This representation allows a simple denoising and restoration procedure by discarding high-frequency channels and performing inversion only in low frequencies. The method was evaluated in bull's eye reconstructions of a realistic cardiac chest phantom with a custom-made liver insert and 99mTc liver-to-heart activity ratios (LHAR) of 0:1, 1.5:1, 2.5:1, and 3.5:1. The cardiac phantom in free air was used as the reference standard. Reconstructions were performed by filtered backprojection using (1) no correction; (2) restoration without attenuation correction; (3) attenuation correction without restoration; and (4) restoration and attenuation correction. The attenuation correction was carried out with the Chang's method for one iteration. Results were compared with those obtained using an optimized prereconstruction Metz filter. Quantitative analysis was performed by calculating the normalized chi-square measure and mean +/- s.d. of bull's eye counts. In reconstructions with high liver activity (LHAR > 2), attenuation correction without restoration severely distorted the polar maps due to the spill-over of liver activity into the inferior myocardial wall. Both restoration methods when combined with an attenuation correction compensated this artifact and yielded uniform polar maps similar to that of the standard reference. There was no visual or quantitative difference between the performance of Metz filtering and multiresolution restoration. However, the main advantage of the multiresolution method is that it states a more concise and straightforward approach to the restoration problem. Multiresolution based methods does not require information about the object image or optimization processes, such as in conventional nuclear medicine restoration filters. In addition, the method is easy to implement using DFT techniques and potentially can be extended to noniterative spatially shift-invariant restorations in SPECT.

Biophysical Phenomena↗

Passively minimizing structural sound radiation using shunted piezoelectric materials.

Two methods are presented to determine optimal inductance and resistance values of the shunt circuit across a piezoceramic material, which is bonded to a simply supported plate in order to minimize sound radiation from the plate. The first method (DH) makes use of den Hartog's damped vibration absorber principle. The second method (SM) uses the Sherman Morrison matrix inversion theorem. The effectiveness of each method is compared with regard to minimizing total acoustic sound-power radiation and acoustic pressure at a point. Optimization algorithms and case studies are presented using a linearized model for the piezoceramic and using a nonlinear model for the piezoceramic that accounts for the inherent dielectric hysteresis. Case studies demonstrate that the second method (SM) results in superior performance, under both linear and nonlinear system assumptions. Studies also illustrate that, if the nonlinearity in the system is significant, it must be incorporated in the optimization process.

Journal Article↗

Lateral-position-based models of interaural discrimination.

This letter investigates the hypothesis that lateral position is the only cue available for interaural discrimination experiments using 500-Hz stimuli. The discussion of this hypothesis is in the context of comparisons of the experimental data to predictions of the "position-variable" model of binaural interaction. The model predicts the mean and variance of the subjective lateral position of stimuli used in the discrimination experiments, assuming that discrimination performance is based on optimal processing of this subjective position. To the extent that the laterality predictions of the model are accurate, data that are inconsistent with its predictions would also be problematical for any model based on the subjective laterality of a single binaural image. The predictions (at least qualitatively) describe much of the observed experimental data, including a number of results that have not been addressed by any previous theory. Nevertheless, the observed performance is significantly better than the corresponding predictions for three types of experiments in which the utility of the position cue has been eliminated by experimental design. We believe that our results indicate that changes in lateral position are the primary cue in most interaural discrimination experiments, but that secondary attributes of the perceptual images can be useful when performance based on position alone would be poor.

Auditory Perception↗

Development and evaluation of a German sentence test for objective and subjective speech intelligibility assessment.

A German sentence test was developed which is comprised of 20 test lists of ten sentences each. The test corpus is a selection from sentences for speech quality evaluation recorded with a male unschooled speaker. Performance-intensity curves were measured for each individual sentence in a speech-simulating babble noise with a total of 40 normal-hearing listeners. Based on these data and the phonemic transcription of the 200 sentences selected from the underlying speech corpus, 20 test lists were composed using a numerical optimization process. These 20 test lists are highly equivalent with respect to their performance-intensity curves, the number of words within each test list, the number of phonemes within each test list, and approximately the frequency distribution of the phonemes which approximates the phoneme frequency distribution of the German language. The equivalence of the respective performance-intensity curves was demonstrated in an independent experiment with 20 normal-hearing listeners. In addition, a comparison was performed between the "objective" intelligibility measurements and two "subjective" speech intelligibility rating methods employing the same materials. As a result, both subjective assessment procedures correlate highly with each other and with the "objective" procedure across sentences. This underlines the applicability and validity of the test in combination with time-saving subjective assessment methods. Moreover, the variability in performance across different sentences correlates inversely with the RMS level of the respective sentence. This indicates that an adjustment of sentence material with respect to RMS level already yield reasonably homogeneous test material with respect to intelligibility.

Adult↗

Path curvature in workspace and in joint space: evidence for coexisting coordinative rules in aiming.

In this study we tried to establish whether point-to-point aiming movements are planned in workspace, joint space, or both. Eight right-handed subjects performed horizontal, vertical, and diagonal aiming movements on a transversal plane. Movements were performed at several speeds. Curvature variations of the hand and corresponding joint-space paths were investigated as a function of position, direction, and speed. Straightness of hand paths predominated for vertical movements but was systematically violated for horizontal and top-right to bottom-left movements. Furthermore, the hand-path curvature of the latter movements increased with speed. Joint-space paths showed more deviation from a straight line than hand paths except for top-left to bottom-right movements in which the paths were equally curved. A comparison of normalized path curvatures at the hand and joint level indicated that in aiming, the coordinative rule of straight-line production seems to apply to both workspace and joint-space planning. The present findings confirm Kawato's (1996) views that optimization processes operate concurrently at the two control levels of arm-trajectory formation under study.

Humans↗

Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in rat plasma.

The routine assessment of xenobiotic in vivo kinetic behavior is currently dependent upon data obtained through animal experimentation, although in vitro surrogates for determining key absorption, distribution, metabolism, and elimination properties are available. Here we present a unique, generic, physiologically based pharmacokinetic (PBPK) model and demonstrate its application to the estimation of rat plasma pharmacokinetics, following intravenous dosing, from in vitro data alone. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature and validated using a separate test set of in vivo discovery compound data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was approximately 0.5 log unit. Around 70% of all the predicted values of a standardized measure of area under the concentration-time curve (AUC) were within 3-fold of the observed values, as were over 90% of the training set t1/2 predictions and 60% of those for the test set; however, there was a tendency to overpredict t1/2 for the test set compounds. The capability of the model to rank compounds according to a given criterion was also assessed: of the 25% of the test set compounds ranked by the model as having the largest values for AUC, 61% were correctly identified. These validation results lead us to conclude that the generic PBPK model is potentially a powerful and cost-effective tool for predicting the mammalian pharmacokinetics of a wide range of organic compounds, from readily available in vitro inputs only.

Algorithms↗

Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in human plasma.

Estimation of xenobiotic kinetics in humans frequently relies upon extrapolation from experimental data generated in animals. In an accompanying paper, we have presented a unique, generic, physiologically based pharmacokinetic model and described its application to the prediction of rat plasma pharmacokinetics from in vitro data alone. Here we demonstrate the application of the same model, parameterized for human physiology, to the estimation of plasma pharmacokinetics in humans and report a comparative evaluation against some recently published predictive methods that involve scaling from in vivo animal data. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature, and validated using a separate test set of published in vivo data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was 0.47 log unit. For the training set, more than 80% of the predicted values of a standardized measure of the area under the concentration-time curve were within 3-fold of the observed values; over 70% of the test set predictions were within the same margin. Furthermore, in terms of predicting human clearance for the test set, the model was found to match or exceed the performance of three published interspecies scaling methods, all of which showed a distinct bias toward overprediction. We conclude that the generic physiologically based pharmacokinetic model, as a means of integrating readily determined in vitro and/or in silico data, is potentially a powerful, cost-effective tool for predicting human xenobiotic kinetics in drug discovery and risk assessment.

Acecainide↗

Isolation of Listeria monocytogenes from raw milk.

During a recent outbreak of listeriosis, we examined 121 raw milk samples and 14 milk socks (filters). Listeria monocytogenes was recovered from 15 (12%) of 121 milk specimens and 2 (14%) of 14 milk socks. The optimal processing method consisted of cold enriching diluted milk for 1 month with culture to selective broth, followed by plating.

Agar↗

Timing of inoculation of the pouch makes no difference in increased detection of Trichomonas vaginalis by the InPouch TV method.

The InPouch TV is a method which combines a wet preparation and a culture method to detect Trichomonas vaginalis. The top portion of the InPouch TV essentially functions as a slide to be examined under the microscope. If the initial examination is negative, the specimen is pushed down into the bottom pouch, which serves as a broth for cultivation. The issue of timing has not been specifically addressed for optimal processing. To assess the effect of timing on the inoculation of the bottom pouch, we conducted a study designed to determine which procedure had better sensitivity, that of delaying inoculation of the bottom pouch until the initial examination on the top pouch is performed (method A) or that of immediately inoculating the bottom pouch (method B). In addition, we compared the sensitivity of the InPouch TV to that of the traditional wet mount. Fifty of 498 specimens were positive. Methods A and B had identical results: 31 specimens were initially positive regardless of transit time, and incubation yielded another 19 positives. The wet preparation detected 36 positive specimens. The sensitivities of the methods were 100% for the InPouch TV (including examination on receipt and after incubation) and 72% for the traditional wet mount. In conclusion, the InPouch TV method is more sensitive than the traditional method and no detectable differences were observed with timing of the inoculation of the top or bottom pouch.

Animals↗

The herpes simplex virus 1 U(L)34 protein interacts with a cytoplasmic dynein intermediate chain and targets nuclear membrane.

To express the function encoded in its genome, the herpes simplex virus 1 capsid-tegument structure released by deenvelopment during entry into cells must be transported retrograde to the nuclear pore where viral DNA is released into the nucleus. This path is essential in the case of virus entering axons of dorsal root ganglia. The objective of the study was to identify the viral proteins that may be involved in the transport. We report the following findings. (i) The neuronal isoform of the intermediate chain (IC-1a) of the dynein complex pulled down, from lysates of [(35)S]methionine-labeled infected cells, two viral proteins identified as the products of U(L)34 and U(L)31 open reading frames, respectively. U(L)34 protein is a virion protein associated with cellular membranes and phosphorylated by the viral kinase U(S)3. U(L)31 protein is a largely insoluble, evenly dispersed nuclear phosphoprotein required for optimal processing and packaging of viral DNA into preformed capsids. Reciprocal pulldown experiments verified the interaction of IC-1a and U(L)34 protein. In similar experiments, U(L)34 protein was found to interact with U(L)31 protein and the major capsid protein ICP5. (ii) To determine whether U(L)34 protein is transported to the nuclear membrane, a requirement if it is involved in transport, the U(L)34 protein was inserted into a baculovirus vector under the cytomegalovirus major early promoter. Cells infected with the recombinant baculovirus expressed U(L)34 protein in a dose-dependent manner, and the U(L)34 protein localized primarily in the nuclear membrane. An unexpected finding was that U(L)34-expressing cells showed a dissociation of the inner and outer nuclear membranes reminiscent of the morphologic changes seen in cells productively infected with herpes simplex virus 1. U(L)34, like many other viral proteins, may have multiple functions expressed both early and late in infection.

Animals↗

Predictive control of nonlinear systems based on identification by backpropagation networks.

Using the property of universal approximation of multilayer perceptron neural network, a class of discrete nonlinear dynamical systems are modeled by a perceptron with two hidden layers. A backpropagation algorithm is then used to train the model to identify the nonlinear systems to a desired level of accuracy. Based on the identified model, a one-step-ahead predictive control scheme is proposed in which the future control inputs are obtained through some nonlinear optimization process. Making use of the online learning properties of neural networks, the predictive control scheme is further developed into an adaptive one which is robust to the incompleteness of identification. Simulation results show that this neural control scheme works well even for some very complicated nonlinear systems.

Mathematics↗

Assessment of mitochondrial membrane potential in proximal tubules after hypoxia-reoxygenation.

Proximal tubules develop a severe energetic deficit during hypoxia-reoxygenation (H/R) that previous studies using fluorescent potentiometric probes have suggested is characterized by sustained, partial mitochondrial deenergization. To validate the primary occurrence of mitochondrial deenergization in the process, optimize approaches for estimating changes in mitochondrial membrane potential (DeltaPsim) in the system, and clarify the mechanisms for the defect, we further investigated the behavior of 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazocarbocyanine iodide (JC-1) in these cells and introduce a more dynamic and quantitative approach employing safranin O for use with the tubule system. Although use of JC-1 can be complicated by decreases in the plasma membrane potential that limit cellular uptake of JC-1 and such behavior was demonstrated in ouabain-treated tubules, changes in DeltaPsim entirely accounted for the decreases in the formation of red fluorescent JC-1 aggregates and in the ratio of red/green fluorescence observed after H/R. The red JC-1 aggregates did not readily dissociate when tubules were deenergized after JC-1 uptake, making it unsuitable for dynamic studies of energization. Safranin O uptake by digitonin-permeabilized tubules required very small numbers of tubules, permitted measurements of DeltaPsim for relatively prolonged periods after the end of the experimental maneuvers, was rapidly reversible during deenergization, and allowed for direct assessment of both substrate-dependent, electron transport-mediated DeltaPsim, and ATP hydrolysis-supported DeltaPsim. Both types of energization measured using safranin O in tubules permeabilized after H/R were impaired, but combining substrates and ATP substantially restored DeltaPsim.

Acute Kidney Injury↗

Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke.

BACKGROUND AND PURPOSE: Hypothermia is effective in improving outcome in experimental models of brain infarction. We studied the feasibility and safety of hypothermia in patients with acute ischemic stroke treated with thrombolysis. METHODS: An open study design was used. All patients presented with major ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score >15) within 6 hours of onset. After informed consent, patients with a persistent NIHSS score of >8 were treated with hypothermia to 32+/-1 degrees C for 12 to 72 hours depending on vessel patency. All patients were monitored in the neurocritical care unit for complications. A modified Rankin Scale was measured at 90 days and compared with concurrent controls. RESULTS: Ten patients with a mean age of 71.1+/-14.3 years and an NIHSS score of 19.8+/-3.3 were treated with hypothermia. Nine patients served as concurrent controls. The mean time from symptom onset to thrombolysis was 3.1+/-1.4 hours and from symptom onset to initiation of hypothermia was 6.2+/-1.3 hours. The mean duration of hypothermia was 47.4+/-20.4 hours. Target temperature was achieved in 3.5+/-1.5 hours. Noncritical complications in hypothermia patients included bradycardia (n=5), ventricular ectopy (n=3), hypotension (n=3), melena (n=2), fever after rewarming (n=3), and infections (n=4). Four patients with chronic atrial fibrillation developed rapid ventricular rate, which was noncritical in 2 and critical in 2 patients. Three patients had myocardial infarctions without sequelae. There were 3 deaths in patients undergoing hypothermia. The mean modified Rankin Scale score at 3 months in hypothermia patients was 3.1+/-2.3. CONCLUSION: Induced hypothermia appears feasible and safe in patients with acute ischemic stroke even after thrombolysis. Refinements of the cooling process, optimal target temperature, duration of therapy, and, most important, clinical efficacy, require further study.

Acute Disease↗

Intercalation/Exfoliation mechanism of hybrid formation in polypropylene/lamellar mesostructured silica nanocomposites.

Understanding the optimal processing conditions for the fabrication of polymer nanocomposites is of fundamental importance in designing materials with balance of properties. To understand these conditions in the case of maleic anhydride grafted polypropylene (PP-g-MA)/layered mesostructured silica (LMS) nanocomposites, the effect of temperature, shear rate, and residence time during processing on the structure of the nanocomposites were studied. The results showed that the combination of temperature, residence time, and mechanical shears have strong effect on the structure of the nanocomposites, rather than just interfacial interactions between the polymer matrix and silicate layers. However, interfacial interactions between the polymer matrix and silicate layers primarily play an important role to the intercalation of polymer chains into the silicate galleries. On the basis of our experimental results, a first explanation of the formulation mechanism of PP-g-MA/LMS nanocomposites is proposed. Finally, a general concept of processing conditions for manufacturing of polymer nanocomposites by melt-compounding process in a batch-mixer is described.

Nanotechnology↗

Biomechanical model for muscular dysfunction of the human pharynx using finite element analysis.

OBJECTIVES: The oropharynx functions to transport food from the oral cavity to the esophagus, as well as to maintain an air passage from the nose to the lungs. By combining data from prior material property experimentation, a 3-dimensional finite element method reconstruction of the pharynx, and the utilization of a optimization process based on an inverse dynamic approach, we can estimate the pressures and associated consecutive pressure gradients created internally when the pharynx functions during swallowing. METHODS: In this study, pharyngeal muscular dysfunction was modeled under 3 scenarios of increasing tissue stiffness. This was done by modifications in the stress-strain relationship material property within the finite element method nodes. This mechanical property was used as a surrogate for clinical changes in muscle function complicating neuromuscular disorders, such as stroke and amyotrophic lateral sclerosis. The pharyngeal tissue and deformation of the cross-sectional area of the pharynx were analyzed while increasing the mechanical stiffness by 25%, 50%, and 75%. RESULTS: Increases in stiffness resulted in modified pressure-area curves predicting diminished movement, primarily in stiffened regions. CONCLUSIONS: These simulation results may act as a clinical index illustrating the association between tissue dysfunction and pharyngeal pressure and movement dysfunction. This type of modeling has the potential to act as an investigational tool, as well as a predictive tool, regarding disease progression, cancer treatment, and perhaps even the effects of aging on swallowing function.

Biomechanical Phenomena↗

Recordings of mucociliary activity in vivo: benefit of fast Fourier transformation of the photoelectric signal.

Investigations of mucociliary activity in vivo are based on photoelectric recordings of light reflections from the mucosa. The alterations in light intensity produced by the beating cilia are picked up by a photodetector and converted to photoelectric signals. The optimal processing of these signals is not known, but in vitro recordings have been reported to benefit from fast Fourier transformation (FFT) of the signal. The aim of the investigation was to study the effect of FFT for frequency analysis of photoelectric signals originating from an artificial light source simulating mucociliary activity or from sinus or nasal mucosa in vivo, as compared to a conventional method of calculating mucociliary wave frequency, in which each peak in the signal is interpreted as a beat (old method). In the experiments with the artificial light source, the FFT system was superior to the conventional method by a factor of 50 in detecting weak signals. By using FFT signal processing, frequency could be correctly calculated in experiments with a compound signal. In experiments in the rabbit maxillary sinus, the spontaneous variations were greater when signals were processed by FFT. The correlation between the two methods was excellent: r = .92. The increase in mucociliary activity in response to the ciliary stimulant methacholine at a dosage of 0.5 microgram/kg was greater measured with the FFT than with the old method (55.3% +/- 8.3% versus 43.0% +/- 8.2%, p < .05, N = 8), and only with the FFT system could a significant effect of a threshold dose (0.05 microgram/kg) of methacholine be detected. In the human nose, recordings from aluminum foil placed on the nasal dorsum and from the nasal septa mucosa displayed some similarities in the lower frequency spectrum (< 5 Hz) attributable to artifacts. The predominant cause of these artifacts was the pulse beat, whereas in the frequency spectrum above 5 Hz, results differed for the two sources of reflected light, the mean frequency in seven healthy volunteers being 7.8 +/- 1.6 Hz for the human nasal mucosa. It is concluded that the FFT system has greater sensitivity in detecting photoelectric signals derived from the mucociliary system, and that it is also a useful tool for analyzing the contributions of artifacts to the signal.

Adult↗