Event marker compliance in actigraphy.

Actigraphy is a versatile tool for evaluating sleep-wake cycles over time in the home-environment. Patients using the Phillips Actiwatch place an event marker when going to sleep and upon awakening. We investigate compliance in pressing the Actiwatch event marker button for patients referred for insomnia, hypersomnia and disorders of circadian rhythm. We retrospectively analysed event markers from 150 patients undergoing actigraphy for 2,117 nights combined. Compliance was evaluated from inspection of actigraphy records, and coded as full or partial. From patient records, a construct called the C-factor, designed to describe poor social resources and chronic unemployment, was used together with age and sex to predict compliance. We found a mean compliance between 54.0% and 76.3% for a median monitoring duration of 14 days. There was an overall insignificant effect of age (p = .081), but when analysed only for females there was a significant effect of 0.56% pr. year (p = .0038). Compliance was higher for women, Cohen's d = 0.65 (p = .01). The C-factor predicts 18.3% (confidence interval 9%-27.5%) lower compliance. Morning and evening compliance are correlated at r = .65. In conclusion, actigraphy event marker compliance is generally moderate or high, with older women exhibiting the highest compliance. C-factor predicts lower compliance, and this pattern may further translate to other circumstances. If compliance is important, clinicians may want to consider the effects of age, sex and C-factor.

Integrating a MRI scanner with a 6 MV radiotherapy accelerator: dose deposition in a transverse magnetic field.

Integrating magnetic resonance imaging (MRI) functionality with a radiotherapy accelerator can facilitate on-line, soft-tissue based, position verification. A technical feasibility study, in collaboration with Elekta Oncology Systems and Philips Medical Systems, led to the preliminary design specifications of a MRI accelerator. Basically the design is a 6 MV accelerator rotating around a 1.5 T MRI system. Several technical issues and the clinical rational are currently under investigation. The aim of this paper is to determine the impact of the transverse 1.5 T magnetic field on the dose deposition. Monte Carlo simulations were used to calculate the dose deposition kernel in the presence of 1.5 T. This kernel in turn was used to determine the dose deposition for larger fields. Also simulations and measurements were done in the presence of 1.1 T. The pencil beam dose deposition is asymmetric. For larger fields the asymmetry persists but decreases. For the latter the distance to dose maximum is reduced by approximately 5 mm, the penumbra is increased by approximately 1 mm, and the 50% isodose line is shifted approximately 1 mm. The dose deposition in the presence of 1.5 T is affected, but the effect can be taken into account in a conventional treatment planning procedure. The impact of the altered dose deposition for clinical IMRT treatments is the topic of further research.

Magnetic fields with photon beams: use of circular current loops.

Strong transverse magnetic fields can produce very large dose enhancements and reductions in localized regions of a patient under irradiation by a photon beam. Through EGS4 Monte Carlo simulations, we have examined the effects of applying a magnetic field produced by a pair of circular current loops to a photon beam penetrating a water phantom of finite thickness. We have indeed found very substantial localized dose enhancements, albeit with no corresponding dose reduction just distal to the region of dose enhancement. (However, dose reduction does occur near the distal end of the phantom.) We have also observed two phenomena to be concerned with, for this configuration: significant broadening of the penumbra close to the current loop, and narrowness of the enhanced dose region in a plane parallel to the planes of the loops. We have also examined the use of a single current loop to produce the magnetic field, and have found great asymmetry in the dose distribution; this asymmetry appears to make it impossible to treat with a single circular magnet a tumor of large dimension extending below the application surface.

Production of an anti-prostate-specific antigen single-chain antibody fragment from Pichia pastoris.

Prostate-specific antigen (PSA) is a widely used marker for screening and monitoring prostate cancer. Because PSA levels are normally quite low, an antibody-based assay must be used to detect PSA. However, not all PSA-specific antibodies bind equally well to PSA or to its different isoforms. Therefore, a better understanding of how PSA interacts with PSA-specific antibodies is of considerable clinical interest. B80.3 is a widely used murine monoclonal anti-PSA antibody (IgG), which has very high affinity for both free and alpha-anti-chymotrypsin complexed PSA. More importantly, its gene sequence is known-making it one of only two anti-PSA antibodies that has been fully cloned and sequenced. To better elucidate the interaction between PSA and B80.3, a single-chain antibody fragment, derived from the variable domain of B80.3 (scFvB80), was cloned into a pPIC9 vector and expressed in Pichia pastoris. The secreted protein was purified using a three-step protocol beginning with a 50% ammonium sulfate precipitation step, followed by a T-gel thio-affinity step and concluding with a simple anion-exchange (DE52) filtration step. NMR studies indicate the protein is correctly folded while competitive enzyme-linked immunosorbant assays show that the purified scFvB80 has approximately 20% of the activity of the full-length B80.3 antibody. The protocol described here provides a quick and convenient route to prepare large quantities of very pure anti-PSA antibody fragments (15-20 mg/L culture medium) for detailed structural and biophysical characterization.

Magnetic fields with photon beams: dose calculation using electron multiple-scattering theory.

Strong transverse magnetic fields can produce large dose enhancements and reductions in localized regions of a patient under irradiation by a photon beam. We have developed a new equation of motion for the transport of charged particles in an arbitrary magnetic field, incorporating both energy loss and multiple scattering. Key to modeling the latter process is a new concept, that of "typical scattered particles." The formulas which we have arrived at are particularly applicable to the transport of, and deposition of energy by, Compton electrons and pair-production electrons and positrons generated within a medium by a photon beam, and we have shown qualitatively how large dose enhancements and reductions can occur. A companion article examines this dose modification effect through systematic Monte Carlo simulations.

Magnetic fields with photon beams: Monte Carlo calculations for a model magnetic field.

Strong transverse magnetic fields can produce very large dose enhancements and reductions in localized regions of a patient under irradiation by a photon beam. We have suggested a model magnetic field which can be expected to produce such large dose enhancements and reductions, and we have carried out EGS4 Monte Carlo calculations to examine this effect for a 6x6 cm2 photon beam of energy 15, 30, or 45 MV penetrating a water phantom. Our model magnetic field has a nominal (center) strength B0 ranging between 1 and 5 T, and a maximum strength within the geometric beam which is 2.2xB0. For all three beam energies, there is significant dose enhancement for B0 = 2 T which increases greatly for B0 = 3 T, but stronger magnetic fields increase the enhancement further only for the 45-MV beam. Correspondingly, there is major reduction in the dose just distal to this region of large dose enhancement, resulting from secondary electrons and positrons originating upstream which are depositing energy in the dose-enhancement region rather than continuing further into the patient. The dose peak region is fairly narrow (in depth), but the magnetic field can be shifted along the longitudinal axis to produce a flat peak region of medium width (approximately 2 cm) or of large width (approximately 4 cm), with rapid dose dropoffs on either side. For the 30-MV beam with B0 = 3 T, we found a dose enhancement of 55% for the narrow-width configuration, 32% for the medium-width configuration, and 23% for the large-width configuration; for the 45-MV beam with B0 = 3 T, the enhancements were quite similar, but for the 15-MV beam they were considerably less. For all of these 30-MV configurations, the dose reductions were approximately 30%, and they were approximately 40% for the 45-MV configurations.

Photon dose calculation based on electron multiple-scattering theory: primary dose deposition kernels.

The transport of the secondary electrons resulting from high-energy photon interactions is essential to energy redistribution and deposition. In order to develop an accurate dose-calculation algorithm for high-energy photons, which can predict the dose distribution in inhomogeneous media and at the beam edges, we have investigated the feasibility of applying electron transport theory [Jette, Med. Phys. 15, 123 (1988)] to photon dose calculation. In particular, the transport of and energy deposition by Compton electron and electrons and positrons resulting from pair production were studied. The primary photons are treated as the source of the secondary electrons and positrons, which are transported through the irradiated medium using Gaussian multiple-scattering theory [Jette, Med. Phys. 15, 123 (1988)]. The initial angular and kinetic energy distribution(s) of the secondary electrons (and positrons) emanating from the photon interactions are incorporated into the transport. Due to different mechanisms of creation and cross-section functions, the transport of and the energy deposition by the electrons released in these two processes are studied and modeled separately based on first principles. In this article, we focus on determining the dose distribution for an individual interaction site. We define the Compton dose deposition kernel (CDK) or the pair-production dose deposition kernel (PDK) as the dose distribution relative to the point of interaction, per unit interaction density, for a monoenergetic photon beam in an infinite homogeneous medium of unit density. The validity of this analytic modeling of dose deposition was evaluated through EGS4 Monte Carlo simulation. Quantitative agreement between these two calculations of the dose distribution and the average energy deposited per interaction was achieved. Our results demonstrate the applicability of the electron dose-calculation method to photon dose calculation.

On the possibility of determining an effective energy spectrum of clinical electron beams from percentage depth dose (PDD) data of broad beams.

Experiments have already shown that obvious differences exist between the dose distribution of electron beams of a clinical accelerator in a water phantom and the dose distribution of monoenergetic electrons of nominal energy of the clinical accelerator in water, because the electron beams which reach the water surface travelling through the collimation system of the accelerator are no longer monoenergetic. It is evident that, while calculating precisely the dose distribution of any incident electron beams, the energy spectrum of the incident electron beam must be taken into consideration. In this note we shall present a method for determining an effective energy spectrum of clinical electron beams from PDD data (percentage depth dose data). It is well known that there is an integral equation of the first kind which links the energy spectrum of an incident electron beam with PDD through the dose distribution of monoenergetic electrons in the medium, as a kernel function in the integral equation. In this note, the integral equation of the first kind will be solved by using the regularization method. The bipartition model of electron transport will be used to calculate the kernel function, namely the energy deposition due to monoenergetic electron beams in the medium.

Photon dose calculation based on electron multiple-scattering theory: practical representation of dose and particle transport integrals.

In modern photon dose-calculation algorithms one is frequently called upon to evaluate the integral at various points throughout the irradiated material of a dose or particle transport quantity multiplied by a weighting factor. For example, for a given dose-calculation point one might be integrating the product of the dose deposited by a monoenergetic beam and the energy distribution of the actual beam, and want to do this throughout the treatment volume. We have developed explicit formulas for replacing such integrations with a weighted sum of two or three functions (of, for example, the point of dose calculation) in order to greatly reduce the calculation time for the algorithm being used. We demonstrate the accuracy of this method of representing dose and particle transport integrals through comparisons with Monte Carlo calculations of dose distributions for two typical problems, in dealing with the energy spectrum of the photon beam and with the energy deposited by all the Compton electrons emerging from a particular interaction point, respectively.

The relationship of lower-limb muscle force to walking ability in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the level of muscle force associated with ability to walk in the community without assistance, in the community with assistance, or at home only in individuals with amyotrophic lateral sclerosis (ALS). SUBJECTS AND METHODS: Percentage of predicted maximal muscle force (%PMF) of lower-extremity muscles was determined, and walking ability was categorized in 118 patients with ALS during periodic visits to the Neuromuscular Research Unit. Data were derived from consecutive visits in which subjects demonstrated declines in walking ability. Means for %PMF of each muscle group and a limb average were calculated at each consecutive visit. RESULTS: The mean lower-extremity average %PMF was: (1) 54.01% (SD=12.76%) for subjects who walked independently in the community and 50.19% (SD=14.38%) during the next visit when these same subjects required assistance in the community (difference=3.82%, 95% confidence interval [CI]= 2.45-5.19);(2) 37.52% (SD=15.17%) during the last visit that subjects walked with assistance in the community and 32.18% (SD=13.83%) during the next visit when they walked only at home (difference=5.33%, 95% CI=3.61-7.06); and (3) 19.12% (SD=9.08%) during the visit when subjects were last able to ambulate at home versus 13.70% (SD=7.36%) when they became unable to walk (difference=5.42%, 95% CI=2.97-7.96). CONCLUSION AND DISCUSSION: The findings suggest there are required levels of lower-extremity muscle force for various categories of walking ability. Variations in forces within and between categories of walking ability, however, indicate the complexity of this relationship.

Are performance-based measures sufficiently reliable for use in multicenter trials? Musculoskeletal Impairment (MSI) Study Group.

BACKGROUND: The literature contains few reports of the test-retest reliability of performance-based measures. The purpose of this study was to determine the test-retest reliability of a battery of seven timed, performance-based measures used to assess the functional limitations of frail, older adults. METHODS: One hundred and five frail, elderly subjects were twice administered a battery of timed tests approximately 2 weeks apart: 8-foot walk, get-up-and-go test, stair climb, single and repetitive standing from a chair, and single and repetitive 10-pound lifts with the upper limbs. Agreement between the mean times recorded for accomplishing each task at the two administrations was assessed. RESULTS: Intraclass correlation coefficients ranged from .25 for the single chair stand to .79 for the 8-foot walk. Only the time taken for the single 10-pound lift was significantly greater at the first administration as compared with the second. CONCLUSIONS: Timed performance-based measures have a wide range of test-retest reliability. Performance-based protocols that reflect familiar tasks with discrete starting and ending points may achieve higher reliability than tasks that are unfamiliar to subjects or may have ambiguous elements in them.

Summary report of the TD-3 workshop: characterization of 83 antibodies against prostate-specific antigen.

Twelve research groups participated in the ISOBM TD-3 Workshop in which the reactivity and specificity of 83 antibodies against prostate-specific antigen (PSA) were investigated. Using a variety of techniques including cross-inhibition assays, Western blotting, BIAcore, immunoradiometric assays and immunohistochemistry, the antibodies were categorized into six major groups which formed the basis for mapping onto two- and three-dimensional (2-D and 3-D) models of PSA. The overall findings of the TD-3 Workshop are summarized in this report. In agreement with all participating groups, three main antigenic domains were identified: free PSA-specific epitopes located in or close to amino acids 86-91; discontinuous epitopes specific for PSA without human kallikrein (hK2) cross-reactivity located at or close to amino acids 158-163; and continuous or linear epitopes shared between PSA and hK2 located close to amino acids 3-11. In addition, several minor and partly overlapping domains were also identified. Clearly, the characterization of antibodies from this workshop and the location of their epitopes on the 3-D model of PSA illustrate the importance of selecting appropriate antibody pairs for use in immunoassays. It is hoped that these findings and the epitope nomenclature described in this TD-3 Workshop are used as a standard for future evaluation of anti-PSA antibodies.

Relative affinity and specificity of monoclonal antibodies against prostate-specific antigen.

The relative affinities of a panel of antibodies submitted to the ISOBM TD-3 PSA Workshop were determined by direct-binding ELISA. The Workshop antibodies were also tested for reactivity with the prostate-specific antigen alpha1-antichymotrypsin complex (PSA-ACT) and cross-reactivity with porcine pancreatic kallikrein. There was a wide range of affinities observed for the panel of antibodies. Twelve antibodies failed to react with the PSA-ACT complex, and 1 antibody was found to recognize an epitope on ACT but not on PSA. Only 2 antibodies were found to react with porcine pancreatic kallikrein, a protein with 64% sequence homology with human glandular kallikrein-2 (hK2).

Electron dose calculation using multiple-scattering theory: a hybrid electron pencil-beam model.

We have embedded the bipartition model into Fermi-Eyges multiple-scattering theory to produce a more accurate hybrid electron pencil-beam model, by using the fact that away from the edges of a large field, the electron distribution function exactly equals that for an infinitely wide electron beam. The bipartition model calculates various electron transport quantities in a homogeneous or horizontally layered medium with very high accuracy, for an infinitely broad beam. In our hybrid model, we use the bipartition model to calculate the longitudinal part of the pencil-beam distribution function, and the Fermi-Eyges theory to calculate its transverse part. Doing this allows calculation not only of dose distribution, but also of such quantities as electron fluence distribution, energy spectrum, angular distribution, and electron-charge distribution. Using the hybrid electron pencil-beam model, we have calculated the dose distribution for collimated electron beams and compared them with experimental data, for rectangular fields.

Lower extremity muscle force measures and functional ambulation in patients with amyotrophic lateral sclerosis.

OBJECTIVE: To examine the relation between lower extremity muscle force production and functional ambulation in patients with amyotrophic lateral sclerosis (ALS). DESIGN: Retrospective analysis of data collected from 1979 to 1995. PATIENTS: Two hundred forty ALS patients referred to the New England Medical Center Neuromuscular Research Unit. MAIN OUTCOME MEASURES: Muscle force production during a maximum, voluntary isometric contraction of ankle dorsiflexors, knee flexors, knee extensors, hip flexors, and hip extensors was calculated as percent predicted maximal force (PPMF). Functional ambulation status was classified as unable, home, or community. RESULTS: The probability of community ambulation compared with home increased with progressively higher PPMF for all muscle groups. Subjects with knee flexion strength greater than 75% PPMF were 395 times more likely to ambulate in the community. Subjects with hip extension strength over 50% PPMF showed improved chance of ambulation at home. CONCLUSION: Lower extremity PPMF is a critical factor determining functional ambulation in patients with ALS. Knee flexors play an important role in community ambulation while the hip extensors are important for home ambulation.

The disablement process in patients with pulmonary disease.

BACKGROUND AND PURPOSE: The purposes of this study were (1) to describe the disabilities of patients with pulmonary disease and (2) to examine the relationships among impairments, functional limitations, and disability, as described by the disablement process model. SUBJECTS: Subjects were 154 patients with chronic pulmonary disease (64% female, 36% male; mean age = 59 years, SD = 14, range = 24-86). METHODS: Information was abstracted from physical therapy records, including measurements of pulmonary impairment, 6-minute walk distance (6MWD), and Functional Status Questionnaire (FSQ) scores. Multivariate analyses were used to examine the relationships among measurements of impairment, 6MWD, and FSQ scores. RESULTS: Mean FSQ scores ranged from 52.6 for instrumental activities of daily living to 83.3 for basic activities of daily living, where 100 represents the highest level of ability. Fifty percent of patients were not working because of health problems. Percentage of predicted 1-second forced expiratory volume (FEV1), oxyhemoglobin saturation, and the ratio of FEV1 to forced vital capacity were related to 6MWD but not to FSQ scores. The 6MWD was associated with scales of the FSQ, including basic activities of daily living (R2 = .24), instrumental activities of daily living (R2 = .35), and social activity (R2 = .26). CONCLUSION AND DISCUSSION: Patients entering a pulmonary rehabilitation program have clinically important disabilities. The results support the use of the disablement process model and suggest that different and important information is obtained from measurements of impairment, functional limitation, and disability in patients with pulmonary disease.

Electron dose calculation using multiple-scattering theory: energy distribution due to multiple scattering.

In 1951, Yang derived formulas for computing the pathlength distribution of particles traversing foils, considering only the multiple-scattering process. We here improve upon the accuracy of that work, by using our second-order small-angle approximation. We derive the general solution for a broad parallel beam, and find simple formulas for Yang's two special cases: the pathlength distribution of all the particles at a particular point, taken together; and the pathlength distribution at a particular point of only those particles with zero net angular deflection. From the pathlength (or excess pathlength) distribution, residual range and energy distributions can immediately be deduced. All this work assumes relatively small energy loss, and we consider 5 MeV electrons penetrating lead, which provides considerable scattering without major energy loss. The second-order energy distribution is found to differ considerably from the (first-order) Yang energy distribution, and to agree more closely with EGS4 Monte Carlo calculations.