Dosimetric impact of geometric errors due to respiratory motion prediction on dynamic multileaf collimator-based four-dimensional radiation delivery

The synchronization of dynamic multileaf collimator (DMLC) response with respiratory motion is critical to ensure the accuracy of DMLC-based four dimensional (4D) radiation delivery. In practice, however, a finite time delay (response time) between the acquisition of tumor position and multileaf collimator response necessitates predictive models of respiratory tumor motion to synchronize radiation delivery. Predicting a complex process such as respiratory motion introduces geometric errors, which have been reported in several publications. However, the dosimetric effect of such errors on 4D radiation delivery has not yet been investigated. Thus, our aim in this work was to quantify the dosimetric effects of geometric error due to prediction under several different conditions. Conformal and intensity modulated radiation therapy (IMRT) plans for a lung patient were generated for anterior-posterior/posterior-anterior (AP/PA) beam arrangements at 6 and 18 MV energies to provide planned dose distributions. Respiratory motion data was obtained from 60 diaphragm-motion fluoroscopy recordings from five patients. A linear adaptive filter was employed to predict the tumor position. The geometric error of prediction was defined as the absolute difference between predicted and actual positions at each diaphragm position. Distributions of geometric error of prediction were obtained for all of the respiratory motion data. Planned dose distributions were then convolved with distributions for the geometric error of prediction to obtain convolved dose distributions. The dosimetric effect of such geometric errors was determined as a function of several variables: response time (0-0.6 s), beam energy (6/18 MV), treatment delivery (3D/4D), treatment type (conformal/IMRT), beam direction (AP/PA), and breathing training type (free breathing/audio instruction/visual feedback). Dose difference and distance-to-agreement analysis was employed to quantify results. Based on our data, the dosimetric impact of prediction (a) increased with response time, (b) was larger for 3D radiation therapy as compared with 4D radiation therapy, (c) was relatively insensitive to change in beam energy and beam direction, (d) was greater for IMRT distributions as compared with conformal distributions, (e) was smaller than the dosimetric impact of latency, and (f) was greatest for respiration motion with audio instructions, followed by visual feedback and free breathing. Geometric errors of prediction that occur during 4D radiation delivery introduce dosimetric errors that are dependent on several factors, such as response time, treatment-delivery type, and beam energy. Even for relatively small response times of 0.6 s into the future, dosimetric errors due to prediction could approach delivery errors when respiratory motion is not accounted for at all. To reduce the dosimetric impact, better predictive models and/or shorter response times are required.

Accurate and robust reconstruction of proximal femur from sparse intraoperative data and dense point distribution model for surgical navigation

Constructing a 3D surface model from sparse-point data is a nontrivial task. Here, we report an accurate and robust approach for reconstructing a surface model of the proximal femur from sparse-point data and a dense-point distribution model (DPDM). The problem is formulated as a three-stage optimal estimation process. The first stage, affine registration, is to iteratively estimate a scale and a rigid transformation between the mean surface model of the DPDM and the sparse input points. The estimation results of the first stage are used to establish point correspondences for the second stage, statistical instantiation, which stably instantiates a surface model from the DPDM using a statistical approach. This surface model is then fed to the third stage, kernel-based deformation, which further refines the surface model. Handling outliers is achieved by consistently employing the least trimmed squares (LTS) approach with a roughly estimated outlier rate in all three stages. If an optimal value of the outlier rate is preferred, we propose a hypothesis testing procedure to automatically estimate it. We present here our validations using four experiments, which include 1 leave-one-out experiment, 2 experiment on evaluating the present approach for handling pathology, 3 experiment on evaluating the present approach for handling outliers, and 4 experiment on reconstructing surface models of seven dry cadaver femurs using clinically relevant data without noise and with noise added. Our validation results demonstrate the robust performance of the present approach in handling outliers, pathology, and noise. An average 95-percentile error of 1.7-2.3 mm was found when the present approach was used to reconstruct surface models of the cadaver femurs from sparse-point data with noise added.

Use of pressure waves to confirm the correct placement of epidural needles in dogs

An epidural puncture was performed using the lumbosacral approach in 18 dogs, and the lack of resistance to an injection of saline was used to determine that the needle was positioned correctly. The dogs' arterial blood pressure and epidural pressure were recorded. They were randomly assigned to two groups: in one group an injection of a mixture of local anaesthetic agents was made slowly over 90 seconds and in the other it was made over 30 seconds. After 10 minutes contrast radiography was used to confirm the correct placement of the needle. The mean (sd) initial pressure in the epidural space was 0.1 (0.7) kPa. After the injection the mean maximum epidural pressure in the group injected slowly was 5.5 (2.1) kPa and in the group injected more quickly it was 6.0 (1.9) kPa. At the end of the period of measurement, the epidural pressure in the slow group was 0.8 (0.5) kPa and in the rapid group it was 0.7 (0.5) kPa. Waves synchronous with the arterial pulse wave were observed in 15 of the dogs before the epidural injection, and in all the dogs after the epidural injection.

Comparison of magnetic resonance imaging of inhaled SF6 with respiratory gas analysis

Magnetic resonance imaging of inhaled fluorinated inert gases ((19)F-MRI) such as sulfur hexafluoride (SF(6)) allows for analysis of ventilated air spaces. In this study, the possibility of using this technique to image lung function was assessed. For this, (19)F-MRI of inhaled SF(6) was compared with respiratory gas analysis, which is a global but reliable measure of alveolar gas fraction. Five anesthetized pigs underwent multiple-breath wash-in procedures with a gas mixture of 70% SF(6) and 30% oxygen. Two-dimensional (19)F-MRI and end-expiratory gas fraction analysis were performed after 4 to 24 inhaled breaths. Signal intensity of (19)F-MRI and end-expiratory SF(6) fraction were evaluated with respect to linear correlation and reproducibility. Time constants were estimated by both MRI and respiratory gas analysis data and compared for agreement. A good linear correlation between signal intensity and end-expiratory gas fraction was found (correlation coefficient 0.99+/-0.01). The data were reproducible (standard error of signal intensity 8% vs. that of gas fraction 5%) and the comparison of time constants yielded a sufficient agreement. According to the good linear correlation and the acceptable reproducibility, we suggest the (19)F-MRI to be a valuable tool for quantification of intrapulmonary SF(6) and hence lung function.

Clinical and microbiological analysis of subjects treated with Brånemark or AstraTech implants: a 7-year follow-up study

AIMS: To assess the impact of different implant systems on the clinical conditions and the microbiota at implants, and whether the presence of bacteria at tooth sites was predictive of the presence at implant sites. MATERIALS AND METHODS: Subjects with either AstraTech or Brånemark in function for 7 years were enrolled. Sub-gingival bacterial samples at tooth and implant sites were collected with sterile endodontic paper points, and analyzed by the checkerboard DNA-DNA hybridization method (40 species). RESULTS: Fifty-four subjects, 27 supplied with AstraTech (n=132 implants) and 27 with Brånemark (n=102) implants, were studied. Test tooth sites had significantly less evidence of bleeding on probing (P<0.001) and presence of plaque (P<0.001) than implant test sites. Implant sites presented with deeper probing pocket depth than tooth sites (mean difference: 1.1 mm, standard error of differences: 0.08, 95% confidence intervals (CI): 0.9-1.3, P<0.001). Tannerella forsythia (P<0.05), Capnocytophaga sputigena (P<0.05), Actinomyces israelii (P<0.05) and Lactobacillus acidophilus (P<0.05) were found at higher levels at tooth surfaces. No differences in bacterial load for any species were found between the two implant systems. The odds of being present/absent at tooth and implants sites were only significant for Staphylococcus aureus [odds ratio (OR): 5.2 : 1, 95% CI: 1.4-18.9, P<0.01]. CONCLUSIONS: After 7 years in function, implants presented with deeper probing depths than teeth. S. aureus was commonly present at both teeth and implants sites. S. aureus at tooth sites was predictive of also being present at implant sites.

Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency

BACKGROUND: Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea metabolism that can lead to hyperammonemic crises and orotic aciduria. To date, a total of 341 causative mutations within the OTC gene have been described. However, in about 20% of the patients with enzymatically confirmed OTC deficiency no mutation can be detected when sequencing of genomic DNA analyzing exons and adjacent intronic segments of the OTC gene is performed. METHODS: Standard genomic DNA analysis of the OTC gene in five consecutive patients from five families revealed no mutation. Hence, liver tissue was obtained by needle sampling or open biopsy and RNA extracted from liver was analyzed. RESULTS: Complex rearrangements of the OTC transcript (three insertions and two deletions) were found in all five patients. CONCLUSION: In patients with a strong suspicion of OTC deficiency despite normal results of sequencing exonic regions of the OTC gene, characterization of liver OTC mRNA is highly effective in resolving the genotype. Liver tissue sampling by needle aspiration allows for both enzymatic analysis and RNA based diagnostics of OTC deficiency.

Basistests Suisse Sport Test Konzept: Validierung einer sportmotorischen Basistestbatterie für den Schul- und Nachwuchssport

Physical fitness can be evaluated in competitive and school sports with different field tests under different conditions and goals. To produce valid results, a field test must be practical and reach high standards of test criteria (objectivity, reliability, validity). The purpose of this study was to investigate the test criteria and the practicability of a group of field tests called «SUISSE Sport Test Konzept Basis Feldtestbatterie». For 20-m sprint, ventral trunk muscle test, standing long jump, 2-kg medicine ball shot, obstacle course and cooper-test, test quality and practicability were evaluated. 221 children and adolescents from competitive sports and different school levels took part in the study. According to school level, they were divided into 3 groups (P: 7–11.5 y, S1: 11.6–15.5 y, S2: 15.6–21.8 y). Objectivity was tested for time or distance measurement in all tests as well as for error rating in obstacle test. For reliability measurement, 162 subjects performed the field tests twice within a few weeks. For validity results of standing long jump were compared with counter movement jump performance on a force plate. Correlation analysis was performed and level of significance was set for p < 0.05. For accuracy standard error was calculated. All tests achieved sufficient to excellent objectiv - ity with correlation-coefficient (r) lying between 0.85 and 0.99. Reliability was very good (r = 0.84–0.97). In cooper- and trunk test, reliability was higher for athletes than for pupils (trunk test: r = 0.95 vs. r = 0.62, cooper-test: r = 0.90 vs. r = 0.78). In those tests the reliability decreases with increasing age (cooper-test: P: r = 0.84, S1: r = 0.69, S2: r = 0.52; trunk-test: P: r = 0.69, S1: r = 0.71; S2: r = 0.39). Validity for standing long jump was good (r = 0.75–0.86). The standard error of the mean was between 4–8%, with the exception for cooper-test (athletes: 6%, pupils: 11%) and trunk test (athletes: 14%, pupils: 46%). The results show that the evaluated group of field tests is a practicable, objective and reliable tool to determine physical skills in young athletes as well as in a scholar setting over a broad age range. Most of the tests achieved the test criteria with the grades good to excellent. The lower coefficient of reliability for cooper- and trunk test by the pupils could be explained by motivational problems in this setting. For up to 20 subjects, a tester can accomplish the tests within 3 h. Finally, age-dependent grades were elaborated

Individualization of 5-fluorocytosine therapy

Using a convenient and fast HPLC procedure we determined serum concentrations of the fungistatic agent 5-fluorocytosine (5-FC) in 375 samples from 60 patients treated with this drug. The mean trough concentration (n = 127) was 64.3 mg/l (range: 11.8-208.0 mg/l), the mean peak concentration (n = 122) was 99.9 mg/l (range: 25.6-263.8 mg/l), the mean nonpeak/nontrough concentration (n = 126) was 80.1 mg/l (range: 10.5-268.0 mg/l). Totally 134 (35.7%) samples were outside the therapeutic range (25-100 mg/l), 108 (28.8%) being too high, 26 (6.9%) being too low. Forty-four (73%) patients showed 5-FC serum concentrations outside the therapeutic range at least once during the treatment course. In a prospective study we performed 65 dosage predictions on 30 patients by use of a 3-point method previously developed for aminoglycoside dosage adaptation. The mean absolute prediction error of the dosage adaptation was +0.7 mg/l (range: -26.0 to +28.0 mg/l). The root mean square prediction error was 10.7 mg/l. The mean predicted concentration (65.3 mg/l) agreed very well with the mean measured concentration (64.6 mg/l). The frequency distribution of 5-FC serum concentrations indicates that 5-FC monitoring is important. The applied pharmacokinetic method allows individual adaptations of 5-FC dosage with a clinically acceptable prediction error.

A system for 3-D reconstruction of a patient-specific surface model from calibrated X-ray images

This paper presents a system for 3-D reconstruction of a patient-specific surface model from calibrated X-ray images. Our system requires two X-ray images of a patient with one acquired from the anterior-posterior direction and the other from the axial direction. A custom-designed cage is utilized in our system to calibrate both images. Starting from bone contours that are interactively identified from the X-ray images, our system constructs a patient-specific surface model of the proximal femur based on a statistical model based 2D/3D reconstruction algorithm. In this paper, we present the design and validation of the system with 25 bones. An average reconstruction error of 0.95 mm was observed.

A comparative study on manual and automatic slice-to-volume registration of CT images

In order to assess the clinical relevance of a slice-to-volume registration algorithm, this technique was compared to manual registration. Reformatted images obtained from a diagnostic CT examination of the lower abdomen were reviewed and manually registered by 41 individuals. The results were refined by the algorithm. Furthermore, a fully automatic registration of the single slices to the whole CT examination, without manual initialization, was also performed. The manual registration error for rotation and translation was found to be 2.7+/-2.8 degrees and 4.0+/-2.5 mm. The automated registration algorithm significantly reduced the registration error to 1.6+/-2.6 degrees and 1.3+/-1.6 mm (p = 0.01). In 3 of 41 (7.3%) registration cases, the automated registration algorithm failed completely. On average, the time required for manual registration was 213+/-197 s; automatic registration took 82+/-15 s. Registration was also performed without any human interaction. The resulting registration error of the algorithm without manual pre-registration was found to be 2.9+/-2.9 degrees and 1.1+/-0.2 mm. Here, a registration took 91+/-6 s, on average. Overall, the automated registration algorithm improved the accuracy of manual registration by 59% in rotation and 325% in translation. The absolute values are well within a clinically relevant range.

fMRI of Emotion

Recent brain imaging work has expanded our understanding of the mechanisms of perceptual, cognitive, and motor functions in human subjects, but research into the cerebral control of emotional and motivational function is at a much earlier stage. Important concepts and theories of emotion are briefly introduced, as are research designs and multimodal approaches to answering the central questions in the field. We provide a detailed inspection of the methodological and technical challenges in assessing the cerebral correlates of emotional activation, perception, learning, memory, and emotional regulation behavior in healthy humans. fMRI is particularly challenging in structures such as the amygdala as it is affected by susceptibility-related signal loss, image distortion, physiological and motion artifacts and colocalized Resting State Networks (RSNs). We review how these problems can be mitigated by using optimized echo-planar imaging (EPI) parameters, alternative MR sequences, and correction schemes. High-quality data can be acquired rapidly in these problematic regions with gradient compensated multiecho EPI or high resolution EPI with parallel imaging and optimum gradient directions, combined with distortion correction. Although neuroimaging studies of emotion encounter many difficulties regarding the limitations of measurement precision, research design, and strategies of validating neuropsychological emotion constructs, considerable improvement in data quality and sensitivity to subtle effects can be achieved. The methods outlined offer the prospect for fMRI studies of emotion to provide more sensitive, reliable, and representative models of measurement that systematically relate the dynamics of emotional regulation behavior with topographically distinct patterns of activity in the brain. This will provide additional information as an aid to assessment, categorization, and treatment of patients with emotional and personality disorders.

Independent association between lower level of social support and higher coagulation activity before and after acute psychosocial stress

OBJECTIVE: To investigate the relationship between social support and coagulation parameter reactivity to mental stress in men and to determine if norepinephrine is involved. Lower social support is associated with higher basal coagulation activity and greater norepinephrine stress reactivity, which in turn, is linked with hypercoagulability. However, it is not known if low social support interacts with stress to further increase coagulation reactivity or if norepinephrine affects this association. These findings may be important for determining if low social support influences thrombosis and possible acute coronary events in response to acute stress. We investigated the relationship between social support and coagulation parameter reactivity to mental stress in men and determined if norepinephrine is involved. METHODS: We measured perceived social support in 63 medication-free nonsmoking men (age (mean +/- standard error of the mean) = 36.7 +/- 1.7 years) who underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. We measured plasma D-dimer, fibrinogen, clotting Factor VII activity (FVII:C), and plasma norepinephrine at rest as well as immediately after stress and 20 minutes after stress. RESULTS: Independent of body mass index, mean arterial pressure, and age, lower social support was associated with higher D-dimer and fibrinogen levels at baseline (p < .012) and with greater increases in fibrinogen (beta = -0.36, p = .001; DeltaR(2) = .12), and D-dimer (beta = -0.21, p = .017; DeltaR(2) = .04), but not in FVII:C (p = .83) from baseline to 20 minutes after stress. General linear models revealed significant main effects of social support and stress on fibrinogen, D-dimer, and norepinephrine (p < .035). Controlling for norepinephrine did not change the significance of the reported associations between social support and the coagulation measures D-dimer and fibrinogen. CONCLUSIONS: Our results suggest that lower social support is associated with greater coagulation activity before and after acute stress, which was unrelated to norepinephrine reactivity.

A comparison of the strength of biodiversity effects across multiple functions

In order to predict which ecosystem functions are most at risk from biodiversity loss, meta-analyses have generalised results from biodiversity experiments over different sites and ecosystem types. In contrast, comparing the strength of biodiversity effects across a large number of ecosystem processes measured in a single experiment permits more direct comparisons. Here, we present an analysis of 418 separate measures of 38 ecosystem processes. Overall, 45 % of processes were significantly affected by plant species richness, suggesting that, while diversity affects a large number of processes not all respond to biodiversity. We therefore compared the strength of plant diversity effects between different categories of ecosystem processes, grouping processes according to the year of measurement, their biogeochemical cycle, trophic level and compartment (above- or belowground) and according to whether they were measures of biodiversity or other ecosystem processes, biotic or abiotic and static or dynamic. Overall, and for several individual processes, we found that biodiversity effects became stronger over time. Measures of the carbon cycle were also affected more strongly by plant species richness than were the measures associated with the nitrogen cycle. Further, we found greater plant species richness effects on measures of biodiversity than on other processes. The differential effects of plant diversity on the various types of ecosystem processes indicate that future research and political effort should shift from a general debate about whether biodiversity loss impairs ecosystem functions to focussing on the specific functions of interest and ways to preserve them individually or in combination.

Quantitative high-resolution warm season rainfall recorded in varved sediments of Lake Oeschinen, northern Swiss Alps: calibration and validation AD 1901–2008

High-resolution, well-calibrated records of lake sediments are critically important for quantitative climate reconstructions, but they remain a methodological and analytical challenge. While several comprehensive paleotemperature reconstructions have been developed across Europe, only a few quantitative high-resolution studies exist for precipitation. Here we present a calibration and verification study of lithoclastic sediment proxies from proglacial Lake Oeschinen (46°30′N, 7°44′E, 1,580 m a.s.l., north–west Swiss Alps) that are sensitive to rainfall for the period AD 1901–2008. We collected two sediment cores, one in 2007 and another in 2011. The sediments are characterized by two facies: (A) mm-laminated clastic varves and (B) turbidites. The annual character of the laminae couplets was confirmed by radiometric dating (210Pb, 137Cs) and independent flood-layer chronomarkers. Individual varves consist of a dark sand-size spring-summer layer enriched in siliciclastic minerals and a lighter clay-size calcite-rich winter layer. Three subtypes of varves are distinguished: Type I with a 1–1.5 mm fining upward sequence; Type II with a distinct fine-sand base up to 3 mm thick; and Type III containing multiple internal microlaminae caused by individual summer rainstorm deposits. Delta-fan surface samples and sediment trap data fingerprint different sediment source areas and transport processes from the watershed and confirm the instant response of sediment flux to rainfall and erosion. Based on a highly accurate, precise and reproducible chronology, we demonstrate that sediment accumulation (varve thickness) is a quantitative predictor for cumulative boreal alpine spring (May–June) and spring/summer (May–August) rainfall (rMJ = 0.71, rMJJA = 0.60, p < 0.01). Bootstrap-based verification of the calibration model reveals a root mean squared error of prediction (RMSEPMJ = 32.7 mm, RMSEPMJJA = 57.8 mm) which is on the order of 10–13 % of mean MJ and MJJA cumulative precipitation, respectively. These results highlight the potential of the Lake Oeschinen sediments for high-resolution reconstructions of past rainfall conditions in the northern Swiss Alps, central and eastern France and south-west Germany.

An analysis of variance type method to describe and compare steady states in clinical data

Identifying and comparing different steady states is an important task for clinical decision making. Data from unequal sources, comprising diverse patient status information, have to be interpreted. In order to compare results an expressive representation is the key. In this contribution we suggest a criterion to calculate a context-sensitive value based on variance analysis and discuss its advantages and limitations referring to a clinical data example obtained during anesthesia. Different drug plasma target levels of the anesthetic propofol were preset to reach and maintain clinically desirable steady state conditions with target controlled infusion (TCI). At the same time systolic blood pressure was monitored, depth of anesthesia was recorded using the bispectral index (BIS) and propofol plasma concentrations were determined in venous blood samples. The presented analysis of variance (ANOVA) is used to quantify how accurately steady states can be monitored and compared using the three methods of measurement.