Inhibiting saccades to a social stimulus: a developmental study.

Faces are an important source of social signal throughout the lifespan. In adults, they have a prioritized access to the orienting system. Here we investigate when this effect emerges during development. We tested 139 children, early adolescents, adolescents and adults in a mixed pro- and anti-saccades task with faces, cars or noise patterns as visual targets. We observed an improvement in performance until about 15 years of age, replicating studies that used only meaningless stimuli as targets. Also, as previously reported, we observed that adults made more direction errors to faces than abstract patterns and cars. The children showed this effect too with regards to noise patterns but it was not specific since performance for cars and faces did not differ. The adolescents, in contrast, made more errors for faces than for cars but as many errors for noise patterns and faces. In all groups latencies for pro-saccades were faster towards faces. We discuss these findings with regards to the development of executive control in childhood and adolescence and the influence of social stimuli at different ages.

A new tissue segmentation method to calculate 3D dose in small animal radiation therapy.

BACKGROUND: In pre-clinical animal experiments, radiation delivery is usually delivered with kV photon beams, in contrast to the MV beams used in clinical irradiation, because of the small size of the animals. At this medium energy range, however, the contribution of the photoelectric effect to absorbed dose is significant. Accurate dose calculation therefore requires a more detailed tissue definition because both density (ρ) and elemental composition (Zeff) affect the dose distribution. Moreover, when applied to cone beam CT (CBCT) acquisitions, the stoichiometric calibration of HU becomes inefficient as it is designed for highly collimated fan beam CT acquisitions. In this study, we propose an automatic tissue segmentation method of CBCT imaging that assigns both density (ρ) and elemental composition (Zeff) in small animal dose calculation. METHODS: The method is based on the relationship found between CBCT number and ρ*Zeff product computed from known materials. Monte Carlo calculations were performed to evaluate the impact of ρZeff variation on the absorbed dose in tissues. These results led to the creation of a tissue database composed of artificial tissues interpolated from tissue values published by the ICRU. The ρZeff method was validated by measuring transmitted doses through tissue substitute cylinders and a mouse with EBT3 film. Measurements were compared to the results of the Monte Carlo calculations. RESULTS: The study of the impact of ρZeff variation over the range of materials, from ρZeff = 2 g.cm- 3 (lung) to 27 g.cm- 3 (cortical bone) led to the creation of 125 artificial tissues. For tissue substitute cylinders, the use of ρZeff method led to maximal and average relative differences between the Monte Carlo results and the EBT3 measurements of 3.6% and 1.6%. Equivalent comparison for the mouse gave maximal and average relative differences of 4.4% and 1.2%, inside the 80% isodose area. Gamma analysis led to a 94.9% success rate in the 10% isodose area with 4% and 0.3 mm criteria in dose and distance. CONCLUSIONS: Our new tissue segmentation method was developed for 40kVp CBCT images. Both density and elemental composition are assigned to each voxel by using a relationship between HU and the product ρZeff. The method, validated by comparing measurements and calculations, enables more accurate small animal dose distribution calculated on low energy CBCT images.

Validation of fast Monte Carlo dose calculation in small animal radiotherapy with EBT3 radiochromic films.

In preclinical studies, the absorbed dose calculation accuracy in small animals is fundamental to reliably investigate and understand observed biological effects. This work investigated the use of the split exponential track length estimator (seTLE), a new kerma based Monte Carlo dose calculation method for preclinical radiotherapy using a small animal precision micro irradiator, the X-RAD 225Cx. Monte Carlo modelling of the irradiator with GATE/GEANT4 was extensively evaluated by comparing measurements and simulations for half-value layer, percent depth dose, off-axis profiles and output factors in water and water-equivalent material for seven circular fields, from 20 mm down to 1 mm in diameter. Simulated and measured dose distributions in cylinders of water obtained for a 360° arc were also compared using dose, distance-to-agreement and gamma-index maps. Simulations and measurements agreed within 3% for all static beam configurations, with uncertainties estimated to 1% for the simulation and 3% for the measurements. Distance-to-agreement accuracy was better to 0.14 mm. For the arc irradiations, gamma-index maps of 2D dose distributions showed that the success rate was higher than 98%, except for the 0.1 cm collimator (92%). Using the seTLE method, MC simulations compute 3D dose distributions within minutes for realistic beam configurations with a clinically acceptable accuracy for beam diameter as small as 1 mm.

[Small animal image-guided radiotherapy: A new era for preclinical studies]. / Radiothérapie guidée par l'image pour les petits animaux: une nouvelle ère pour les études précliniques.

Preclinical external beam radiotherapy irradiations used to be delivered with a static broad beam. To promote the transfer from animal to man, the preclinical treatment techniques dedicated to the animal have been optimized to be similar to those delivered to patients in clinical practice. In this context, preclinical irradiators have been developed. Due to the small sizes of the animals, and the irradiation beams, the scaling to the small animal dimensions involves specific problems. Reducing the size and energy of the irradiation beams require very high technical performance, especially for the mechanical stability of the irradiator and the spatial resolution of the imaging system. In addition, the determination of the reference absorbed dose rate must be conducted with a specific methodology and suitable detectors. To date, three systems are used for preclinical studies in France. The aim of this article is to present these new irradiators dedicated to small animals from a physicist point of view, including the commissioning and the quality control.

Split exponential track length estimator for Monte-Carlo simulations of small-animal radiation therapy.

We propose the split exponential track length estimator (seTLE), a new kerma-based method combining the exponential variant of the TLE and a splitting strategy to speed up Monte Carlo (MC) dose computation for low energy photon beams. The splitting strategy is applied to both the primary and the secondary emitted photons, triggered by either the MC events generator for primaries or the photon interactions generator for secondaries. Split photons are replaced by virtual particles for fast dose calculation using the exponential TLE. Virtual particles are propagated by ray-tracing in voxelized volumes and by conventional MC navigation elsewhere. Hence, the contribution of volumes such as collimators, treatment couch and holding devices can be taken into account in the dose calculation.We evaluated and analysed the seTLE method for two realistic small animal radiotherapy treatment plans. The effect of the kerma approximation, i.e. the complete deactivation of electron transport, was investigated. The efficiency of seTLE against splitting multiplicities was also studied. A benchmark with analog MC and TLE was carried out in terms of dose convergence and efficiency.The results showed that the deactivation of electrons impacts the dose at the water/bone interface in high dose regions. The maximum and mean dose differences normalized to the dose at the isocenter were, respectively of 14% and 2% . Optimal splitting multiplicities were found to be around 300. In all situations, discrepancies in integral dose were below 0.5% and 99.8% of the voxels fulfilled a 1%/0.3 mm gamma index criterion. Efficiency gains of seTLE varied from 3.2 × 10(5) to 7.7 × 10(5) compared to analog MC and from 13 to 15 compared to conventional TLE.In conclusion, seTLE provides results similar to the TLE while increasing the efficiency by a factor between 13 and 15, which makes it particularly well-suited to typical small animal radiation therapy applications.

Underestimation of dose delivery in preclinical irradiation due to scattering conditions.

UNLABELLED: The aim of this study was to evaluate, by comparing simulation results with measurement results, the impact of the lack of scattering volume in experimental conditions of preclinical irradiation. First, a Monte Carlo model of a small animal irradiator, the Faxitron CP-160, was developed with GATE (Geant4 Application for Tomography Emission). To validate the model, simulated data were compared to depth dose and off-axis ratio profiles measured with a plane-parallel ionization chamber and Gafchromic(®) EBT films, respectively, in a solid water phantom. The AAPM TG-61 protocol was applied to measure the dose rate at the surface of a semi-infinite reference phantom. Then, the model was used to determine the dose distributions in three different phantom settings: a semi-infinite water phantom, a 2.8-cm-thick water phantom and a 2.8-cm-diameter cylindrical water phantom. The dose distributions measured and simulated with Monte Carlo methods in a semi-infinite water phantom were similar (<2%), thus validating our Monte Carlo model. The highest dose underestimation was observed between the reference and the cylindrical phantom (more than 15% difference for the entrance dose) and was due to the lack of lateral scatter and backscatter. The use of standard backscatter factors and AAPM TG-61 protocol may result in a significant underestimation of the dose absorbed by small irradiated phantoms, such as mice or cells, in preclinical studies. BACKGROUND: For preclinical radiotherapy studies, radiobiologists were used to determine the irradiation time depending only on the source surface distance. This work aimed to demonstrate that scatter conditions have a large impact on dose rate. Measurements and Monte Carlo simulations were used.

Monte Carlo simulations of clinical PET and SPECT scans: impact of the input data on the simulated images.

Monte Carlo simulations of emission tomography have proven useful to assist detector design and optimize acquisition and processing protocols. The more realistic the simulations, the more straightforward the extrapolation of conclusions to clinical situations. In emission tomography, accurate numerical models of tomographs have been described and well validated under specific operating conditions (collimator, radionuclide, acquisition parameters, count rates, etc). When using these models under these operating conditions, the realism of simulations mostly depends on the activity distribution used as an input for the simulations. It has been proposed to derive the input activity distribution directly from reconstructed clinical images, so as to properly model the heterogeneity of the activity distribution between and within organs. However, reconstructed patient images include noise and have limited spatial resolution. In this study, we analyse the properties of the simulated images as a function of the properties of the reconstructed images used to define the input activity distributions in (18)F-FDG PET and (131)I SPECT simulations. The propagation through the simulation/reconstruction process of the noise and spatial resolution in the input activity distribution was studied using simulations. We found that the noise properties of the images reconstructed from the simulated data were almost independent of the noise in the input activity distribution. The spatial resolution in the images reconstructed from the simulations was slightly poorer than that in the input activity distribution. However, using high-noise but high-resolution patient images as an input activity distribution yielded reconstructed images that could not be distinguished from clinical images. These findings were confirmed by simulated highly realistic (131)I SPECT and (18)F-FDG PET images from patient data. In conclusion, we demonstrated that (131)I SPECT and (18)F-FDG PET images indistinguishable from real scans can be simulated using activity maps with spatial resolution higher than that used in routine clinical applications.

Frequency and cost of serious adverse drug reactions in a department of general medicine.

AIMS: To assess the frequency and cost of drug reactions causing or prolonging hospitalization. METHODS: All patients admitted to an internal medicine ward over 6 months were evaluated to identify serious adverse reactions. The number of drug classes on admission or at the time of the adverse drug reaction (ADR) was counted. Excess ADR-related hospital stay was computed using a) raw excess duration of hospital stay, b) correction of duration of hospital stay by age, sex, and number of drug classes, and c) estimation by investigator of excess hospital stay. RESULTS: Three hundred and twenty-nine patients were evaluated: 212 male, 117 female, mean age 57.2 (males: 52.2, females: 66.2 (P < 0.05)), range 17-95 years. They stayed a total of 3720 hospital days (mean stay 11.3 days). 298 had no ADR (mean age 55.8, taking a mean of 2.7 drug classes, 10.7 days hospital stay); 31 had ADRs: in 10, the ADR caused admission in patients with a mean age of 84 (P < 0.01 vs the two other groups), taking 6.3 drug classes, who stayed a mean of 15.1 days; 21 occurred in hospital in patients with a mean age of 63.6, taking 4.2 drug classes (P < 0.01), who stayed a mean of 19.2 days (P < 0.01 vs patients without ADRs). In four the ADR was fatal (13% of ADRs, 40% of deaths). Raw ADR-related excess hospital stay was 318 days (8.6% of all hospital days), after multivariate correction 282 days (7.6% of all hospital days), and with investigator estimation 197 days (5.3% of all hospital days). Point prevalence of ADRs at admission was 3%, incidence rate in hospital was 5.6/1000 patient-days. CONCLUSIONS: 3% of the admissions were related to ADRs. In addition, 6.6% of hospitalized patients had significant ADRs. Between 5 and 9% of hospital costs were related to ADRs. In 24 of the 31 patients with ADRs (77%), these were related to the pharmacological properties of the involved drugs, and may possibly have been avoidable.

Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database.

AIMS: To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database. METHODS: The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non-case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA). RESULTS: 428 of 93,338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33-48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25-2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57-112)), disopyramide (OR 32 (22-46)), nifedipine (OR 2.16 (1.32-3.51)), diltiazem (OR 1.76 (1.01-3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16-3.16)) and frusemide (OR 1.89 (1.31-1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5-1.4) and 1.2 (0.7-2.2), respectively). The same was found for other drugs except cibenzoline. CONCLUSION: The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.

[Focus on the safety of ibuprofen at the analgesic-antipyretic dose]. / Mise au point sur la sécurité de l'ibuprofène à dose antalgique-antipyrétique.

Ibuprofen is a non-steroidal anti-inflammatory drug, available over the counter in most countries at analysis doses (600-1200 mg/day). After several years of such use, it would seem worthwhile to review recent safety data for this drug compared to reference analgesics. Spontaneous reporting to drug surveillance systems suggests one adverse reaction for every 5 million (UK) to 25 million (USA) 200 mg tablets sold, with one reported fatality for 0.6 to 23 billion tablets sold. During clinical and post-marketing studies, the frequency of adverse events was similar to that found with placebo or paracetamol. In a meta-analysis involving 46000 patients, the incidence of digestive events was 5 per cent, with 0.02 per cent upper GI bleeds. A prospective trial in 84000 children reported 0.007 per cent GI bleeds. Case-control studies of upper GI bleeding found odds ratios of the association with ibuprofen between 1 and 3, lower than those associated with aspirin, even at the low 'cardiovascular' doses. Other risks, such as the risk of renal failure, appear equally low. In the case of voluntary overdose, there appear to be little renal or other risk for ingested quantities below 6 g (30 tablets). Less than 1 per cent of the intoxications are rated as severe, and there have been even fewer fatalities. The favourable safety profile of ibuprofen may be related to short term use of low doses in otherwise healthy young patients, associated to a short product half-life, and may be to specific product properties. The quality of patient information may also be an important safety factor. When the safety of the drug in overdose is considered, substitution of aspirin or paracetamol, by ibuprofen, may actually reduce overall risk for the population.