Population Pharmacokinetics and Dosing Optimization of Vancomycin in Infants, Children, and Adolescents with Augmented Renal Clearance.

Augmented renal clearance (ARC) can cause underexposure to vancomycin, thereby increasing the risk of treatment failure. Our objective was to evaluate population pharmacokinetics and optimize the dosing regimen of vancomycin in a pediatric population with ARC. Sparse pharmacokinetic sampling and therapeutic drug monitoring (TDM) data were collected from pediatric patients with ARC treated with vancomycin. A pharmacokinetic model was developed using NONMEM 7.2. The dosing regimen was optimized using Monte Carlo dose simulations. A total of 242 vancomycin serum concentrations from 113 patients (age range, 0.4 to 14.9 years; 49 females and 64 males) were available. The mean vancomycin dose was 58.8 mg/kg body weight/day (13.6 mg/kg/dose), and the mean vancomycin serum trough concentration was 6.5 mg/liter. A one-compartment pharmacokinetic model with first-order elimination was developed. Body weight and age were the most significant and positive covariates for clearance and volume of distribution. For the pediatric population with ARC, the current recommended vancomycin dose of 60 mg/kg/day was associated with a high risk of underdosing. To reach the target area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) ratio of 400 to 700 in these pediatric patients, the vancomycin dose should be increased to 75 mg/kg/day for infants and children between 1 month and 12 years of age and 70 mg/kg/day for adolescents between 12 and 18 years of age. In conclusion, a one-compartment pharmacokinetic model with first-order elimination was established with body weight and age as significant covariates. An optimal dosing regimen was developed in pediatric patients with ARC aged 1 month to 18 years.

Uterine transposition versus uterine ventrofixation before radiotherapy as a fertility sparing option in young women with pelvic malignancies: Systematic review of the literature and dose simulation.

BACKGROUND: (Chemo)radiation may be a required treatment in young women with pelvic malignancies. Irradiation may result in ovarian and uterine failure, compromising the fertility of those patients. While ovarian transposition is an established method to move the ovaries away from the irradiation field, similar surgical procedures regarding the uterus remain investigational. The aim of this study was to carry out a systematic review of the literature on uterine displacement techniques (ventrofixation/transposition) and to simulate the radiation dose received by the uterus in different heights place after the procedures. METHODS: The systematic review was performed according PRISMA guidelines. PubMed, Scopus, Web of Science and EMBASE were queried to identify included study until March 2023. Retrospectively, a dosimetric study was also performed and Volumetric Modulated Arc Therapy (VMAT) radiotherapy treatment plans were calculated, to assess the dose received by the uterus according to hypothetical different displacement positions taking the case of irradiation for rectal or anal cancer as model. RESULTS: A total of 187 studies were included, after the screening 9 studies were selected for synthesis. Data from the dose simulation revealed that the transposition approach was the most protective with a maximum dose of about 3 and 8 Gy for anal and rectal cancer respectively. None of the simulated ventrofixation positions received a Dmean surpassing 14 Gy. CONCLUSION: According to the literature review and the simulation results of the present study we may conclude are feasible and safe as fertility sparing approach in young rectal/anal cancer patients.

Impacts of vertical variations in soil properties on H*(10) simulations for 137Cs deposition.

Photon transport simulations based on the Monte Carlo method have played a crucial role in assessing and estimating the ambient dose equivalent rates H*(10), resulting from the deposition of 137Cs in soil following the nuclear power plant accident in Fukushima. However, a comprehensive examination of the effect of vertical variations in soil properties on the simulation outcomes has not yet been performed. Disregarding the vertical distribution of soil properties not only leads to potential inaccuracies in the shielding responses of soil layers but also in the determination of the radioactive source inventory, particularly when using the concentration data in Bq/kg. These oversights diminish the reliability of the simulation results. This study addresses several soil property factors that could potentially influence the simulation results, including variations in chemical composition induced by water content, bulk density profile, and estimated inventory profile, all evaluated through an examined simulation model. The results show that inappropriate assignment of the soil density profile can cause considerable errors in the H*(10) simulation outcomes. Furthermore, the sensitivity of H*(10) to variations in soil vertical density is analyzed, with the results indicating that H*(10) can be highly sensitive to changes in the bulk density of the top 0-5 cm soil layers. These results should facilitate the establishment of appropriate simulation strategies and support the reassessment of past simulation results.

A practical method to simulate realistic reduced-exposure CT images by the addition of computationally generated noise.

Computed tomography (CT) scanning protocols should be optimized to minimize the radiation dose necessary for imaging. The addition of computationally generated noise to the CT images facilitates dose reduction. The objective of this study was to develop a noise addition method that reproduces the complexity of the noise texture present in clinical images with directionality that varies over images according to the underlying anatomy, requiring only Digital Imaging and Communications in Medicine (DICOM) images as input data and commonly available phantoms for calibration. The developed method is based on the estimation of projection data by forward projection from images, the addition of Poisson noise, and the reconstruction of new images. The method was validated by applying it to images acquired from cylindrical and thoracic phantoms using source images with exposures up to 49 mAs and target images between 39 and 5 mAs. 2D noise spectra were derived for regions of interest in the generated low-dose images and compared with those from the scanner-acquired low-dose images. The root mean square difference between the standard deviations of noise was 4%, except for very low exposures in peripheral regions of the cylindrical phantom. The noise spectra from the corresponding regions of interest exhibited remarkable agreement, indicating that the complex nature of the noise was reproduced. A practical method for adding noise to CT images was presented, and the magnitudes of noise and spectral content were validated. This method may be used to optimize CT imaging.

An efficient numerical tool for dose deposition prediction applied to synchrotron medical imaging and radiation therapy.

Medical imaging and radiation therapy are widely used synchrotron-based techniques which have one thing in common: a significant dose delivery to typically biological samples. Among the ways to provide the experimenters with image guidance techniques indicating optimization strategies, Monte Carlo simulation has become the gold standard for accurately predicting radiation dose levels under specific irradiation conditions. A highly important hampering factor of this method is, however, its slow statistical convergence. A track length estimator (TLE) module has been coded and implemented for the first time in the open-source Monte Carlo code GATE/Geant4. Results obtained with the module and the procedures used to validate them are presented. A database of energy-absorption coefficients was also generated, which is used by the TLE calculations and is now also included in GATE/Geant4. The validation was carried out by comparing the TLE-simulated doses with experimental data in a synchrotron radiation computed tomography experiment. The TLE technique shows good agreement versus both experimental measurements and the results of a classical Monte Carlo simulation. Compared with the latter, it is possible to reach a pre-defined statistical uncertainty in about two to three orders of magnitude less time for complex geometries without loss of accuracy.

Race, socioeconomic status, and air pollution exposure in North Carolina.

BACKGROUND: Although studies suggest that exposure to pollutants is associated with race/ethnicity and socio-economic status (SES), many studies are limited to the geographic regions where monitoring stations are located. OBJECTIVES: This study uses modeled predictive surfaces to examine the relationship between air pollution exposure, race/ethnicity, and measures of SES across the entire State of North Carolina. METHODS: The daily predictions of particulate matter <2.5 µm in aerodynamic diameter (PM2.5) and ozone (O3) were determined using a spatial model that fused data from two sources: point air monitoring data and gridded numerical output. These daily predicted pollution levels for 2002 were linked with Census data. We examine the relationship between the census-tract level predicted concentration measures, SES, and racial composition. RESULTS: SES and race/ethnicity were related to predicted concentrations of both PM2.5 and O3 for census tracts in North Carolina. Lower SES and higher proportion minority population were associated with higher levels of PM2.5. An interquartile range (IQR) increase of median household income reduced the predicted average PM2.5 level by 0.10 µg/m3. The opposite relationship was true for O3. An IQR increase of median household income increased the predicted average O3 measure by 0.11 ppb. CONCLUSIONS: The analyses demonstrate that SES and race/ethnicity are related to predicted estimates of PM2.5 and O3 for census tracts in North Carolina. These findings offer a baseline for future exposure modeling work involving SES and air pollution for the entire state and not just among the populations residing near monitoring networks.

A novel simulation-driven reconstruction approach for x-ray computed tomography.

PURPOSE: Radiation dose reduction is critical to the success of x-ray computed tomography (CT). Many advanced reconstruction techniques have been developed over the years to combat noise resulting from the low-dose CT scans. These algorithms rely on accurate local estimation of the image noise to determine reconstruction parameters or to select inferencing models. Because of the difficulties in the noise estimation for heterogeneous objects, the performance of many algorithms is inconsistent and suboptimal. Here, we propose a novel approach to overcome such shortcoming. METHOD: By injecting appropriate amount of noise in the CT raw data, a computer simulation approach is capable of accurately estimating the local statistics of the raw data and the local noise in the reconstructed images. This information is then used to guide the noise-reduction process during the reconstruction. As an initial implementation, a scaling map is generated based on the noise predicted from the simulation and the noise estimated from existing reconstruction algorithms. Images generated with existing algorithms are subsequently modified based on the scaling map. In this study, both iterative reconstruction (IR) and deep learning image reconstruction (DLIR) algorithms are evaluated. RESULTS: Phantom experiments were conducted to evaluate the performance of the simulation-based noise estimation in terms of the standard deviation and noise power spectrum. Quantitative results have demonstrated that the noise measured from the original image matches well with the noise estimated from the simulation. Clinical datasets were utilized to further confirm the accuracy of the proposed approach under more challenging conditions. To validate the performance of the proposed reconstruction approach, clinical scans were used. Performance comparison was carried out qualitatively and quantitatively. Two existing advanced reconstruction techniques, IR and DLIR, were evaluated against the proposed approach. Results have shown that the proposed approach outperforms existing IR and DLIR algorithms in terms of noise suppression and, equally importantly, noise uniformity across the entire imaging volume. Visual assessment of the images also reveals that the proposed approach does not endure noise texture issues faced by some of the existing reconstruction algorithms today. CONCLUSION: Phantom and clinical results have demonstrated superior performance of the proposed approach with regard to noise reduction as well as noise homogeneity. Visual inspection of the noise texture further confirms the clinical utility of the proposed approach. Future enhancements on the current implementation are explored regarding image quality and computational efficiency. Because of the limited scope of this paper, detailed investigation on these enhancement features will be covered in a separate report.

Danofloxacin pharmacokinetics and tissue residues in Bilgorajska geese.

Danofloxacin is a fluoroquinolone developed for veterinary medicine and used in avian species for the treatment of numerous bacterial infections. However, no pharmacokinetic data have been reported in geese. The aim of the study was three-fold: (i) to evaluate the pharmacokinetics of danofloxacin in geese after single oral (PO) and intravenous (IV) administrations; (ii) to define its residue depletion profile in different goose tissues, and (iii) to recreate a multiple-dose simulation in the practical context of large-scale breeding. Twenty-four healthy geese were randomly divided in three groups each composed of eight animals. Group 1 received danofloxacin IV (5 mg/kg) and groups 2 and 3 were treated PO with the same dose. Blood was collected until 24 h (IV; group 1) and 48 h (PO; group 2) after administration. Two animals from group 3 were sacrificed at 6, 10, 24 and 48 h to collect samples of muscle, heart, kidney, liver, and lung. Danofloxacin was quantified in each matrix using a validated high-performance liquid chromatography method with spectrofluorimetric detection and the pharmacokinetic analysis was performed using non-compartmental and compartmental approaches. Danofloxacin showed a moderate elimination half-life (6.61 h), a slow clearance (0.35 mL/g*h) and a large volume of distribution (1.46 mL/g). The peak plasma concentration after PO administration and the time to reach it were 0.96 µg/mL and 1.70 h, respectively. The oral bioavailability was moderate (58%). Higher residue concentration was found in liver and kidney, compared to the other tissues. If the AUC(0-24) value found in the present study is included in the pharmacokinetic/pharmacodynamic index (AUC(0-24)/MIC) for the prediction of fluoroquinolones' efficacy, danofloxacin seems to be effective in geese against gram-negative bacteria with a minimum inhibitory concentration (MIC) < 0.076 µg/mL and against S. pneumoniae with a MIC < 0.29 µg/mL after a single PO dose of 5 mg/kg. Liver and kidney showed the highest drug tissue penetration value, with an explorative withdrawal time of 2.6 and 3.8 days, respectively. A practical multiple-dose regimen simulation does not lead to significant plasma drug accumulation.

[Assessment of imaging performance of digital breast tomosynthesis based on systematic simulation].

OBJECTIVE: To assess the imaging performance of digital breast tomography (DBT) based on systematic simulation. OBJECTIVE: The raw measurements of physical phantoms at a variety of radiation dose levels and clinical patients at the normal radiation dose were acquired from a clinical DBT system for low-dose simulation and reconstruction using 3 reconstruction algorithms, namely Feldkamp-Davis-Kress (FDK), simultaneous algebraic reconstruction technique (SART) and adaptive steepest-descent projection onto convex sets with total-variation constraint (ASDPOCS-TV) algorithms. The image quality was compared across different radiation dose levels and reconstruction algorithms in terms of signal-to-noise ratio (SNR), peak signal-to-noise ratio (PSNR), noise-power spectrum (NPS), artifact spread function (ASF) and full width at half maximum (FWHM) of ASF indexes. OBJECTIVE: The reliability of low-dose DBT simulation strategy was verified by the experiment. Within a suitable range of dose levels, increasing the doses resulted in reduced high-frequency noise component and significantly increased SNR (P < 0.05). But when the value of exposure was below 40 mAs, the images acquired at different dose levels had similar representation. The performance of the 3 reconstruction algorithms varied for different anatomical structures, and the image quality of ASDPOCS-TV algorithm was generally superior to SART and FDK algorithms with less through-plane artifacts and noise. OBJECTIVE: The quality of DBT images is significantly affected by both radiation dose and reconstruction algorithms. A tradeoff of the parameters, the overall image quality and the clinical needs for diagnostic purposes should be considered to achieve the optimal imaging performance on a given clinical task.

New model for an epoxy-based brachytherapy source to be used in spinal cancer treatment.

The present work described the cold fabrication of a P-32 radioactive source to be used in CNS cancer using epoxy resin. The epoxy plaque fabricated with Teflon mold presented better agreement. MCNP simulation evaluated the radiation dose. Special attention was given to factors that can impact dose distribution. Average dose was 16.44 ± 2.89% cGy/s. Differences of less than 0.01 cm in thickness within the plaque lead to differences of up to 12% in the dose rate.

Utilizing High-Throughput Screening Data, Integrative Toxicological Prioritization Index Score, and Exposure-Activity Ratios for Chemical Prioritization: A Case Study of Endocrine-Active Pesticides in Food Crops.

Endocrine-active chemicals can directly act on nuclear receptors and trigger the disturbances of metabolism and a homeostatic system, which are important risk factors for complicating chronic diseases in humans. The endocrine-active potentials of pesticides acting on estrogen, androgen, and thyroid hormone receptors have been extensively evaluated for pesticides; however, the effects on other receptors are less understood. This study aims to comprehensively characterize and prioritize the endocrine-active pesticides using an exposure-activity ratio (EAR) method and toxicological prioritization index (ToxPi). The aggregate exposure assessment of pesticides was performed using a computational exposure model [stochastic human exposure and dose simulation high-throughput model (SHEDS-HT)]. Minimum in vitro point of departure values were converted to human oral equivalent doses via in vitro-to-in vivo extrapolation. The overall endocrine-disrupting potentials of pesticides were evaluated via 76 assays, representing 11 nuclear receptors. EARs and ToxPi scores were then derived to prioritize 79 pesticides in food. This case study demonstrates that EAR profiling can inform the regulatory agencies for a relevant chemical prioritization, which would direct in-depth health risk assessments in the future.

Dosimetric Comparison of Three-Dimensional Conformal Radiotherapy (3D-CRT) and Intensity Modulated Radiotherapy Techniques (IMRT) with Radiotherapy Dose Simulations for Left-Sided Mastectomy Patients.

OBJECTIVE: To compare 3-dimensional conformal radiotherapy (3D-CRT) and intensity modulated radiotherapy (IMRT) techniques on the target tissue and critical organ doses in terms of dosimetry, during treatment planning of patient's post-mastectomy radiotherapy (PMRT) to the left chest wall. MATERIALS AND METHODS: Twenty breast cancer patients with left-sided post-mastectomy have selected for PMRT both 3D-CRT and IMRT techniques. Dosimetric calculation of dose simulation in Eclipse treatment planning system have been performed. Organs at risk with the maximum dose, minimum dose, mean dose, D95, conformity and homogeneity indexes and total monitor unit for the Planning Target Volume were compared in terms of the critical organ doses. RESULTS: There was no significant difference between the two treatment planning techniques in terms of maximum, minimum, mean dose and heterogeneity index (p>0.05). At low doses, the dose received at the heart was significantly lower with the 3D-CRT technique, but there was no statistically significant difference between the two techniques at the maximum and average doses in the high dose regions. CONCLUSION: For PMRT to the left chest wall, IMRT significantly improves the conformity of plan and reduce the high-dose volumes of ipsilateral lung and heart compared to 3D-CRT, but 3D-CRT is superior in terms of low-dose volume.

Influence of deformable image registration on 4D dose simulation for extracranial SBRT: A multi-registration framework study.

BACKGROUND AND PURPOSE: To evaluate the influence of deformable image registration approaches on correspondence model-based 4D dose simulation in extracranial SBRT by means of open source deformable image registration (DIR) frameworks. MATERIAL AND METHODS: Established DIR algorithms of six different open source DIR frameworks were considered and registration accuracy evaluated using freely available 4D image data. Furthermore, correspondence models (regression-based correlation of external breathing signal measurements and internal structure motion field) were built and model accuracy evaluated. Finally, the DIR algorithms were applied for motion field estimation in radiotherapy planning 4D CT data of five lung and five liver lesion patients, correspondence model formation, and model-based 4D dose simulation. Deviations between the original, statically planned and the 4D-simulated VMAT dose distributions were analyzed and correlated to DIR accuracy differences. RESULTS: Registration errors varied among the DIR approaches, with lower DIR accuracy translating into lower correspondence modeling accuracy. Yet, for lung metastases, indices of 4D-simulated dose distributions widely agreed, irrespective of DIR accuracy differences. In contrast, liver metastases 4D dose simulation results strongly vary for the different DIR approaches. CONCLUSIONS: Especially in treatment areas with low image contrast (e.g. the liver), DIR-based 4D dose simulation results strongly depend on the applied DIR algorithm, drawing resulting dose simulations and indices questionable.

Diuretic activity of the aqueous crude extract and hot tea infusion of Moringa stenopetala (Baker f.) Cufod. leaves in rats.

Moringa stenopetala (Baker f.) Cufod. is a medicinal plant that has been used for the treatment of different ailments such as hypertension and diabetes in Ethiopia. This study aims to assess the diuretic activity of the aqueous crude extract and hot tea infusion of M. stenopetala leaves in saline-loaded rats. Male Wistar rats were divided into ten groups (n = 5). The control group received distilled water (5 mL/kg), whereas the reference group received Furosemide (10 mg/kg). Groups III-X orally received different doses of aqueous crude extract (62.5, 125, 250, and 500 mg/kg) and hot tea infusion (1, 2, 4, and 6 teaspoons [Tsp]) based on community use. Urine volume was recorded every hour until the end of the 5th hour, and total urine volume of each animal was calculated. The diuretic activity and diuretic action were determined based on the urine output. Additionally, concentration of urinary sodium, chloride, and potassium ions was determined. The urinary Na+/K+ ratio and carbonyl anhydrase activity (Cl-/(Na+/K+)) were also assessed. The findings verified that the aqueous crude extract as well as the hot tea infusion of the leaves of M. stenopetala possesses significant (P < 0.01) diuretic, natriuretic, and kaliuretic effects. The aqueous crude extract (125 mg/kg) and hot tea infusion (2 Tsp) displayed the highest diuretic activity (101% and 96%, respectively) comparable to the reference drug, Furosemide (10 mg/kg). They also displayed a good natriuretic activity. The aqueous crude extract and hot tea infusion revealed a significant Na+ urinary excretion (P < 0.001) and Na+/K+ ratio (P < 0.05) at all test doses. There was also a significant (P < 0.01) Cl- urinary excretion at all test doses of aqueous crude extract except 62.5 mg/kg and all test doses of hot tea infusion except higher doses (4 and 6 Tsp). Thus, the aqueous crude extract as well as the hot tea infusion of the leaves of M. stenopetala causes a plausible increase in the urine volume and concentration of urinary electrolytes in rats.

Population pharmacokinetics and dose simulation of vancomycin in critically ill patients during high-volume haemofiltration.

This study aimed to describe the population pharmacokinetics of vancomycin in critically ill patients with refractory septic shock undergoing continuous venovenous high-volume haemofiltration (HVHF) and to define appropriate dosing for these patients. This was a prospective pharmacokinetic study in the ICU of a university hospital. Eight blood samples were taken over one vancomycin dosing interval. Samples were analysed by a validated liquid chromatography-tandem mass spectrometry assay. Non-linear mixed-effects modelling was used to describe the population pharmacokinetics. Dosing simulations were used to define therapeutic vancomycin doses for different HVHF settings. Nine patients were included (five male). The mean weight and SOFA score were 70 kg and 11, respectively. Mean HVHF settings were: blood flow rate, 240 mL/min; and haemofiltration exchange rate, 100 mL/kg/h. A linear two-compartment model with zero-order input adequately described the data. Mean parameter estimates were: clearance, 2.9 L/h; volume of distribution of central compartment (V(1)), 11.8L; volume of distribution of peripheral compartment (V(2)), 18.0 L; and intercompartmental clearance, 9.3 L/h. HVHF intensity was strongly associated with vancomycin clearance (P < 0.05) and was a covariate in the final model. Simulations indicate that after a loading dose, vancomycin doses required for different HVHF intensities would be 750 mg every 12h (q12h) for 69 mL/kg/h, 1000 mg q12h for 100 mL/kg/h and 1500 mg q12h for 123 mL/kg/h. Continuous infusion would also be a valuable administration strategy. In conclusion, variable and much higher than standard vancomycin doses are required to achieve therapeutic concentrations during different HVHF settings.