PET/SPECT/Spectral-CT/CBCT imaging in a small-animal radiation therapy platform: A Monte Carlo study-Part II: Biologically guided radiotherapy.

BACKGROUND: This study addresses the technical gap between clinical radiation therapy (RT) and preclinical small-animal RT, hindering the comprehensive validation of innovative clinical RT approaches in small-animal models of cancer and the translation of preclinical RT studies into clinical practices. PURPOSE: The main aim was to explore the feasibility of biologically guided RT implemented within a small-animal radiation therapy (SART) platform, with integrated quad-modal on-board positron emission tomography (PET), single-photon emission computed tomography, photon-counting spectral CT, and cone-beam CT (CBCT) imaging, in a Monte Carlo model as a proof-of-concept. METHODS: We developed a SART workflow employing quad-modal imaging guidance, integrating multimodal image-guided RT and emission-guided RT (EGRT). The EGRT algorithm was outlined using positron signals from a PET radiotracer, enabling near real-time adjustments to radiation treatment beams for precise targeting in the presence of a 2-mm setup error. Molecular image-guided RT, incorporating a dose escalation/de-escalation scheme, was demonstrated using a simulated phantom with a dose painting plan. The plan involved delivering a low dose to the CBCT-delineated planning target volume (PTV) and a high dose boosted to the highly active biological target volume (hBTV) identified by the 18F-PET image. Additionally, the Bayesian eigentissue decomposition method illustrated the quantitative decomposition of radiotherapy-related parameters, specifically iodine uptake fraction and virtual noncontrast (VNC) electron density, using a simulated phantom with Kidney1 and Liver2 inserts mixed with an iodine contrast agent at electron fractions of 0.01-0.02. RESULTS: EGRT simulations generated over 4,000 beamlet responses in dose slice deliveries and illustrated superior dose coverage and distribution with significantly lower doses delivered to normal tissues, even with a 2-mm setup error introduced, demonstrating the robustness of the novel EGRT scheme compared to conventional image-guided RT. In the dose-painting plan, doubling the dose to the hBTV while maintaining a low dose for the PTV resulted in an organ-at-risk (OAR) dose comparable to the low-dose treatment for the PTV alone. Furthermore, the decomposition of radiotherapy-related parameters in Kidney1 and Liver2 inserts, including iodine uptake fractions and VNC electron densities, exhibited average relative errors of less than 1.0% and 2.5%, respectively. CONCLUSIONS: The results demonstrated the successful implementation of biologically guided RT within the proposed quad-model image-guided SART platform, with potential applications in preclinical RT and adaptive RT studies.

Very high-energy electron therapy as light-particle alternative to transmission proton FLASH therapy - An evaluation of dosimetric performances.

PURPOSE: Clinical translation of FLASH-radiotherapy (RT) to deep-seated tumours is still a technological challenge. One proposed solution consists of using ultra-high dose rate transmission proton (TP) beams of about 200-250 MeV to irradiate the tumour with the flat entrance of the proton depth-dose profile. This work evaluates the dosimetric performance of very high-energy electron (VHEE)-based RT (50-250 MeV) as a potential alternative to TP-based RT for the clinical transfer of the FLASH effect. METHODS: Basic physics characteristics of VHEE and TP beams were compared utilizing Monte Carlo simulations in water. A VHEE-enabled research treatment planning system was used to evaluate the plan quality achievable with VHEE beams of different energies, compared to 250 MeV TP beams for a glioblastoma, an oesophagus, and a prostate cancer case. RESULTS: Like TP, VHEE above 100 MeV can treat targets with roughly flat (within ± 20 %) depth-dose distributions. The achievable dosimetric target conformity and adjacent organs-at-risk (OAR) sparing is consequently driven for both modalities by their lateral beam penumbrae. Electron beams of 400[500] MeV match the penumbra of 200[250] MeV TP beams and penumbra is increased for lower electron energies. For the investigated patient cases, VHEE plans with energies of 150 MeV and above achieved a dosimetric plan quality comparable to that of 250 MeV TP plans. For the glioblastoma and the oesophagus case, although having a decreased conformity, even 100 MeV VHEE plans provided a similar target coverage and OAR sparing compared to TP. CONCLUSIONS: VHEE-based FLASH-RT using sufficiently high beam energies may provide a lighter-particle alternative to TP-based FLASH-RT with comparable dosimetric plan quality.

Diamond based integrated detection system for dosimetric and microdosimetric characterization of radiotherapy ion beams.

BACKGROUND: Ion beam therapy allows for a substantial sparing of normal tissues and higher biological efficacy. Synthetic single crystal diamond is a very good material to produce high-spatial-resolution and highly radiation hard detectors for both dosimetry and microdosimetry in ion beam therapy. PURPOSE: The aim of this work is the design, fabrication and test of an integrated waterproof detector based on synthetic single crystal diamond able to simultaneously perform dosimetric and microdosimetric characterization of clinical ion beams. METHODS: The active elements of the integrated diamond device, that is, dosimeter and microdosimeter, were both realized in a Schottky diode configuration featured by different area, thickness, and shape by means of photolithography technologies for the selective growth of intrinsic and boron-doped CVD diamond. The cross-section of the sensitive volume of the dosimetric element is 4 mm2 and 1 µm-thick, while the microdosimetric one has an active cross-sectional area of 100 × 100 µm2 and a thickness of about 6.2 µm. The dosimetric and microdosimetric performance of the developed device was assessed at different depths in a water phantom at the MedAustron ion beam therapy facility using a monoenergetic uniformly scanned carbon ion beam of 284.7 MeV/u and proton beam of 148.7 MeV. The particle flux in the region of the microdosimeter was 6·107  cm2 /s for both irradiation fields. At each depth, dose and dose distributions in lineal energy were measured simultaneously and the dose mean lineal energy values were then calculated. Monte Carlo simulations were also carried out by using the GATE-Geant4 code to evaluate the relative dose, dose averaged linear energy transfer (LETd ), and microdosimetric spectra at various depths in water for the radiation fields used, by considering the contribution from the secondary particles generated in the ion interaction processes as well. RESULTS: Dosimetric and microdosimetric quantities were measured by the developed prototype with relatively low noise (∼2 keV/µm). A good agreement between the measured and simulated dose profiles was found, with discrepancies in the peak to plateau ratio of about 3% and 4% for proton and carbon ion beams respectively, showing a negligible LET dependence of the dosimetric element of the device. The microdosimetric spectra were validated with Monte Carlo simulations and a good agreement between the spectra shapes and positions was found. Dose mean lineal energy values were found to be in close agreement with those reported in the literature for clinical ion beams, showing a sharp increase along the Bragg curve, being also consistent with the calculated LETd for all depths within the experimental error of 10%. CONCLUSIONS: The experimental indicate that the proposed device can allow enhanced dosimetry in particle therapy centers, where the absorbed dose measurement is implemented by the microdosimetric characterization of the radiation field, thus providing complementary results. In addition, the proposed device allows for the reduction of the experimental uncertainties associated with detector positioning and could facilitate the partial overcoming of some drawbacks related to the low sensitivity of diamond microdosimeters to low LET radiation.

Monte Carlo based dosimetry of extraoral photobiomodulation for prevention of oral mucositis.

Photobiomodulation therapy (PBMT) is recommended for prevention and treatment of oral mucositis, a painful condition that occurs in cancer patients. Intraoral PBMT is limited to treating distal oral mucosa and oropharynx. Extraoral PBMT may provide a more efficient intervention. The goal of this study was to develop a clinically viable protocol for extraoral PBMT. Monte Carlo modeling was used to predict the distribution of 850 nm light for four treatment sites, using anatomical data obtained from MRI and optical properties from the literature. Simulated incident light power density was limited to 399 mW/cm2 to ensure treatment safety and to prevent tissue temperature increase. The results reveal that total tissue thickness determines fluence rate at the oral mucosa, whereas the thickness of individual tissue layers and melanin content are of minor importance. Due to anatomical differences, the fluence rate varied greatly among patients. Despite these variations, a universal protocol was established using a median treatment time methodology. The determined median treatment times required to deliver efficacious dose between 1 and 6 J/cm2 were within 15 min. The developed PBMT protocol can be further refined using the combination of pretreatment imaging and the Monte Carlo simulation approach implemented in this study.

Monte Carlo-based optimization of glioma capsule design for enhanced brachytherapy.

The use of radiotherapy in tumor treatment has become increasingly prominent and has emerged as one of the main tools for treating malignant tumors. Current radiation therapy for glioma employs 125I seeds for brachytherapy, which cannot be combined with radiotherapy and chemotherapy. To address this limitation, this paper proposes a dual-microcavity capsule structure that integrates radiotherapy and chemotherapy. The Monte Carlo simulation method is used to simulate the structure of the dual-microcavity capsule with a 125I liquid radioactive source. Based on the simulation results, two kinds of dual-microcavity capsule structures are optimized, and the optimized dual-microcavity capsule structure is obtained. Finally, the dosimetric parameters of the two optimized dual-microcavity capsule structures are analyzed and compared with those of other 125I seeds. The optimization tests show that the improved dual-capsule dual-microcavity structure is more effective than the single-capsule dual-microcavity structure. At an activity of 5 mCi, the average absorbed dose rate is 71.2 cGy/h in the center of the optimized dual-capsule dual-microcavity structure and 45.8 cGy/h in the center of the optimized single-capsule dual-microcavity structure. Although the radial dose function and anisotropy function exhibite variations from the data of other 125I seeds, they are generally similar. The absorbed dose rate decreases exponentially with increasing distance from the center of the capsule, which can reduce the damage to the surrounding tissues and organs while increasing the dose. The capsule structure has a better irradiation effect than conventional 125I seeds and can accomplish long-term, stable, low-dose continuous irradiation to form local high-dose radiation therapy for glioma.

Novel intraocular shielding device for eye plaque brachytherapy using magnetite nanoparticles: A proof-of-concept study using radiochromic film and Monte Carlo simulations.

PURPOSE: Eye plaque brachytherapy is a mainstay treatment for uveal melanomas despite potential toxicities to normal tissues. This work proposes a nanoparticle ferrofluid as a novel intraocular shielding device. With a modified magnetic plaque, the shielding particles are drawn to the tumor surface, attenuating dose beyond the tumor while maintaining prescription dose to the target. METHODS AND MATERIALS: Ferromagnetic nanoparticles suspended in a silicone polymer were synthesized to provide a high-density shielding medium. The ferrofluid's half-value layer (HVL) was quantified for 125I photons using radiochromic film and Monte Carlo methods. A magnetic COMS plaque was created and evaluated in its ability to attract ferrofluid over the tumor. Two ferrofluid shielding mediums were evaluated in their ability to attenuate dose at adjacent structures with in vitro measurements using radiochromic film, in addition to Monte Carlo studies. RESULTS: The shielding medium's HVL measured approximately 1.3 mm for an 125I photon spectrum, using film and Monte Carlo methods. With 0.8 mL of shielding medium added to the vitreous humor, it proved to be effective at reducing dose to normal tissues of the eye. Monte Carlo-calculated dose reductions of 65%, 80%, and 78% at lateral distances 5, 10, and 18 mm from a tumor (5-mm apical height) in a modeled 20-mm COMS plaque. CONCLUSIONS: The magnitude of dose reduction could reduce the likelihood of normal tissue side effects for plaque brachytherapy patients, including patients with normal tissues close to the plaque or tumor. Additional studies, safety considerations, and preclinical work must supplement these findings before use.

An efficient quasi-Monte Carlo method with forced fixed detection for photon scatter simulation in CT.

Detected scattered photons can cause cupping and streak artifacts, significantly degrading the quality of CT images. For fast and accurate estimation of scatter intensities resulting from photon interactions with a phantom, we first transform the path probability of photons interacting with the phantom into a high-dimensional integral. Secondly, we develope a new efficient algorithm called gQMCFFD, which combines graphics processing unit(GPU)-based quasi-Monte Carlo (QMC) with forced fixed detection to approximate this integral. QMC uses low discrepancy sequences for simulation and is deterministic versions of Monte Carlo. Numerical experiments show that the results are in excellent agreement and the efficiency improvement factors are 4 ∼ 46 times in all simulations by gQMCFFD with comparison to GPU-based Monte Carlo methods. And by combining gQMCFFD with sparse matrix method, the simulation time is reduced to 2 seconds in a single projection angle and the relative difference is 3.53%.

ESTIMATION OF THE GAMMA-RAY FIELD IN AIR FROM RADIOACTIVE SOURCES IN THE GROUND BY NUMERICAL SOLUTION OF THE BOLTZMANN TRANSPORT EQUATION.

Gamma-ray field in air from radioactive sources uniformly distributed in the ground is calculated by numerically solving the photon transport equation. The scattered flux is developed on the Legendre polynomials basis of the spherical harmonics method and a double P1 approximation is applied. The method is implemented in the Octave programming package. The calculation of the gamma-ray field is also done by Monte Carlo simulation using an optimised geometry model of the soil-air medium that is implemented in Geant4 simulation code. The results obtained by the two methods are in good agreement. The computing time for the spherical harmonics deterministic method is significantly less than the Monte Carlo simulation. Dose rate conversion factors in the air are calculated for the natural radioactive series of 238U and 232Th and for 40K nuclide and for soils contaminated by various radionuclides. The results are in agreement with the published theoretical and experimental studies.

Sensitivity of a bone-equivalent polymer gel dosimeter for measuring the dose to bone during radiation therapy.

Treatment planning systems that use the Monte Carlo algorithm can calculate the dose to the medium (Dm) in non-water-equivalent tissues such as bones. However, Dm cannot be verified using actual measurements; therefore, it is necessary to develop tissue-equivalent dosimeters. In this study, we developed a bone-equivalent polymer gel dosimeter (BPGD) that can measure the dose absorbed by the bone and investigated its sensitivity. The BPGDs were prepared by adding 3.0 mol of calcium hydrogen phosphate dihydrate as a component of bone to an improved dose-sensitive polyacrylamide gelatin and tetrakis hydroxymethyl phosphonium chloride (iPAGAT). One day after preparation, the BPGDs were irradiated with a field size of 15 × 15 cm2 using a 10 MV X-ray beam to evaluate the dose sensitivity, dose-rate dependence, and dose-integration dependence. One day after dose exposure, the BPGDs were scanned using a 0.4 T MRI APERTO Eterna (Hitachi, Tokyo, Japan) to obtain R2 values. The difference between the R2 values of 6 Gy and 0 Gy was up to 5 s-1, and the R2 curve plateaued in the high-dose region. Moreover, the BPGD did not depend on the integration of the dose and dose rates. Therefore, the BPGDs that we developed can determine the radiation dose to bones.

Biophysical characterization of collimated and uncollimated fields in pencil beam scanning proton therapy.

Objective. The lateral dose fall-off in proton pencil beam scanning (PBS) technique remains the preferred choice for sparing adjacent organs at risk as opposed to the distal edge due to the proton range uncertainties and potentially high relative biological effectiveness. However, because of the substantial spot size along with the scattering in the air and in the patient, the lateral penumbra in PBS can be degraded. Combining PBS with an aperture can result in a sharper dose fall-off, particularly for shallow targets.Approach. The aim of this work was to characterize the radiation fields produced by collimated and uncollimated 100 and 140 MeV proton beams, using Monte Carlo simulations and measurements with a MiniPIX-Timepix detector. The dose and the linear energy transfer (LET) were then coupled with publishedin silicobiophysical models to elucidate the potential biological effects of collimated and uncollimated fields.Main results. Combining an aperture with PBS reduced the absorbed dose in the lateral fall-off and out-of-field by 60%. However, the results also showed that the absolute frequency-averaged LET (LETF) values increased by a maximum of 3.5 keVµm-1in collimated relative to uncollimated fields, while the dose-averaged LET (LETD) increased by a maximum of 7 keVµm-1. Despite the higher LET values produced by collimated fields, the predicted DNA damage yields remained lower, owing to the large dose reduction.Significance. This work demonstrated the dosimetric advantages of combining an aperture with PBS coupled with lower DNA damage induction. A methodology for calculating dose in water derived from measurements with a silicon-based detector was also presented. This work is the first to demonstrate experimentally the increase in LET caused by combining PBS with aperture, and to assess the potential DNA damage which is the initial step in the cascade of events leading to the majority of radiation-induced biological effects.

Application of Geant4-DNA for simulating water radiolysis induced by Auger electron-emitting radionuclides.

Auger-emitting radionuclides have potential application in targeted radiotherapy, particularly for metastatic cancers. This possibility, especially, is stemmed from their characteristic short-range (a few µm) in biological systems allowing localization of high dose within small tumours. To explore this potential application, a Geant4 Monte Carlo toolkit has been employed to simulate the energy deposition of different radionuclides in a water model. The Geant4 Monte Carlo toolkit has model packages to simulate the interaction of radiation with matter and with diverse applications such as studies in science and medicine. In this study, the Geant4-DNA package was used to simulate the radiolytic yields induced by some Auger electron-emitting (AE) radionuclides including; I-131, I-125 and Pd-103, In-111, Ru-97 and Rh-103 m in water model. The results showed that the transient yield of the radiolytic species is characterized by the kinetic energies of the emitted electrons. It was observed that almost all the radionuclides, except I-131, deposited more energy in their proximity thereby inducing a high density of spurs to interact in a short time. It is, therefore, important to consider the kinetic energies of the emitted particles in choosing a radionuclide for specified targeted radiotherapy. This means that apart from their toxicity, compatibility with chelator and carrier molecules, and method of production, we can predict radionuclides such as In-111, Ru-97, Pb-103 m and I-125 could be relevant for targeted radiotherapy for the treatment of metastasis lesions, or tiny tumours at the cellular level, and tumours after surgical resection.

Transitioning from a COMS-based plaque brachytherapy program to using eye physics plaques and plaque simulator treatment planning system: A single institutional experience.

The aim of this work is to describe the implementation and commissioning of a plaque brachytherapy program using Eye Physics eye plaques and Plaque Simulator treatment planning system based on the experience of one institution with an established COMS-based plaque program. Although commissioning recommendations are available in official task groups publications such as TG-129 and TG-221, we found that there was a lack of published experiences with the specific details of such a transition and the practical application of the commissioning guidelines. The specific issues addressed in this paper include discussing the lack of FDA approval of the Eye Physics plaques and Plaque Simulator treatment planning system, the commissioning of the plaques and treatment planning system including considerations of the heterogeneity corrected calculations, and the implementation of a second check using an FDA-approved treatment planning system. We have also discussed the use of rental plaques, the analysis of plans using dose histograms, and the development of a quality management program. By sharing our experiences with the commissioning of this program this document will assist other institutions with the same task and act as a supplement to the recommendations in the recently published TG-221.

Dealing with correlations in the multichannel EEG using bipolar derivations and Monte Carlo simulations: application to the detection of auditory steady-state responses.

The multichannel objective response detection (MORD) techniques are statistical methods, which use information from more than one electroencephalography (EEG) channel, to infer the presence of evoked potential. However, the correlation level between the channels can lead to a decrease in MORD performance, such as an increase in the false positive (FP) rate and/or a decrease in the detection rate (DR). The present study aims to propose a method to deal with the correlations in the multichannel EEG. The method consists of making an adjustment in the Monte Carlo simulation, considering the information between channels. The MORD techniques with and without the new method were applied to an auditory steady-state response (ASSR) database, composed of the EEG multichannel of eleven volunteers during multifrequency stimulation. The proposed method kept the FP rate at values equal to or less than the significance level of the test and led to an increase of 8.51% in the DR in relation to non-application of the method. Results of this study indicate that the proposed method is an alternative to deal with the effect of the correlation between channels in situations where MORD techniques are applied.

Cefepime, not Piperacillin/Tazobactam use, for empirical treatment of bloodstream infections caused by Enterobacter spp.: Results from a population pharmacokinetic/pharmacodynamic analysis.

OBJECTIVE: There is a paucity of published data to evaluate the efficacy and safety of imipenem, cefepime and piperacillin/tazobactam dosing regimens against bloodstream infections caused by Klebsiella aerogenes (BSIs-Kae) and Enterobacter cloacae complex (BSIs-Ecc) in patients with various degrees of renal function. METHODS: Pathogens were isolated from China's blood bacterial resistant investigation network. The dosing regimens of imipenem, cefepime and piperacillin were simulated with intermittent infusion and extended infusion. Monte Carlo simulation was performed to calculate the probability of target attainment and a cumulative fraction of response (CFR) against BSIs-Kae/Ecc. RESULTS: In total, 203 BSIs-Kae, and 785 BSIs-Ecc were isolated from the surveillance network. Imipenem showed the highest in vitro activity against BSIs-Kae/Ecc, followed by cefepime (85%) and piperacillin/tazobactam (70-80%). The MIC90 values of imipenem, cefepime and piperacillin/tazobactam aginst BSIs-Kae and BSIs-Ecc were 1/1 mg/L, 16/16 mg/L, and 64/128 mg/L, respectively. The simulation results showed imipenem achieved the highest CFRs in patients with normal or decreased renal function, with values of 91-99%, followed by FEP (88-96%), without risk of excessive dosing. However, the intermittent and extended dosing regimens of piperacillin/tazobactam were unlikely to provide adequate exposure for empirical management of BSIs-Kae/Ecc (CFRs, 50-80%), regardless of renal function. Besides, the traditional intermittent piperacillin/tazobactam dosing regimens were highly likely to contribute to suboptimal therapeutic exposure when MIC was close to clinical breakpoints. CONCLUSIONS: Cefepime, not piperacillin/tazobactam, can be a reasonable carbapenem-sparing option in empirically treating BSIs-Kae/Ecc.

Superiority of ceftazidime off-label high-dose regimen in PK/PD target attainment during treatment of extensively drug-resistant Pseudomonas aeruginosa infections in cancer patients.

AIM: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. METHODS: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. RESULTS: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. CONCLUSION: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.

Delayed neutron counting of uranium pins using moderated neutrons from portable DD neutron generator in high frequency mode.

Delayed neutron counting is often used to verify the characteristics of nuclear material. Use of portable neutron generators in high frequency pulsing mode enables effective analysis with higher counting efficiency and lower radiation protection demands. The paper deals with delayed neutron counting of uranium pins with P385 portable DD neutron generator in polyethylene-based setup. Counting is performed in high frequency mode of neutron generator. The viability of such measurement in the frequency range from 100 Hz to 250 Hz was demonstrated and optimal pulsing parameters for P385 neutron generator were found. Delayed neutron counting was then performed for two types of uranium rods. Delayed neutrons were counted both inbetween neutron pulses during neutron generation and once the emission of neutrons stopped. The results were further validated by Monte Carlo (MCNP) simulations. For the geometry of studied rods, the MCNP calculation were done to calculate the dependence of the response to delayed neutrons on rod enrichment, to show the viability to use the method for rod enrichment verification. An option of using cadmium inset in irradiation channel to overcome the effect of self-shielding for samples with higher enrichment was proposed, experimentally tested, and evaluated through MCNP calculations.

Risk assessment of 3-monochloropropane-1,2-diol esters through dietary exposure from edible oils for the Zhejiang population in China by Monte Carlo simulation.

The purpose of this study was to assess the risk of 3-monochoropropane-1,2-diol (3-MCPD) esters from edible oils for the Zhejiang population in China. Exposure assessment of 3-MCPD esters was evaluated by Monte Carlo simulation based on the concentrations of 3-MCPD esters in edible oils combined with survey data on the eating habits of Chinese residents classified by age group and gender. The simulation results indicated that the mean daily intakes (CDI) of 3-MCPD esters for children 7-10 years old were 2.154 µg (kg BW d)-1 for boys and 2.049 µg (kg BW d)-1 for girls, which are lower than the provisional maximum tolerable daily intake (PMTDI) of 4 µg (kg BW d)-1 for 3-MCPD and 3-MCPD esters individually or in combination, set by the Joint FAO/WHO Expert Committee on Food Additives. The range of mean dietary intakes of 3-MCPD esters in different subpopulation groups ranged 1.242-1.672 µg (kg BW d)-1, which was lower than the PMTDI. However, the CDI values of 3-MCPD esters in high percentile exposure subgroups (95th, 99th) of males (7-49 years old) and females (7-10 and 50-75 years old) were all above 4µg (kg bw d)-1. Outside of the senior group (50-75 years old), males had more exposure to 3-MCPD than females. The average hazard indexes (HI) of 3-MCPD esters to male and female children were 1.257 and 1.024, respectively, indicating there was a risk, but no immediate measures are required to address this risk. The average HI of 3-MCPD esters to adolescent, adult, and seniors were all below 1, indicating risk for those age groups were at an acceptable level.

Measurement of polycyclic aromatic hydrocarbons in edible oils and potential health risk to consumers using Monte Carlo simulation, southwest Iran.

Persistent organic pollutants, such as polycyclic aromatic hydrocarbons, are hazardous trace contaminants frequently observed in food ingredients, such as edible oils. This study aimed to measure PAHs in forty brands of edible oils marketed in southwest Iran. Additionally, we characterized the daily intake of MOE and ILCR using Monte Carlo simulation. To analyze the content of PAHs, the liquid-liquid extraction method followed by GC-MS was utilized. The average concentration of PAHs was mostly lower than the maximum value for individual PAH (2 µg/Kg); however, the average concentration of fluorene (3.86 µg/Kg) and benzo(a)anthracene (3.13 µg/Kg) was more than the permitted level. The highest residual concentrations of PAHs were mostly observed in canola and corn oils. The daily intake of BaP and 4-PAH for 95% of consumers was 0.01 ng/kg BW/day and 0.04 ng/kg BW/day, respectively. Also, MOE was more than 10,000 for the percentiles of 5%, 50%, and 95%. The modeled ILCR showed that consumption of oil does not currently pose a cancer risk for Iranian consumers due to PAHs exposure. Concerning potential health risks, consumption of edible oils is safe; however, regular monitoring and assessment are required.

Dose optimization of cefotaxime as pre-emptive treatment in critically ill adult patients: A population pharmacokinetic study.

AIMS: To describe the pharmacokinetics (PK) of cefotaxime as pre-emptive treatment in critically ill adult patients, including covariates and to determine the probability of target attainment (PTA) of different dosage regimens for Enterobacterales and Staphylococcus aureus. METHODS: Five samples were drawn during 1 dosage interval in critically ill patients treated with cefotaxime 1 g q6h or q4h. PK parameters were estimated using NONMEM (v7.4.2). The percentage of patients reaching 100% fT>MICECOFF was used to compare different dosage regimens for Enterobacterales and S. aureus. RESULTS: This study included 92 patients (437 samples). The best structural model was a 2-compartment model with a combined error, interindividual variability on clearance, central volume and intercompartmental clearance. Correlations between interindividual variability were included. Clearance increased with higher estimated glomerular filtration rate (eGFR; creatinine clearance) and albumin concentration. For Enterobacterales, 1 g q8h reached 95% PTA and continuous infusion (CI) of 4 g 24 h-1 100% PTA at the highest eGFR and albumin concentration. For S. aureus the predefined target of 95% PTA was not reached with higher eGFR and/or albumin concentrations. CI of 6 g 24 h-1 for S. aureus resulted in a minimum of 99% PTA. CONCLUSION: Cefotaxime PK in critically ill patients was best described by a 2-compartment model with eGFR and albumin concentration as covariates influencing clearance. For Enterobacterales 1 g q8h or CI of 4 g 24 h-1 was adequate for all combinations of eGFR and albumin concentration. For S. aureus CI of 6 g 24 h-1 would be preferred if eGFR and albumin concentration exceed 80 mL min-1 and 40 g L-1 respectively.

0.342 nW Class-AB enhanced flipped source follower low pass filter for biomedical applications.

Owing to the impact of process voltage and temperature variations, the design of low-power low-pass filters (LPFs) with improved linearity is still one of the most challenging tasks for effective biological signal processing. This paper presents the design of a fourth-order Class-AB enhanced flipped source follower (EFSF) LPF circuit aimed at the detection of electroencephalography signals. The simulated results attained using complementary metal-oxide-semiconductor 180 nm technology node in Cadence Analog Design Environment demonstrate that the EFSF LPF emulates a DC-gain of -88 mdB with a bandwidth of 100 Hz and consumes 0.342 nW power from a supply voltage of 0.5 V. The calculated figure of merit for the proposed filter is 5.983 × 10-15 J with a dynamic range (DR) of 43.54 dB and input-referred noise of 91 µVrms. It consumes an area of 0.0458 mm2. To check the robustness of the proposed filter circuit, we performed Monte Carlo simulations with 200 runs. The statistical results achieved for the DC-gain, DR, and total harmonic distortion of the proposed filter show mean values of -188.09 mdB, 43.10 dB, and -41.85 dB along with standard deviation values of 285.21 mdB, 718.72 mdB, and 4.52 dB, respectively. The proposed Class-AB EFSF LPF can be used to achieve high power efficiency in future low-voltage and low-power biological systems.