NASA has encouraged studies on 226Ra deposition in the human brain to investigate the effects of exposure to alpha particles with high linear energy transfer, which could mimic some of the exposure astronauts face during space travel. However, this approach was criticized, noting that radium is a bone-seeker and accumulates in the skull, which means that the radiation dose from alpha particles emitted by 226Ra would be heavily concentrated in areas close to cranial bones rather than uniformly distributed throughout the brain. In the high background radiation areas of Ramsar, Iran, extremely high levels of 226Ra in soil contribute to a large proportion of the inhabitants' radiation exposure. A prospective study on Ramsar residents with a calcium-rich diet was conducted to improve the dose uniformity due to 226Ra throughout the cerebral and cerebellar parenchyma. The study found that exposure of the human brain to alpha particles did not significantly affect working memory but was significantly associated with increased reaction times. This finding is crucial because astronauts on deep space missions may face similar cognitive impairments due to exposure to high charge and energy particles. The current study was aimed to evaluate the validity of the terrestrial model using the Geant4 Monte Carlo toolkit to simulate the interactions of alpha particles and representative cosmic ray particles, acknowledging that these radiation types are only a subset of the complete space radiation environment.
- MeSH
- DNA MeSH
- lidé MeSH
- lineární přenos energie MeSH
- metoda Monte Carlo MeSH
- mozek MeSH
- prospektivní studie MeSH
- radium * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: In-vivo monitoring methods of carbon ion radiotherapy (CIRT) includes explorations of nuclear reaction products generated by carbon-ion beams interacting with patient tissues. Our research group focuses on in-vivo monitoring of CIRT using silicon pixel detectors. Currently, we are conducting a prospective clinical trial as part of the In-Vivo Monitoring project (InViMo) at the Heidelberg Ion Beam Therapy Center (HIT) in Germany. We are using an innovative, in-house developed, non-contact fragment tracking system with seven mini-trackers based on the Timepix3 technology developed at CERN. PURPOSE: This article focuses on the implementation of the mini-tracker in Monte Carlo (MC) based on FLUKA simulations to monitor secondary charged nuclear fragments in CIRT. The main objective is to systematically evaluate the simulation accuracy for the InViMo project. METHODS: The implementation involved integrating the mini-tracker geometry and the scoring mechanism into the FLUKA MC simulation, utilizing the finely tuned HIT beam line. The systematic investigation included varying mini-tracker angles (from 15∘$15^\circ$ to 45∘$45^\circ$ in 5∘$5^\circ$ steps) during the irradiation of a head-sized phantom with therapeutic carbon-ion pencil beams. To evaluate our implemented FLUKA framework, a comparison was made between the experimental data and data obtained from MC simulations. To ensure the fidelity of our comparison, experiments were performed at the HIT using the parameters and setup established in the simulations. RESULTS: Our research demonstrates high accuracy in reproducing characteristic behaviors and dependencies of the monitoring method in terms of fragment distributions in the mini-tracker, track angles, emission profiles, and fragment numbers. Discrepancies in the number of detected fragments between the experimental data and the data obtained from MC simulations are less than 4% for the angles of interest in the InViMo detection system. CONCLUSIONS: Our study confirms the potential of our simulation framework to investigate the performance of monitoring inter-fractional anatomical changes in patients undergoing CIRT using secondary nuclear charged fragments escaping from the irradiated patient.
- MeSH
- fantomy radiodiagnostické MeSH
- lidé MeSH
- metoda Monte Carlo * MeSH
- radioterapie těžkými ionty * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- validační studie MeSH
BACKGROUND: Ultra high dose rate (UHDR) radiotherapy using ridge filter is a new treatment modality known as conformal FLASH that, when optimized for dose, dose rate (DR), and linear energy transfer (LET), has the potential to reduce damage to healthy tissue without sacrificing tumor killing efficacy via the FLASH effect. PURPOSE: Clinical implementation of conformal FLASH proton therapy has been limited by quality assurance (QA) challenges, which include direct measurement of UHDR and LET. Voxel DR distributions and LET spectra at planning target margins are paramount to the DR/LET-related sparing of organs at risk. We hereby present a methodology to achieve experimental validation of these parameters. METHODS: Dose, DR, and LET were measured for a conformal FLASH treatment plan involving a 250-MeV proton beam and a 3D-printed ridge filter designed to uniformly irradiate a spherical target. We measured dose and DR simultaneously using a 4D multi-layer strip ionization chamber (MLSIC) under UHDR conditions. Additionally, we developed an "under-sample and recover (USRe)" technique for a high-resolution pixelated semiconductor detector, Timepix3, to avoid event pile-up and to correct measured LET at high-proton-flux locations without undesirable beam modifications. Confirmation of these measurements was done using a MatriXX PT detector and by Monte Carlo (MC) simulations. RESULTS: MC conformal FLASH computed doses had gamma passing rates of >95% (3 mm/3% criteria) when compared to MatriXX PT and MLSIC data. At the lateral margin, DR showed average agreement values within 0.3% of simulation at 100 Gy/s and fluctuations ∼10% at 15 Gy/s. LET spectra in the proximal, lateral, and distal margins had Bhattacharyya distances of <1.3%. CONCLUSION: Our measurements with the MLSIC and Timepix3 detectors shown that the DR distributions for UHDR scenarios and LET spectra using USRe are in agreement with simulations. These results demonstrate that the methodology presented here can be used effectively for the experimental validation and QA of FLASH treatment plans.
AIMS: Abiraterone treatment requires regular drug intake under fasting conditions due to pronounced food effect, which may impact patient adherence. The aim of this prospective study was to evaluate adherence to abiraterone treatment in patients with prostate cancer. To achieve this aim, an abiraterone population pharmacokinetic model was developed and patients' adherence has been estimated by comparison of measured levels of abiraterone with population model-based simulations. METHODS: A total of 1469 abiraterone plasma levels from 83 healthy volunteers collected in a bioequivalence study were analysed using a nonlinear mixed-effects model. Monte Carlo simulation was used to describe the theoretical distribution of abiraterone pharmacokinetic profiles at a dose of 1000 mg once daily. Adherence of 36 prostate cancer patients treated with abiraterone was then evaluated by comparing the real abiraterone concentration measured in each patient during follow-up visit with the theoretical distribution of profiles based on simulations. Patients whose abiraterone levels were ˂5th or ˃95th percentile of the distribution of simulated profiles were considered to be non-adherent. RESULTS: Based on this evaluation, 13 patients (36%) have been classified as non-adherent. We observed significant association (P = .0361) between richness of the breakfast and rate of non-adherence. Adherent patients reported significantly better overall condition in self-assessments (P = .0384). A trend towards a higher occurrence of adverse effects in non-adherent patients was observed. CONCLUSIONS: We developed an abiraterone population pharmacokinetic model and proposed an advanced approach to medical adherence evaluation. Due to the need for administration under fasting conditions, abiraterone therapy is associated with a relatively high rate of non-adherence.
- MeSH
- adherence k farmakoterapii * statistika a číselné údaje MeSH
- androsteny * farmakokinetika aplikace a dávkování terapeutické užití MeSH
- biologické modely * MeSH
- dospělí MeSH
- interakce mezi potravou a léky MeSH
- lidé středního věku MeSH
- lidé MeSH
- metoda Monte Carlo MeSH
- nádory prostaty * farmakoterapie MeSH
- omezení příjmu potravy MeSH
- prospektivní studie MeSH
- protinádorové látky farmakokinetika aplikace a dávkování MeSH
- senioři MeSH
- terapeutická ekvivalence MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
Objective.There is an increasing interest in calculating and measuring linear energy transfer (LET) spectra in particle therapy in order to assess their impact in biological terms. As such, the accuracy of the particle fluence energy spectra becomes paramount. This study focuses on quantifying energy depositions of distinct proton, helium, carbon, and oxygen ion beams using a silicon pixel detector developed at CERN to determine LET spectra in silicon.Approach.While detection systems have been investigated in this pursuit, the scarcity of detectors capable of providing per-ion data with high spatial and temporal resolution remains an issue. This gap is where silicon pixel detector technology steps in, enabling online tracking of single-ion energy deposition. The used detector consisted of a 300μm thick silicon sensor operated in partial depletion.Main results.During post-processing, artifacts in the acquired signals were identified and methods for their corrections were developed. Subsequently, a correlation between measured and Monte Carlo-based simulated energy deposition distributions was performed, relying on a two-step recalibration approach based on linear and saturating exponential models. Despite the observed saturation effects, deviations were confined below 7% across the entire investigated range of track-averaged LET values in silicon from 0.77 keVμm-1to 93.16 keVμm-1.Significance.Simulated and measured mean energy depositions were found to be aligned within 7%, after applying artifact corrections. This extends the range of accessible LET spectra in silicon to clinically relevant values and validates the accuracy and reliability of the measurements. These findings pave the way towards LET-based dosimetry through an approach to translate these measurements to LET spectra in water. This will be addressed in a future study, extending functionality of treatment planning systems into clinical routine, with the potential of providing ion-beam therapy of utmost precision to cancer patients.
- MeSH
- křemík MeSH
- lineární přenos energie * MeSH
- metoda Monte Carlo MeSH
- radiometrie přístrojové vybavení MeSH
- Publikační typ
- časopisecké články MeSH
This study aimed to explore pharmacokinetics of voriconazole and its covariates in lung transplant recipients using population approach in order to propose dosing individualization. Data from routine therapeutic drug monitoring in adult lung transplant recipients treated with oral voriconazole were analysed with a three-stage population pharmacokinetic model using nonlinear mixed-effects modelling. Monte Carlo simulations based on final voriconazole pharmacokinetic model were used to generate the theoretical distribution of pharmacokinetic profiles at various dosing regimens. A total of 78 voriconazole serum concentrations collected from 40 patients were included in pharmacokinetic analysis. The only significant covariate was age for voriconazole clearance. Population voriconazole apparent clearance started at 32.26 L/h and decreased by 0.021 L/h with each year of patient's age, while population apparent volume of distribution was 964.46 L. Based on this model, we have proposed an easy-to-use dosing regimen consisting of a loading dose of 400 mg every 12 h for the first 48 h of treatment followed by maintenance dose of 300 mg every 12 h in patients aged up to 59 years, or by maintenance dose of 200 mg every 12 h in patients aged above 59 years.
- MeSH
- biologické modely MeSH
- dospělí MeSH
- lidé MeSH
- metoda Monte Carlo MeSH
- monitorování léčiv * MeSH
- plíce MeSH
- příjemce transplantátu * MeSH
- senioři MeSH
- vorikonazol farmakokinetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: The objective of this study was to develop a population pharmacokinetic model of meropenem in a heterogeneous population of patients with a serious bacterial infection in order to propose dosing optimisation leading to improved achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target. METHODS: A total of 174 meropenem serum levels obtained from 144 patients during therapeutic drug monitoring were analysed using a non-linear mixed-effects modelling approach and Monte Carlo simulation was then used to compare various dosing regimens in order to optimise PK/PD target attainment. RESULTS: The meropenem volume of distribution of the patient population was 54.95 L, while clearance started at 3.27 L/hour and increased by 0.91 L/hour with each 1 mL/s/1.73 m2 of estimated glomerular filtration rate. Meropenem clearance was also 0.31 L/hour higher in postoperative patients with central nervous system infection. Meropenem administration by continuous infusion showed a significantly higher probability of attaining the PK/PD target than a standard 30 min infusion (95.3% vs 49.5%). CONCLUSIONS: A daily meropenem dose of 3 g, 6 g and 10.5 g administered by continuous infusion was shown to be accurate for patients with moderate to severe renal impairment, normal renal function to mild renal impairment and augmented renal clearance, respectively.
- MeSH
- antibakteriální látky * farmakokinetika aplikace a dávkování MeSH
- bakteriální infekce * farmakoterapie MeSH
- biologické modely * MeSH
- dospělí MeSH
- intravenózní infuze MeSH
- lidé středního věku MeSH
- lidé MeSH
- meropenem * farmakokinetika aplikace a dávkování MeSH
- metoda Monte Carlo MeSH
- monitorování léčiv metody MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The aim of this study was to evaluate the inorganic elemental composition (49 elements) of 29 botanical preparations obtained from fruits, leaves, peels, seeds, roots, fungi, and spirulina by using inductively coupled-mass spectrometry and a mercury analyzer. Simultaneously, the risk associated with the chronic dietary exposure to 12 toxic metals and metalloids among the European population was evaluated by using a probabilistic approach based on Monte Carlo simulations. The analysis revealed worrying intake levels of Al, As, and Ni, primarily stemming from the consumption of spirulina-, peel-, and leaf-based botanicals by younger age groups. The intake of As from all analyzed botanicals posed a significant risk for infants, yielding margins of exposure (MOEs) below 1, while those deriving from peel-based botanicals raised concerns across all age groups (MOEs = 0.04-2.3). The consumption of peel-based botanicals contributed substantially (13-130%) also to the tolerable daily intake of Ni for infants, toddlers, and children, while that of spirulina-based botanicals raised concerns related to Al intake also among adults, contributing to 11-176% of the tolerable weekly intake of this element. The findings achieved underscore the importance of implementing a monitoring framework to address chemical contamination of botanicals, thus ensuring their safety for regular consumers.
- MeSH
- dietární expozice * MeSH
- dítě MeSH
- dospělí MeSH
- hodnocení rizik MeSH
- kojenec MeSH
- kontaminace potravin * analýza MeSH
- kovy analýza toxicita MeSH
- lidé MeSH
- metoda Monte Carlo MeSH
- mladiství MeSH
- mladý dospělý MeSH
- polokovy * analýza toxicita MeSH
- předškolní dítě MeSH
- rostlinné přípravky chemie analýza MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
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.
- MeSH
- antibakteriální látky škodlivé účinky farmakokinetika MeSH
- ceftazidim škodlivé účinky farmakokinetika MeSH
- chromatografie kapalinová MeSH
- lidé MeSH
- metoda Monte Carlo MeSH
- mikrobiální testy citlivosti MeSH
- nádory * komplikace farmakoterapie MeSH
- off-label použití léčivého přípravku MeSH
- pseudomonádové infekce * farmakoterapie MeSH
- Pseudomonas aeruginosa MeSH
- tandemová hmotnostní spektrometrie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE: A supervised deep learning (DL) approach for frequency and phase correction (FPC) of MRS data recently showed encouraging results, but obtaining transients with labels for supervised learning is challenging. This work investigates the feasibility and efficiency of unsupervised deep learning-based FPC. METHODS: Two novel deep learning-based FPC methods (deep learning-based Cr referencing and deep learning-based spectral registration), which use a priori physics domain knowledge, are presented. The proposed networks were trained, validated, and evaluated using simulated, phantom, and publicly accessible in vivo MEGA-edited MRS data. The performance of our proposed FPC methods was compared with other generally used FPC methods, in terms of precision and time efficiency. A new measure was proposed in this study to evaluate the FPC method performance. The ability of each of our methods to carry out FPC at varying SNR levels was evaluated. A Monte Carlo study was carried out to investigate the performance of our proposed methods. RESULTS: The validation using low-SNR manipulated simulated data demonstrated that the proposed methods could perform FPC comparably with other methods. The evaluation showed that the deep learning-based spectral registration over a limited frequency range method achieved the highest performance in phantom data. The applicability of the proposed method for FPC of GABA-edited in vivo MRS data was demonstrated. Our proposed networks have the potential to reduce computation time significantly. CONCLUSIONS: The proposed physics-informed deep neural networks trained in an unsupervised manner with complex data can offer efficient FPC of large MRS data in a shorter time.
