Exact parameter identification in PET pharmacokinetic modeling using the irreversible two tissue compartment model.

OBJECTIVE: In quantitative dynamic positron emission tomography (PET), time series of images, reflecting the tissue response to the arterial tracer supply, are reconstructed. This response is described by kinetic parameters, which are commonly determined on basis of the tracer concentration in tissue and the arterial input function. In clinical routine the latter is estimated by arterial blood sampling and analysis, which is a challenging process and thus, attempted to be derived directly from reconstructed PET images. However, a mathematical analysis about the necessity of measurements of the common arterial whole blood activity concentration, and the concentration of free non-metabolized tracer in the arterial plasma, for a successful kinetic parameter identification does not exist. Here we aim to address this problem mathematically. Approach: We consider the identification problem in simultaneous pharmacokinetic modeling of multiple regions of interests of dynamic PET data using the irreversible two-tissue compartment model analytically. In addition to this consideration, the situation of noisy measurements is addressed using Tikhonov regularization. Furthermore, numerical simulations with a regularization approach are carried out to illustrate the analytical results in a synthetic application example. Main results: We provide mathematical proofs showing that, under reasonable assumptions, all metabolic tissue parameters can be uniquely identified without requiring additional blood samples to measure the arterial input function. A connection to noisy measurement data is made via a consistency result, showing that exact reconstruction of the ground-truth tissue parameters is stably maintained in the vanishing noise limit. Furthermore, our numerical experiments suggest that an approximate reconstruction of kinetic parameters according to our analytic results is also possible in practice for moderate noise levels. Significance: The analytical result, which holds in the idealized, noiseless scenario, suggests that for irreversible tracers, fully quantitative dynamic PET imaging is in principle possible without costly arterial blood sampling and metabolite analysis.

Identifying physiological determinants of 800 m running performance using post-exercise blood lactate kinetics.

PURPOSE: The aims of the present study were to investigate blood lactate kinetics following high intensity exercise and identify the physiological determinants of 800 m running performance. METHODS: Fourteen competitive 800 m runners performed two running tests. First, participants performed a multistage graded exercise test to determine physiological indicators related to endurance performance. Second, participants performed four to six 30-s high intensity running bouts to determine post-exercise blood lactate kinetics. Using a biexponential time function, lactate exchange ability (γ1), lactate removal ability (γ2), and the quantity of lactate accumulated (QLaA) were calculated from individual blood lactate recovery data. RESULTS: 800 m running performance was significantly correlated with peak oxygen consumption (r = -0.794), γ1 and γ2 at 800 m race pace (r = -0.604 and -0.845, respectively), and QLaA at maximal running speed (r = -0.657). V ˙ O2peak and γ2 at 800 m race pace explained 83% of the variance in 800 m running performance. CONCLUSION: Our results indicate that (1) a high capacity to exchange and remove lactate, (2) a high capacity for short-term lactate accumulation and, (3) peak oxygen consumption, are critical elements of 800 m running performance. Accordingly, while lactate has primarily been utilized as a performance indicator for long-distance running, post-exercise lactate kinetics may also prove valuable as a performance determinant in middle-distance running.

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

Stochastic Compartment Model with Mortality and Its Application to Epidemic Spreading in Complex Networks.

We study epidemic spreading in complex networks by a multiple random walker approach. Each walker performs an independent simple Markovian random walk on a complex undirected (ergodic) random graph where we focus on the Barabási-Albert (BA), Erdös-Rényi (ER), and Watts-Strogatz (WS) types. Both walkers and nodes can be either susceptible (S) or infected and infectious (I), representing their state of health. Susceptible nodes may be infected by visits of infected walkers, and susceptible walkers may be infected by visiting infected nodes. No direct transmission of the disease among walkers (or among nodes) is possible. This model mimics a large class of diseases such as Dengue and Malaria with the transmission of the disease via vectors (mosquitoes). Infected walkers may die during the time span of their infection, introducing an additional compartment D of dead walkers. Contrary to the walkers, there is no mortality of infected nodes. Infected nodes always recover from their infection after a random finite time span. This assumption is based on the observation that infectious vectors (mosquitoes) are not ill and do not die from the infection. The infectious time spans of nodes and walkers, and the survival times of infected walkers, are represented by independent random variables. We derive stochastic evolution equations for the mean-field compartmental populations with the mortality of walkers and delayed transitions among the compartments. From linear stability analysis, we derive the basic reproduction numbers RM,R0 with and without mortality, respectively, and prove that RM1, the healthy state is unstable, whereas for zero mortality, a stable endemic equilibrium exists (independent of the initial conditions), which we obtained explicitly. We observed that the solutions of the random walk simulations in the considered networks agree well with the mean-field solutions for strongly connected graph topologies, whereas less well for weakly connected structures and for diseases with high mortality. Our model has applications beyond epidemic dynamics, for instance in the kinetics of chemical reactions, the propagation of contaminants, wood fires, and others.

Noninvasive ROS imaging and drug delivery monitoring in the tumor microenvironment.

Reactive oxygen species (ROS) that are overproduced in certain tumors can be considered an indicator of oxidative stress levels in the tissue. Here, we report a magnetic resonance imaging (MRI)-based probe capable of detecting ROS levels in the tumor microenvironment (TME) using ROS-responsive manganese ion (Mn2+)-chelated, biotinylated bilirubin nanoparticles (Mn@bt-BRNPs). These nanoparticles are disrupted in the presence of ROS, resulting in the release of free Mn2+, which induces T1-weighted MRI signal enhancement. Mn@BRNPs show more rapid and greater MRI signal enhancement in high ROS-producing A549 lung carcinoma cells compared with low ROS-producing DU145 prostate cancer cells. A pseudo three-compartment model devised for the ROS-reactive MRI probe enables mapping of the distribution and concentration of ROS within the tumor. Furthermore, doxorubicin-loaded, cancer-targeting ligand biotin-conjugated Dox/Mn@bt-BRNPs show considerable accumulation in A549 tumors and also effectively inhibit tumor growth without causing body weight loss, suggesting their usefulness as a new theranostic agent. Collectively, these findings suggest that Mn@bt-BRNPs could be used as an imaging probe capable of detecting ROS levels and monitoring drug delivery in the TME with potential applicability to other inflammatory diseases.

Dynamic rubidium-82 PET/CT as a novel tool for quantifying hemodynamic differences in renal blood flow using a one-tissue compartment model.

PURPOSE: Assessing renal perfusion in-vivo is challenging and quantitative information regarding renal hemodynamics is hardly incorporated in medical decision-making while abnormal renal hemodynamics might play a crucial role in the onset and progression of renal disease. Combining physiological stimuli with rubidium-82 positron emission tomography/computed tomography (82Rb PET/CT) offers opportunities to test the kidney perfusion under various conditions. The aim of this study is: (1) to investigate the application of a one-tissue compartment model for measuring renal hemodynamics with dynamic 82Rb PET/CT imaging, and (2) to evaluate whether dynamic PET/CT is sensitive to detect differences in renal hemodynamics in stress conditions compared to resting state. METHODS: A one-tissue compartment model for the kidney was applied to cardiac 82Rb PET/CT scans that were obtained for ischemia detection as part of clinical care. Retrospective data, collected from 17 patients undergoing dynamic myocardial 82Rb PET/CT imaging in rest, were used to evaluate various CT-based volumes of interest (VOIs) of the kidney. Subsequently, retrospective data, collected from 10 patients (five impaired kidney functions and five controls) undergoing dynamic myocardial 82Rb PET/CT imaging, were used to evaluate image-derived input functions (IDIFs), PET-based VOIs of the kidney, extraction fractions, and whether dynamic 82Rb PET/CT can measure renal hemodynamics differences using the renal blood flow (RBF) values in rest and after exposure to adenosine pharmacological stress. RESULTS: The delivery rate (K1) values showed no significant (p = 0.14) difference between the mean standard deviation (SD) K1 values using one CT-based VOI and the use of two, three, and four CT-based VOIs, respectively 2.01(0.32), 1.90(0.40), 1.93(0.39), and 1.94(0.40) mL/min/mL. The ratio between RBF in rest and RBF in pharmacological stress for the controls were overall significantly lower compared to the impaired kidney function group for both PET-based delineation methods (region growing and iso-contouring), with the smallest median interquartile range (IQR) of 0.40(0.28-0.66) and 0.96(0.62-1.15), respectively (p < 0.05). The K1 of the impaired kidney function group were close to 1.0 mL/min/mL. CONCLUSIONS: This study demonstrated that obtaining renal K1 and RBF values using 82Rb PET/CT was feasible using a one-tissue compartment model. Applying iso-contouring as the PET-based VOI of the kidney and using AA as an IDIF is suggested for consideration in further studies. Dynamic 82Rb PET/CT imaging showed significant differences in renal hemodynamics in rest compared to when exposed to adenosine. This indicates that dynamic 82Rb PET/CT has potential to detect differences in renal hemodynamics in stress conditions compared to the resting state, and might be useful as a novel diagnostic tool for assessing renal perfusion.

Patient-specific radiation dose for Chinese pediatric patients undergoing whole-body PET/CT examinations.

Objective.To assess potential variations in the absorbed dose between Chinese and Caucasian children exposed to18F-FDG PET scan and to investigate the factors contributing to dose differences, this work employed patient-specific phantoms and our compartment model for calculating the patient-specific absorbed dose in Chinese children.Approach.Data of 29 Chinese pediatric patients undergoing whole-body18F-FDG PET/CT studies were retrospectively collected, including PET images for activity distributions and corresponding CT images for organ segmentation and phantom construction. A biokinetic compartment model was implemented to obtain cumulated activities. Absorbed radiation dose for both CT and PET component were calculated using Monte Carlo simulations. Regression models were fitted to time integrated activity coefficient (TIAC) and organ absorbed dose for each patient.Main results.TIACs of all the organs in our compartment model and the organ dose for 12 organs were correlated with patients' weight. Young children have significantly large uptake in brain compared to adults. The distinctions of anatomical and biological characteristics between Chinese and Caucasian children contribute to variations in the absorbed dose of18F-FDG PET scans. PET contributed more in organ dose than CT did in most organs, especially in brain and bladder. The average effective dose (± SD) was 4.5 mSv (± 1.12 mSv), 7.8 mSv (± 3.2 mSv) and 12.3 mSv (± 3.5 mSv) from CT, PET and their sum respectively. PET contributed 1.7 times higher than CT.Significance.To the best of our knowledge, this work represents the first attempt to estimate patient-specific radiation doses from PET/CT for Chinese pediatric patients. TIACs derived from our methodology in both age groups exhibited significant differences from the that reported in ICRP 128. Substantial differences in absorbed and effective doses were observed between Chinese and Caucasian children across all age groups. These disparities are attributed to markedly distinct anatomical and pharmacokinetic characteristics among adults and pediatric patients, and different racial groups. The application of data derived from adults to pediatric patients introduces considerable uncertainty. Our methodology offers a valuable approach not only for estimating pharmacokinetic characteristics and patient-specific radiation doses in pediatric patients undergoing18F-FDG studies but also for other cohorts with similar characteristics.

Estimating averted illnesses from influenza vaccination for children and pregnant women - El Salvador, Panama, and Peru, 2011-2018.

BACKGROUND: Estimating the burden of disease averted by vaccination can assist policymakers to implement, adjust, and communicate the value of vaccination programs. Demonstrating the use of a newly available modeling tool, we estimated the burden of influenza illnesses averted by seasonal influenza vaccination in El Salvador, Panama, and Peru during 2011-2017 among two influenza vaccine target populations: children aged 6-23 months and pregnant women. METHODS: We derived model inputs, including incidence, vaccine coverage, vaccine effectiveness, and multipliers from publicly available country-level influenza surveillance data and cohort studies. We also estimated changes in illnesses averted when countries' vaccine coverage was achieved using four different vaccine deployment strategies. RESULTS: Among children aged 6-23 months, influenza vaccination averted an estimated cumulative 2,161 hospitalizations, 81,907 medically-attended illnesses, and 126,987 overall illnesses during the study period, with a prevented fraction ranging from 0.3 % to 12.5 %. Among pregnant women, influenza vaccination averted an estimated cumulative 173 hospitalizations, 6,122 medically attended illnesses, and 16,412 overall illnesses, with a prevented fraction ranging from 0.2 % to 10.9 %. Compared to an influenza vaccine campaign with equal vaccine distribution during March-June, scenarios in which total cumulative coverage was achieved in March and April consistently resulted in the greatest increase in averted illness (23 %-3,129 % increase among young children and 22 %-3,260 % increase among pregnant women). DISCUSSION: Influenza vaccination campaigns in El Salvador, Panama, and Peru conducted between 2011 and 2018 prevented hundreds to thousands of influenza-associated hospitalizations and illnesses in young children and pregnant women. Existing vaccination programs could prevent additional illnesses, using the same number of vaccines, by achieving the highest possible coverage within the first two months of an influenza vaccine campaign.

Automatic Brain Tissue and Lesion Segmentation and Multi-Parametric Mapping of Contrast-Enhancing Gliomas without the Injection of Contrast Agents: A Preliminary Study.

This study aimed to develop a rapid, 1 mm3 isotropic resolution, whole-brain MRI technique for automatic lesion segmentation and multi-parametric mapping without using contrast by continuously applying balanced steady-state free precession with inversion pulses throughout incomplete inversion recovery in a single 6 min scan. Modified k-means clustering was performed for automatic brain tissue and lesion segmentation using distinct signal evolutions that contained mixed T1/T2/magnetization transfer properties. Multi-compartment modeling was used to derive quantitative multi-parametric maps for tissue characterization. Fourteen patients with contrast-enhancing gliomas were scanned with this sequence prior to the injection of a contrast agent, and their segmented lesions were compared to conventionally defined manual segmentations of T2-hyperintense and contrast-enhancing lesions. Simultaneous T1, T2, and macromolecular proton fraction maps were generated and compared to conventional 2D T1 and T2 mapping and myelination water fraction mapping acquired with MAGiC. The lesion volumes defined with the new method were comparable to the manual segmentations (r = 0.70, p < 0.01; t-test p > 0.05). The T1, T2, and macromolecular proton fraction mapping values of the whole brain were comparable to the reference values and could distinguish different brain tissues and lesion types (p < 0.05), including infiltrating tumor regions within the T2-lesion. Highly efficient, whole-brain, multi-contrast imaging facilitated automatic lesion segmentation and quantitative multi-parametric mapping without contrast, highlighting its potential value in the clinic when gadolinium is contraindicated.

Mapping 18F-FDG Kinetics Together with Patient-Specific Bootstrap Assessment of Uncertainties: An Illustration with Data from a PET/CT Scanner with a Long Axial Field of View.

The purpose of this study was to examine a nonparametric approach to mapping kinetic parameters and their uncertainties with data from the emerging generation of dynamic whole-body PET/CT scanners. Methods: Dynamic PET 18F-FDG data from a set of 24 cancer patients studied on a long-axial-field-of-view PET/CT scanner were considered. Kinetics were mapped using a nonparametric residue mapping (NPRM) technique. Uncertainties were evaluated using an image-based bootstrapping methodology. Kinetics and bootstrap-derived uncertainties are reported for voxels, maximum-intensity projections, and volumes of interest (VOIs) corresponding to several key organs and lesions. Comparisons between NPRM and standard 2-compartment (2C) modeling of VOI kinetics are carefully examined. Results: NPRM-generated kinetic maps were of good quality and well aligned with vascular and metabolic 18F-FDG patterns, reasonable for the range of VOIs considered. On a single 3.2-GHz processor, the specification of the bootstrapping model took 140 min; individual bootstrap replicates required 80 min each. VOI time-course data were much more accurately represented, particularly in the early time course, by NPRM than by 2C modeling constructs, and improvements in fit were statistically highly significant. Although 18F-FDG flux values evaluated by NPRM and 2C modeling were generally similar, significant deviations between vascular blood and distribution volume estimates were found. The bootstrap enables the assessment of quite complex summaries of mapped kinetics. This is illustrated with maximum-intensity maps of kinetics and their uncertainties. Conclusion: NPRM kinetics combined with image-domain bootstrapping is practical with large whole-body dynamic 18F-FDG datasets. The information provided by bootstrapping could support more sophisticated uses of PET biomarkers used in clinical decision-making for the individual patient.

A compartment and metapopulation model of Rocky Mountain spotted fever in southwestern United States and northern Mexico.

Rocky Mountain spotted fever (RMSF) is a fatal tick-borne zoonotic disease that has emerged as an epidemic in western North America since the turn of the 21st century. Along the US south-western border and across northern Mexico, the brown dog tick, Rhipicephalus sanguineus, is responsible for spreading the disease between dogs and humans. The widespread nature of the disease and the ongoing epidemics contrast with historically sporadic patterns of the disease. Because dogs are amplifying hosts for the Rickettsia rickettsii bacteria, transmission dynamics between dogs and ticks are critical for understanding the epidemic. In this paper, we developed a compartment metapopulation model and used it to explore the dynamics and drivers of RMSF in dogs and brown dog ticks in a theoretical region in western North America. We discovered that there is an extended lag-as much as two years-between introduction of the pathogen to a naïve population and epidemic-level transmission, suggesting that infected ticks could disseminate extensively before disease is detected. A single large city-size population of dogs was sufficient to maintain the disease over a decade and serve as a source for disease in surrounding smaller towns. This model is a novel tool that can be used to identify high risk areas and key intervention points for epidemic RMSF spread by brown dog ticks.

Improved data analysis techniques for calculating more accurate radon and thoron exhalation rates from building interior solid walls.

The impacts of mathematical models and associated parameters on radon (222Rn) and thoron (220Rn) exhalation rates based on in-situ testing at building interior solid walls were demonstrated to improve data analysis techniques. The results showed that the heterogeneity of their activity concentrations within the measurement system was more significant for thoron than radon. The diurnal variation in indoor radon should be considered for better data quality. In conclusion, a model should be appropriately made and selected under the purposes and accuracy requirements of the exhalation test.

Pharmacokinetic study of multicomponent in Hong-Hua-Xiao-Yao tablet.

Hong-Hua-Xiao-Yao tablet (HHXYT) is attracting attention increasingly because of its use in treatment of mammary gland hyperplasia (MGH) and menopausal syndrome. However, its pharmacokinetics remains unclear. This study developed a sensitive and rapid method for simultaneous determination of 10 compounds of HHXYT in rat plasma by liquid chromatography-tandem mass spectrometry and to compare the pharmacokinetics of these compounds in MGH rats and sham operated rats. The linearity, accuracy, precision, stability and matrix effect were within acceptable ranges. This established method was successfully applied to a pharmacokinetics study of 10 compounds in sham operated and MGH rats. According to the results, the bioavailability of glycyrrhetinic acid was highest in MGH rats and sham operated rats. The mean residence times of glycyrrhetinic acid and glycyrrhetinic acid 3-O-glucuronide were higher than those of the other compounds while the mean residence time and half-life of liquiritin, isoliquiritin and paeoniflorin were lower. Some pharmacokinetic parameters of ormononetin, liquiritigenin, isoliquiritigenin, liquiritin, isoliquiritin, paeoniflorin, protocatechuic acid and senkyunolide I were significantly different between MGH rats and sham operated rats. This study elucidated the dynamic changes of multiple components in rats after oral administration of HHXYT systematically and comprehensively, which provided guidance for clinical application.

Decomposition of dynamic transcriptomic responses during effector-triggered immunity reveals conserved responses in two distinct plant cell populations.

Rapid plant immune responses in the appropriate cells are needed for effective defense against pathogens. Although transcriptome analysis is often used to describe overall immune responses, collection of transcriptome data with sufficient resolution in both space and time is challenging. We reanalyzed public Arabidopsis time-course transcriptome data obtained after low-dose inoculation with a Pseudomonas syringae strain expressing the effector AvrRpt2, which induces effector-triggered immunity in Arabidopsis. Double-peak time-course patterns are prevalent among thousands of upregulated genes. We implemented a multi-compartment modeling approach to decompose the double-peak pattern into two single-peak patterns for each gene. The decomposed peaks reveal an "echoing" pattern: the peak times of the first and second peaks correlate well across most upregulated genes. We demonstrated that the two peaks likely represent responses of two distinct cell populations that respond either cell autonomously or indirectly to AvrRpt2. Thus, the peak decomposition has extracted spatial information from the time-course data. The echoing pattern also indicates a conserved transcriptome response with different initiation times between the two cell populations despite different elicitor types. A gene set highly overlapping with the conserved gene set is also upregulated with similar kinetics during pattern-triggered immunity. Activation of a WRKY network via different entry-point WRKYs can explain the similar but not identical transcriptome responses elicited by different elicitor types. We discuss potential benefits of the properties of the WRKY activation network as an immune signaling network in light of pressure from rapidly evolving pathogens.

Longitudinal Magnetic Resonance Imaging with ROS-Responsive Bilirubin Nanoparticles Enables Monitoring of Nonalcoholic Steatohepatitis Progression to Cirrhosis.

Despite the vital importance of monitoring the progression of nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), an efficient imaging modality that is readily available at hospitals is currently lacking. Here, a new magnetic-resonance-imaging (MRI)-based imaging modality is presented that allows for efficient and longitudinal monitoring of NAFLD and NASH progression. The imaging modality uses manganese-ion (Mn2+)-chelated bilirubin nanoparticles (Mn@BRNPs) as a reactive-oxygen-species (ROS)-responsive MRI imaging probe. Longitudinal T1-weighted MR imaging of NASH model mice is performed after injecting Mn@BRNPs intravenously. The MR signal enhancement in the liver relative to muscle gradually increases up to 8 weeks of NASH progression, but decreases significantly as NASH progresses to the cirrhosis-like stage at weeks 10 and 12. A new dual input pseudo-three-compartment model is developed to provide information on NASH stage with a single MRI scan. It is also demonstrated that the ROS-responsive Mn@BRNPs can be used to monitor the efficacy of potential anti-NASH drugs with conventional MRI. The findings suggest that the ROS-responsive Mn@BRNPs have the potential to serve as an efficient MRI contrast for monitoring NASH progression and its transition to the cirrhosis-like stage.

An Automatic Method for Generation of CFD-Based 3D Compartment Models: Towards Real-Time Mixing Simulations.

This article aims to develop a method to automatically generate CFD-based compartment models. This effort to simplify mixing models aims at capturing the interactions between material transport and chemical/biochemical conversions in large-scale reactors. The proposed method converts the CFD results into a system of mass balance equations for each defined component. The compartmentalization method is applied to two bioreactor geometries and was able to replicate tracer mixing profiles observed in CFD simulations. The generated compartment models were successfully coupled with, a simple Monod-type biokinetic model describing microbial growth, substrate consumption and product formation. The coupled model was used to simulate a four-hour fermentation in a 190 L reactor and a 10 m3 reactor. Resolving the substrate gradients had a clear impact on the biokinetics, increasing with the scale of the reactor. Moreover, the coupled model could simulate the fermentation faster than real-time. Having a real-time-solvable model is essential for implementations in digital twins and other real-time applications using the models as predictive tools.

Modeling the effect of daughter migration on dosimetry estimates for unlabeled actinium-225.

BACKGROUND: Actinium-225 (225Ac) is an alpha emitting radionuclide which has demonstrated promising results in Targeted Alpha Therapy (TAT). A concern with 225Ac is that the decay energy can break the bond to the targeting vehicle, resulting in the release of free alpha-emitting daughter radionuclides in the body. PURPOSE: The aim of this work is to develop a compartment model to describe the movement of unlabeled 225Ac in a human where the daughter isotopes of 225Ac have unique biokinetics. METHOD: The ICRP Occupational Intake of Radionuclides reports were used to construct a compartment model for the 225Ac decay chain where the daughter isotopes of 225Ac are assigned their own unique transfer coefficients (TCs) between compartments. Computer simulations were performed for unlabeled 225Ac uniformly placed in the plasma and only the dose from alpha particles was considered. Absorbed doses to normal organs were determined for the liver, kidneys, bone, soft tissue, active marrow, and blood. Simulations were performed for the case when: (1) the daughters have unique biokinetics and (2) the daughters decay at the site of 225Ac. RESULTS: When the daughters have unique biokinetics, the organs that receive the highest absorbed dose are the liver (male: 1466.6 mGy/MBq, female: 1885.7 mGy/MBq), bone (male: 293.6 mGy/MBq, female: 403.6 mGy/MBq) and kidneys (male: 260.8 mGy/MBq, female: 294.0 mGy/MBq). These doses were compared to the case when the daughters of 225Ac decay at the site of 225Ac. There was a 13.5% increase in kidney dose, a 0.8% decrease in liver dose, and <0.1% decrease in bone dose calculations when the daughters have unique biokinetics compared to assuming the daughters decay at the site of 225Ac. CONCLUSIONS: The kidneys received a large dose estimate (260-295 mGy/MBq) as well as a considerable change in dose of +13.5% when the daughters have unique biokinetics compared to assuming the daughters decay at the site of 225Ac. Therefore, to accurately determine the kidney dose from unlabeled 225Ac in a human, the biokinetics of the daughter isotopes should be considered.

The Shortfalls of Mental Health Compartment Models: A Call to Improve Mental Health Investment Cases in Developing Countries.

OBJECTIVES: There are irregularities in investment cases generated by the Mental Health Compartment Model. We discuss these irregularities and highlight the costing techniques that may be introduced to improve mental health investment cases. METHODS: This analysis uses data from the World Bank, the World Health Organization Mental Health Compartment Model, the United Nations Development Program, the Kenya Ministry of Health, and Statistics from the Kenyan National Commission of Human Rights. RESULTS: We demonstrate that the Mental Health Compartment Model produces irrelevant outcomes that are not helpful for clinical settings. The model inflated the productivity gains generated from mental health investment. In some cases, the model underestimated the economic costs of mental health. Such limitation renders the investment cases poor in providing valuable intervention points from the perspectives of both the users and the providers. CONCLUSIONS: There is a need for further calibration and validation of the investment case outcomes. The current estimated results cannot be used to guide service provision, research, and mental health programming comprehensively.

Influence of different time framings, reconstruction algorithms and post-processing methods on the quantification of myocardial blood flow from 13 N-NH3 PET images.

BACKGROUND: The aim was to investigate to what extent the quantification of myocardial blood flow (MBF) from dynamic 13 N-NH3 positron emission tomography (PET) images is affected by time frame schemes, time-of-flight (ToF), reconstruction algorithms, blood pool volume of interest (VOI) locations and compartment models in patients with suspected chronic coronary syndrome. METHODS: A standard MBF value was determined from 25 patients' rest/stress 13 N-NH3 PET/CT images reconstructed with ordered subset expectation maximization (OSEM), 5 s time frame for the first frames without ToF, subsequently analyzed using a basal VOI and the deGrado compartment model. MBFs calculated using 2 or 10 s for the first frames, ToF, block-sequential regularized expectation maximization (BSREM), apical or large VOI, Hutchins or Krivokapich compartment models were compared to MBFstandard in Bland-Altman plots (bias ± SD). RESULTS: Good agreement in global rest/stress MBF (mL/min/g) was found when changing the time frame scheme or reconstruction algorithm (MBFstandard vs. MBF2s : -0.02 ± 0.06; MBF10s : 0.01 ± 0.07; MBFBSREM : 0.01 ± 0.07), while a lower level of agreement was found when altering the other factors (MBFstandard vs. MBFToF : -0.07 ± 0.10; MBFapical VOI : -0.27 ± 0.25; MBFlarge VOI : -0.11 ± 0.10; MBFHutchins : -0.08 ± 0.10; MBFKrivokapich : -0.47 ± 0.50). CONCLUSIONS: Quantification of MBF from 13 N-NH3 PET images is more affected by choice of compartment models, ToF and blood pool VOIs than by different time frame schemes and reconstruction algorithms.

Estimation of per- and polyfluoroalkyl substances (PFAS) half-lives in human studies: a systematic review and meta-analysis.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) constitute a heterogeneous group of synthetic compounds widely used in industrial applications. The estimation of PFAS half-life (t1/2) is essential to quantify their persistence, their toxicity and mechanism of action in humans. OBJECTIVES: The purpose of this review is to summarize the evidence on PFAS half-lives in humans from the available literature, and to investigate the limitations and uncertainties characterizing half-life estimation. METHODS: The search was conducted on PubMed, Scopus, and Embase databases up to July 03, 2023 and was aimed at identifying all papers that estimated PFAS half-life in human populations. We excluded studies on temporal trends or providing estimates of half-life based solely on renal clearance. As persistent and ongoing exposures can influence half-life estimation, we decided to include only studies that were conducted after the main source of exposure to PFAS had ceased. A random-effects meta-analysis was conducted on studies that reported perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) or perfluorohexanesulfonic acid (PFHxS) half-life estimation. Risk of bias was evaluated using the OHAT tool. RESULTS: A total of 13 articles were included in the review, with 5 studies conducted in exposed general populations and 8 studies conducted in exposed workers; the estimated mean half-life ranged from 1.48 to 5.1 years for PFOA, from 3.4 to 5.7 years for total PFOS, and from 2.84 to 8.5 years for PFHxS. High heterogeneity among studies was observed; potential reasons include the variability among the investigated populations, discrepancies in considering ongoing exposures, variability in PFAS isomeric compositions, accounting for background exposure, time since exposure stopped and methods used for half-life estimation. DISCUSSION: Despite the efforts made to better understand PFAS toxicokinetics, further studies are needed to identify important characteristics of these persistent chemicals. Biomonitoring studies should focus on persistent and unaccounted sources of exposure to PFAS and on individual characteristics potentially determining half-life, to ensure accurate estimates.