Impact of different parametric Patlak imaging approaches and comparison with a 2-tissue compartment pharmacokinetic model with a long axial field-of-view (LAFOV) PET/CT in oncological patients.

AIM: The recently introduced Long-Axial-Field-of-View (LAFOV) PET-CT scanners allow for the first-time whole-body dynamic- and parametric imaging. Primary aim of this study was the comparison of direct and indirect Patlak imaging as well as the comparison of different time frames for Patlak calculation with the LAFOV PET-CT in oncological patients. Secondary aims of the study were lesion detectability and comparison of Patlak analysis with a two-tissue-compartment model (2TCM). METHODOLOGY: 50 oncological patients with 346 tumor lesions were enrolled in the study. All patients underwent [18F]FDG PET/CT (skull to upper thigh). Here, the Image-Derived-Input-Function) (IDIF) from the descending aorta was used as the exclusive input function. Four sets of images have been reviewed visually and evaluated quantitatively using the target-to-background (TBR) and contrast-to-noise ratio (CNR): short-time (30 min)-direct (STD) Patlak Ki, short-time (30 min)-indirect (STI) Patlak Ki, long-time (59.25 min)-indirect (LTI) Patlak Ki, and 50-60 min SUV (sumSUV). VOI-based 2TCM was used for the evaluation of tumor lesions and normal tissues and compared with the results of Patlak model. RESULTS: No significant differences were observed between the four approaches regarding the number of tumor lesions. However, we found three discordant results: a true positive liver lesion in all Patlak Ki images, a false positive liver lesion delineated only in LTI Ki which was a hemangioma according to MRI and a true negative example in a patient with an atelectasis next to a lung tumor. STD, STI and LTI Ki images had superior TBR in comparison with sumSUV images (2.9-, 3.3- and 4.3-fold higher respectively). TBR of LTI Ki were significantly higher than STD Ki. VOI-based k3 showed a 21-fold higher TBR than sumSUV. Parameters of different models vary in their differential capability between tumor lesions and normal tissue like Patlak Ki which was better in normal lung and 2TCM k3 which was better in normal liver. 2TCM Ki revealed the highest correlation (r = 0.95) with the LTI Patlak Ki in tumor lesions group and demonstrated the highest correlation with the STD Patlak Ki in all tissues group and normal tissues group (r = 0.93 and r = 0.74 respectively). CONCLUSIONS: Dynamic [18F]-FDG with the new LAFOV PET/CT scanner produces Patlak Ki images with better lesion contrast than SUV images, but does not increase the lesion detection rate. The time window used for Patlak imaging plays a more important role than the direct or indirect method. A combination of different models, like Patlak and 2TCM may be helpful in parametric imaging to obtain the best TBR in the whole body in future.

Pharmacokinetics of Efmoroctocog alfa by Two-Compartment Model Highlights Hemophilia A Patients with Biphasic Decay, Long Mean Residence Time, and Beta Half-Life.

Background/Objectives: A compartmental pharmacokinetics (PK) analysis of new extended half-life FVIII concentrates has never been performed in a large cohort of hemophilia patients. An improved PK analysis of individual outcomes may help to tailor hemophilia replacement treatment. Methods: PK outcomes after the infusion of a standard single dose of Efmoroctocog alfa were collected from 173 patients with severe/moderately severe hemophilia A in 11 Italian hemophilia centers. Factor VIII clotting activity (FVIII:C) was measured by one-stage clotting assay (OSA) in all patients, and chromogenic substrate assay (CSA) in a subgroup (n = 52). Fifty patients underwent a comparative PK assessment with standard half-life (SHL) recombinant FVIII (rFVIII) products. Non-compartmental analysis (NCA), one compartment model (OCM), and TCM were used to analyze the decay curves of all patients, and one-way paired ANOVA to compare the PK outcomes. Results: All 173 PKs conformed to the NCA and OCM, but only 106 (61%) conformed to the TCM based on the biphasic features of their decay curves. According to the TCM, the Beta HL and MRT of rFVIIIFc were 20.42 ± 7.73 and 25.64 ± 7.61 h, respectively. ANOVA analysis of the outcomes from the three PK models showed significant differences in clearance, half-life (HL), and mean residence time (MRT) (p < 0.001 for all parameters). As anticipated, the HL and MRT of rFVIIIFc were longer than those of SHL rFVIII. Comparing OSA with CSA outcomes, Cmax resulted higher when measured by CSA (p = 0.05) and, according to TCM, Beta HL resulted longer when measured by OSA (p = 0.03). FVIII:C trough levels obtained with SHL concentrates were significantly lower than those obtained with rFVIIIFc at each post-infusion time point. Conclusions: In a large group of hemophilia A (HA) patients, three different PK models confirmed the improved pharmacokinetic (PK) characteristics of rFVIIIFc, compared with standard half-life rFVIII concentrates. The TCM only fits two-thirds of the PKs, highlighting their biphasic decay and a long Beta half-life. In these patients, the TCM would be preferable to properly evaluate individual PK features.

Modelling the role of tourism in the spread of HIV: A case study from Malaysia.

This study aimed to assess the role of tourism in the spread of human immunodeficiency virus (HIV) using Malaysian epidemiological data on HIV and acquired immunodeficiency syndrome (AIDS) incidence from 1986 to 2004. A population-level mathematical model was developed with the following compartments: the population susceptible to HIV infection, the clinically confirmed HIV-positive population, the population diagnosed with AIDS, and the tourist population. Additionally, newborns infected with HIV were considered. Sensitivity analyses and variations in fixed parameter values were used to explore the effect of changes to various parameter values on HIV incidence in the model. It was determined that variations in the rate of HIV-positive inbound tourist entries and the rate of foreign tourist exits (i.e., the duration of time tourists spent in Malaysia) significantly impacted the predicted incidence of HIV and AIDS in Malaysia. The model's fit to observed HIV and AIDS incidence was evaluated, resulting in adjusted R2 values of 53.3% and 53.2% for HIV and AIDS, respectively. Furthermore, the reproduction number (R0) was also calculated to quantify the stability of the HIV endemicity in Malaysia. The findings suggest that a steady-state level of HIV in Malaysia is achievable based on the low value of R 0  = 0.0136, and the disease-free equilibrium was stable from the negative eigenvalues obtained, which is encouraging from a public health perspective. The Partial Rank Correlation Coefficient (PRCC) values between the proportion of newborns born HIV-positive, the rate of Malaysian tourist entries returning home after contracting HIV, and the rate of foreign tourist exits have a significant impact on the R 0 . The methods provide a framework for epidemiological modelling of HIV spread through transient population groups. The model results suggest that the role of tourism should not be overlooked within the set of available measures to mitigate the spread of HIV.

Iohexol plasma clearance measurement protocol standardization for adults: a consensus paper of the European Kidney Function Consortium.

International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation.

Flow reduction due to arterial catheterization during stroke treatment - A computational study using a distributed compartment model.

The effectiveness of various stroke treatments depends on the anatomical variability of the cerebral vasculature, particularly the collateral blood vessel network. Collaterals at the level of the Circle of Willis and distal collaterals, such as the leptomeningeal arteries, serve as alternative avenues of flow when the primary pathway is obstructed during an ischemic stroke. Stroke treatment typically involves catheterization of the primary pathway, and the potential risk of further flow reduction to the affected brain area during this treatment has not been previously investigated. To address this clinical question, we derived the lumped parameters for catheterized blood vessels and implemented a corresponding distributed compartment (0D) model. This 0D model was validated against an experimental model and benchmark test cases solved using a 1D model. Additionally, we compared various off-center catheter trajectories modeled using a 3D solver to this 0D model. The differences between them were minimal, validating the simplifying assumption of the central catheter placement in the 0D model. The 0D model was then used to simulate blood flows in realistic cerebral arterial networks with different collateralization characteristics. Ischemic strokes were modeled by occlusion of the M1 segment of the middle cerebral artery in these networks. Catheters of different diameters were inserted up to the obstructed segment and flow alterations in the network were calculated. Results showed up to 45% maximum blood flow reduction in the affected brain region. These findings suggest that catheterization during stroke treatment may have a further detrimental effect for some patients with poor collateralization.

A data-driven analysis on the mediation effect of compartment models between control measures and COVID-19 epidemics.

By collecting various control policies taken by 127 countries/territories during the first wave of COVID-19 pandemic until July 2nd, 2020, we evaluate their impacts on the epidemic dynamics quantitatively through a combination of the multiple linear regression, neural-network-based nonlinear regression and sensitivity analysis. Remarkable differences in the public health policies are observed across these countries, which affect the spreading rate and infected population size to a great extent. Several key dynamical features, like the normalized cumulative numbers of confirmed/cured/death cases on the 100th day and the half time, show statistically significant linear correlations with the control measures, which thereby confirms their dramatic impacts. Most importantly, we perform the mediation analysis on the SEIR-QD model, a representative of general compartment models, by using the structure equation modeling for multiple mediators operating in parallel. This, to the best of our knowledge, is the first of its kind in the field of epidemiology. The infection rate and the protection rate of the SEIR-QD model are confirmed to exhibit a statistically significant mediation effect between the control measures and dynamical features of epidemics. The mediation effect along the pathway from control measures in Category 2 to four dynamical features through the infection rate, highlights the crucial role of nucleic acid testing and suspected cases tracing in containing the spread of the epidemic. Our data-driven analysis offers a deeper insight into the inherent correlations between the effectiveness of public health policies and the dynamic features of COVID-19 epidemics.

Auditory nerve fiber excitability for alternative electrode placement in the obstructed human cochlea: electrode insertion in scala vestibuli versus scala tympani.

Objective. The cochlear implant (CI) belongs to the most successful neuro-prostheses. Traditionally, the stimulating electrode arrays are inserted into the scala tympani (ST), the lower cochlear cavity, which enables simple surgical access. However, often deep insertion is blocked, e.g. by ossification, and the auditory nerve fibers (ANFs) of lower frequency regions cannot be stimulated causing severe restrictions in speech understanding. As an alternative, the CI can be inserted into the scala vestibuli (SV), the other upper cochlear cavity.Approach. In this computational study, the excitability of 25 ANFs are compared for stimulation with ST and SV implants. We employed a 3-dimensional realistic human cochlear model with lateral wall electrodes based on aµ-CT dataset and manually traced fibers. A finite element approach in combination with a compartment model of a spiral ganglion cell was used to simulate monophasic stimulation with anodic (ANO) and cathodic (CAT) pulses of 50µs.Main results. ANO thresholds are lower in ST (mean/std =µ/σ= 189/55µA) stimulation compared to SV (µ/σ= 323/119µA) stimulation. Contrary, CAT thresholds are higher for the ST array (µ/σ= 165/42µA) compared to the SV array (µ/σ= 122/46µA). The threshold amplitude depends on the specific fiber-electrode spatial relationship, such as lateral distance from the cochlear axis, the angle between electrode and target ANF, and the curvature of the peripheral process. For CAT stimulation the SV electrodes show a higher selectivity leading to less cross-stimulation of additional fibers from different cochlear areas.Significance. We present a first simulation study with a human cochlear model that investigates an additional CI placement into the SV and its impact on the excitation behavior. Results predict comparable outcomes to ST electrodes which confirms that SV implantation might be an alternative for patients with a highly obstructed ST.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.