Establishing non-fasting reference values for plasma lipids levels based on age, sex, and puberty stage in a French-Canadian pediatric population.

BACKGROUND: Dyslipidemias, including familial hypercholesterolemia (FH), are a significant risk factor for cardiovascular diseases. FH is a genetic disorder resulting in elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased probability of early cardiovascular disorders. Heterozygous familial hypercholesterolemia (HeFH) is the most common form, affecting approximately 1 in 250 individuals worldwide, with a higher prevalence among the French-Canadian population. Childhood is a critical period for screening risk factors, but the recommendation for non-fasting screening remains controversial due to a lack of specific reference values for this state. This study aims to establish reference values for lipid levels in non-fasting children from Sherbrooke, Quebec, Canada, that will be specific for sex, age, and pubertal stages. METHODS: Blood samples and corresponding anthropometric data were collected from 356 healthy children aged from 6 to 13. They were categorized either into two age groups: Cohort 6-8 and Cohort 9-13, or into pubertal stages. Reference values, specifically the 2.5th, 5th, 10th, 50th, 90th, 95th, and 97.5th percentiles were determined using the CLSI C28-A3 guidelines. RESULTS: Lipid profiles did not significantly differ between sexes, except for higher levels of high-density lipoprotein (HDL-C) in boys within Cohort 6-8. HDL-C levels significantly increased, while LDL-C and non-HDL-C levels significantly decreased in both sexes with age. Non-fasting age- and pubertal stages-specific reference values were established. CONCLUSION: This study established reference intervals for lipid markers in non-fasting state within the pediatric French-Canadian population. These findings could be used in dyslipidemia screening in daily practice.

Alteration of Fatty Acid Profile in Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most prevalent monogenic cause of Autism Spectrum Disorders (ASDs). Despite a common genetic etiology, the affected individuals display heterogenous metabolic abnormalities including hypocholesterolemia. Although changes in the metabolism of fatty acids (FAs) have been reported in various neuropsychiatric disorders, it has not been explored in humans with FXS. In this study, we investigated the FA profiles of two different groups: (1) an Argentinian group, including FXS individuals and age- and sex-matched controls, and (2) a French-Canadian group, including FXS individuals and their age- and sex-matched controls. Since phospholipid FAs are an indicator of medium-term diet and endogenous metabolism, we quantified the FA profile in plasma phospholipids using gas chromatography. Our results showed significantly lower levels in various plasma FAs including saturated, monosaturated, ω-6 polyunsaturated, and ω-3 polyunsaturated FAs in FXS individuals compared to the controls. A decrease in the EPA/ALA (eicosapentaenoic acid/alpha linoleic acid) ratio and an increase in the DPA/EPA (docosapentaenoic acid/eicosapentaenoic acid) ratio suggest an alteration associated with desaturase and elongase activity, respectively. We conclude that FXS individuals present an abnormal profile of FAs, specifically FAs belonging to the ω-3 family, that might open new avenues of treatment to improve core symptoms of the disorder.

Development and validation of a liquid chromatography-tandem mass spectrometry assay to quantify plasma 24(S)-hydroxycholesterol and 27-hydroxycholesterol: A new approach integrating the concept of ion ratio.

Accurate quantification of 24(S)-hydroxycholesterol and 27-hydroxycholesterol holds substantial biological significance due to their involvement in pivotal cellular processes, encompassing cholesterol homeostasis, inflammatory responses, neuronal signaling, and their potential as disease biomarkers. The plasma determination of these oxysterols is challenging considering their low concentrations and similarities in terms of empirical formulae, molecular structure, and physicochemical properties across all human endogenous plasma oxysterols. To overcome these sensitivity and specificity issues, we developed and validated a quantification method using liquid chromatography coupled to a tandem mass spectrometry instrument. Validation studies were designed inspired by Clinical and Laboratory Standards Institute (CLSI) C62-A Guidelines. The linearity ranged between 20 and 300 nM for both oxysterols with limits of quantification at 20 nM and 30 nM for 24(S)-OHC and 27-OHC, respectively. Inter-day precision coefficient variations (CV) were lower than 10% for both oxysterols. An optimal separation of 25-OHC was obtained from 24(S)-OHC and 27-OHC with a resolution (Rs) > 1.25. The determination and validation of ion ratios for 24(S)-OHC and 27-OHC enabled another quality check in identifying interferents that could impact the quantification. Our developed and validated LC-MS/MS method allows consistent and reliable quantification of human plasmatic 24(S)-OHC and 27-OHC that is warranted in fundamental and clinical research projects.

Clinical significance of matrix metalloproteinase-9 in Fragile X Syndrome.

High plasma matrix metalloproteases-9 (MMP-9) levels have been reported in Fragile X Syndrome in a limited number of animal and human studies. Since the results obtained are method-dependent and not directly comparable, the clinical utility of MMP-9 measurement in FXS remains unclear. This study aimed to compare quantitative gel zymography and ELISA and to determine which method better discriminates abnormal MMP-9 levels of individuals with FXS from healthy controls and correlates with the clinical profile. The active and total forms of MMP-9 were quantified respectively, by gel zymography and ELISA in a cohort of FXS (n = 23) and healthy controls (n = 20). The clinical profile was assessed for the FXS group using the Aberrant Behavior Checklist FXS adapted version (ABC-CFX), Adaptive Behavior Assessment System (ABAS), Social Communication Questionnaire (SCQ), and Anxiety Depression and Mood Scale questionnaires. Method comparison showed a disagreement between gel zymography and ELISA with a constant error of - 0.18 [95% CI: - 0.35 to - 0.02] and a proportional error of 2.31 [95% CI: 1.53 to 3.24]. Plasma level of MMP-9 active form was significantly higher in FXS (n = 12) as compared to their age-sex and BMI matched controls (n = 12) (p = 0.039) and correlated with ABC-CFX (rs = 0.60; p = 0.039) and ADAMS (rs = 0.57; p = 0.043) scores. As compared to the plasma total form, the plasma MMP-9 active form better enables the discrimination of individuals with FXS from controls and correlates with the clinical profile. Our results highlight the importance of choosing the appropriate method to quantify plasma MMP-9 in future FXS clinical studies.

Prediction of in-plane organ deformation during free-breathing radiotherapy via discriminative spatial transformer networks.

External beam radiotherapy is a commonly used treatment option for patients with cancer in the thoracic and abdominal regions. However, respiratory motion constitutes a major limitation during the intervention. It may stray the pre-defined target and trajectories determined during planning from the actual anatomy. We propose a novel framework to predict the in-plane organ motion. We introduce a recurrent encoder-decoder architecture which leverages feature representations at multiple scales. It simultaneously learns to map dense deformations between consecutive images from a given input sequence and to extrapolate them through time. Subsequently, several cascade-arranged spatial transformers use the predicted deformation fields to generate a future image sequence. We propose the use of a composite loss function which minimizes the difference between ground-truth and predicted images while maintaining smooth deformations. Our model is trained end-to-end in an unsupervised manner, thus it does not require additional information beyond image data. Moreover, no pre-processing steps such as segmentation or registration are needed. We report results on 85 different cases (healthy subjects and patients) belonging to multiples datasets across different imaging modalities. Experiments were aimed at investigating the importance of the proposed multi-scale architecture design and the effect of increasing the number of predicted frames on the overall accuracy of the model. The proposed model was able to predict vessel positions in the next temporal image with a median accuracy of 0.45 (0.55) mm, 0.45 (0.74) mm and 0.28 (0.58) mm in MRI, US and CT datasets, respectively. The obtained results show the strong potential of the model by achieving accurate matching between the predicted and target images on several imaging modalities.

Automatic self-gated 4D-MRI construction from free-breathing 2D acquisitions applied on liver images.

PURPOSE: MRI slice reordering is a necessary step when three-dimensional (3D) motion of an anatomical region of interest has to be extracted from multiple two-dimensional (2D) dynamic acquisition planes, e.g., for the construction of motion models used for image-guided radiotherapy. Existing reordering methods focus on obtaining a spatially coherent reconstructed volume for each time. However, little attention has been paid to the temporal coherence of the reconstructed volumes, which is of primary importance for accurate 3D motion extraction. This paper proposes a fully automatic self-sorting four-dimensional MR volume construction method that ensures the temporal coherence of the results. METHODS: First, a pseudo-navigator signal is extracted for each 2D dynamic slice acquisition series. Then, a weighted graph is created using both spatial and motion information provided by the pseudo-navigator. The volume at a given time point is reconstructed following the shortest paths in the graph starting that time point of a reference slice chosen based on its pseudo-navigator signal. RESULTS: The proposed method is evaluated against two state-of-the-art slice reordering algorithms on a prospective dataset of 12 volunteers using both spatial and temporal quality metrics. The automated end-exhale extraction showed results closed to the median value of the manual operators. Furthermore, the results of the validation metrics show that the proposed method outperforms state-of-the-art methods in terms of both spatial and temporal quality. CONCLUSION: Our approach is able to automatically detect the end-exhale phases within one given anatomical position and cope with irregular breathing.

Magnetic Resonance Navigation for Targeted Embolization in a Two-Level Bifurcation Phantom.

This work combines a particle injection system with our proposed magnetic resonance navigation (MRN) sequence with the intention of validating MRN in a two-bifurcation phantom for endovascular treatment of hepatocellular carcinoma (HCC). A theoretical physical model used to calculate the most appropriate size of the magnetic drug-eluting bead (MDEB, 200 µm) aggregates was proposed. The aggregates were injected into the phantom by a dedicated particle injector while a trigger signal was automatically sent to the MRI to start MRN which consists of interleaved tracking and steering sequences. When the main branch of the phantom was parallel to B0, the aggregate distribution ratio in the (left-left, left-right, right-left and right-right divisions was obtained with results of 8, 68, 24 and 0% respectively at baseline (no MRN) and increased to 84%, 100, 84 and 92% (p < 0.001, p = 0.004, p < 0.001, p < 0.001) after implementing our MRN protocol. When the main branch was perpendicular to B0, the right-left branch, having the smallest baseline distribution rate of 0%, reached 80% (p < 0.001) after applying MRN. Moreover, the success rate of MRN was always more than 92% at the 1st bifurcation in the experiments above.

Selective embolization with magnetized microbeads using magnetic resonance navigation in a controlled-flow liver model.

PURPOSE: The purpose of this study was to demonstrate the feasibility of using a custom gradient sequence on an unmodified 3T magnetic resonance imaging (MRI) scanner to perform magnetic resonance navigation (MRN) by investigating the blood flow control method in vivo, reproducing the obtained rheology in a phantom mimicking porcine hepatic arterial anatomy, injecting magnetized microbead aggregates through an implantable catheter, and steering the aggregates across arterial bifurcations for selective tumor embolization. MATERIALS AND METHODS: In the first phase, arterial hepatic velocity was measured using cine phase-contrast imaging in seven pigs under free-flow conditions and controlled-flow conditions, whereby a balloon catheter is used to occlude arterial flow and saline is injected at different rates. Three of the seven pigs previously underwent selective lobe embolization to simulate a chemoembolization procedure. In the second phase, the measured in vivo controlled-flow velocities were approximately reproduced in a Y-shaped vascular bifurcation phantom by injecting saline at an average rate of 0.6 mL/s with a pulsatile component. Aggregates of 200-µm magnetized particles were steered toward the right or left hepatic branch using a 20-mT/m MRN gradient. The phantom was oriented at 0°, 45°, and 90° with respect to the B0 magnetic field. The steering differences between left-right gradient and baseline were calculated using Fisher's exact test. A theoretical model of the trajectory of the aggregate within the main phantom branch taking into account gravity, magnetic force, and hydrodynamic drag was also designed, solved, and validated against the experimental results to characterize the physical limitations of the method. RESULTS: At an injection rate of 0.5 mL/s, the average flow velocity decreased from 20 ± 15 to 8.4 ± 5.0 cm/s after occlusion in nonembolized pigs and from 13.6 ± 2.0 to 5.4 ± 3.0 cm/s in previously embolized pigs. The pulsatility index measured to be 1.7 ± 1.8 and 1.1 ± 0.1 for nonembolized and embolized pigs, respectively, decreased to 0.6 ± 0.4 and 0.7 ± 0.3 after occlusion. For MRN performed at each orientation, the left-right distribution of aggregates was 55%, 25%, and 75% on baseline and 100%, 100%, and 100% (P < 0.001, P = 0.003, P = 0.003) after the application of MRN, respectively. According to the theoretical model, the aggregate reaches a stable transverse position located toward the direction of the gradient at a distance equal to 5.8% of the radius away from the centerline within 0.11 s, at which point the aggregate will have transited through a longitudinal distance of 1.0 mm from its release position. CONCLUSION: In this study, we showed that the use of a balloon catheter reduces arterial hepatic flow magnitude and variation with the aim to reduce steering failures caused by fast blood flow rates and low magnetic steering forces. A mathematical model confirmed that the reduced flow rate is low enough to maximize steering ratio. After reproducing the flow rate in a vascular bifurcation phantom, we demonstrated the feasibility of MRN after injection of microparticle aggregates through a dedicated injector. This work is an important step leading to MRN-based selective embolization techniques in humans.

MRI-Compatible Injection System for Magnetic Microparticle Embolization.

OBJECTIVE: Dipole field navigation and magnetic resonance navigation exploit B0 magnetic fields and imaging gradients for targeted intra-arterial therapies by using magnetic drug-eluting beads (MDEBs). The strong magnetic strength (1.5 or 3 T) of clinical magnetic resonance imaging (MRI) scanners is the main challenge preventing the formation and controlled injection of specific-sized particle aggregates. Here, an MRI-compatible injector is proposed to solve the above problem. METHODS: The injector consists of two peristaltic pumps, an optical counter, and a magnetic trap. The magnetic property of microparticles, the magnetic compatibility of different parts within the injector, and the field distribution of the MRI system were studied to determine the optimal design and setup of the injector. The performance was investigated through 30.4-emu/g biocompatible magnetic microparticles (230 ± 35 µm in diameter) corresponding to the specifications needed for trans-arterial chemoembolization in human adults. RESULTS: The system can form aggregates containing 20 to 60 microparticles with a precision of six particles. The corresponding aggregate lengths range from 1.6 to 3.2 mm. Based on the injections of 50 MRI-visible boluses into a phantom which mimics realistic physiological conditions, 82% of the aggregates successfully reached subbranches. CONCLUSION AND SIGNIFICANCE: This system has the capability to operate within the strong magnetic field of a clinical 3-T MRI, to form proper particle aggregates and to automatically inject these aggregates into the MRI bore. Moreover, the versatility of the proposed injector renders it suitable for selective injections of MDEBs during MR-guided embolization procedures.

Patient-Specific Biomechanical Modeling for Guidance During Minimally-Invasive Hepatic Surgery.

During the minimally-invasive liver surgery, only the partial surface view of the liver is usually provided to the surgeon via the laparoscopic camera. Therefore, it is necessary to estimate the actual position of the internal structures such as tumors and vessels from the pre-operative images. Nevertheless, such task can be highly challenging since during the intervention, the abdominal organs undergo important deformations due to the pneumoperitoneum, respiratory and cardiac motion and the interaction with the surgical tools. Therefore, a reliable automatic system for intra-operative guidance requires fast and reliable registration of the pre- and intra-operative data. In this paper we present a complete pipeline for the registration of pre-operative patient-specific image data to the sparse and incomplete intra-operative data. While the intra-operative data is represented by a point cloud extracted from the stereo-endoscopic images, the pre-operative data is used to reconstruct a biomechanical model which is necessary for accurate estimation of the position of the internal structures, considering the actual deformations. This model takes into account the patient-specific liver anatomy composed of parenchyma, vascularization and capsule, and is enriched with anatomical boundary conditions transferred from an atlas. The registration process employs the iterative closest point technique together with a penalty-based method. We perform a quantitative assessment based on the evaluation of the target registration error on synthetic data as well as a qualitative assessment on real patient data. We demonstrate that the proposed registration method provides good results in terms of both accuracy and robustness w.r.t. the quality of the intra-operative data.

Atlas-based transfer of boundary conditions for biomechanical simulation.

An environment composed of different types of living tissues (such as the abdominal cavity) reveals a high complexity of boundary conditions, which are the attachments (e.g. connective tissues, ligaments) connecting different anatomical structures. Together with the material properties, the boundary conditions have a significant influence on the mechanical response of the organs, however corresponding correct mechanical modeling remains a challenging task, as the connective structures are difficult to identify in certain standard imaging modalities. In this paper, we present a method for automatic modeling of boundary conditions in deformable anatomical structures, which is an important step in patient-specific biomechanical simulations. The method is based on a statistical atlas which gathers data defining the connective structures attached to the organ of interest. In order to transfer the information stored in the atlas to a specific patient, the atlas is registered to the patient data using a physics-based technique and the resulting boundary conditions are defined according to the mean position and variance available in the atlas. The method is evaluated using abdominal scans of ten patients. The results show that the atlas provides a sufficient information about the boundary conditions which can be reliably transferred to a specific patient. The boundary conditions obtained by the atlas-based transfer show a good match both with actual segmented boundary conditions and in terms of mechanical response of deformable organs.