Search

Abstract Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10−3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10−4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10−3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10−7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

Drought and water shortage effects are normally exacerbated due to collateral impacts on water quality, since low streamflow affects water quality in rivers and water uses depend on it. One of the most common problems during drought conditions is maintaining a good water quality while securing the water supply to demands. This research analyses the case of the Turia River Water Resource System located in Eastern Spain. Its main water demand comes as urban demand from Valencia City, which intake is located in the final stretch of the river, where streamflow may become very low during droughts. As a result, during drought conditions concentrations of pathogens and other contaminants increase, compromising the water supply to Valencia City. In order to define possible solutions for the above-mentioned problem, we have developed an integrated model for simulating water management and water quality in the Turia River Basin to propose solutions for water quality problems under water scarcity. For this purpose, the Decision Support System Shell AQUATOOL has been used. The results demonstrate the importance of applying environmental flows as a measure of reducing pollutant's concentration depending on the evolution of a drought event and the state of the water resources system.

For the purpose of MR-guided high-dose-rate (HDR) brachytherapy, a method for real-time localization of an HDR brachytherapy source was developed, which requires high spatial and temporal resolutions. MR-based localization of an HDR source serves two main aims. First, it enables real-time treatment verification by determination of the HDR source positions during treatment. Second, when using a dummy source, MR-based source localization provides an automatic detection of the source dwell positions after catheter insertion, allowing elimination of the catheter reconstruction procedure. Localization of the HDR source was conducted by simulation of the MR artifacts, followed by a phase correlation localization algorithm applied to the MR images and the simulated images, to determine the position of the HDR source in the MR images. To increase the temporal resolution of the MR acquisition, the spatial resolution was decreased, and a subpixel localization operation was introduced. Furthermore, parallel imaging (sensitivity encoding) was applied to further decrease the MR scan time. The localization method was validated by a comparison with CT, and the accuracy and precision were investigated. The results demonstrated that the described method could be used to determine the HDR source position with a high accuracy (0.4–0.6 mm) and a high precision (⩽0.1 mm), at high temporal resolutions (0.15–1.2 s per slice). This would enable real-time treatment verification as well as an automatic detection of the source dwell positions. [ABSTRACT FROM AUTHOR]

In the process of developing a robotic MRI-guided high-dose-rate (HDR) prostate brachytherapy treatment, the influence of the MRI scanner’s magnetic field on the dose distribution needs to be investigated. A magnetic field causes a deflection of electrons in the plane perpendicular to the magnetic field, and it leads to less lateral scattering along the direction parallel with the magnetic field. Monte Carlo simulations were carried out to determine the influence of the magnetic field on the electron behavior and on the total dose distribution around an Ir-192 source. Furthermore, the influence of air pockets being present near the source was studied. The Monte Carlo package Geant4 was utilized for the simulations. The simulated geometries consisted of a simplified point source inside a water phantom. Magnetic field strengths of 0 T, 1.5 T, 3 T, and 7 T were considered. The simulation results demonstrated that the dose distribution was nearly unaffected by the magnetic field for all investigated magnetic field strengths. Evidence was found that, from a dose perspective, the HDR prostate brachytherapy treatment using Ir-192 can be performed safely inside the MRI scanner. No need was found to account for the magnetic field during treatment planning. Nevertheless, the presence of air pockets in close vicinity to the source, particularly along the direction parallel with the magnetic field, appeared to be an important point for consideration. [ABSTRACT FROM AUTHOR]

To address the quality assurance (QA) of a MR-linac which is an MRI combined with a linear accelerator (linac), the traditional linac QA-tests need to be redesigned, since the presence of the static magnetic field in the MR-linac alters the electron trajectory. The latter causes the asymmetry in the dose kernel which is introduced by the magnetic field and hinders accurate geometrical QA-tests for the MR-linac. We introduced the use of electron dense materials (e.g. copper) to reduce the size of the dose kernel and thereby the magnetic field effect on the dose deposition. Two examples of QA-tests are presented in which the geometrical accuracy of the MR-linac was addressed; beam profile and star-shot measurements. The introduced setup was compared with a reference setup and both were tested on a conventional and the MR-linac. The results showed that the symmetry of the recorded beam profile was restored in presence of the copper material and that the isocenter size of the MR-linac can be determined accurately with the introduced star-shot setup. The use of electron dense materials is not limited to the presented QA-tests but has a broad application for beam-specific QA-tests in presence of a magnetic field. [ABSTRACT FROM AUTHOR]

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10 -3 ; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10 -4 ) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10 -3 ). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10 -7 ) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia., (© 2022. The Author(s).)

Background and Purpose: Magnetic resonance imaging (MRI)-guided focal salvage high-dose-rate brachytherapy (FS-HDR-BT) is one of the treatment options for radiorecurrent localized prostate cancer. However, due to the invasive nature of the treatment, not all patients are eligible. Magnetic resonance linear accelerator (MR-Linac) systems open up new treatment possibilities and could potentially replace FS-HDR-BT treatment. We conducted a planning study to investigate the feasibility of delivering a single 19 Gy dose to the recurrent lesion using a 1.5 Tesla MR-Linac system., Materials and Methods: Thirty patients who underwent FS-HDR-BT were included. The clinical target volume (CTV) encompassed the visible lesion plus a 5 mm margin. Treatment plans were created for a 1.5 Tesla MR-Linac system using a 1 mm planning target volume (PTV) margin. A dose of 19 Gy was prescribed to ≥ 95% of the PTV. In case this target could not be reached, i.e. when organs-at-risk (OAR) constraints were violated, a dose of ≥ 17 Gy to ≥ 90% of the PTV was accepted. MR-Linac plans were compared to clinical FS-HDR-BT plans., Results: Target dose coverage was achieved in 14/30 (47%) FS-HDR-BT plans and 17/30 (57%) MR-Linac plans, with comparable median D95% and D90%. In FS-HDR-BT plans, a larger volume reached ≥ 150% of the prescribed dose. Urethra D10%, rectum D1cm 3 , and rectum D2cm 3 were lower in the FS-HDR-BT plans, while bladder dose was comparable for both modalities., Conclusion: Single fraction treatment of recurrent prostate cancer lesions may be feasible using stereotactic body radiotherapy (SBRT) on a MR-Linac system., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

In this work, we present a new method for visualization of fiducial markers (FMs) in the prostate for MRI-only radiotherapy with a positive contrast directly at the MR console. The method is based on high bandwidth phase-cycled balanced steady-state free precession (bSSFP) sequence, which is available on many clinical scanners, does not require any additional post-processing or software, and has a higher signal-to-noise (SNR) compared to conventional gradient-echo (GE) imaging. Complex phase-cycled bSSFP data is acquired with different RF phase increment settings such that the manifestation of the artifacts around FMs in the acquired complex images is different for each dynamic acquisition and depends on the RF phase increment used. First, we performed numerical simulations to investigate the complex-valued phase-cycled bSSFP signal in the presence of a gold FM, and to investigate the relation of the true physical location of the FM with the geometrical manifestation of the artifacts. Next, to validate the simulations, we performed phantoms and in vivo studies and compared the experimentally obtained artifacts with those predicted in simulations. The accuracy of the method was assessed by comparing the distances between the FM's centers and the center of mass of FMs system measured using phase-cycled bSSFP MR images and using reference CT (or MRI-only) images. The results show accurate (within 1 mm) matching of FMs localization between CT and MR images on five patients, proving the feasibility of in vivo FMs detection on MR images only. The FMs show a positive contrast with respect to the prostate background on real/imaginary phase-cycled bSSFP images, which was confirmed by simulations. The proposed method facilitates robust FMs visualization with positive contrast directly at the MR console, allowing RT technicians to obtain immediate feedback on the anticipated feasibility of accurate FMs localization while the patient is being scanned.

For the purpose of magnetic resonance imaging (MRI) guidance of prostate high-dose-rate (HDR) brachytherapy, this paper presents a study on the potential of clinically relevant MRI sequences to facilitate tracking or localization of brachytherapy devices (HDR source/titanium needle), and which could simultaneously be used to visualize the anatomy. The tracking or localization involves simulation of the MRI artifact in combination with a template matching algorithm. Simulations of the MRI artifacts induced by an HDR brachytherapy source and a titanium needle were implemented for four types of sequences: spoiled gradient echo, spin echo, balanced steady-state free precession (bSSFP) and bSSFP with spectral attenuated inversion recovery (SPAIR) fat suppression. A phantom study was conducted in which mentioned sequences (in 2D) as well as the volumetric MRI sequences of the current clinical scan protocol were applied to obtain the induced MRI artifacts for an HDR source and a titanium needle. Localization of the objects was performed by a phase correlation based template matching algorithm. The simulated images demonstrated high correspondences with the acquired MR images, and allowed localization of the objects. A comparison between the object positions obtained for all applied MRI sequences showed deviations (from the average position) of 0.2-0.3 mm, proving that all MRI sequences were suitable for localization of the objects, irrespective of their 2D or volumetric nature. This study demonstrated that the MRI artifact induced by an HDR source or a titanium needle could be simulated for the four investigated types of MRI sequences (spoiled gradient echo, spin echo, bSSFP and bSSFP-SPAIR), valuable for real-time object localization in clinical practice. This leads to more flexibility in the choice of MRI sequences for guidance of HDR brachytherapy, as they are suitable for both object localization and anatomy visualization.

Purpose: For the purpose of magnetic resonance imaging (MRI)-guided high-dose-rate (HDR) brachytherapy, a prototype magnetic resonance (MR) conditional afterloader was developed. This study demonstrates the development and testing of the prototype, while operating simultaneously with MRI. In combination with an MR-based method for HDR source localization, this development enables treatment verification of HDR brachytherapy. Additionally, this allows a direct reconstruction of the source dwell positions after catheter insertion (when using a dummy source) and introduction of a clinical workflow where the patient remains in the same position during dwell position reconstruction, treatment planning and irradiation., Methods and Materials: A prototype MR conditional afterloader was developed by providing radiofrequency (RF) shielding and a plastic source cable containing a dummy source. Simultaneous functioning of the afterloader and MRI acquisition was tested in an experimental setting where the afterloader was placed next to the scanner and programmed to send the source to predefined positions within a phantom, while acquiring MR images. The HDR source positions were determined using MR artifact simulation and matching of the MR images to the simulated artifact. Additionally, the impact of the presence and use of the afterloader on the MRI performance was investigated by assessment of RF interference, signal-to-noise ratio (SNR), and B 0 field homogeneity., Results: The experiments demonstrated that the prototype MR conditional afterloader and the MRI scanner fully functioned while operating simultaneously, without influencing the other system. The step sizes between the source positions obtained from the MR images corresponded with the afterloader settings. Besides, the MRI performance tests demonstrated no deterioration due to the presence or functioning of the afterloader next to the scanner., Conclusions: This research has demonstrated the feasibility of simultaneous MR acquisition and employment of an MR conditional afterloader. This development enables real-time HDR source localization for treatment verification of MRI-guided HDR brachytherapy using an MR conditional afterloader., (Copyright © 2018 Elsevier Inc. All rights reserved.)

For the purpose of MR-guided high-dose-rate (HDR) brachytherapy, a method for real-time localization of an HDR brachytherapy source was developed, which requires high spatial and temporal resolutions. MR-based localization of an HDR source serves two main aims. First, it enables real-time treatment verification by determination of the HDR source positions during treatment. Second, when using a dummy source, MR-based source localization provides an automatic detection of the source dwell positions after catheter insertion, allowing elimination of the catheter reconstruction procedure. Localization of the HDR source was conducted by simulation of the MR artifacts, followed by a phase correlation localization algorithm applied to the MR images and the simulated images, to determine the position of the HDR source in the MR images. To increase the temporal resolution of the MR acquisition, the spatial resolution was decreased, and a subpixel localization operation was introduced. Furthermore, parallel imaging (sensitivity encoding) was applied to further decrease the MR scan time. The localization method was validated by a comparison with CT, and the accuracy and precision were investigated. The results demonstrated that the described method could be used to determine the HDR source position with a high accuracy (0.4-0.6 mm) and a high precision (⩽0.1 mm), at high temporal resolutions (0.15-1.2 s per slice). This would enable real-time treatment verification as well as an automatic detection of the source dwell positions.

Purpose: Dynamic contrast enhanced (DCE) imaging is a widely used technique in oncologic imaging. An essential prerequisite for obtaining quantitative values from DCE-MRI is the determination of the arterial input function (AIF). However, it is very challenging to accurately estimate the AIF using MR. A comprehensive model, which uses complex data instead of either magnitude or phase, was developed to improve AIF estimation., Theory and Methods: The model was first applied to simulated data. Subsequently, the accuracy of the estimated contrast agent concentration was validated in a phantom. Finally the method was applied to existing DCE scans of 13 prostate cancer patients., Results: The complex signal method combines the complementary strengths of the magnitude and phase method, increasing the precision and accuracy of concentration estimation in simulated and phantom data. The in vivo AIFs show a good agreement between arterial voxels (standard deviation in the peak and tail equal 0.4 mM and 0.12 mM, respectively). Furthermore, the dynamic behavior closely followed the AIF obtained with DCE-CT in the same patients (mean correlation coefficient: 0.92)., Conclusion: By using the complex signal, the AIF estimation becomes more accurate and precise. This might enable patient specific AIFs, thereby improving the quantitative values obtained from DCE-MRI. Magn Reson Med 76:1236-1245, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

In the process of developing a robotic MRI-guided high-dose-rate (HDR) prostate brachytherapy treatment, the influence of the MRI scanner's magnetic field on the dose distribution needs to be investigated. A magnetic field causes a deflection of electrons in the plane perpendicular to the magnetic field, and it leads to less lateral scattering along the direction parallel with the magnetic field. Monte Carlo simulations were carried out to determine the influence of the magnetic field on the electron behavior and on the total dose distribution around an Ir-192 source. Furthermore, the influence of air pockets being present near the source was studied. The Monte Carlo package Geant4 was utilized for the simulations. The simulated geometries consisted of a simplified point source inside a water phantom. Magnetic field strengths of 0 T, 1.5 T, 3 T, and 7 T were considered. The simulation results demonstrated that the dose distribution was nearly unaffected by the magnetic field for all investigated magnetic field strengths. Evidence was found that, from a dose perspective, the HDR prostate brachytherapy treatment using Ir-192 can be performed safely inside the MRI scanner. No need was found to account for the magnetic field during treatment planning. Nevertheless, the presence of air pockets in close vicinity to the source, particularly along the direction parallel with the magnetic field, appeared to be an important point for consideration.

To address the quality assurance (QA) of a MR-linac which is an MRI combined with a linear accelerator (linac), the traditional linac QA-tests need to be redesigned, since the presence of the static magnetic field in the MR-linac alters the electron trajectory. The latter causes the asymmetry in the dose kernel which is introduced by the magnetic field and hinders accurate geometrical QA-tests for the MR-linac. We introduced the use of electron dense materials (e.g. copper) to reduce the size of the dose kernel and thereby the magnetic field effect on the dose deposition. Two examples of QA-tests are presented in which the geometrical accuracy of the MR-linac was addressed; beam profile and star-shot measurements. The introduced setup was compared with a reference setup and both were tested on a conventional and the MR-linac. The results showed that the symmetry of the recorded beam profile was restored in presence of the copper material and that the isocenter size of the MR-linac can be determined accurately with the introduced star-shot setup. The use of electron dense materials is not limited to the presented QA-tests but has a broad application for beam-specific QA-tests in presence of a magnetic field.

The circadian activity rhythm was assessed over a one-week period using a wrist-worn activity monitor in 59 patients with a history of recurrent suicide attempts. In 40 of these patients a second recording was made 6 months later. Platelet serotonin (5-HT) and monoamine oxidase-B activity (MAO) were measured. Suicidal ideation, borderline personality disorder and impulsiveness were associated with the absence of a clear 24-hour periodicity in motor activity. Depressive mood and hopelessness were associated with a less regular bed-in time and a lower daytime activity. Platelet 5-HT as well as MAO correlated negatively with the amplitude of the circadian activity rhythm. Our results support the suggested link between suicidality, altered circadian activity and serotonergic function.