Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

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.

MR-based source localization for MR-guided HDR brachytherapy.

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.

Monte Carlo study of the impact of a magnetic field on the dose distribution in MRI-guided HDR brachytherapy using Ir-192.

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.

Minimizing the magnetic field effect in MR-linac specific QA-tests: the use of electron dense materials.

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.

Carcino-embryonic antigen--no help with the differential diagnosis.

Two patients who were referred because of an increase in serum carcino-embryonic antigen (CEA) were diagnosed after a number of years as having a medullary thyroid carcinoma. The relationship between CEA and medullary thyroid carcinoma is discussed. The serum level of CEA is neither sensitive nor specific enough to serve as a diagnostic tool. Its determination, however, is useful in the follow-up of patients with carcinoma of the breast, colo-rectal carcinoma and medullary thyroid carcinoma.

Suicidality, circadian activity rhythms and platelet serotonergic measures in patients with recurrent suicidal behaviour.

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.