Severe Dissociative Experiences beyond Detachment in a Large Clinical Sample of Inpatients with Post-Traumatic Stress Disorder: Diagnostic and Treatment Implications.

INTRODUCTION: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) contains a dissociative subtype of post-traumatic stress disorder (PTSD) characterized by depersonalization and derealization. Yet, there is evidence that dissociative symptoms in PTSD go beyond this kind of detachment dissociation and that some patients present with additional compartmentalization dissociation in the form of auditory-verbal hallucination, amnesia, and identity alteration. METHODS: Hence, in this study, we examined latent profiles of childhood trauma (Childhood Trauma Questionnaire), PTSD (Impact-of-Event Scale-Revised), and pathological dissociation (Dissociative Experiences Scale-Taxon; DES-T) in a large sample of severely traumatized inpatients with PTSD (N = 1,360). RESULTS: Results support a three-class solution of the latent profile analysis with a PTSD class, a dissociative subtype class, and a third class characterized by more complex and more severe dissociative symptoms. Importantly, in our inpatient sample of patients with severe PTSD, the latter class was found to be the most prevalent. Both the exploratory character of our retrospective analysis of clinical routine data and the use of the DES-T limit the generalizability of our findings, which require methodologically more rigorous replication. CONCLUSION: In severe PTSD, dissociative symptoms beyond detachment are highly prevalent. Diagnostic and treatment implications are discussed.

Prostate cancer risk assessment and avoidance of prostate biopsies using fully automatic deep learning in prostate MRI: comparison to PI-RADS and integration with clinical data in nomograms.

OBJECTIVES: Risk calculators (RCs) improve patient selection for prostate biopsy with clinical/demographic information, recently with prostate MRI using the prostate imaging reporting and data system (PI-RADS). Fully-automated deep learning (DL) analyzes MRI data independently, and has been shown to be on par with clinical radiologists, but has yet to be incorporated into RCs. The goal of this study is to re-assess the diagnostic quality of RCs, the impact of replacing PI-RADS with DL predictions, and potential performance gains by adding DL besides PI-RADS. MATERIAL AND METHODS: One thousand six hundred twenty-seven consecutive examinations from 2014 to 2021 were included in this retrospective single-center study, including 517 exams withheld for RC testing. Board-certified radiologists assessed PI-RADS during clinical routine, then systematic and MRI/Ultrasound-fusion biopsies provided histopathological ground truth for significant prostate cancer (sPC). nnUNet-based DL ensembles were trained on biparametric MRI predicting the presence of sPC lesions (UNet-probability) and a PI-RADS-analogous five-point scale (UNet-Likert). Previously published RCs were validated as is; with PI-RADS substituted by UNet-Likert (UNet-Likert-substituted RC); and with both UNet-probability and PI-RADS (UNet-probability-extended RC). Together with a newly fitted RC using clinical data, PI-RADS and UNet-probability, existing RCs were compared by receiver-operating characteristics, calibration, and decision-curve analysis. RESULTS: Diagnostic performance remained stable for UNet-Likert-substituted RCs. DL contained complementary diagnostic information to PI-RADS. The newly-fitted RC spared 49% [252/517] of biopsies while maintaining the negative predictive value (94%), compared to PI-RADS ≥ 4 cut-off which spared 37% [190/517] (p < 0.001). CONCLUSIONS: Incorporating DL as an independent diagnostic marker for RCs can improve patient stratification before biopsy, as there is complementary information in DL features and clinical PI-RADS assessment. CLINICAL RELEVANCE STATEMENT: For patients with positive prostate screening results, a comprehensive diagnostic workup, including prostate MRI, DL analysis, and individual classification using nomograms can identify patients with minimal prostate cancer risk, as they benefit less from the more invasive biopsy procedure. KEY POINTS: The current MRI-based nomograms result in many negative prostate biopsies. The addition of DL to nomograms with clinical data and PI-RADS improves patient stratification before biopsy. Fully automatic DL can be substituted for PI-RADS without sacrificing the quality of nomogram predictions. Prostate nomograms show cancer detection ability comparable to previous validation studies while being suitable for the addition of DL analysis.

Detection of myeloma-associated osteolytic bone lesions with energy-integrating and photon-counting detector CT.

BACKGROUND: A recent innovation in computed tomography (CT) imaging has been the introduction of photon-counting detector CT (PCD-CT) systems, which are able to register the number and the energy level of incoming x­ray photons and have smaller detector elements compared with conventional CT scanners that operate with energy-integrating detectors (EID-CT). OBJECTIVES: The study aimed to evaluate the potential benefits of a novel, non-CE certified PCD-CT in detecting myeloma-associated osteolytic bone lesions (OL) compared with a state-of-the-art EID-CT. MATERIALS AND METHODS: Nine patients with multiple myeloma stage III (according to Durie and Salmon) underwent magnetic resonance imaging (MRI), EID-CT, and PCD-CT of the lower lumbar spine and pelvis. The PCD-CT and EID-CT images of all myeloma lesions that were visible in clinical MRI scans were reviewed by three radiologists for corresponding OL. Additionally, the visualization of destructions to cancellous or cortical bone, and trabecular structures, was compared between PCD-CT and EID-CT. RESULTS: Readers detected 21% more OL in PCD-CT than in EID-CT images (138 vs. 109; p < 0.0001). The sensitivity advantage of PCD-CT in lesion detection increased with decreasing lesion size. The visualization quality of cancellous and cortical destructions as well as of trabecular structures was rated higher by all three readers in PCD-CT images (mean image quality improvements for PCD-CT over EID-CT were +0.45 for cancellous and +0.13 for cortical destructions). CONCLUSIONS: For myeloma-associated OL, PCD-CT demonstrated significantly higher sensitivity, especially with small size. Visualization of bone tissue and lesions was considered significantly better in PCD-CT than in EID-CT. This implies that PCD-CT scanners could potentially be used in the early detection of myeloma-associated bone lesions.

Whole-Brain Vascular Architecture Mapping Identifies Region-Specific Microvascular Profiles in Vivo.

BACKGROUND AND PURPOSE: The novel MR imaging technique of vascular architecture mapping allows in vivo characterization of local changes in cerebral microvasculature, but reference ranges for vascular architecture mapping parameters in healthy brain tissue are lacking, limiting its potential applicability as an MR imaging biomarker in clinical practice. We conducted whole-brain vascular architecture mapping in a large cohort to establish vascular architecture mapping parameter references ranges and identify region-specific cortical and subcortical microvascular profiles. MATERIALS AND METHODS: This was a single-center examination of adult patients with unifocal, stable low-grade gliomas with multiband spin- and gradient-echo EPI sequence at 3T using parallel imaging. Voxelwise plotting of resulting values for gradient-echo (R2*) versus spin-echo (R2) relaxation rates during contrast agent bolus administration generates vessel vortex curves that allow the extraction of vascular architecture mapping parameters representative of, eg, vessel type, vessel radius, or CBV in the underlying voxel. Averaged whole-brain parametric maps were calculated for 9 parameters, and VOI analysis was conducted on the basis of a standardized brain atlas and individual cortical GM and WM segmentation. RESULTS: Prevalence of vascular risk factors among subjects (n = 106; mean age, 39.2 [SD, 12.5] years; 56 women) was similar to those in the German population. Compared with WM, we found cortical GM to have larger mean vascular calibers (5.80 [SD, 0.59] versus 4.25 [SD, 0.62] P < .001), increased blood volume fraction (20.40 [SD, 4.49] s-1 versus 11.05 [SD, 2.44] s-1; P < .001), and a dominance of venous vessels. Distinct microvascular profiles emerged for cortical GM, where vascular architecture mapping vessel type indicator differed, eg, between the thalamus and cortical GM (mean, -2.47 [SD, 4.02] s-2 versus -5.41 [SD, 2.84] s-2; P < .001). Intraclass correlation coefficient values indicated overall high test-retest reliability for vascular architecture mapping parameter mean values when comparing multiple scans per subject. CONCLUSIONS: Whole-brain vascular architecture mapping in the adult brain reveals region-specific microvascular profiles. The obtained parameter reference ranges for distinct anatomic and functional brain areas may be used for future vascular architecture mapping studies on cerebrovascular pathologies and might facilitate early discovery of microvascular changes, in, eg, neurodegeneration and neuro-oncology.

Non-contrast free-breathing liver perfusion imaging using velocity selective ASL combined with prospective motion compensation.

PURPOSE: To apply velocity selective arterial spin labeling (VSASL) combined with a navigator-based (NAV) prospective motion compensation method for a free-breathing liver perfusion measurement without contrast agent. METHODS: Sinc-modulated Velocity Selective Inversion (sinc-VSI) pulses were applied as labeling and control pulses. In order to account for respiratory motion, a navigator was employed in the form of a single gradient-echo projection readout, located at the diaphragm along the inferior-superior direction. Prior to each transverse imaging slice of the spin-echo EPI based readouts, navigator and fat suppression were incorporated. Motion data was obtained from the navigator and transmitted back to the sequence, allowing real-time adjustments to slice positioning. The sinc-VSI without velocity-selective gradients during the control condition but with velocity-selective gradients along all three directions during labeling was chosen for the VSASL. The VSASL was compared with pseudo-continuous ASL (pCASL) methods, which selectively tagged the moving spins using a tagging plane placed at the portal vein and hepatic artery. RESULTS: The motion caused by respiratory activity was effectively computed using the navigator signal. The coefficients of variation (CoV) of average liver voxel in NAV were significantly decreased when compared to breath-hold (BH), with an average reduction of 29.4 ±â€¯18.44% for control images, and 29.89 ±â€¯20.83% for label images (p < 0.001). The resulting maps of normalized ASL signal (normalized to M0) showed significantly higher perfusion weightings in the NAV-compensated VSASL, when compared to the NAV-compensated pCASL techniques. CONCLUSIONS: This study demonstrates the feasibility of using a navigator-based prospective motion compensation technique in conjunction with VSASL for the measurement of liver perfusion without the use of contrast agents while allowing for free-breathing.

Radiomics workflow definition & challenges - German priority program 2177 consensus statement on clinically applied radiomics.

OBJECTIVES: Achieving a consensus on a definition for different aspects of radiomics workflows to support their translation into clinical usage. Furthermore, to assess the perspective of experts on important challenges for a successful clinical workflow implementation. MATERIALS AND METHODS: The consensus was achieved by a multi-stage process. Stage 1 comprised a definition screening, a retrospective analysis with semantic mapping of terms found in 22 workflow definitions, and the compilation of an initial baseline definition. Stages 2 and 3 consisted of a Delphi process with over 45 experts hailing from sites participating in the German Research Foundation (DFG) Priority Program 2177. Stage 2 aimed to achieve a broad consensus for a definition proposal, while stage 3 identified the importance of translational challenges. RESULTS: Workflow definitions from 22 publications (published 2012-2020) were analyzed. Sixty-nine definition terms were extracted, mapped, and semantic ambiguities (e.g., homonymous and synonymous terms) were identified and resolved. The consensus definition was developed via a Delphi process. The final definition comprising seven phases and 37 aspects reached a high overall consensus (> 89% of experts "agree" or "strongly agree"). Two aspects reached no strong consensus. In addition, the Delphi process identified and characterized from the participating experts' perspective the ten most important challenges in radiomics workflows. CONCLUSION: To overcome semantic inconsistencies between existing definitions and offer a well-defined, broad, referenceable terminology, a consensus workflow definition for radiomics-based setups and a terms mapping to existing literature was compiled. Moreover, the most relevant challenges towards clinical application were characterized. CRITICAL RELEVANCE STATEMENT: Lack of standardization represents one major obstacle to successful clinical translation of radiomics. Here, we report a consensus workflow definition on different aspects of radiomics studies and highlight important challenges to advance the clinical adoption of radiomics. KEY POINTS: Published radiomics workflow terminologies are inconsistent, hindering standardization and translation. A consensus radiomics workflow definition proposal with high agreement was developed. Publicly available result resources for further exploitation by the scientific community.

Epstein-Barr Virus Lytic Transcripts Correlate with the Degree of Myocardial Inflammation in Heart Failure Patients.

The Epstein-Barr virus (EBV) is frequently found in endomyocardial biopsies (EMBs) from patients with heart failure, but the detection of EBV-specific DNA has not been associated with progressive hemodynamic deterioration. In this paper, we investigate the use of targeted next-generation sequencing (NGS) to detect EBV transcripts and their correlation with myocardial inflammation in EBV-positive patients with heart failure with reduced ejection fraction (HFrEF). Forty-four HFrEF patients with positive EBV DNA detection and varying degrees of myocardial inflammation were selected. EBV-specific transcripts from EMBs were enriched using a custom hybridization capture-based workflow and, subsequently, sequenced by NGS. The short-read sequencing revealed the presence of EBV-specific transcripts in 17 patients, of which 11 had only latent EBV genes and 6 presented with lytic transcription. The immunohistochemical staining for CD3+ T lymphocytes showed a significant increase in the degree of myocardial inflammation in the presence of EBV lytic transcripts, suggesting a possible influence on the clinical course. These results imply the important role of EBV lytic transcripts in the pathogenesis of inflammatory heart disease and emphasize the applicability of targeted NGS in EMB diagnostics as a basis for specific treatment.

Reproducible Radiomics Features from Multi-MRI-Scanner Test-Retest-Study: Influence on Performance and Generalizability of Models.

BACKGROUND: Radiomics models trained on data from one center typically show a decline of performance when applied to data from external centers, hindering their introduction into large-scale clinical practice. Current expert recommendations suggest to use only reproducible radiomics features isolated by multiscanner test-retest experiments, which might help to overcome the problem of limited generalizability to external data. PURPOSE: To evaluate the influence of using only a subset of robust radiomics features, defined in a prior in vivo multi-MRI-scanner test-retest-study, on the performance and generalizability of radiomics models. STUDY TYPE: Retrospective. POPULATION: Patients with monoclonal plasma cell disorders. Training set (117 MRIs from center 1); internal test set (42 MRIs from center 1); external test set (143 MRIs from center 2-8). FIELD STRENGTH/SEQUENCE: 1.5T and 3.0T; T1-weighted turbo spin echo. ASSESSMENT: The task for the radiomics models was to predict plasma cell infiltration, determined by bone marrow biopsy, noninvasively from MRI. Radiomics machine learning models, including linear regressor, support vector regressor (SVR), and random forest regressor (RFR), were trained on data from center 1, using either all radiomics features, or using only reproducible radiomics features. Models were tested on an internal (center 1) and a multicentric external data set (center 2-8). STATISTICAL TESTS: Pearson correlation coefficient r and mean absolute error (MAE) between predicted and actual plasma cell infiltration. Fisher's z-transformation, Wilcoxon signed-rank test, Wilcoxon rank-sum test; significance level P < 0.05. RESULTS: When using only reproducible features compared with all features, the performance of the SVR on the external test set significantly improved (r = 0.43 vs. r = 0.18 and MAE = 22.6 vs. MAE = 28.2). For the RFR, the performance on the external test set deteriorated when using only reproducible instead of all radiomics features (r = 0.33 vs. r = 0.44, P = 0.29 and MAE = 21.9 vs. MAE = 20.5, P = 0.10). CONCLUSION: Using only reproducible radiomics features improves the external performance of some, but not all machine learning models, and did not automatically lead to an improvement of the external performance of the overall best radiomics model. TECHNICAL EFFICACY: Stage 2.

[Historical aspects of ethics in psychiatry : From the end of humanitarianism up to the Human Rights Convention]. / Historisches zur Ethik in der Psychiatrie : Vom Ende der Humanität zur Menschenrechtskonvention.

The establishment of academic psychiatry was completed around 1900. Simultaneously, in view of the societal crisis phenomenon the professional self-concept of the psychiatrist was shifted to a self-image, according to which psychiatry had to place its expertise at the service of the people and the country. This was particularly expressed in World War I in the brutal dealing with the so-called war neurotics. In association with the so-called death by starvation of ca. 70,000 institution inmates, in the post-war period Karl Bonhoeffer debated a transformation of the term humanitarianism. The worst consequence of the rejection of humanitarian thoughts are the murders of invalids under National Socialism; however, legitimization of such crimes by alluding to collective ethics, as attempted by Karl Brandt, seems to be less than convincing. The reform of psychiatry initiated in the 1960s and the United Nations Convention on the Rights of Persons with Disabilities, which came into force in 2008, have achieved prerequisites for a supportive psychiatry with reduced coercion, whereby many questions also in the legal and social systems must still be clarified.

[Historical comments on ethics in psychiatry : Challenges in the 19th century]. / Historische Anmerkungen zur Ethik in der Psychiatrie : Herausforderungen im 19. Jahrhundert.

With the emergence of an early psychiatry around 1800, a number of questions arose on dealing with a group of persons whose "alien", irritating and disruptive behavior was considered to be a phenomenon of being sick. In the context of the growing importance of human rights, the term humanitarianism attained a high relevance as the reference for early psychiatrists. Based on historical sources it is shown that despite a multitude of psychiatric beliefs on humanitarianism the established psychiatric practice was dominated by patriarchal order regimes up to the first decade of the twentieth century, later superimposed by the challenges of somatophysiological and experimental research as well as perceptions of biological racism. The associated new ethical questions were partially addressed within psychiatry but did not prevent an increase in the assessment of the mentally ill as "inferior".

Effects of small extracellular vesicles derived from normoxia- and hypoxia-treated prostate cancer cells on the submandibular salivary gland epithelium in vitro.

Small extracellular vesicles (sEVs) are an important part of intercellular communication. They are phospholipid bilayer particles that carry active biomolecules such as proteins, various nucleic acids, and lipids. In recipient cells, sEVs can alter cellular functions, including cancer development and premetastatic niche formation in distant organs. Moreover, sEVs can carry cancer-specific features, which makes them promising biomarker candidates. However, the interactions of sEVs with biological barriers and consequences thereof, are not clarified yet. The blood-saliva barrier is crucial for preventing the entry of pathogens and (in)organic substances into the bloodstream, as well as molecule filtration from blood to saliva. The effects of brain derived DU145 prostate cancer (PCa) sEVs on a human submandibular salivary gland barrier (SSGB) in vitro were investigated. Small EVs were harvested from normoxic (N, atmospheric O2) or hypoxic (H, 1% O2) conditions, fluorescently labeled with CellTrackerTM Orange and thoroughly characterized. HTB-41 B2 cells were used as SSGB model cultured on 24-well ThinCert® inserts. After model optimization indicating effects of serum and serum-sEVs on barrier properties, PCa sEVs were applied to the basolateral (blood) side in either 10% serum, or serum-free conditions, and barrier integrity was continuously monitored for 40 hours. This study found that H and N PCa sEVs were uptaken by the SSGB in vitro model in similar quantities regardless of the media composition in the basolateral compartment. Permeation of fluorescent PCa sEVs into the apical compartment was not detectable with the applied methods. However, treatment with H and N sEVs under different serum conditions revealed distinct molecular clusters after hierarchical analysis of mRNA data measured by high-throughput qPCR, which were partly reflected at the protein level. For example, serum-reduction dependent decrease of barrier properties was accompanied with the decrease of CDH1 or Claudin-7 expression. Interestingly, the presence of H sEVs significantly increased the number of sEV-sized particles in the apical compartment of the SSGB model compared to basolaterally added N sEVs. This functional effect on the number of particles in the saliva (apical) compartment induced by different sEVs applied in the blood (basolateral) compartment might be a new approach to understand one possible mechanism how differences of salivary EVs might occur which then could be used as biomarker.

Navigator-based motion compensation for liver BOLD measurement with five-echo SAGE EPI and breath-hold task.

PURPOSE: The purpose of this work is to apply multi-echo spin- and gradient-echo (SAGE) echo-planar imaging (EPI) combined with a navigator-based (NAV) prospective motion compensation method for a quantitative liver blood oxygen level dependent (BOLD) measurement with a breath-hold (BH) task. METHODS: A five-echo SAGE sequence was developed to quantitatively measure T2 and T2* to depict function with sufficient signal-to-noise ratio, spatial resolution and sensitivity to BOLD changes induced by the BH task. To account for respiratory motion, a navigator was employed in the form of a single gradient-echo projection readout, located at the diaphragm along the inferior-superior direction. Prior to each transverse imaging slice of the spin-echo EPI-based readouts, navigator acquisition and fat suppression were incorporated. Motion data was obtained from the navigator and transmitted back to the sequence, allowing real-time adjustments to slice positioning. Six healthy volunteers and three patients with liver carcinoma were included in this study. Quantitative T2 and T2* were calculated at each time point of the BH task. Parameters of t value from first-level analysis using a general linear model and hepatovascular reactivity (HVR) of Echo1, T2 and T2* were calculated. RESULTS: The motion caused by respiratory activity was successfully compensated using the navigator signal. The average changes of T2 and T2* during breath-hold were about 1% and 0.7%, respectively. With the help of NAV prospective motion compensation whole liver t values could be obtained without motion artifacts. The quantified liver T2 (34.7 ± 0.7 ms) and T2* (29 ± 1.2 ms) values agreed with values from literature. In healthy volunteers, the distribution of statistical t value and HVR was homogeneous throughout the whole liver. In patients with liver carcinoma, the distribution of t value and HVR was inhomogeneous due to metastases or therapy. CONCLUSIONS: This study demonstrates the feasibility of using a NAV prospective motion compensation technique in conjunction with five-echo SAGE EPI for the quantitative measurement of liver BOLD with a BH task.

Risk-adjusted Screening for Prostate Cancer-Defining the Low-risk Group by Data from the PROBASE Trial.

BACKGROUND: Risk-adjusted screening for prostate cancer (PCa) aims to reduce harms by less frequent retesting, especially in men at a low risk of PCa. Definitions of low risk are based mainly on studies in men starting screening at age 55-60 yr. OBJECTIVE: To identify men at age 45 yr with a low risk of PCa. DESIGN, SETTING, AND PARTICIPANTS: A population-based, risk-adjusted PCa screening trial was conducted in Germany using baseline prostate-specific antigen (PSA) starting in young men (PROBASE). INTERVENTION: PSA measurements starting at the age of 45 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The incidence of PCa within 5 yr was assessed in men with screen-negative baseline PSA <1.5 ng/ml compared with those with PSA 1.5-≤3.0 ng/ml. RESULTS AND LIMITATIONS: Of 23301 men who received a first PSA test at age 45 yr, 0.79% had a screen-positive PSA value of ≥3 ng/ml. Among the 89% of men who had a screen-negative baseline PSA value of <1.5 ng/ml, only 0.45% received a positive PSA test ≥3 ng/ml upon retesting after 5 yr. By contrast, for those with a screen-negative baseline PSA value of 1.5-3 ng/ml, 13% surpassed 3 ng/ml upon biennial testing within the next 4 yr. The incidence of PCa in subsequent screening rounds increased with increasing baseline PSA levels, from 0.13 per 1000 person-years for men with initial PSA level of <1.5 ng/ml to 8.0 per 1000 person-years for those with PSA levels of 1.5-3.0 ng/ml. A limitation is a follow-up time of only 5 yr, so far. CONCLUSIONS: Men with baseline PSA <1.5 ng/ml at age 45 yr are at a very low risk of PCa over the next 5 yr. PATIENT SUMMARY: The PROBASE study showed that men with baseline prostate-specific antigen (PSA) <1.5 ng/ml at age 45 yr have a very low prostate cancer detection rate over 5 yr and do not need PSA retesting during this time.

Transport of Non-Steroidal Anti-Inflammatory Drugs across an Oral Mucosa Epithelium In Vitro Model.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently associated with adverse effects due to their inhibitory effect on the constitutively expressed cyclooxygenase enzyme 1 (COX-1) in, for instance, the gastrointestinal tract. A systemic delivery, such as a buccal delivery, of NSAIDs would be beneficial and additionally has the advantage of a non-invasive administration route, especially favourable for children or the elderly. To investigate the transport of NSAIDs across the buccal mucosa and determine their potential for buccal therapeutic usage, celecoxib, diclofenac, ibuprofen and piroxicam were tested using an established oral mucosa Transwell® model based on human cell line TR146. Carboxyfluorescein and diazepam were applied as internal paracellular and transcellular marker molecule, respectively. Calculated permeability coefficients revealed a transport ranking of ibuprofen > piroxicam > diclofenac > celecoxib. Transporter protein inhibitor verapamil increased the permeability for ibuprofen, piroxicam and celecoxib, whereas probenecid increased the permeability for all tested NSAIDs. Furthermore, influence of local inflammation of the buccal mucosa on the transport of NSAIDs was mimicked by treating cells with a cytokine mixture of TNF-α, IL-1ß and IFN-γ followed by transport studies with ibuprofen (+ probenecid). Cellular response to pro-inflammatory stimuli was confirmed by upregulation of cytokine targets at the mRNA level, increased secreted cytokine levels and a significant decrease in the paracellular barrier. Permeability of ibuprofen was increased across cell layers treated with cytokines, while addition of probenecid increased permeability of ibuprofen in controls, but not across cell layers treated with cytokines. In summary, the suitability of the in vitro oral mucosa model to measure NSAID transport rankings was demonstrated, and the involvement of transporter proteins was confirmed; an inflammation model was established, and increased NSAID transport upon inflammation was measured.

Clinical Workflow of Cone Beam Computer Tomography-Based Daily Online Adaptive Radiotherapy with Offline Magnetic Resonance Guidance: The Modular Adaptive Radiotherapy System (MARS).

PURPOSE: The Ethos (Varian Medical Systems) radiotherapy device combines semi-automated anatomy detection and plan generation for cone beam computer tomography (CBCT)-based daily online adaptive radiotherapy (oART). However, CBCT offers less soft tissue contrast than magnetic resonance imaging (MRI). This work aims to present the clinical workflow of CBCT-based oART with shuttle-based offline MR guidance. METHODS: From February to November 2023, 31 patients underwent radiotherapy on the Ethos (Varian, Palo Alto, CA, USA) system with machine learning (ML)-supported daily oART. Moreover, patients received weekly MRI in treatment position, which was utilized for daily plan adaptation, via a shuttle-based system. Initial and adapted treatment plans were generated using the Ethos treatment planning system. Patient clinical data, fractional session times (MRI + shuttle transport + positioning, adaptation, QA, RT delivery) and plan selection were assessed for all fractions in all patients. RESULTS: In total, 737 oART fractions were applied and 118 MRIs for offline MR guidance were acquired. Primary sites of tumors were prostate (n = 16), lung (n = 7), cervix (n = 5), bladder (n = 1) and endometrium (n = 2). The treatment was completed in all patients. The median MRI acquisition time including shuttle transport and positioning to initiation of the Ethos adaptive session was 53.6 min (IQR 46.5-63.4). The median total treatment time without MRI was 30.7 min (IQR 24.7-39.2). Separately, median adaptation, plan QA and RT times were 24.3 min (IQR 18.6-32.2), 0.4 min (IQR 0.3-1,0) and 5.3 min (IQR 4.5-6.7), respectively. The adapted plan was chosen over the scheduled plan in 97.7% of cases. CONCLUSION: This study describes the first workflow to date of a CBCT-based oART combined with a shuttle-based offline approach for MR guidance. The oART duration times reported resemble the range shown by previous publications for first clinical experiences with the Ethos system.

Dosimetric benefit of online treatment plan adaptation in stereotactic ultrahypofractionated MR-guided radiotherapy for localized prostate cancer.

Background: Apart from superior soft tissue contrast, MR-guided stereotactic body radiation therapy (SBRT) offers the chance for daily online plan adaptation. This study reports on the comparison of dose parameters before and after online plan adaptation in MR-guided SBRT of localized prostate cancer. Materials and methods: 32 consecutive patients treated with ultrahypofractionated SBRT for localized prostate cancer within the prospective SMILE trial underwent a planning process for MR-guided radiotherapy with 37.5 Gy applied in 5 fractions. A base plan, derived from MRI simulation at an MRIdian Linac, was registered to daily MRI scans (predicted plan). Following target and OAR recontouring, the plan was reoptimized based on the daily anatomy (adapted plan). CTV and PTV coverage and doses at OAR were compared between predicted and adapted plans using linear mixed regression models. Results: In 152 out of 160 fractions (95%), an adapted radiation plan was delivered. Mean CTV and PTV coverage increased by 1.4% and 4.5% after adaptation. 18% vs. 95% of the plans had a PTV coverage ≥95% before and after online adaptation, respectively. 78% vs. 100% of the plans had a CTV coverage ≥98% before and after online adaptation, respectively. The D0.2cc for both bladder and rectum were <38.5 Gy in 93% vs. 100% before and after online adaptation. The constraint at the urethra with a dose of <37.5 Gy was achieved in 59% vs. 93% before and after online adaptation. Conclusion: Online adaptive plan adaptation improves target volume coverage and reduces doses to OAR in MR-guided SBRT of localized prostate cancer. Online plan adaptation could potentially further reduce acute and long-term side effects and improve local failure rates in MR-guided SBRT of localized prostate cancer.

Starting DNA Synthesis: Initiation Processes during the Replication of Chromosomal DNA in Humans.

The initiation reactions of DNA synthesis are central processes during human chromosomal DNA replication. They are separated into two main processes: the initiation events at replication origins, the start of the leading strand synthesis for each replicon, and the numerous initiation events taking place during lagging strand DNA synthesis. In addition, a third mechanism is the re-initiation of DNA synthesis after replication fork stalling, which takes place when DNA lesions hinder the progression of DNA synthesis. The initiation of leading strand synthesis at replication origins is regulated at multiple levels, from the origin recognition to the assembly and activation of replicative helicase, the Cdc45-MCM2-7-GINS (CMG) complex. In addition, the multiple interactions of the CMG complex with the eukaryotic replicative DNA polymerases, DNA polymerase α-primase, DNA polymerase δ and ε, at replication forks play pivotal roles in the mechanism of the initiation reactions of leading and lagging strand DNA synthesis. These interactions are also important for the initiation of signalling at unperturbed and stalled replication forks, "replication stress" events, via ATR (ATM-Rad 3-related protein kinase). These processes are essential for the accurate transfer of the cells' genetic information to their daughters. Thus, failures and dysfunctions in these processes give rise to genome instability causing genetic diseases, including cancer. In their influential review "Hallmarks of Cancer: New Dimensions", Hanahan and Weinberg (2022) therefore call genome instability a fundamental function in the development process of cancer cells. In recent years, the understanding of the initiation processes and mechanisms of human DNA replication has made substantial progress at all levels, which will be discussed in the review.

A versatile look-up algorithm for mapping pH values and magnesium ion content using 31P MRSI.

31P MRSI allows for the non-invasive mapping of pH and magnesium ion content (Mg) in vivo, by translating the chemical shifts of inorganic phosphate and adenosine-5'-triphosphate (ATP) to pH and Mg via suitable calibration equations, such as the modified Henderson-Hasselbalch equation. However, the required constants in these calibration equations are typically only determined for physiological conditions, posing a particular challenge for their application to diseased tissue, where the biochemical conditions might change manyfold. In this article, we propose a multi-parametric look-up algorithm aiming at the condition-independent determination of pH and Mg by employing multiple quantifiable 31P spectral properties simultaneously. To generate entries for an initial look-up table, measurements from 114 model solutions prepared with varying chemical properties were made at 9.4 T. The number of look-up table entries was increased by inter- and extrapolation using a multi-dimensional function developed based on the Hill equation. The assignment of biochemical parameters, that is, pH and Mg, is realized using probability distributions incorporating specific measurement uncertainties on the quantified spectral parameters, allowing for an estimation of most plausible output values. As proof of concept, we applied a version of the look-up algorithm employing only the chemical shifts of γ- and ß-ATP for the determination of pH and Mg to in vivo 3D 31P MRSI data acquired at 7 T from (i) the lower leg muscles of healthy volunteers and (ii) the brains of patients with glioblastoma. The resulting volumetric maps showed plausible values for pH and Mg, partly revealing differences from maps generated using the conventional calibration equations.

Daily AI-Based Treatment Adaptation under Weekly Offline MR Guidance in Chemoradiotherapy for Cervical Cancer 1: The AIM-C1 Trial.

(1) Background: External beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy (BT), offer a standard of care for patients with locally advanced cervical carcinoma. Conventionally, large safety margins are required to compensate for organ movement, potentially increasing toxicity. Lately, daily high-quality cone beam CT (CBCT)-guided adaptive radiotherapy, aided by artificial intelligence (AI), became clinically available. Thus, online treatment plans can be adapted to the current position of the tumor and the adjacent organs at risk (OAR), while the patient is lying on the treatment couch. We sought to evaluate the potential of this new technology, including a weekly shuttle-based 3T-MRI scan in various treatment positions for tumor evaluation and for decreasing treatment-related side effects. (2) Methods: This is a prospective one-armed phase-II trial consisting of 40 patients with cervical carcinoma (FIGO IB-IIIC1) with an age ≥ 18 years and a Karnofsky performance score ≥ 70%. EBRT (45-50.4 Gy in 25-28 fractions with 55.0-58.8 Gy simultaneous integrated boosts to lymph node metastases) will be accompanied by weekly shuttle-based MRIs. Concurrent platinum-based chemotherapy will be given, followed by 28 Gy of BT (four fractions). The primary endpoint will be the occurrence of overall early bowel and bladder toxicity CTCAE grade 2 or higher (CTCAE v5.0). Secondary outcomes include clinical feasibility, quality of life, and imaging-based response assessment.