Extended MRI-based PET motion correction for cardiac PET/MRI.

PURPOSE: A 2D image navigator (iNAV) based 3D whole-heart sequence has been used to perform MRI and PET non-rigid respiratory motion correction for hybrid PET/MRI. However, only the PET data acquired during the acquisition of the 3D whole-heart MRI is corrected for respiratory motion. This study introduces and evaluates an MRI-based respiratory motion correction method of the complete PET data. METHODS: Twelve oncology patients scheduled for an additional cardiac 18F-Fluorodeoxyglucose (18F-FDG) PET/MRI and 15 patients with coronary artery disease (CAD) scheduled for cardiac 18F-Choline (18F-FCH) PET/MRI were included. A 2D iNAV recorded the respiratory motion of the myocardium during the 3D whole-heart coronary MR angiography (CMRA) acquisition (~ 10 min). A respiratory belt was used to record the respiratory motion throughout the entire PET/MRI examination (~ 30-90 min). The simultaneously acquired iNAV and respiratory belt signal were used to divide the acquired PET data into 4 bins. The binning was then extended for the complete respiratory belt signal. Data acquired at each bin was reconstructed and combined using iNAV-based motion fields to create a respiratory motion-corrected PET image. Motion-corrected (MC) and non-motion-corrected (NMC) datasets were compared. Gating was also performed to correct cardiac motion. The SUVmax and TBRmax values were calculated for the myocardial wall or a vulnerable coronary plaque for the 18F-FDG and 18F-FCH datasets, respectively. RESULTS: A pair-wise comparison showed that the SUVmax and TBRmax values of the motion corrected (MC) datasets were significantly higher than those for the non-motion-corrected (NMC) datasets (8.2 ± 1.0 vs 7.5 ± 1.0, p < 0.01 and 1.9 ± 0.2 vs 1.2 ± 0.2, p < 0.01, respectively). In addition, the SUVmax and TBRmax of the motion corrected and gated (MC_G) reconstructions were also higher than that of the non-motion-corrected but gated (NMC_G) datasets, although for the TBRmax this difference was not statistically significant (9.6 ± 1.3 vs 9.1 ± 1.2, p = 0.02 and 2.6 ± 0.3 vs 2.4 ± 0.3, p = 0.16, respectively). The respiratory motion-correction did not lead to a change in the signal to noise ratio. CONCLUSION: The proposed respiratory motion correction method for hybrid PET/MRI improved the image quality of cardiovascular PET scans by increased SUVmax and TBRmax values while maintaining the signal-to-noise ratio. Trial registration METC162043 registered 01/03/2017.

Non-rigid motion-compensated 3D whole-heart T2 mapping in a hybrid 3T PET-MR system.

PURPOSE: Simultaneous PET-MRI improves inflammatory cardiac disease diagnosis. However, challenges persist in respiratory motion and mis-registration between free-breathing 3D PET and 2D breath-held MR images. We propose a free-breathing non-rigid motion-compensated 3D T2 -mapping sequence enabling whole-heart myocardial tissue characterization in a hybrid 3T PET-MR system and provides non-rigid respiratory motion fields to correct also simultaneously acquired PET data. METHODS: Free-breathing 3D whole-heart T2 -mapping was implemented on a hybrid 3T PET-MRI system. Three datasets were acquired with different T2 -preparation modules (0, 28, 55 ms) using 3-fold undersampled variable-density Cartesian trajectory. Respiratory motion was estimated via virtual 3D image navigators, enabling multi-contrast non-rigid motion-corrected MR reconstruction. T2 -maps were computed using dictionary-matching. Approach was tested in phantom, 8 healthy subjects, 14 MR only and 2 PET-MR patients with suspected cardiac disease and compared with spin echo reference (phantom) and clinical 2D T2 -mapping (in-vivo). RESULTS: Phantom results show a high correlation (R2 = 0.996) between proposed approach and gold standard 2D T2 mapping. In-vivo 3D T2 -mapping average values in healthy subjects (39.0 ± 1.4 ms) and patients (healthy tissue) (39.1 ± 1.4 ms) agree with conventional 2D T2 -mapping (healthy = 38.6 ± 1.2 ms, patients = 40.3 ± 1.7 ms). Bland-Altman analysis reveals bias of 1.8 ms and 95% limits of agreement (LOA) of -2.4-6 ms for healthy subjects, and bias of 1.3 ms and 95% LOA of -1.9 to 4.6 ms for patients. CONCLUSION: Validated efficient 3D whole-heart T2 -mapping at hybrid 3T PET-MRI provides myocardial inflammation characterization and non-rigid respiratory motion fields for simultaneous PET data correction. Comparable T2 values were achieved with both 3D and 2D methods. Improved image quality was observed in the PET images after MR-based motion correction.

Free-breathing, Contrast Agent-free Whole-Heart MTC-BOOST Imaging: Single-Center Validation Study in Adult Congenital Heart Disease.

Purpose: To assess the clinical performance of the three-dimensional, free-breathing, Magnetization Transfer Contrast Bright-and-black blOOd phase-SensiTive (MTC-BOOST) sequence in adult congenital heart disease (ACHD). Materials and Methods: In this prospective study, participants with ACHD undergoing cardiac MRI between July 2020 and March 2021 were scanned with the clinical T2-prepared balanced steady-state free precession sequence and proposed MTC-BOOST sequence. Four cardiologists scored their diagnostic confidence on a four-point Likert scale for sequential segmental analysis on images acquired with each sequence. Scan times and diagnostic confidence were compared using the Mann-Whitney test. Coaxial vascular dimensions at three anatomic landmarks were measured, and agreement between the research sequence and the corresponding clinical sequence was assessed with Bland-Altman analysis. Results: The study included 120 participants (mean age, 33 years ± 13 [SD]; 65 men). The mean acquisition time of the MTC-BOOST sequence was significantly lower compared with that of the conventional clinical sequence (9 minutes ± 2 vs 14 minutes ± 5; P < .001). Diagnostic confidence was higher for the MTC-BOOST sequence compared with the clinical sequence (mean, 3.9 ± 0.3 vs 3.4 ± 0.7; P < .001). Narrow limits of agreement and mean bias less than 0.08 cm were found between the research and clinical vascular measurements. Conclusion: The MTC-BOOST sequence provided efficient, high-quality, and contrast agent-free three-dimensional whole-heart imaging in ACHD, with shorter, more predictable acquisition time and improved diagnostic confidence compared with the reference standard clinical sequence.Keywords: MR Angiography, Cardiac Supplemental material is available for this article. Published under a CC BY 4.0 license.

SARS-CoV-2 and HIV: Impact on Pulmonary Epithelial Cells.

The SARS-CoV-2 pandemic provides a natural opportunity for the collision of coronavirus disease-2019 (COVID-19) with chronic infections, which place numerous individuals at high risk of severe COVID-19. Infection with Human Immunodeficiency Virus (HIV), a global epidemic, remains a major public health concern. Whether prior HIV+ status exacerbates COVID-19 warrants investigation. Herein, we characterized the impact of SARS-CoV-2 in human bronchial epithelial cells (HBECs) previously exposed to HIV. We optimized the air-liquid interface (ALI) cell culture technique to allow for challenges with HIV at the basolateral cell surface and SARS-CoV-2 spike protein on the apical surface, followed by genetic analyses for cellular stress/toxicity and innate/adaptive immune responses. Our results suggest that the IL-10 pathway was consistently activated in HBECs treated with spike, HIV, or a combination. Recombinant spike protein elicited COVID-19 cytokine storms while HIV activated different signaling pathways. HIV-treated HBECs could no longer activate NF-kB, pro-inflammatory TRAF-6 ubiquitination nor RIP1 signaling. Combinations of HIV and SARS-CoV-2 spike increased gene expression for activation of endoplasmic reticulum-phagosome pathway and downregulated non-canonical NF-kB pathways that are key in functional regulatory T cells and RNA Polymerase II transcription. Our in vitro studies suggest that prior HIV infection may not exacerbate COVID-19. Further in vivo studies are warranted to advance this field.

Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension.

People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals.

Whole-heart non-rigid motion corrected coronary MRA with autofocus virtual 3D iNAV.

PURPOSE: Respiratory motion-corrected coronary MR angiography (CMRA) has shown promise for assessing coronary disease. By incorporating coronal 2D image navigators (iNAVs), respiratory motion can be corrected for in a beat-to-beat basis using translational correction in the foot-head (FH) and right-left (RL) directions and in a bin-to-bin basis using non-rigid motion correction addressing the remaining FH, RL and anterior-posterior (AP) motion. However, with this approach beat-to-beat AP motion is not corrected for. In this work we investigate the effect of remaining beat-to-beat AP motion and propose a virtual 3D iNAV that exploits autofocus motion correction to enable beat-to-beat AP and improved RL intra-bin motion correction. METHODS: Free-breathing 3D whole-heart CMRA was acquired using a 3-fold undersampled variable-density Cartesian trajectory. Beat-to-beat 3D translational respiratory motion was estimated from the 2D iNAVs in FH and RL directions, and in AP direction with autofocus assuming a linear relationship between FH and AP movement of the heart. Furthermore, motion in RL was also refined using autofocus. This virtual 3D (v3D) iNAV was incorporated in a non-rigid motion correction (NRMC) framework. The proposed approach was tested in 12 cardiac patients, and visible vessel length and vessel sharpness for the right (RCA) and left (LAD) coronary arteries were compared against 2D iNAV-based NRMC. RESULTS: Average vessel sharpness and length in v3D iNAV NRMC was improved compared to 2D iNAV NRMC (vessel sharpness: RCA: 56 ± 1% vs 52 ± 11%, LAD: 49 ± 8% vs 49 ± 7%; visible vessel length: RCA: 5.98 ± 1.37 cm vs 5.81 ± 1.62 cm, LAD: 5.95 ± 1.85 cm vs 4.83 ± 1.56 cm), however these improvements were not statistically significant. CONCLUSION: The proposed virtual 3D iNAV NRMC reconstruction further improved NRMC CMRA image quality by reducing artefacts arising from residual AP motion, however the level of improvement was subject-dependent.

Reduction of IL-2 fragmentation during manufacturing of a novel immunocytokine by DoE process optimization.

Interleukin-2 (IL-2) is a potent molecule in cancer therapy. Clinical application, however, is limited due to its strong side effects during the treatment. We developed an IL-2 variant (IL-2v) immunocytokine to circumvent the drawbacks of the current IL-2 therapy. During the production of the IL-2v immunocytokine in Chinese hamster ovary (CHO) cells, molecules with fragmented IL-2v and therefore reduced cytokine activity can be observed. To control product fragmentation different production process conditions were investigated. By shifting temperature or pH after the cell growth phase to lower values, fragmented species can be reduced from 10% to 12% to about 4%. However, with the adopted process conditions, the effective titer is decreased concomitantly. Moreover, fermentation length and inoculation cell density are parameters to adjust fragmentation and effective titer. A suitable method for efficient process optimization is the design of experiment approach. With this procedure, novel optimal values for temperature, pH value, harvest day, and inoculation cell densities were proposed and tested subsequently. In comparison to the former process, the improved process reduces fragmentation by 66% while keeping the effective titer comparable. In summary, these findings will help to control fragmentation in CHO production processes of different IL-2v or IL-2 containing therapeutic proteins.

Acute and chronic wound fluids influence keratinocyte function differently.

Wound healing requires a proper functioning of keratinocytes that migrate, proliferate and lead to a competent wound closure. Impaired wound healing might be due to a disturbed keratinocyte function caused by the wound environment. Basically, chronic wound fluid (CWF) differs from acute wound fluid (AWF). The aim of this study was to analyse the effects of AWF and CWF on keratinocyte function. We therefore investigated keratinocyte migration and proliferation under the influence of AWF and CWF using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] test and scratch assay. We further measured the gene expression by qRT-PCR regarding growth factors and matrixmetalloproteinases (MMPs) involved in regeneration processes. AWF had a positive impact on keratinocyte proliferation over time, whereas CWF had an anti-proliferative effect. Keratinocyte migration was significantly impaired by CWF in contrast to an undisturbed wound closure under the influence of AWF. MMP-9 expression was strongly upregulated by CWF compared with AWF. Keratinocyte function was significantly impaired by CWF. An excessive induction of MMP-9 by CWF might lead to a permanent degradation of extracellular matrix and thereby prevent wounds from healing.

Fetal magnetocardiography: development of the fetal cardiac time intervals.

OBJECTIVES: To analyse the physiologic development of fetal cardiac time intervals throughout gestation using fetal magnetocardiography (FMCG). METHODS: FMCG data of 163 uncomplicated pregnancies (19th and 42nd gestational week) were analysed. Mean value, standard deviation, minimum and maximum of the duration of the P-wave, the QRS-complex, the PR and the QT-interval were plotted against gestational age. RESULTS: QRS-complex, P wave and QT-interval showed a significant lengthening between the 20th and 42nd gestational week. The mean of the QRS complex raised from 36+/-4.7 ms (week 21-24) up to 48+/-5.2 ms (> or =37th week), (p=0.0001). The mean of the P-wave was between 47+/-5.9 ms (week 21-24) and 53+/-9.5 ms (> or =37th week), (p=0.05) and the mean of the QT-interval was 198+/-18 ms (week 21-24) and increased up to 244+/-23.9 ms (> or =37th week), (p=0.009). The PR-interval did not show a correlation with gestational age. CONCLUSION: FMCG provides sufficient information about all parts of the fetal cardiac conduction system from the 19th gestational week on. It offers the possibility to analyse the shape and the duration of the PQRST-complex.