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Abstract Background To intraindividually compare the diagnostic performance of positron emission computed tomography (F-18-FDG-PET/CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) in a non-inferiority design for the discrimination of peripheral nerve sheath tumours as benign (BPNST), atypical (ANF), or malignant (MPNST) in patients with neurofibromatosis type 1 (NF1). Results In this prospective single-centre study, thirty-four NF1 patients (18 male; 30 ± 11 years) underwent F-18-FDG-PET/CT and multi-b-value DW-MRI (11 b-values 0 – 800 s/mm²) at 3T. Sixty-six lesions corresponding to 39 BPNST, 11 ANF, and 16 MPNST were evaluated. Two radiologists independently assessed the maximum standardized uptake value (SUVmax) and mean and minimum apparent diffusion coefficient (ADCmean/min) as well as the ADC in areas of lowest signal intensity in each lesion (ADCdark). The AUCs of DW-MRI and F-18-FDG-PET/CT were compared to determine whether the ADC is non-inferior to SUVmax (non-inferiority margin equal to -10%). Follow-up of ≥ 24 months (BPNST) or histopathological evaluation (MPNST + ANF) served as diagnostic reference standard. Both SUVmax and ADC parameters demonstrated good diagnostic accuracy (AUCSUVmax 94.0%; AUCADCmean/min/dark 91.6% / 90.1% / 92.5%). However, non-inferiority could not be demonstrated for any of the three ADC parameters (lower limits of the confidence intervals of the difference between the AUC of ADCmean/min/dark and SUVmax -12.9% / -14.5% / -11.6%). Inter-rater reliability was excellent for both imaging techniques (Krippendorff’s alpha all > 0.94). Conclusions Both PET/CT-derived SUVmax and MRI-derived ADC allow sensitive and non-invasive differentiation of benign and (pre)-malignant peripheral nerve sheath tumours. Nevertheless, DW-MRI cannot be considered as non-inferior to F-18-FDG-PET/CT in this prospective single-centre study.

Abstract Background Patients with neurofibromatosis type 1 (NF1) can develop plexiform neurofibromas (PN). Large tumor burden is a predictor for the development of malignant peripheral nerve sheath tumors. Whole-body magnetic resonance imaging (WB-MRI) is the recommended imaging method for the evaluation of PN. WB-MRI is recommended for NF1 patients at transition from adolescence to adulthood. In the absence of internal PN further follow-up WB-MRI is not considered necessary. PN are often detected in early childhood, leading to the assumption that they may be congenital lesions. It remains unclear whether this invariably applies to all patients or whether patients who initially displayed no tumors can still develop PN over time. Therefore, we retrospectively reviewed WB-MRI scans of pediatric patients with NF1 without initial tumor burden and compared these with long-term follow-up scans for presence of newly developed PN. Methods We retrospectively reviewed WB-MRI scans of 17 NF1-children (twelve male; median age at initial scan: 9 [IQR 6.1–11.9] years) who initially displayed no PN. MRI scans with a follow-up interval of at least 6 years (median follow-up interval: 9 [IQR 5.6–12.4] years) were reviewed in consensus by two radiologists regarding the development of new PN over time. Results New PN were identified in two out of 17 children without initial tumor burden in follow-up examinations. One of these two patients developed two larger distinct PN of 4.5 cm on the right upper arm and of 2.5 cm on the left thoracic wall between the age of ten and twelve. The second child developed multiple smaller PN along the major peripheral nerves between the age of eleven and 16. In addition, 15 of the children without initial tumor burden did not develop any distinct tumors for a period of at least 6 years. Conclusion Our results indicate that PN can be newly detected in pediatric patients over time, even if no PN were detected on initial MRI scans. Therefore, it seems reasonable to perform at least a second MRI in pediatric NF1 patients at transition to adulthood, even if they did not display any tumor burden on initial MRI, and when the MRI was performed significantly under the age of 18. With this approach, tumors that may have developed between scans can be detected and patients at risk for complications can be identified.

Abstract Pulmonary embolism is a potentially fatal condition with increased mortality if anticoagulation is delayed. This study aimed to find influencing factors on the duration from requesting a computed tomography (CT) pulmonary angiography (CTPA) to performing a CTPA in suspected acute pulmonary embolism. In 1849 cases, automatically generated time data were extracted from the radiological information system. The impact of the distance to the scanner, case-related features (sector of patient care, triage), and workload (demand for CTs, performed CTs, available staff, hospital occupancy) were investigated retrospectively using multiple regression. The time to CTPA was shorter in cases from the emergency room (ER) than in inpatients and outpatients at distances below 160 m and 240 m, respectively. While requests from the ER were also performed faster than cases from regular wards (

Background Biomarkers simplifying the diagnostic workup by discriminating between non–ST‐segment–elevation myocardial infarction (NSTEMI) and infarct‐like myocarditis are an unmet clinical need. Methods and Results A total of 105 subjects were categorized into groups as follows: ST‐segment−elevation myocardial infarction (n=36), NSTEMI (n=22), infarct‐like myocarditis (n=19), cardiomyopathy‐like myocarditis (n=18), and healthy control (n=10). All subjects underwent cardiac magnetic resonance imaging, and serum concentrations of matrix metalloproteinase‐1 (MMP‐1) and procollagen type I carboxy terminal propeptide (PICP) were measured. Biomarker concentrations in subjects presenting with acute coronary syndrome and non‐ST‐segment‐elevation, for example NSTEMI or infarct‐like myocarditis, categorized as the non−ST‐segment−elevation acute coronary syndrome−like cohort, were of particular interest for this study. Compared with healthy controls, subjects with myocarditis had higher serum concentrations of MMP‐1 and PICP, while no difference was observed in individuals with myocardial infarction. In the non−ST‐segment−elevation acute coronary syndrome−like cohort, MMP‐1 concentrations discriminated infarct‐like myocarditis and NSTEMI with an area under the receiver operating characteristic curve (AUC) of 0.95 (95% CI, 0.89−1.00), whereas high‐sensitivity cardiac troponin T performed inferiorly (AUC, 0.74 [95% CI, 0.58−0.90]; P=0.012). Application of an optimal MMP‐1 cutoff had 94.4% sensitivity (95% CI, 72.7%−99.9%) and 90.9% specificity (95% CI, 70.8%−98.9%) for the diagnosis of infarct‐like myocarditis in this cohort. The AUC of PICP in this context was 0.82 (95% CI, 0.68−0.97). As assessed by likelihood ratio tests, incorporating MMP‐1 or PICP with age and C‐reactive protein into composite prediction models enhanced their diagnostic performance. Conclusions MMP‐1 and PICP could potentially be useful biomarkers for differentiating between NSTEMI and infarct‐like myocarditis in individuals with non−ST‐segment−elevation acute coronary syndrome‐like presentation, though further research is needed to validate their clinical applicability.

Abstract Background In many cardiac diseases, myocardial scar tissue detected by late gadolinium enhancement (LGE) is a risk factor for cardiac arrhythmia and sudden cardiac death. Previous studies in athletes reported an increased risk for cardiac events in this group of ostensibly healthy subjects. However, the currently available longitudinal studies on this topic included fairly old marathon runners with a mean age of 57 ± 6 years or represent a case–control study in athletes with preexisting ventricular arrhythmia. The purpose of this prospective study was to analyze the prognostic relevance of LGE cardiac magnetic resonance (CMR) in middle-aged endurance athletes without known preexisting cardiac disorders. Methods Three-hundred and twelve apparently healthy athletes were prospectively enrolled. Inclusion criteria were a training for a minimum of 10 h per week and regularly participation in competitions. LGE CMR was obtained at baseline in all athletes and presence of LGE was classified visually according to established criteria as ischemic LGE, major or minor non-ischemic LGE or absent LGE. Follow-up consisted of a standardized questionnaire and an additional phone call in case of incomplete data. An event was defined as fatal myocardial infarction, ventricular tachycardia, ventricular fibrillation or sudden cardiac death (SCD). Results Complete follow-up was available for 293/312 athletes (94%) including 145 triathletes, 74 marathon runners and 74 cyclists after a median of 5.6 [quartiles 4,3, 6,4] years. Median age was 44 [35, 50] years at study enrollment. Spiroergometry did not reveal heart rhythm disturbances or significant ECG changes in the study population. LGE CMR revealed myocardial scar/focal fibrosis in 80 of 293 athletes (27%) including 7 athletes (2%) with ischemic subendocardial LGE of the left ventricle (LV), 16 athletes (6%) with major non-ischemic LGE of the LV and 57 athletes (19%) with minor non-ischemic LGE. During follow-up, two athletes experienced SCD. One marathon runner died during a training run and one cyclist died suddenly at rest. Both athletes had ischemic LGE of the LV. The event rate for SCD was 0.7% in the entire study population and 28% in the 7 athletes with ischemic LGE (p

Abstract Gastrointestinal bleeding, as a potentially life-threatening condition, is typically diagnosed by radiation-based imaging modalities like computed tomography or more invasively catheter-based angiography. Endoscopy enables examination of the upper gastrointestinal tract and the colon but not of the entire small bowel. Magnetic Particle Imaging (MPI) enables non-invasive, volumetric imaging without ionizing radiation. The aim of this study was to evaluate the feasibility of detecting gastrointestinal bleeding by single- and multi-contrast MPI using human-sized organs. A 3D-printed small bowel phantom and porcine small bowel specimens were prepared with a defect within the bowel wall as the source of a bleeding. For multi-contrast MPI, the bowel lumen was filled with an intestinal tracer representing an orally administered tracer. MPI was performed to evaluate the fluid exchange between the vascular compartment of the bowel wall and the lumen while a blood pool tracer was applied. Leakage of the blood pool tracer was observed to the bowel lumen. Multi-contrast MPI enabled co-registration of both tracers at the same location within the bowel lumen indicating gastrointestinal bleeding. Single- and multi-contrast MPI are feasible to visualize gastrointestinal bleeding. Therefore, MPI might emerge as a useful tool for radiation-free detection of bleeding within the entire gastrointestinal tract.

Abstract Sarcopenia, the loss of muscle mass and quality, contributes to worse clinical outcome in patients with end-stage liver disease, but its impact on short- and long-term survival remains insufficiently understood. The aim of this study was to evaluate the development of computed tomography (CT) muscle parameters and their impact on short-term and long-term survival after liver transplantation. This retrospective study included patients with liver transplantation between 2011 and 2015 and a pre-transplant CT scan. Clinical characteristics, CT muscle mass and density were assessed pre-transplant, and in available CT scans at short-term (11 months) and long-term follow-up (56 months). Overall, 93/152 (61%) patients (109 male, 55 ± 10 years) suffered from sarcopenia pre-transplant. In short- (n = 50) and long-term follow-up (n = 52) the muscle mass (− 2.65 cm2/m2 95% CI [− 4.52, − 0.77], p = 0.007; − 2.96 cm2/m2 [− 4.7, − 1.23], p = 0.001, respectively), and muscle density (− 3 HU [− 6, − 1], p = 0.007; − 2 HU [− 4, 0], p = 0.069) decreased. Myosteatosis was associated with a higher post-transplant mortality (survival probability: 3 months 72% vs. 95%, 1 year 63% vs. 90%, 5 years 54% vs. 84%, p = 0.001), while muscle mass was not. In conclusion, muscle mass and quality did not improve after transplant. Muscle quality predicts short- and long-term survival and could help to identify a patient’s risk profile.

Fusarium verticillioides produces fumonisins, which are mycotoxins inhibiting sphingolipid biosynthesis in humans, animals, and other eukaryotes. Fumonisins are presumed virulence factors of plant pathogens, but may also play a role in interactions between competing fungi. We observed higher resistance to added fumonisin B1 (FB1) in fumonisin-producing Fusarium verticillioides than in nonproducing F. graminearum, and likewise between isolates of Aspergillus and Alternaria differing in production of sphinganine-analog toxins. It has been reported that in F. verticillioides, ceramide synthase encoded in the fumonisin biosynthetic gene cluster is responsible for self-resistance. We reinvestigated the role of FUM17 and FUM18 by generating a double mutant strain in a fum1 background. Nearly unchanged resistance to added FB1 was observed compared to the parental fum1 strain. A recently developed fumonisin-sensitive baker’s yeast strain allowed for the testing of candidate ceramide synthases by heterologous expression. The overexpression of the yeast LAC1 gene, but not LAG1, increased fumonisin resistance. High-level resistance was conferred by FUM18, but not by FUM17. Likewise, strong resistance to FB1 was caused by overexpression of the presumed F. verticillioides “housekeeping” ceramide synthases CER1, CER2, and CER3, located outside the fumonisin cluster, indicating that F. verticillioides possesses a redundant set of insensitive targets as a self-resistance mechanism.

The use of lactic acid bacteria as a low-cost sustainable management tool to prevent further build-up of Fusarium mycotoxins during grain storage is increasingly propagated. It has been reported that even deoxynivalenol contamination already formed in the field can be reduced by such treatment in unknown ways. An enigmatic deoxynivalenol derivative, 3-lactyl-deoxynivalenol, has been reported already in 1982 as the toxic principle of Fusarium-infected barley from China, but very little is known about this metabolite. Here, we show that the enzymatic machinery of Fusarium graminearum is sufficient for its biosynthesis. Similarly, when challenged with propionic acid, F. graminearum can form a novel modified mycotoxin, 3-propionyl-deoxynivalenol. Lactic acid and propionic acid are first converted into lactyl-CoA and propionyl-CoA, respectively. These acyl-CoA derivatives can subsequently be used by the 3-O-acyltransferase encoded by TRI101. We expressed the respective genes in E. coli and utilized the affinity-purified proteins for enzymatic synthesis of the reference substances 3-lactyl- and 3-propionyl-deoxynivalenol. The structures of the purified compounds were confirmed by nuclear magnetic resonance spectroscopy. Preliminary toxicological assessment using in vitro translation assays indicated residual toxicity, most likely due to reactivation of deoxynivalenol by de-acylation. In conclusion, this study reports a method to synthesize 3-lactyl- and 3-propionyl-deoxynivalenol reference substances, which will be highly useful to determine occurrences of these acylated deoxynivalenol-derivatives in cereal samples and to perform more detailed studies to evaluate their toxicological relevance.

Background & Aims: Cirrhosis is associated with an increased surgical morbidity and mortality. Portal hypertension and the surgery type have been established as critical determinants of postoperative outcome. We aim to evaluate the hypothesis that preoperative transjugular intrahepatic portosystemic shunt (TIPS) placement in patients with cirrhosis is associated with a lower incidence of in-house mortality/liver transplantation (LT) after surgery. Methods: A retrospective database search for the years 2010–2020 was carried out. We identified 64 patients with cirrhosis who underwent surgery within 3 months after TIPS placement and 131 patients with cirrhosis who underwent surgery without it (controls). Operations were categorised into low-risk and high-risk procedures. The primary endpoint was in-house mortality/LT. We analysed the influence of high-risk surgery, preoperative TIPS placement, age, sex, baseline creatinine, presence of ascites, Chronic Liver Failure Consortium Acute Decompensation (CLIF-C AD), American Society of Anesthesiologists (ASA), and model for end-stage liver disease (MELD) scores on in-house mortality/LT by multivariable Cox proportional hazards regression. Results: In both the TIPS and the control cohort, most patients presented with a Child-Pugh B stage (37/64, 58% vs. 70/131, 53%) at the time of surgery, but the median MELD score was higher in the TIPS cohort (14 vs. 11 points). Low-risk and high-risk procedures amounted to 47% and 53% in both cohorts. The incidence of in-house mortality/LT was lower in the TIPS cohort (12/64, 19% vs. 52/131, 40%), also when further subdivided into low-risk (0/30, 0% vs. 10/61, 16%) and high-risk surgery (12/34, 35% vs. 42/70, 60%). Preoperative TIPS placement was associated with a lower rate for postoperative in-house mortality/LT (hazard ratio 0.44, 95% CI 0.19–1.00) on multivariable analysis. Conclusions: A preoperative TIPS might be associated with reduced postoperative in-house mortality in selected patients with cirrhosis. Impact and implications: Patients with cirrhosis are at risk for more complications and a higher mortality after surgical procedures. A transjugular intrahepatic portosystemic shunt (TIPS) is used to treat complications of cirrhosis, but it is unclear if it also helps to lower the risk of surgery. This study takes a look at complications and mortality of patients undergoing surgery with or without a TIPS, and we found that patients with a TIPS develop less complications and have an improved survival. Therefore, a preoperative TIPS should be considered in selected patients, especially if indicated by ascites.

ABSTRACT: Background: The presence of myocardial scar is associated with poor prognosis in several underlying diseases. Late-gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging reveals clinically silent “unrecognized myocardial scar” (UMS), but the etiology of UMS often remains unclear. This population-based CMR study evaluated prevalence, localization, patterns, and risk factors of UMS. Methods: The study population consisted of 1064 consecutive Hamburg City Health Study participants without a history of coronary heart disease or myocarditis. UMS was assessed by standard-phase-sensitive-inversion-recovery LGE CMR. Results: Median age was 66 [quartiles 59, 71] years and 37% (388/1064) were females. UMS was detected in 244 (23%) participants. Twenty-five participants (10%) had ischemic, and 217 participants (89%) had non-ischemic scar patterns, predominantly involving the basal inferolateral left-ventricular (LV) myocardium (75%). Two participants (1%) had coincident ischemic and non-ischemic scar. The presence of any UMS was independently associated with LV ejection fraction (odds ratios (OR) per standard deviation (SD) 0.77 (confidence interval (CI) 0.65–0.90), p = 0.002) and LV mass (OR per SD 1.54 (CI 1.31–1.82), p

Abstract Cardiac manifestation of classical Fabry disease (cFD) varies with sex and presence of left ventricular hypertrophy. p.D313Y/p.A143T variants (vFD) represent milder late-onset phenotypes, however, data on vFD are scarce. Patients with FD (cFD = 37;vFD = 14) and 14 healthy controls underwent 1.5 T CMR including Cine, LGE, native T1 mapping(nT1) and myocardial strain(CMR-FT). CMR-FT was assessed using ventricular longitudinal, circumferential, radial (LV-GLS/RV-GLS, LV-GCS/LV-GRS), and atrial longitudinal strain (LA/RATotal, LA/RAConduit, LA/RABooster). In cFD reduced myocardial strain (LV-GLS: −20 ± 4 vs. −24 ± 3%,p = 0.007; LV-GCS: −20 ± 4 vs. −26 ± 4%,p = 0.002, LA Total -GLS: 29 ± 10 vs. 37 ± 6%,p = 0.007; LA Conduit -GLS: 15 ± 10 vs. 23 ± 5%,p = 0.003) and nT1 values (951 ± 51 ms vs. 1036 ± 20 ms, p 0.05) for discrimination of cFD versus controls. Significantly lower LV-GLS/LV-GCS was found in male compared to female cFD (−19 ± 4 vs. −22 ± 4%, p = 0.03). In six non-hypertrophied female cFD with normal nT1 LATotal -GLS was the only discriminating parameter with an accuracy of 86%. LV-GLS, LV-GCS and LATotal -GLS can detect impaired cardiac mechanics of cFD besides nT1. LATotal -GLS might identify non-hypertrophied female cFD. Variants p.D313Y/p.A143T did not reveal cardiac involvement by multiparametric CMR.

Abstract Background Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) is feasible for portal blood flow evaluation after placement of transjugular intrahepatic portosystemic shunts (TIPS) in patients with liver cirrhosis. However, clinical acceptance of 4D flow CMR in TIPS patients is limited due to the lack of validation studies. The purpose of this study was to validate 4D flow CMR-derived measurements in TIPS stent grafts using a three-dimensional (3D)-printed flow phantom. Methods A translucent flow phantom of the portal vasculature was 3D-printed. The phantom consisted of the superior mesenteric vein and the splenic vein draining into the portal vein, the TIPS-tract, and the hepatic vein. A TIPS stent graft (Gore® Viatorr®) was positioned within the TIPS-tract. Superior mesenteric vein and splenic vein served as inlets for blood-mimicking fluid. 4D flow CMR acquisitions were performed at 3T at preset flow rates of 0.8 to 2.8 l/min using velocity encoding of both 1.0 and 2.0 m/s. Flow rates and velocities were measured at predefined levels in the portal vasculature and within the stent graft. Accuracy of 4D flow CMR was assessed through linear regression with reference measurements obtained by flow sensors and two-dimensional (2D) phase contrast (PC) CMR. Intra- and interobserver agreement were assessed through Bland–Altman analyses. Results At a velocity encoding of 2.0 m/s, 4D flow CMR-derived flow rates and velocities showed an excellent correlation with preset flow rates and 2D PC CMR-derived flow velocities at all vascular levels and within the stent graft (all r ≥ 0.958, p ≤ 0.003). At a velocity encoding of 1.0 m/s, aliasing artifacts were present within the stent graft at flow rates ≥ 2.0 l/min. 4D flow CMR-derived measurements revealed high intra- and interobserver agreement. Conclusions The in vitro accuracy and precision of 4D flow CMR is unaffected by the presence of TIPS stent grafts, suggesting that 4D flow CMR may be used to monitor TIPS patency in patients with liver cirrhosis.

Abstract Strain is an important imaging parameter to determine myocardial deformation. This study sought to 1) assess changes in left ventricular strain and ejection fraction (LVEF) from acute to chronic ST-elevation myocardial infarction (STEMI) and 2) analyze strain as a predictor of late gadolinium enhancement (LGE). 32 patients with STEMI and 18 controls prospectively underwent cardiac magnetic resonance imaging. Patients were scanned 8 $$\pm$$ ± 5 days and six months after infarction (± 1.4 months). Feature tracking was performed and LVEF was calculated. LGE was determined visually and quantitatively on short-axis images and myocardial segments were grouped according to the LGE pattern (negative, non-transmural and transmural). Global strain was impaired in patients compared to controls, but improved within six months after STEMI (longitudinal strain from −14 ± 4 to −16 ± 4%, p

Fusarium is a genus that mostly consists of plant pathogenic fungi which are able to produce a broad range of toxic secondary metabolites. In this study, we focus on a type A trichothecene-producing isolate (15-39) of Fusarium sporotrichioides from Lower Austria. We assessed the secondary metabolite profile and optimized the toxin production conditions on autoclaved rice and found that in addition to large amounts of T-2 and HT-2 toxins, this strain was able to produce HT-2-glucoside. The optimal conditions for the production of T-2 toxin, HT-2 toxin, and HT-2-glucoside on autoclaved rice were incubation at 12 °C under constant light for four weeks, darkness at 30 °C for two weeks, and constant light for three weeks at 20 °C, respectively. The HT-2-glucoside was purified, and the structure elucidation by NMR revealed a mixture of two alpha-glucosides, presumably HT-2-3-O-alpha-glucoside and HT-2-4-O-alpha-glucoside. The efforts to separate the two compounds by HPLC were unsuccessful. No hydrolysis was observed with two the alpha-glucosidases or with human salivary amylase and Saccharomyces cerevisiae maltase. We propose that the two HT-2-alpha-glucosides are not formed by a glucosyltransferase as they are in plants, but by a trans-glycosylating alpha-glucosidase expressed by the fungus on the starch-containing rice medium.

Abstract Background PSMA PET/CT is the recommended imaging test in cases with prostate-specific antigen (PSA) recurrence after primary therapy of prostate cancer (PCa). However, imaging protocols remain a topic of active research. The aim of the presented study was to examine the impact of additional late scans of the pelvis in [68 Ga]Ga-PSMA-I&T PET/CT of patients with rising PSA after prostatectomy. Methods A total of 297 patients (median PSA 0.35 ng/ml, interquartile range (IQR) 0.2–0.8) who underwent early whole-body [68 Ga]Ga-PSMA-I&T PET/CT (median dose 141 MBq, IQR 120–163; median 86 min, IQR 56–107) and additional late scans of the pelvis (median 180 min, IQR 170–191) were investigated retrospectively. Early and late images were staged separately according to the PROMISE criteria and compared with a final consensus of both. Standardized uptake values were analyzed for early and late scans. Results One hundred and thirty-four (45.1%) [68 Ga]Ga-PSMA-I&T PET/CT showed evidence of recurrent PCa (114/38.4% early, 131/44.1% late). Of 195 lesions, 144 (73.8%) were identified correctly on early scans. 191 (97.9%) lesions were detected on late imaging. The lesion SUVmax (median 3.4, IQR 0.4–6.5 vs. median 3.9, IQR 2.6–8.2) as well as the SUVmax to background ratio (median 9.4, IQR 1.7–19.1 vs. median 15.5, IQR 9.6–34.1) increased significantly between the imaging time points (p T0 N0 M0) were up- and/or downstaged. In 4 (1.3%) cases, PCa-related lesions were only detectable on early PET/CT leading to upstagings of late imaging. Conclusions Additional late scans of the pelvis in [68 Ga]Ga-PSMA-I&T PET/CT detected more lesions and an increasing contrast compared to early imaging. This influenced the final miTNM-staging substantially.

Abstract Transthoracic echocardiography (TTE) and cine cardiac magnetic resonance imaging (CMR) are established imaging methods of the aortic root. We aimed to evaluate the comparability of measurements in TTE and standard cine CMR sequences of the aortic root. Our study included 741 subjects (mean age 63.5 ± 8 years, 43.7% female) from the Hamburg City Health Study (HCHS). Subjects underwent CMR and TTE. Aortic root measurements were performed at the level of the aortic annulus (AoAn), sinus of Valsalva (SoV), and sinotubular junction (STJ) by standard cine CMR in left ventricular long axis and left ventricular outflow tract view. Measurements were performed applying the leading-edge to leading-edge (LL) convention and inner-edge to inner-edge (II) convention in TTE and the II convention in CMR. Inter correlation coefficients (ICCs) demonstrated high inter- and intraobserver reproducibility for CMR and TTE measurements of SoV and STJ (ICCs 0.9–0.98) and moderate reproducibility for AoAn (ICCs 0.68–0.91). CMR measurements of SoV and STJ showed strong agreement with TTE: while correlations were comparable (r = 0.75–0.85) bias was lower with TTE II (bias − 0.1 to − 0.74) versus TTE LL measurements (mean bias − 1.49 to − 2.58 mm). The agreement for AoAn was fair (r = 0.51–0.57) with variable bias (mean bias 0.39–3.9). Standard cine CMR and TTE derived aortic root measurements are reproducible and comparable with higher agreement for TTE II instead of LL measurements. These results support an interchangeable application of TTE and standard CMR for screening of aortic root diseases thereby possibly reducing redundant multimodality imaging.

BackgroundTo assess whether cardiac T1 mapping for detecting myocardial fibrosis enables preoperative identification of patients at risk for early left ventricular dysfunction after surgery of aortic regurgitation.Methods1.5 Tesla cardiac magnetic resonance imaging was performed in 40 consecutive aortic regurgitation patients before aortic valve surgery. Native and post-contrast T1 mapping was performed using a modified Look-Locker inversion-recovery sequence. Serial echocardiography was performed at baseline and 8 ± 5 days after aortic valve surgery to quantify LV dysfunction. Receiver operating characteristic analysis was performed to determine the diagnostic accuracy of native T1 mapping and extracellular volume for predicting postoperative LV ejection fraction decrease >−10% after aortic valve surgery.ResultsNative T1 was significantly increased in patients with a postoperatively decreased LVEF (n = 15) vs. patients with a preserved postoperative LV ejection fraction (n = 25) (i.e., 1,071 ± 67 ms vs. 1,019 ± 33 ms, p = .001). Extracellular volume was not significantly different between patients with preserved vs. decreased postoperative LV ejection fraction. With a cutoff-of value of 1,053 ms, native T1 yielded an area under the curve (AUC) of .820 (95% CI: .683–.958) for differentiating between patients with preserved vs. reduced LV ejection fraction with 70% sensitivity and 84% specificity.ConclusionIncreased preoperative native T1 is associated with a significantly higher risk of systolic LV dysfunction early after aortic valve surgery in aortic regurgitation patients. Native T1 could be a promising tool to optimize the timing of aortic valve surgery in patients with aortic regurgitation to prevent early postoperative LV dysfunction.

Abstract To compare the patient radiation doses during angiographic selective adrenal vein sampling (AVS) before and after an imaging technology upgrade. In this retrospective single-center-study, cumulative air kerma (AK), cumulative dose area product (DAP), fluoroscopy time and contrast agent dosage were recorded from 70 patients during AVS. 35 procedures were performed before and 35 after an imaging processing technology upgrade. Mean values were calculated and compared using an unpaired student’s t-test. DSA image quality was assessed independently by two blinded readers using a four-point Likert scale (1 = poor; 4 = excellent) and compared using Wilcoxon signed-rank test. After the technology upgrade we observed a significant reduction of 35% in AK (1.7 ± 0.7 vs. 1.1 ± 0.7 Gy, p = 0.01) and a significant reduction of 28% in DAP (235.1 ± 113 vs. 170.1 ± 94 Gy*cm2, p = 0.01) in comparison to procedures before the upgrade. There were no significant differences between the number of exposure frames (143 ± 86 vs. 132 ± 61 frames, p = 0.53), fluoroscopy time (42 ± 23 vs. 36 ± 18 min, p = 0.22), or the amount of contrast medium used (179.5 ± 84 vs. 198.1 ± 109 ml, p = 0.41). There was also no significant difference regarding image quality (3 (2–4) vs. 3 (2–4), p = 0.67). The angiographic imaging technology upgrade significantly decreases the radiation dose during adrenal vein sampling without increasing time of fluoroscopy or contrast volume and without compromising image quality.

Abstract Background This cardiovascular magnetic resonance (CMR) study investigates the impact of trabeculae and papillary muscles (TPM) on diastolic function parameters by differentiation of the time-volume curve. Differentiation causes additional problems, which is overcome by standardization. Methods Cine steady-state free-precession imaging at 1.5 T was performed in 40 healthy volunteers stratified for age (age range 7–78y). LV time-volume curves were assessed by software-assisted delineation of endocardial contours from short axis slices applying two different methods: (1) inclusion of TPM into the myocardium and (2) inclusion of TPM into the LV cavity blood volume. Diastolic function was assessed from the differentiated time-volume curves defining the early and atrial peaks, their filling rates, filling volumes, and further dedicated diastolic measures, respectively. Results Only inclusion of TPM into the myocardium allowed precise assessment of early and atrial peak filling rates (EPFR, APFR) with clear distinction of EPFR and APFR expressed by the minimum between the early and atrial peak (EAmin) (100% vs. 36% for EAmin

Objectives Infections are common complications in venous access ports. The presented analysis aimed to investigate the incidence, microbiological spectrum, and acquired resistances of pathogens in upper arm port associated infections to provide a decision aid in the choice of therapy. Materials and methods In total, 2667 implantations and 608 explantations were performed at a high-volume tertiary medical center between 2015 and 2019. In cases with infectious complications (n = 131, 4.9%), procedural conditions and results of microbiological testing were reviewed retrospectively. Results Of 131 port associated infections (median dwell time 103 days, interquartile range 41–260), 49 (37.4%) were port pocket infections (PPI) and 82 (62.6%) were catheter infections (CI). Infectious complications occurred more often after implantation in inpatients compared to outpatients (P < 0.01). PPI were mainly caused by Staphylococcus aureus (S. aureus, 48.3%) and coagulase-negative staphylococci (CoNS, 31.0%). Other gram-positive and gram-negative species were encountered in 13.8% and 6.9%, respectively. CI were caused less frequently by S. aureus (8.6%) than CoNS (39.7%). Other gram-positive and gram-negative strains were isolated in 8.6% and 31.0%, respectively. Candida species were seen in 12.1% of CI. An acquired antibiotic resistance was detected in 36.0% of all significant isolates, occurring especially in CoNS (68.3%) and gram-negative species (24.0%). Conclusions Staphylococci comprised the largest group of pathogens in upper arm port associated infections. However, gram-negative strains and Candida species should also be considered as a cause of infection in CI. Due to the frequent detection of potential biofilm-forming pathogens, port explantation is an important therapeutic measure, especially in severely ill patients. Acquired resistances must be anticipated when choosing an empiric antibiotic treatment.

RationaleRecent studies have demonstrated the feasibility of CD38-specific antibody constructs for in vivo imaging of multiple myeloma. However, detecting multiple myeloma in daratumumab-pretreated patients remains difficult due to overlapping binding epitopes of the CD38-specific imaging antibody constructs and daratumumab. Therefore, the development of an alternative antibody construct targeting an epitope of CD38 distinct from that of daratumumab is needed. We report the generation of a fluorochrome-conjugated nanobody recognizing such an epitope of CD38 to detect myeloma cells under daratumumab therapy in vitro, ex vivo, and in vivo.MethodsWe conjugated the CD38-specific nanobody JK36 to the near-infrared fluorescent dye Alexa Fluor 680. The capacity of JK36AF680 to bind and detect CD38-expressing cells pretreated with daratumumab was evaluated on CD38-expressing tumor cell lines in vitro, on primary myeloma cells from human bone marrow biopsies ex vivo, and in a mouse tumor model in vivo.ResultsFluorochrome-labeled nanobody JK36AF680 showed specific binding to CD38-expressing myeloma cells pretreated with daratumumab in vitro and ex vivo and allowed for specific imaging of CD38-expressing xenografts in daratumumab-pretreated mice in vivo.ConclusionsOur study demonstrates that a nanobody recognizing a distinct, non-overlapping epitope of CD38 allows the specific detection of myeloma cells under daratumumab therapy in vitro, ex vivo, and in vivo.

Abstract Transjugular intrahepatic portosystemic shunt (TIPS) reduces portal hypertension in patients with liver cirrhosis. The exact cardiac consequences of subsequent increase of central blood volume are unknown. Cardiovascular magnetic resonance (CMR) imaging is the method of choice for quantifying cardiac volumes and ventricular function. The aim of this study was to investigate effects of TIPS on the heart using CMR, laboratory, and imaging cardiac biomarkers. 34 consecutive patients with liver cirrhosis were evaluated for TIPS. Comprehensive CMR with native T1 mapping, transthoracic echocardiography, and laboratory biomarkers were assessed before and after TIPS insertion. Follow-up (FU) CMR was obtained in 16 patients (47%) 207 (170–245) days after TIPS. From baseline (BL) to FU, a significant increase of all indexed cardiac chamber volumes was observed (all P

Abstract This methodical work describes the measurement and calculation of pulmonary blood volume in mice based on two imaging techniques namely by using magnetic particle imaging (MPI) and cardiac magnetic resonance imaging (MRI). Besides its feasibility aspects that may influence quantitative analysis are studied. Eight FVB mice underwent cardiac MRI to determine stroke volumes and anatomic MRI as morphological reference for functional MPI data. Arrival time analyses of boli of 1 µl of 1 M superparamagnetic tracer were performed by MPI. Pulmonary transit time of the bolus was determined by measurements in the right and left ventricles. Pulmonary blood volume was calculated out of stroke volume, pulmonary transit time and RR-interval length including a maximal error analysis. Cardiac stroke volume was 31.7 µl ± 2.3 µl with an ejection fraction of 71% ± 6%. A sharp contrast bolus profile was observed by MPI allowing subdividing the first pass into three distinct phases: tracer arrival in the right ventricle, pulmonary vasculature, and left ventricle. The bolus full width at half maximum was 578 ms ± 144 ms in the right ventricle and 1042 ms ± 150 ms in the left ventricle. Analysis of pulmonary transit time revealed 745 ms ± 81 ms. Mean RR-interval length was 133 ms ± 12 ms. Pulmonary blood volume resulted in 177 µl ± 27 µl with a mean maximal error limit of 27 µl. Non-invasive assessment of the pulmonary blood volume in mice was feasible. This technique can be of specific value for evaluation of pulmonary hemodynamics in mouse models of cardiac dysfunction or pulmonary disease. Pulmonary blood volume can complement cardiac functional parameters as a further hemodynamic parameter.

CD38 is a target for immunotherapy of multiple myeloma. Llama-derived CD38-specific nanobodies allow easy reformatting into mono-, bi- and multispecific proteins. To evaluate the utility of nanobodies for constructing CD38-specific nanobody-based killer cell engagers (nano-BiKEs), we generated half-life extended nano-BiKEs (HLE-nano-BiKEs) by fusing a CD38-specific nanobody to a CD16-specific nanobody for binding to the Fc-receptor on NK cells and further to an albumin-specific nanobody to extend the half-life in vivo. HLE-nano-BiKEs targeting three different epitopes (E1, E2, E3) of CD38 were expressed in transiently transfected HEK-6E cells. We verified specific and simultaneous binding to CD38 on myeloma cells, CD16 on NK cells, and to albumin. We tested the capacity of these HLE-nano-BiKEs to mediate cytotoxicity against CD38-expressing multiple myeloma cell lines and primary myeloma cells from human bone marrow biopsies in bioluminescence and flowcytometry assays with NK92 cells as effector cells. The results revealed specific time- and dose-dependent cytolysis of CD38+ myeloma cell lines and effective depletion of CD38-expressing multiple myeloma cells from primary human bone marrow samples. Our results demonstrate the efficacy of CD38-specific HLE-nano-BiKEs in vitro and ex vivo, warranting further preclinical evaluation in vivo of their therapeutic potential for the treatment of multiple myeloma.

Abstract Background Diffuse interstitial lung disease have been described in Neurofibromatosis type 1 (NF1), but its diversity and prevalence remain unknown. The aim of this study was to assess the prevalence and characteristics of (NF1)-associated lung manifestations in a large single-center study using multidetector computed tomography (MDCT) and to evaluate the smoking history, patients’ age, genetics, and the presence of malignant peripheral nerve sheath tumors (MPNST) as potential influencing factors for lung pathologies. Methods In this retrospective study, 71 patients with NF1 were evaluated for the presence of distinctive lung manifestations like reticulations, consolidations, type of emphysema, pulmonary nodules and cysts. All patients underwent F-18-FDG PET/CT scans, which were reviewed by two experienced radiologists in consensus. Patients’ subgroups were formed based on their smoking history (current smokers/previous smokers/never smokers), age ( 18 years), and presence of MPNST (MPNST/no MPNST). In 57 patients (80%), genetic analysis of sequences coding for the neurofibromin on chromosome 17 was performed, which was correlated with different lung pathologies. Results Among all NF1 patients (33 ± 14 years, 56% females), 17 patients (24%) were current smokers and 62 patients (87%) were > 18 years old. Pulmonary cysts, nodules, and paraseptal emphysema were the most common pulmonary findings (35%, 32%, 30%). The presence of pulmonary metastases, MPNST and centrilobular emphysema was associated with smoking. Cysts were observed only in adults, whereas no significant correlation between age and all other pulmonary findings was found (p > 0.05). Presence of MPNST was accompanied by higher rates of intrapulmonary nodules and pulmonary metastasis. Neither the presence nor absence of any of the specific gene mutations was associated with any particular lung pathology (p > 0.05). Conclusions All pulmonary findings in NF1 patients occurred independently from specific mutation subtypes, suggesting that many NF1 mutations can cause various pulmonary pathologies. The presence of pulmonary metastases, MPNST and centrilobular emphysema was associated with smoking, indicating the value of smoking secession or the advice not to start smoking in NF1 patients as preventive strategy for clinicians. For screening of pulmonary manifestations in NF1 patients, an MDCT besides medical history and physical examination is mandatory in clinical routine.

Abstract Background Aortic valve repair has become a treatment option for adults with symptomatic bicuspid (BAV) or unicuspid (UAV) aortic valve insufficiency. Our aim was to demonstrate the feasibility of 4D flow cardiovascular magnetic resonance (CMR) to assess the impact of aortic valve repair on changes in blood flow dynamics in patients with symptomatic BAV or UAV. Methods Twenty patients with adult congenital heart disease (median 35 years, range 18–64; 16 male) and symptomatic aortic valve regurgitation (15 BAV, 5 UAV) were prospectively studied. All patients underwent 4D flow CMR before and after aortic valve repair. Aortic valve regurgitant fraction and systolic peak velocity were estimated. The degree of helical and vortical flow was evaluated according to a 3-point scale. Relative flow displacement and wall shear stress (WSS) were quantified at predefined levels in the thoracic aorta. Results All patients underwent successful aortic valve repair with a significant reduction of aortic valve regurgitation (16.7 ± 9.8% to 6.4 ± 4.4%, p

Environmental exposure to xenoestrogens, i.e., chemicals that imitate the hormone 17β-estradiol, has the potential to influence hormone homeostasis and action. Detailed knowledge of xenobiotic biotransformation processes in cell models is key when transferring knowledge learned from in vitro models to in vivo relevance. This study elucidated the metabolism of two naturally-occurring phyto- and mycoestrogens; namely genistein and zearalenone, in an estrogen receptor positive breast cancer cell line (MCF-7) with the aid of stable isotope-assisted metabolomics and the bioinformatic tool MetExtract II. Metabolism was studied in a time course experiment after 2 h, 6 h and 24 h incubation. Twelve and six biotransformation products of zearalenone and genistein were detected, respectively, clearly demonstrating the abundant xenobiotic biotransformation capability of the cells. Zearalenone underwent extensive phase-I metabolism resulting in α-zearalenol (α-ZEL), a molecule known to possess a significantly higher estrogenicity, and several phase-II metabolites (sulfo- and glycoconjugates) of the native compound and the major phase I metabolite α-ZEL. Moreover, potential adducts of zearalenone with a vitamin and several hydroxylated metabolites were annotated. Genistein metabolism resulted in sulfation, combined sulfation and hydroxylation, acetylation, glucuronidation and unexpectedly adduct formation with pentose- and hexose sugars. Kinetics of metabolite formation and subsequent excretion into the extracellular medium revealed a time-dependent increase in most biotransformation products. The untargeted elucidation of biotransformation products formed during cell culture experiments enables an improved and more meaningful interpretation of toxicological assays and has the potential to identify unexpected or unknown metabolites.

BackgroundTo identify magnetic resonance (MR) angiography derived predictors of progressive dilatation and surgery of the aortic root in Marfan syndrome.Material and methodsWe retrospectively included 111 patients (32.7±16.5 years, range: 7-75 years) with a total of 446 MR angiographies. Aortic diameter growth rates of the entire thoracic aorta and Z-scores were estimated from annual diameter measurements. Aortic root shape was subdivided into three different types: (T0) normal; (T1) localized dilatation; (T2) generalized aortic root dilatation. Aortic diameter, Z-score, age, and aortic root shape at baseline were tested as predictors of aortic root dilatation using a multivariate logistic regression model.ResultsThe highest aortic growth rate was observed at the level of the sinuses of Valsalva. Higher aortic root diameters and Z-scores at baseline predicted an increased growth of the aortic root (p = 0.003 and p0.05). However, significantly more patients undergoing surgery had a generalized aortic dilatation (19/28, 76.9%) than a localized aortic root dilatation (9/28, 32.1%) (p = 0.001).ConclusionLarger baseline aortic root diameter and Z-score as well as young age predict solely progressive aortic root dilatation in Marfan patients. MR angiography derived type of aortic root shape does not predict aortic growth, but patients with generalized aortic root dilatation are referred more frequently for aortic surgery.

PurposeAdrenal vein sampling (AVS) is the reference standard for evaluation of lateralized hormone production in primary aldosteronism. We aimed to investigate the impact of pre-interventional right renal vein (RRV) to right adrenal vein (RAV) distance measurement on fluoroscopy time, contrast agent exposure and radiation dose during AVS.Materials and methodsForty-five patients with primary aldosteronism undergoing AVS were enrolled in our retrospective study and divided into three groups. In the group "ruler" (n = 14), RRV-RAV-distances were determined pre-interventionally by cross-sectional imaging (CT/MRI) and AVS was performed by one interventional radiologist with limited experience in AVS. CT/MRI-derived and fluoroscopy-derived RRV-RAV-distances were correlated for aimed cannulation of the RAV. Patients in group "no ruler" (n = 24, three interventional radiologists with limited experience in AVS) and in group "expert", (n = 7, one expert interventional radiologist) underwent AVS without pre-interventional estimation of RRV-RAV-distances. Procedure parameters (fluoroscopy time, contrast agent volume, radiation dose) of group "ruler" were compared to both other groups by Kruskal-Wallis rank-sum test.ResultsCorrelation of CT/MRI-derived and fluoroscopy-derived RRV-RAV-distances was good (r = 0.74;p = 0.003). The median RRV-RAV-distance was 4.5cm at CT/MRI (95%-CI:4.2-5.0cm) and 4.0cm at fluoroscopy (95%-CI:3.8-4.5cm). Fluoroscopy time (p0.05).ConclusionsCT/MRI-derived pre-interventional renal-adrenal vein distance measurements correlate well with angiographic distance measurements. Pre-interventional estimation of the RRV-RAV-distance allows for aimed cannulation of the RAV with potential reduction of fluoroscopy time, contrast agent exposure and radiation-dose during AVS.

Persisting patellar maltracking following surgical realignment often remains unseen. The aim of this study was to analyze the effects of realignment procedures on patellofemoral kinematics in patients with patellofemoral instability (PFI) and patellofemoral maltracking (PM) by using dynamic magnetic resonance imaging (MRI). Patients planned for surgical patellar realignment due to PFI and a clinically and radiologically apparent PM between December 2019 and May 2022 were included. Patients without PM, limited range of motion, joint effusion, or concomitant injuries were excluded. Dynamic mediolateral translation (dMPT) and patella tilt (dPT) were measured preoperatively and three months postoperatively. In 24 patients (7 men, 17 women; mean age 23.0 years), 10 tibial tubercle transfers, 5 soft tissue patella tendon transfers, 6 trochleoplasties, 3 lateral lengthenings, 1 varizating distal femoral osteotomy (DFO), and 1 torsional DFO were performed. At final follow-up, dMPT (from 10.95 ± 5.93 mm to 4.89 ± 0.40 mm, p < 0.001) and dPT (from 14.50° ± 10.33° to 8.44° ± 7.46°, p = 0.026) were significantly improved. All static radiological parameters were corrected to physiological values. Surgical patellar realignment contributed to the significant improvement of patellofemoral kinematics, with an approximation to normal values. The postoperative application of dynamic MRI allowed for a quantification of the performed correction, allowing for a postoperative control of success.

CD38 is the major NAD+-hydrolyzing ecto-enzyme in most mammals. As a type II transmembrane protein, CD38 is also a promising target for the immunotherapy of multiple myeloma (MM). Nanobodies are single immunoglobulin variable domains from heavy chain antibodies that naturally occur in camelids. Using phage display technology, we isolated 13 mouse CD38-specific nanobodies from immunized llamas and produced these as recombinant chimeric mouse IgG2a heavy chain antibodies (hcAbs). Sequence analysis assigned these hcAbs to five distinct families that bind to three non-overlapping epitopes of CD38. Members of families 4 and 5 inhibit the GDPR-cyclase activity of CD38. Members of families 2, 4 and 5 effectively induce complement-dependent cytotoxicity against CD38-expressing tumor cell lines, while all families effectively induce antibody dependent cellular cytotoxicity. Our hcAbs present unique tools to assess cytotoxicity mechanisms of CD38-specific hcAbs in vivo against tumor cells and potential off-target effects on normal cells expressing CD38 in syngeneic mouse tumor models, i.e. in a fully immunocompetent background.

The plant pathogen Fusarium graminearum is a proficient producer of mycotoxins and other in part still unknown secondary metabolites, some of which might act as virulence factors on wheat. The PKS15 gene is expressed only in planta, so far hampering the identification of an associated metabolite. Here we combined the activation of silent gene clusters by chromatin manipulation (kmt6) with blocking the metabolic flow into the competing biosynthesis of the two major mycotoxins deoxynivalenol and zearalenone. Using an untargeted metabolomics approach, two closely related metabolites were found in triple mutants (kmt6 tri5 pks4,13) deficient in production of the major mycotoxins deoxynivalenol and zearalenone, but not in strains with an additional deletion in PKS15 (kmt6 tri5 pks4,13 pks15). Characterization of the metabolites, by LC-HRMS/MS in combination with a stable isotope-assisted tracer approach, revealed that they are likely hybrid polyketides comprising a polyketide part consisting of malonate-derived acetate units and a structurally deviating part. We propose the names gramiketide A and B for the two metabolites. In a biological experiment, both gramiketides were formed during infection of wheat ears with wild-type but not with pks15 mutants. The formation of the two gramiketides during infection correlated with that of the well-known virulence factor deoxynivalenol, suggesting that they might play a role in virulence.

Neurofibromatosis type-1 (NF1) patients suffer from cutaneous and subcutaneous neurofibromas (CNF) and large plexiform neurofibromas (PNF). Whole gene deletions of the NF1 gene can cause a more severe phenotype compared to smaller intragenic changes. Two distinct groups of NF1 whole gene deletions are type-1 deletions and atypical deletions. Our aim was to assess volumes and averaged annual growth-rates of CNF and PNF in patients with NF1 whole gene deletions and to compare these with NF1 patients without large deletions of the NF1 gene. We retrospectively evaluated 140 whole-body MR examinations of 38 patients with NF1 whole gene deletions (type-1 group: n = 27/atypical group n = 11) and an age- and sex matched collective of 38 NF1-patients. Age-dependent subgroups were created (0-18 vs >18 years). Sixty-four patients received follow-up MRI examinations (NF1whole gene deletion n = 32/control group n = 32). Whole-body tumor-volumes were semi-automatically assessed (MedX, V3.42). Tumor volumes and averaged annual growth-rates were compared. Median tumor-burden was significantly higher in the type-1 group (418ml; IQR 77 - 950ml, p = 0.012) but not in the atypical group (356ml;IQR 140-1190ml, p = 0.099) when compared to the controls (49ml; IQR 11-691ml). Averaged annual growth rates were significantly higher in both the type-1 group (14%/year; IQR 45-36%/year, p = 0.004) and atypical group (11%/year; IQR 5-23%/year, p = 0.014) compared to the controls (4%/year; IQR1-8%/year). Averaged annual growth rates were significantly higher in pediatric patients with type-1 deletions (21%/year) compared with adult patients (8%/year, p = 0.014) and also compared with pediatric patients without large deletions of the NF1 gene (3.3%/year, p = 0.0015). NF1 whole gene deletions cause a more severe phenotype of NF1 with higher tumor burden and higher growth-rates compared to NF1 patients without large deletions of the NF1 gene. In particular, pediatric patients with type-1 deletions display a pronounced tumor growth.

Oat is susceptible to several Fusarium species that cause contamination with different trichothecene mycotoxins. The molecular mechanisms behind Fusarium resistance in oat have yet to be elucidated. In the present work, we identified and characterised two oat UDP-glucosyltransferases orthologous to barley HvUGT13248. Overexpression of the latter in wheat had been shown previously to increase resistance to deoxynivalenol (DON) and nivalenol (NIV) and to decrease disease the severity of both Fusarium head blight and Fusarium crown rot. Both oat genes are highly inducible by the application of DON and during infection with Fusarium graminearum. Heterologous expression of these genes in a toxin-sensitive strain of Saccharomyces cerevisiae conferred high levels of resistance to DON, NIV and HT-2 toxins, but not C4-acetylated trichothecenes (T-2, diacetoxyscirpenol). Recombinant enzymes AsUGT1 and AsUGT2 expressed in Escherichia coli rapidly lost activity upon purification, but the treatment of whole cells with the toxin clearly demonstrated the ability to convert DON into DON-3-O-glucoside. The two UGTs could therefore play an important role in counteracting the Fusarium virulence factor DON in oat.

ObjectivesThe aim of this study was to investigate possible patterns of demand for chest imaging during the first wave of the SARS-CoV-2 pandemic and derive a decision aid for the allocation of resources in future pandemic challenges.Materials and methodsTime data of requests for patients with suspected or confirmed coronavirus disease 2019 (COVID-19) lung disease were analyzed between February 27th and May 27th 2020. A multinomial logistic regression model was used to evaluate differences in the number of requests between 3 time intervals (I1: 6am - 2pm, I2: 2pm - 10pm, I3: 10pm - 6am). A cosinor model was applied to investigate the demand per hour. Requests per day were compared to the number of regional COVID-19 cases.Results551 COVID-19 related chest imagings (32.8% outpatients, 67.2% in-patients) of 243 patients were conducted (33.3% female, 66.7% male, mean age 60 ± 17 years). Most exams for outpatients were required during I2 (I1 vs. I2: odds ratio (OR) = 0.73, 95% confidence interval (CI) 0.62-0.86, p = 0.01; I2 vs. I3: OR = 1.24, 95% CI 1.04-1.48, p = 0.03) with an acrophase at 7:29 pm. Requests for in-patients decreased from I1 to I3 (I1 vs. I2: OR = 1.24, 95% CI 1.09-1.41, p = 0.01; I2 vs. I3: OR = 1.16, 95% CI 1.05-1.28, p = 0.01) with an acrophase at 12:51 pm. The number of requests per day for outpatients developed similarly to regional cases while demand for in-patients increased later and persisted longer.ConclusionsThe demand for COVID-19 related chest imaging displayed distinct distribution patterns depending on the sector of patient care and point of time during the SARS-CoV-2 pandemic. These patterns should be considered in the allocation of resources in future pandemic challenges with similar disease characteristics.

Butenolide (BUT, 4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone) is a secondary metabolite produced by several Fusarium species and is co-produced with the major trichothecene mycotoxin deoxynivalenol (DON) on cereal grains throughout the world. BUT has low acute toxicity and only very limited occurrence and exposure data are available. The intestinal epithelium represents the first physiological barrier against food contaminants. We aimed to elucidate the intestinal inflammatory response of the human, non-cancer epithelial HCEC-1CT cells to BUT and to characterize potential combinatory interactions with co-occurring trichothecenes, such as DON and NX-3. Using a reporter gene approach, BUT (≥5 μM, 20 h) was found to decrease lipopolysaccharide (LPS; 10 ng/mL) induced nuclear factor kappa B (NF-κB) activation in a dose-dependent manner, and in combinatory treatments BUT represses trichothecene-induced enhancement of this important inflammatory pathway. Analysis of transcription and secretion levels of NF-κB-dependent, pro-inflammatory cytokines, revealed a significant down-regulation of IL-1β, IL-6, and TNF-α in IL-1β-stimulated (25 ng/mL) HCEC-1CT cells after BUT exposure (10 μM). Trichothecene-induced expression of pro-inflammatory cytokines by the presence of 1 μM DON or NX-3 was substantially suppressed in the presence of 10 μM BUT. The emerging mycotoxin BUT has the ability to suppress NF-κB-induced intestinal inflammatory response mechanisms and to modulate substantially the immune responsiveness of HCEC-1CT cells after trichothecene treatment. Our results suggest that BUT, present in naturally occurring mixtures of Fusarium fungal metabolites, should be increasingly monitored, and the mechanism of inhibition of NF-κB that might affect the pathogenesis or progression of intestinal inflammatory disorders, should be further investigated.

Abstract Background The purpose of this work is to describe the objectives and design of cardiovascular magnetic resonance (CMR) imaging in the single center, prospective, population-based Hamburg City Health study (HCHS). The HCHS aims at improving risk stratification for coronary artery disease (CAD), atrial fibrillation (AF) and heart failure (HF). Methods The HCHS will finally include 45,000 inhabitants of the city of Hamburg (Germany) between 45 and 74 years who undergo an extensive cardiovascular evaluation and collection of biomaterials. Risk-scores for CAD, AF and HF are used to create enriched subpopulations who are invited for CMR. A total number of approximately 12,362 subjects will undergo CMR and incident CAD, AF and HF will be assessed after 6 years follow-up. The standard CMR protocol includes cine-CMR, T1 and T2 mapping, aortic/mitral valve flow measurements, Late gadolinium enhancement, angiographies and measurements of aortic distensibility. A stress-perfusion scan is added in individuals at risk for CAD. The workflow of CMR data acquisition and analyses was evaluated in a pilot cohort of 200 unselected subjects. Results The obtained CMR findings in the pilot cohort agree with current reference values and demonstrate the ability of the established workflow to accomplish the objectives of HCHS. Conclusions CMR in HCHS promises novel insights into major cardiovascular diseases, their subclinical precursors and the prognostic value of novel imaging biomarkers. The HCHS database will facilitate combined analyses of imaging, clinical and molecular data (“Radiomics”).

Abstract Background Fetal cardiovascular magnetic resonance (CMR) imaging may provide a valuable adjunct to fetal echocardiography in the evaluation of congenital cardiovascular pathologies. However, dynamic fetal CMR is difficult due to the lack of direct in-utero cardiac gating. The aim of this study was to investigate the effectiveness of a newly developed Doppler ultrasound (DUS) device in humans for fetal CMR gating. Methods Fifteen fetuses (gestational age 30–39 weeks) were examined using 1.5 T CMR scanners at three different imaging sites. A newly developed CMR-compatible DUS device was used to generate gating signals from fetal cardiac motion. Gated dynamic balanced steady-state free precession images were acquired in 4-chamber and short-axis cardiac views. Gating signals during data acquisition were analyzed with respect to trigger variability and sensitivity. Image quality was assessed by measuring endocardial blurring (EB) and by image evaluation using a 4-point scale. Left ventricular (LV) volumetry was performed using the single-plane ellipsoid model. Results Gating signals from the fetal heart were detected with a variability of 26 ± 22 ms and a sensitivity of trigger detection of 96 ± 4%. EB was 2.9 ± 0.6 pixels (4-chamber) and 2.5 ± 0.1 pixels (short axis). Image quality scores were 3.6 ± 0.6 (overall), 3.4 ± 0.7 (mitral valve), 3.4 ± 0.7 (foramen ovale), 3.6 ± 0.7 (atrial septum), 3.7 ± 0.5 (papillary muscles), 3.8 ± 0.4 (differentiation myocardium/lumen), 3.7 ± 0.5 (differentiation myocardium/lung), and 3.9 ± 0.4 (systolic myocardial thickening). Inter-observer agreement for the scores was moderate to very good (kappa 0.57–0.84) for all structures. LV volumetry revealed mean values of 2.8 ± 1.2 ml (end-diastolic volume), 0.9 ± 0.4 ml (end systolic volume), 1.9 ± 0.8 ml (stroke volume), and 69.1 ± 8.4% (ejection fraction). Conclusion High-quality dynamic fetal CMR was successfully performed using a newly developed DUS device for direct fetal cardiac gating. This technique has the potential to improve the utility of fetal CMR in the evaluation of congenital pathologies.