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Objectives 4D flow MRI enables quantitative assessment of helical flow. We sought to generate normal values and elucidate changes of helical flow (duration, volume, length, velocities and rotational direction) and flow jet (displacement, flow angle) as well as wall shear stress (WSS). Methods We assessed the temporal helical existence (THEX), maximum helical volume (HVmax), accumulated helical volume (HVacc), accumulated helical volume length (HVLacc), maximum forward velocity (maxVfor), maximum circumferential velocity (maxVcirc), rotational direction (RD) and maximum wall shear stress (WSS) as reported elsewhere using the software tool Bloodline in 86 healthy volunteers (46 females, mean age 41 ± 13 years). Results WSS decreased by 42.1% and maxVfor by 55.7% across age. There was no link between age and gender regarding the other parameters. Conclusion This study provides age-dependent normal values regarding WSS and maxVfor and age- and gender-independent normal values regarding THEX, HVmax, HVacc, HVLacc, RD and maxVcirc. Key Points • 4D flow provides numerous new parameters; therefore, normal values are mandatory. • Wall shear stress decreases over age. • Maximum helical forward velocity decreases over age.

Background: Neutrophil gelatinase-associated lipocalin (NGAL) and hepcidin-25 are involved in catalytic iron-related kidney injury after cardiac surgery with cardiopulmonary bypass. We explored the predictive value of plasma NGAL, plasma hepcidin-25, and the plasma NGAL:hepcidin-25 ratio for major adverse kidney events (MAKE) after cardiac surgery. Methods: We compared the predictive value of plasma NGAL, hepcidin-25, and plasma NGAL:hepcidin-25 with that of serum creatinine (Cr) and urinary output and protein for primary-endpoint MAKE (acute kidney injury [AKI] stages 2 and 3, persistent AKI >48 hours, acute dialysis, and in-hospital mortality) and secondary-endpoint AKI in 100 cardiac surgery patients at intensive care unit (ICU) admission. We performed ROC curve, logistic regression, and reclassification analyses. Results: At ICU admission, plasma NGAL, plasma NGAL:hepcidin-25, plasma interleukin-6, and Cr predicted MAKE (area under the ROC curve [AUC]: 0.77, 0.79, 0.74, and 0.74, respectively) and AKI (0.73, 0.89, 0.70, and 0.69). For AKI prediction, plasma NGAL:hepcidin-25 had a higher discriminatory power than Cr (AUC difference 0.26 [95% CI 0.00-0.53]). Urinary output and protein, plasma lactate, C-reactive protein, creatine kinase myocardial band, and brain natriuretic peptide did not predict MAKE or AKI (AUC

Perpendicular vascular changes (PVC) are markers of tumor-induced neoangiogenesis at the vocal folds. Contact endoscopy with narrow-band imaging (CE-NBI) allows a detailed analysis of such vascular changes.This work intends to evaluate the potential of CE-NBI for diagnosis of benign, dysplastic, and malignant lesions of the vocal folds. In addition, it should be determined whether CE-NBI offers an additional benefit in detecting PVC compared to white-light endoscopy (WLE) and NBI alone.Three examiners evaluated histologically verified cases of benign, dysplastic, and malignant lesions of the larynx in WLE, NBI, and CE-NBI (n = 60). In each mode, they examined the lesion for PVC and assessed the lesion's dignity. The proportion of lesions with detected PVC, the statistical measures of performance in detecting high-grade dysplasia and carcinoma, and the interrater variability for each mode were calculated.CE-NBI proved superior to the other investigated diagnostic methods in terms of detecting PVC and in terms of sensitivity and accuracy in the diagnosis of high-grade dysplasia and carcinoma. A clear association of such pathologies with PVC was seen.CE-NBI detects PVC more frequently and reliably than the other methods investigated. The association of these vascular patterns to high-grade dysplasia and vocal fold carcinomas could be confirmed. Compared to WLE and NBI endoscopy, the diagnostic quality for detecting high-grade dysplasia and carcinoma is increased. Thus, CE-NBI can improve endoscopic differentiation between benign and malignant lesions of the vocal folds by enhancing the detection of PVC.HINTERGRUND: Perpendikuläre Gefäßveränderungen (PGV) sind Marker der tumorinduzierten Neoangiogenese der Stimmlippen. Die Kontaktendoskopie mit Narrow Band Imaging (KE-NBI) ermöglicht eine detaillierte Analyse solcher Gefäßveränderungen.In dieser Arbeit wurde das Potenzial der KE-NBI bei der Diagnostik benigner, dysplastischer und maligner Veränderungen der Stimmlippen untersucht. Außerdem sollte bei der Detektion von PGV die Aussagekraft des KE-NBI im Vergleich zur Weißlichtendoskopie (WLE) und zur alleinigen Narrow-Band-Imaging-Endoskopie (NBI) bestimmt werden.Dazu befundeten 3 Untersucher histopathologisch verifizierte benigne, dysplastische oder maligne Läsionen der Stimmlippen (n = 60) jeweils im Modus WLE, NBI und KE-NBI. Die Läsionen wurden auf PGV hin untersucht und ihre Dignität beurteilt. Ermittelt wurden der Anteil der Läsionen mit detektierten PGV sowie die diagnostische Güte für jeden Modus und die Interratervariabilität bei der Erkennung von höhergradigen Dysplasien und Karzinomen.Die KE-NBI zeigte sich den anderen Modi bei der Detektion von PGV und hinsichtlich Sensitivität und Genauigkeit bei der Erkennung von höhergradigen Dysplasien und Karzinomen überlegen. Die Autoren sahen eine deutliche Assoziation dieser pathologischen Veränderungen mit PGV.Mittels KE-NBI werden PGV häufiger und zuverlässiger als mit den anderen Methoden erkannt. Die Assoziation dieser Gefäßveränderungen mit höhergradigen Dysplasien und Karzinomen der Stimmlippen wurde bestätigt. Im Vergleich zu WLE und NBI zeigte sich eine erhöhte diagnostische Güte. Somit kann die KE-NBI durch bessere Detektion der PGV die endoskopische Differenzierung zwischen benignen und malignen Läsionen der Stimmlippen verbessern.

AimsThe aim of this study was to validate the tricuspid annular plane systolic excursion/systolic pulmonary artery (PA) pressure (TAPSE/PASP) ratio with the invasive pressure–volume (PV) loop-derived end-systolic right ventricular (RV) elastance/PA elastance (Ees/Ea) ratio in patients with heart failure with reduced ejection fraction (HFREF) and secondary pulmonary hypertension (PH).Methods and resultsThe relationship of TAPSE and TAPSE/PASP with RV-PV loop (single-beat)-derived contractility Ees, afterload Ea, and Ees/Ea was assessed in 110 patients with HFREF with and without secondary PH. The results were compared with other surrogate parameters such as the fractional area change/PASP ratio. The association of the surrogates with all-cause mortality was evaluated. In patients with PH (n = 74, 67%), TAPSE significantly correlated with Ees (r = 0.356), inverse with Ea (r = −0.514) but was most closely associated with Ees/Ea (r = 0.77). Placing TAPSE in a ratio with PASP slightly reduced the relationship to Ees/Ea (r = 0.71) but was more closely related to the parameters of PA vascular load, diastolic RV function, and RV energetics. The area under the curve of TAPSE/PASP and TAPSE for discriminating overall survival in receiver operating characteristic analysis was not different (P = 0.78. Prognostic relevant cut-offs were 17 mm for TAPSE and 0.38 mm/mmHg for TAPSE/PASP. Both parameters in multivariate cox regression remained independently prognostically relevant.ConclusionTAPSE is an easily and reliably obtainable and valid surrogate parameter for RV–PA coupling in PH due to HFREF. Putting TAPSE into a ratio with PASP did not further improve the coupling information or prognostic assessment.Trial IdentifierDRKS—German Clinical Trials Register (DRKS00011133; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011133).

Background The ability of urinary biomarkers to complement established clinical risk prediction models for postoperative adverse kidney events is unclear. We assessed the effect of urinary biomarkers linked to suspected pathogenesis of cardiac surgery-induced acute kidney injury (AKI) on the performance of the Cleveland Score, a risk assessment model for postoperative adverse kidney events. Methods This pilot study included 100 patients who underwent open-heart surgery. We determined improvements to the Cleveland Score when adding urinary biomarkers measured using clinical laboratory platforms (neutrophil gelatinase-associated lipocalin [NGAL], interleukin-6) and those in the preclinical stage (hepcidin-25, midkine, alpha-1 microglobulin), all sampled immediately post-surgery. The primary endpoint was major adverse kidney events (MAKE), and the secondary endpoint was AKI. We performed ROC curve analysis, assessed baseline model performance (odds ratios [OR], 95% CI), and carried out statistical reclassification analyses to assess model improvement. Results NGAL (OR [95% CI] per 20 concentration-units wherever applicable): (1.07 [1.01-1.14]), Interleukin-6 (1.51 [1.01-2.26]), midkine (1.01 [1.00-1.02]), 1-hepcidin-25 (1.08 [1.00-1.17]), and NGAL/hepcidin-ratio (2.91 [1.30-6.49]) were independent predictors of MAKE and AKI (1.38 [1.03-1.85], 1.08 [1.01-1.15], 1.01 [1.00-1.02], 1.09 [1.01-1.18], and 3.45 [1.54-7.72]). Category-free net reclassification improvement identified interleukin-6 as a model-improving biomarker for MAKE and NGAL for AKI. However, only NGAL/hepcidin-25 improved model performance for event- and event-free patients for MAKE and AKI. Conclusions NGAL and interleukin-6 measured immediately post cardiac surgery may complement the Cleveland Score. The combination of biomarkers with hepcidin-25 may further improve diagnostic discrimination.

4D flow MRI enables quantitative assessment of helical flow. Current methods are susceptible to noise. To evaluate helical flow patterns in healthy volunteers and patients with bicuspid aortic valves (BAV) at 1.5 T and 3 T using pressure-based helix-extraction in 4D flow MRI. Two intraindividual 4D flow MRI examinations were performed at 1.5 T and 3 T in ten healthy volunteers (5 females, 32 ± 3 years) and 2 patients with BAV using different acceleration techniques (kt-GRAPPA and centra). Several new quantitative parameters for the evaluation of volumes [ml], lengths [mm] as well as temporal parameters [ms] of helical flow were introduced and analyzed using the software tool Bloodline. We found good correlations between measurements in volunteers at 1.5 T and 3 T regarding helical flow volumes (R = 0.98) and temporal existence (R = 0.99) of helices in the ascending aorta. Furthermore, we found significantly larger (11.7 vs. 77.6 ml) and longer lasting (317 vs. 769 ms) helices in patients with BAV than in volunteers. The assessed parameters do not depend on the magnetic field strength used for the acquisition. The technique of pressure-based extraction of 4D flow MRI pattern is suitable for differentiation of normal and pathological flow.

Purpose Interstitial high-dose-rate brachytherapy (BT) is an alternative treatment option to stereotactic body radiotherapy (SBRT) for the ablative treatment of liver malignancies. The aim of the present comparative planning study was to reveal the possibilities and limitations of both techniques with regard to dosimetric properties. Methods and Materials Eighty-five consecutive patients with liver malignancy diagnosis were treated with interstitial BT between 12/2008 and 09/2009. The prescription dose of BT varied between 15 and 20 Gy, depending on histology. For dosimetric comparison, virtual SBRT treatment plans were generated using the original BT planning CTs. Additional margins reflecting the respiratory tumor motion were added to the target volumes for SBRT planning. Results The mean PTVBT was 34.7 cm3 (0.5–410.0 cm3) vs. a mean PTVSBRT of 73.2 cm3 (6.1–593.4 cm3). Regarding the minimum peripheral dose (D99.9), BT achieved the targeted prescription dose of 15 Gy/20 Gy better without violating organ at risk constraints. The dose exposure of the liver was significantly influenced by treatment modality. The liver exposure to 5 Gy was statistically lower with 611 ± 43 cm3 for BT as compared with 694 ± 37 cm3 for SBRT plans (20-Gy group, p = 0.001), corresponding to 41.8% vs. 45.9% liver volume, respectively. Conclusions To the best of our knowledge, this is the first report on the comparison of clinically treated liver BT treatments with virtually planned SBRT treatments. The planning study showed a superior outcome of BT regarding dose coverage of the target volume and exposed liver volume. Nevertheless, further studies are needed to determine ideal applicability for each treatment approach.

In contrast to adults, meningiomas are uncommon tumors in childhood and adolescence. Whether adult and pediatric meningiomas differ on a molecular level is unclear. Here we report detailed genomic analyses of 37 pediatric meningiomas by sequencing and DNA methylation profiling. Histologically, the series was dominated by meningioma subtypes with aggressive behavior, with 70% of patients suffering from WHO grade II or III meningiomas. The most frequent cytogenetic aberrations were loss of chromosomes 22 (23/37 [62%]), 1 (9/37 [24%]), 18 (7/37 [19%]), and 14 (5/37 [14%]). Tumors with NF2 alterations exhibited overall increased chromosomal instability. Unsupervised clustering of DNA methylation profiles revealed separation into three groups: designated group 1 composed of clear cell and papillary meningiomas, whereas group 2A comprised predominantly atypical meningiomas and group 2B enriched for rare high-grade subtypes (rhabdoid, chordoid). Meningiomas from NF2 patients clustered exclusively within groups 1 and 2A. When compared with a dataset of 105 adult meningiomas, the pediatric meningiomas largely grouped separately. Targeted panel DNA sequencing of 34 tumors revealed frequent NF2 alterations, while other typical alterations found in adult non-NF2 tumors were absent. These data demonstrate that pediatric meningiomas are characterized by molecular features distinct from adult tumors.

Background and aims Failure of right ventricular (RV) function worsens outcome in pulmonary hypertension (PH). The adaptation of RV contractility to afterload, the RV-pulmonary artery (PA) coupling, is defined by the ratio of RV end-systolic to PA elastances (Ees/Ea). Using pressure volume loop (PV-L) technique we aimed to identify an Ees/Ea cutoff predictive for overall survival and to assess hemodynamic and morphologic conditions for adapted RV function in secondary PH due to Heart Failure with Reduced Ejection Fraction (HFREF). Methods This post hoc analysis is based on 112 patients of the prospective Magdeburger Resynchronization Responder Trial. All patients underwent right and left heart echocardiography, and a baseline PV-L and RV catheter measurement. A subgroup of patients (n=50) without a pre-implanted cardiac device underwent MRI at baseline. Results The analysis revealed that 0.68 is an optimal Ees/Ea cutoff (area under the curve: 0.697, p160ml, RV-mass/volume-ratio 171ml, odds ratio, OR 0.96, p=0.021), high pulsatile load (PA compliance Conclusions The RV-PA coupling ratio Ees/Ea predicts overall survival in PH due to HFREF and is mainly affected by pulsatile load, RV remodeling and LV dysfunction. Prognostically favorable coupling (RV-Ees/Ea ≥0.68) in PH was associated with preserved RV size/function and mid-term survival, comparable to HFREF without PH. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boston Scientific

BACKGROUND Acute kidney injury requiring renal replacement therapy (AKI-RRT) is strongly associated with mortality after cardiac surgery; however, options for early identification of patients at high risk for AKI-RRT are extremely limited. Early after cardiac surgery, the predictive ability for AKI-RRT even of one of the most extensively evaluated novel urinary biomarkers, neutrophil gelatinase-associated lipocalin (NGAL), appears to be only moderate. We aimed to determine whether the NGAL/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) early after surgery may compare favorably to NGAL for identification of high-risk patients after cardiac surgery. METHODS This is a prospective substudy of the BICARBONATE trial, a multicenter parallel-randomized controlled trial comparing perioperative bicarbonate infusion for AKI prevention to usual patient care. At a tertiary referral center, 198 patients at increased kidney risk undergoing cardiac surgery with cardiopulmonary bypass were included into the present study. The primary outcome measure was defined as AKI-RRT. Secondary outcomes were in-hospital mortality and long-term mortality. We compared area under the curve of the receiver operating characteristic (AUC-ROC) of urinary NGAL with that of the urinary NGAL/hepcidin-25 ratio within 60 minutes after end of surgery. We compared adjusted AUC and performed cross-validated reclassification statistics of the (logarithmic) urinary NGAL/hepcidin-25 ratio adjusted to Cleveland risk score/EuroScore, cross-clamp time, age, volume of packed red blood cells, and (logarithmic) urinary NGAL concentration. The association of the NGAL/hepcidin-25 ratio with long-term patient survival was assessed using Cox proportional hazard regression analysis adjusting for EuroScore, aortic cross-clamp time, packed red blood cells and urinary NGAL. RESULTS Patients with AKI-RRT (n = 13) had 13.7-times higher NGAL and 3.3-times lower hepcidin-25 concentrations resulting in 46.9-times higher NGAL/hepcidin-25 ratio early after surgery compared to patients without AKI-RRT. The NGAL/hepcidin-25 ratio had higher AUC-ROC compared with NGAL for risk of AKI-RRT and in-hospital mortality (unadjusted AUC-ROC difference 0.087, 95% confidence interval [CI], 0.036-0.138, P < .001; 0.082, 95% CI, 0.018-0.146, P = .012). For AKI-RRT, the NGAL/hepcidin-25 ratio increased adjusted category-free net reclassification improvement (cfNRI; 0.952, 95% CI, 0.437-1.468; P < .001) and integrated discrimination improvement (IDI; 0.040, 95% CI, 0.008-0.073; P = .016) but not AUC difference. For in-hospital mortality, the ratio improved AUC of the reference model (AUC difference 0.056, 95% CI, 0.003-0.108; P = .037) and cfNRI but not IDI. The urinary NGAL/hepcidin-25 ratio remained significantly associated with long-term mortality after adjusting for the model covariates. CONCLUSIONS The urinary NGAL/hepcidin-25 ratio appears to early identify high-risk patients and outperform NGAL after cardiac surgery. Confirmation of our findings in other cardiac surgery centers is now needed.

Tests based on pairwise distance measures for multivariate sample vectors are common in ecological studies but are usually restricted to two-sided tests for differences. In this paper, we investigate extensions to tests for superiority, equivalence and non-inferiority.

Aims Failure of right ventricular (RV) function worsens outcome in pulmonary hypertension (PH). The adaptation of RV contractility to afterload, the RV‐pulmonary artery (PA) coupling, is defined by the ratio of RV end‐systolic to PA elastances (Ees/Ea). Using pressure–volume loop (PV‐L) technique we aimed to identify an Ees/Ea cut‐off predictive for overall survival and to assess hemodynamic and morphologic conditions for adapted RV function in secondary PH due to heart failure with reduced ejection fraction (HFREF). Methods and results This post hoc analysis is based on 112 patients of the prospective Magdeburger Resynchronization Responder Trial. All patients underwent right and left heart echocardiography and a baseline PV‐L and RV catheter measurement. A subgroup of patients (n = 50) without a pre‐implanted cardiac device underwent magnetic resonance imaging at baseline. The analysis revealed that 0.68 is an optimal Ees/Ea cut‐off (area under the curve: 0.697, P 160 mL, RV‐mass/volume‐ratio ≤0.37 g/mL) and dysfunction (right ventricular ejection fraction 171 mL, odds ratio (OR) 0.96, P = 0.021], high pulsatile load (PA compliance

OBJECTIVES Complex blood flow profiles in the aorta are known to contribute to vessel dilatation. We studied flow profiles in the aorta in patients with aortic valve disease before and after surgical aortic valve replacement (AVR). METHODS Thirty-four patients with aortic valve disease underwent 4-dimensional velocity-encoded magnetic resonance imaging before and after AVR (biological valve = 27, mechanical valve = 7). Seven healthy volunteers served as controls. Eccentricity (ES) and complex flow scores (CFS) were determined from the degree of helicity, vorticity and eccentricity of flow profiles in the aorta. Model-based therapy planning was used in 4 cases to improve in silico postoperative flow profiles by personalized adjustment of size, rotation and angulation of the valve as well as aorta diameter. RESULTS Patients with aortic valve disease showed more complex flow than controls [median ES 2.5 (interquartile range (IQR) 2.3–2.7) vs 1.0 (IQR 1.0–1.0), P CONCLUSIONS Abnormal flow profiles in the aorta more frequently persist after surgical AVR. Model-based therapy planning might have the potential to optimize treatment for best possible individual outcome. Clinical trial registration number clinicaltrials.gov NCT03172338, 1 June 2017, retrospectively registered; NCT02591940, 30 October 2015, retrospectively registered.

Purpose Flexible transnasal endoscopy is a common examination technique for the evaluation of laryngeal lesions, while the use of narrow band imaging (NBI) has been reported to enhance the diagnostic value of white light endoscopy (WLE). The purpose of this study is to assess observer variability and diagnostic value of both modalities and investigate the possible influence of previous laryngeal surgery on the detection rates of laryngeal malignancy. Methods The study was based on the retrospective evaluation of 170 WLE and NBI images of laryngeal lesions by three observers in a random order. The histopathological diagnoses serve as the gold standard. Results In identifying laryngeal malignancy, the sensitivity of NBI proved to be higher than that of WLE (93.3% vs. 77.0%). NBI was also superior to WLE in terms of accuracy (96.3% vs. 92%) and diagnostic odds ratio (501.83 vs. 120.65). Both modalities had a specificity of 97.3%. The inter-observer agreement was substantial (kappa = 0.661) for WLE and almost perfect (kappa = 0.849) for NBI. Both WLE and NBI showed a high level of intra-observer agreement. The sensitivity was significantly lower in images with history of previous laryngeal surgery compared to those without. Conclusions Flexible transnasal endoscopy has been proved to be a valuable tool in the diagnosis of laryngeal malignancy. The use of NBI can increase the sensitivity and observer reliability in that context and can also provide a diagnostic gain in cases with previous laryngeal surgery

We know of no current published data on the prevalence of craniosynostosis in Germany, so our objective in this study was to contribute to the limited knowledge of its epidemiology by assessing time trends, the frequency of prenatal diagnosis, and the timing of diagnosis and treatment. Data were collected in Saxony-Anhalt during the period 2000-17, and we designed a retrospective multicentre cohort study. The prevalence was 4.8 cases of craniosynostosis/10 000 births, and did not increase during that time. We compared the data of 91 patients with those of 273 controls. There were 75 boys and 16 girls (ratio 4.7:1). Fifty-one children had isolated craniosynostosis, consisting of 46 with a single-suture, and five with a multisuture, synostosis. Twenty-nine were associated with other congenital malformations, and 11 were syndromic. Three cases had been diagnosed prenatally, and 34 had skull deformities diagnosed immediately after birth at a mean (SD) age of 3.4 (4.7) months. The mean (SD) age at the time of first admission to hospital in one of the three surgical centres of Saxony-Anhalt was 5.9 (5.5) months, and 65 patients were operated on at a mean age of 9.1 (6.3) months. In contrast to published reports we found a prevalence of 4.8 cases of craniosynostosis/10 000 births that did not increase during the period 2000-16. Although we found a low prenatal detection rate, the diagnosis and treatment in this cohort study seemed timely.

Summary: Background: Pseudoaneurysms (PSAs) are concerning complications after arterial invasive interventions. Therapeutic options include manual ultrasound-assisted compression, pressure dressings, surgical intervention and thrombin injection. Compression of neighboring veins is obvious. However, the incidence of deep vein thrombosis (DVT) in patients with PSA has not previously been investigated. Patients and methods: In this retrospective, nonrandomized study 238 patients with PSA were analyzed from 2013 to 2018. In 149 patients, all of the parameters were complete for participating. PSAs were treated according to the local standard therapy with either ultrasound-guided compression followed by compression bandage or thrombin injection. Treatment success was evaluated 24 hours later, and the venous system was examined for the presence of DVT. Results: Peripheral DVT was found in 25.4% patients after ultrasound-assisted compression and subsequent pressure bandages, but only 6.4% of patients had DVT after thrombin injection (p = 0.013). Lower leg veins, particularly veins of the crural muscles, were primarily affected. Significantly more PSAs were successfully treated without the occurrence of DVT in the thrombin injection group compared to the compression group (93.6 vs. 69.0%; p = 0.001). Conclusions: Our study revealed that the use of thrombin injections resulted in a significantly lower rate of postinterventional DVT and a higher total number of successfully treated PSAs compared to compression therapy.

Background: Cancer regularly disrupts health and developmental trajectories in adolescents and young adults (AYAs). Parents have been shown to have a substantial impact on the health and cancer survivorship activities of AYA patients in the form of symptom management. However, no randomized controlled trial has evaluated a coping support intervention (CSI) program for parents of AYAs with cancer aged 18 to 40 years. Patients and Methods: From November 30, 2012, to August 29, 2016, parents of AYAs with hematologic malignancies were randomized in a phase III controlled trial (1:1 ratio, stratified sampling) to either the research-based CSI AYA-Parents group (CSI group; n=82) or the standard care (SC) group (n=70). CSI consisted of 5 sessions to achieve the enhancement of parental adaptive coping as the primary outcome (per the adaptive coping scale of the 28-item Brief COPE, a validated multidimensional self-assessment-questionnaire recommended for clinical cancer research). Measures of adaptive coping, depression, and mental health were collected at pre-CSI (measurement date T1), at the end of the intervention sessions (measurement date T2), and at follow-up (3 months). We calculated mean change scores in outcomes and estimated intervention effect sizes (Cohen’s d) for changes from T1 to T2/T3, with 0.2 indicating a small effect, 0.5 a medium effect, and 0.8 a large effect. All statistical tests were 2-sided. Results: In the intention-to-treat analysis, the CSI group significantly improved their adaptive coping compared with the SC group (95% CI, 0.30–2.54; P=.013; d=0.405), whereas adaptive coping in the SC group deteriorated. The CSI group also experienced a significant decrease in depressive symptoms and improved mental health with clinical significance (95% CI, –1.98 to –0.30; P=.008; d=0.433, and 95% CI, –0.19 to 3.97; P=.074; d=0.292, respectively). Sensitivity analyses confirmed the robustness of the main intention-to-treat analysis. Conclusions: CSI improved effectively adaptive coping and depression in parents of AYAs with hematologic malignancies. It may represent a novel family-based approach in AYA oncology care.

Background Alcohol consumption is commonly accepted in Western societies and is a known risk factor in pregnancy, which could lead to fetal alcohol spectrum disorders (FASDs). Prevalence of alcohol consumption during pregnancy is mostly unknown. Prevalence estimates in publications based on questionnaires are limited by possible underreporting due to social stigmatization. The aim of this study was to estimate the prevalence of harmful alcohol consumption in a large cohort of pregnant women using different biomarkers related to alcohol consumption and compare the findings with those of non-pregnant women METHODS: Routine parameters known to be influenced by alcohol consumption (γ-glutamyltransferase, GGT; carbohydrate-deficient transferrin, CDT/%CDT; mean corpuscular/cell volume, MCV; combined parameter of GGT and %CDT, GGT-CDT) were analyzed in serum samples of 2,182 pregnant women and 743 non-pregnant, age-matched females. Data were tested for (i) differences between pregnant and non-pregnant women and (ii) changes across the 3 trimesters of pregnancy. Results Prevalence rates differ greatly according to the parameter and cutoff, which reflects the limitations of assessing alcohol consumption with biomarkers. The prevalence of harmful alcohol consumption on the basis of a single or several elevated parameters was 13.8% (95% CI: 12.4 to 15.2) in pregnant women and 18.6% (95% CI: 15.8 to 21.4) in non-pregnant women, though 85.0% of the elevated measurements were attributable to an isolated elevation in %CDT only. Using GGT-CDT as the parameter with the highest specificity according to the literature, the estimated prevalence of harmful alcohol consumption in pregnancy is 0.5% (95% CI: 0.2 to 0.7). Conclusion Estimated prevalence rates differ greatly with respect to the biomarkers and cutoffs used. The use of CDT/%CDT alone appears to overestimate harmful alcohol consumption during pregnancy.

Summary Background Women with complete androgen insensitivity syndrome (CAIS) after gonadectomy have complained about reduced psychological wellbeing and sexual satisfaction. The aim of this study was to compare the effectiveness of hormone-replacement therapy with either androgen or oestrogen in women with 46,XY karyotype and CAIS after gonadectomy. Methods This national, multicentre, double-blind, randomised crossover trial was performed at three university medical centres and three specialised treatment institutions in Germany. Eligible participants were women aged 18–54 years with 46,XY karyotype, genetically diagnosed CAIS, and removed gonads. Participants were randomly assigned (14:12) by a central computer-based minimisation method to either oestradiol 1·5 mg/day for 6 months followed by crossover to testosterone 50 mg/day for 6 months (sequence A) or to testosterone 50 mg/day for 6 months followed by crossover to oestradiol 1·5 mg/day for 6 months (sequence B). Participants also received oestradiol or testosterone dummy to avoid identification of the active substance. All participants received oestradiol 1·5 mg/day during a 2 months' run-in phase. The primary outcome was mental health-related quality of life, as measured with the standardised German version of the SF-36 questionnaire. Secondary outcomes were psychological wellbeing, as measured with the Brief Symptom Inventory (BSI), sexual function, as measured with the Female Sexual Function Index (FSFI), and somatic effects, such as signs of virilisation and effects on metabolic blood values. The primary analysis included all patients who were available at least until visit 5, even if protocol violations occurred. The safety analysis included all patients who received at least oestradiol during the run-in phase. This trial is registered with the German Clinical Trials Register, number DRKS00003136, and with the European Clinical Trials Database, number 2010-021790-37. Findings We enrolled 26 patients into the study, with the first patient enrolled on Nov 7, 2011, and the last patient leaving the study on Jan 23, 2016. 14 patients were assigned to sequence A and 12 were assigned to sequence B. Ten participants were withdrawn from the study, two of whom attended at least five visits and so could be included in the primary analysis. Mental health-related quality of life did not differ between treatment groups (linear mixed model, p=0·794), nor did BSI scores for psychological wellbeing (global severity index, p=0·638; positive symptom distress index, p=0·378; positive symptom total, p=0·570). For the FSFI, testosterone was superior to oestradiol only in improving sexual desire (linear mixed model, p=0·018). No virilisation was observed, and gonadotrophin concentrations remained stable in both treatment groups. Oestradiol and testosterone concentrations changed substantially during the study in both treatment groups. 28 adverse events were reported for patients receiving oestradiol (23 grade 1 and five grade 2), and 38 adverse events were reported for patients receiving testosterone (34 grade 1, three grade 2, and one grade 3). One serious adverse event (fibrous mastopathy) and 20 adverse events (16 grade 1 and four grade 2) were reported during the run-in phase, and 12 adverse events during follow-up (nine grade 1 and three grade 2). Interpretation Testosterone was well tolerated and as safe as oestrogen for hormone-replacement therapy. Testosterone can be an alternative hormone substitution in CAIS, especially for woment with reduced sexual functioning. Funding German Federal Ministry of Education and Research.

Aim: To assess weather doctors’ clinical risk-assessment for major adverse kidney events (MAKE) and acute kidney injury (AKI) after open-heart surgery would improve when being informed about neutrophil gelatinase-associated lipocalin (NGAL) test result at ICU admission. Patients & Methods: Clinical risk-assessment for MAKE and AKI were performed with and without providing NGAL test result and compared in an exploratory- and a validation-cohort using reclassification metrics, exemplary category-free net reclassification improvement (cfNRI). Results: Exploratory cohort: doctors’ prediction of MAKE (cfNRI = 0.750 [0.130–1.370]; p = 0.018) and AKI (cfNRI = 0.565 [0.001–1.129]; p = 0.049) improved being provided with NGAL test information. This finding was confirmed in the validation-cohort (MAKE cfNRI = 0.930 [0.188–1.672]; p = 0.014) and the combined-cohort (MAKE: cfNRI = 0.847 [0.371–1.323], p

The aim of this study was to compare the assessment of low-grade meniscal tears and cartilage damage in ultrahigh-field magnetic resonance imaging (MRI) at 7 T to routine clinical MRI at 3 T.This study was approved by the local ethics committee, and written informed consent was obtained from each patient. Forty-one patients with suspected meniscal damage or mild osteoarthritis (Kellgren-Lawrence score, 0-2) received 7 T as well as routine clinical 3 T consecutively. The imaging protocol at both field strengths consisted of PD-weighted imaging with more than doubled resolution at 7 T. Images were read blinded regarding field strength and patient characteristics by 3 readers with different experience in musculoskeletal MRI (3 years, 6 years, and 10 years) according to a modified whole-organ MRI score of the knee in osteoarthritis and the Score of the International Cartilage Repair Society. Arthroscopic reports as a criterion standard were available for 12 patients. A multifactorial mixed model analysis was performed.The mean cumulated diagnostic score at 7 T was significantly closer to the criterion standard compared with 3 T in patients where criterion standard was available (P0.001). In all 41 patients, the damages were rated more severely at 7 T reflected by a mean higher cumulative score in cartilage (P0.001) and in the meniscus (P0.001). No difference in interreader variability between 3 T and 7 T was observed. Imaging acquisition time was nearly identical.Morphologic imaging of cartilage and meniscal damage of the knee in ultrahigh-field MRI at 7 T with PD-weighted TSE sequences seemed to have a significantly higher diagnostic accuracy than 3 T and can be performed with equal acquisition times while exploiting higher resolution of 7 T.

Introduction Worldwide the prevalence of neuropsychiatric illness among women of reproductive age is higher than ever before. This study investigates the influences of maternal substance abuse/dependence and neuropsychiatric illness on pregnancy and neonatal outcomes. Patients and Methods Using a retrospective study design 185 pregnancies in women with neuropsychiatric illnesses or substance abuse were identified at a single centre over a period of 3.25 years and compared to 4907 pregnancies in healthy women without mental illness. Differences in pre-, peri- and postnatal pregnancy parameters were studied. Results Numbers of previous abortions on obstetric history were significantly higher in cases compared to controls, women with depression being especially affected. The number of antenatal visits was also higher among cases, especially in women with depression. The caesarean section rate was significantly higher in cases compared to controls. Children of women with neuropsychiatric illness were born at lower gestational ages than those of healthy control mothers, however there were no significant differences between case and control groups for birth weight, head circumference or Apgar scores. Some isolated differences were found for disease-specific case subgroups compared to controls. Conclusion The study shows a relationship between maternal neuropsychiatric illness and pregnancy outcomes independent of medication use. Rates of spontaneous abortion were higher. Children were born earlier, yet the neonatal outcomes birth weight, head circumference and Apgar score were not worse than children of mentally healthy women.

Zusammenfassung Hintergrund Postoperativer Schmerz nach Tonsillektomie (TE) kann in der Regel durch die Gabe von Analgetika aus der Gruppe der nicht steroidalen Antirheumatika (NSAR) suffizient behandelt werden. Bei einigen Patienten besteht jedoch eine außergewöhnlich therapieresistente Schmerzsymptomatik, welche zudem häufig einseitig stärker ausgeprägt ist. Unsere klinisch praktische Erfahrung hat gezeigt, dass bei diesen Patienten häufig eine Blockierung der oberen Kopfgelenke vorliegt, die durch Manuelle Medizin (MM) erfolgreich therapiert werden kann. In dieser prospektiven, randomisierten, placebo-kontrollierten, einfach verblindeten Studie sollte deshalb untersucht werden, ob sich der schmerzlindernde Effekt dieser Therapie statistisch nachweisen lässt. Material und Methoden 52 erwachsene Patienten mit außergewöhnlich starken (VAS > 4) und / oder einseitigen Schmerzen nach TE (1. bis 4. Tag postoperativ) wurden hinsichtlich des Schmerzverlaufs mittels Visueller Analogskala (VAS) zu 4 Zeitpunkten untersucht: direkt vor (t0) und sofort nach der MM (t1), dann 4 Stunden nach MM (t2) sowie 24 Stunden nach MM (t3). Ergebnisse Die Ergebnisse zeigen eine signifikant höhere Schmerzreduktion (jeweils als Differenz zu t0) in der Verum- als in der Placebogruppe zum Zeitpunkt t1 und t3 (t1: p = 0,012, t3: p = 0,012, beides Bonferroni-adjustiert). Zum Zeitpunkt t2 war die Differenz mit p = 0,54 nicht signifikant. Schlussfolgerungen Anhand der Studie konnte die Wirksamkeit von Manueller Medizin zur Schmerzreduktion bei erwachsenen Patienten mit außergewöhnlich starken bzw. einseitigen Schmerzen nach TE und Hypomobilität der Halswirbelsäule nachgewiesen werden.

In der Akutversorgung stellen sich Patienten vor, die durch fremde Personen geschadigt wurden. Trotz der medizinischen Behandlungsnotwendigkeit sollen auch juristische Konsequenzen berucksichtigt werden. Ziel dieser Arbeit war die Analyse der Konsilanforderungen an das Institut fur Rechtsmedizin des Universitatsklinikums Halle (Saale) und der Vergleich mit der Opferstatistik des Landeskriminalamtes (LKA) Sachsen-Anhalt. Die Konsilanforderungen der Jahre 2012–2015 wurden hinsichtlich der Alters- und Geschlechtsverteilung, den Vorstellungsgrunden und der Latenz bis zur Konsilanforderung ausgewertet. Anschliesend erfolgte ein prozentualer Vergleich mit den Opferstatistiken des LKA Sachsen-Anhalt 2014–2015. Es konnten 536 Falle mit 55,6 % mannlichen und 44,4 % weiblichen Patienten ausgewertet werden. 62,1 % der Patienten waren

Introduction: We aimed to investigate whether sonographic peripheral cross-sectional nerve area (CSA) and progranulin (PGRN), a neuritic growth factor, are related to each other and whether they interact to predict clinical and paraclinical measures in amyotrophic lateral sclerosis (ALS). Methods: We included 55 ALS patients who had forearm median and ulnar nerve CSA, cerebrospinal fluid (CSF) PGRN and serum PGRN measures available. CSF PGRN was normalized against the CSF/serum albumin ratio (Qalb). Using age, sex, height and weight adjusted general linear models we examined CSA x CSF PGRN interaction effects on various measures. Results: There was a medium-effect size inverse relationship between CSA and CSF PGRN, but not between CSA and serum PGRN. Lower CSA values together with higher CSF PGRN levels were linked to smaller motor amplitudes. Discussion: In ALS, the constellation of peripheral nerve atrophy together with higher CSF PGRN levels indicates pronounced axonal damage. This article is protected by copyright. All rights reserved.

Background Skull base meningiomas are considered to be difficult for surgical treatment. We wondered whether genetic alterations recently identified in benign non-NF2-mutated World Health Organization (WHO) grade I meningiomas are related to clinical features of skull base meningiomas and whether druggable signaling pathways are activated. Methods We analyzed 93 skull base meningiomas (82 WHO grade I, 11 WHO grade II) for mutations of hot spots or the most relevant exons of AKT1, KLF4/TRAF7, SMO, PI3K, and the TERT promoter. Results The AKT1E17K mutation was present in 31% of patients and was related to meningothelial histology. AKT1E17K had a negative effect on the time to tumor recurrence. Analyses of activated signaling proteins revealed among AKT1E17K tumors a significantly higher rate of phospho-mammalian target of rapamycin (mTOR) and phospho-p70S6K+ tumors. AKT1E17K tumors with immunoexpression of phospho-extracellular signal-regulated kinase 1 or 2 (ERK1/2) were characterized by significantly shorter time to tumor recurrence compared with AKT1wt tumors expressing phospho-ERK1/2 (P = .046). KLF4 mutations (K409Q) were present in 11.8% of cases, with significant association to the secretory/transitional subtype (P < .001). The presence of the KLF4 K409Q mutation was associated with favorable outcome. One phosphatidylinositol-3 kinase (PI3K) mutation but no SMO or TERT promoter mutation was found. Conclusions AKT1E17K mutation is frequent in skull base meningiomas, results in activation of the mTOR and ERK1/2 signaling pathways, and has negative impact on tumor recurrence. Patients with skull base meningiomas with AKT1E17K mutation might benefit from additional treatment targeting the mTOR pathway. Generally, the PI3K-Akt-mTOR axis might be a potential target for kinase inhibitors in these tumors.

Background Right ventricular (RV) to pulmonary artery (PA) coupling (C), quantified by pressure volume (PV) loop analysis, predicts RV function, and is independently associated with long term survival in systolic heart failure (HFrEF). However, the PV loop technique is invasive and complex to carry out, especially when used to do RV functional analyses. Different echo-surrogate parameters are proposed to measure RV-PA-C, such as the tricuspid annular plane systolic excursion, TAPSE/PAsystolic pressure (SP) and FAC (fractional area change)/PASP as the most promising parameters. However, up to now, no validation of these non-invasive coupling indices with the invasive gold standard method of RV-PV-loops has been done. Methods In 111 patients with advanced HFrEF (Post-hoc analysis of Magdeburger CRT Responder Trial, DRKS00011133), echo-derived TAPSE and FAC, and their relationship to PASP were related to the RV PV-loop-derived parameters of intrinsic RV contractility (Ees), pulmonary load (Ea), and the RV-PA-C efficiency (Ees/Ea) by linear regression analysis. Within a MRI substudy (n=49 patients) we examined the relationship of pure longitudinal contraction (MRI-TAPSE) and radial free wall to septum contraction (area change of 5 RV segments from tricuspid valve to apex in the short axis view) to the invasive RV-PA-C. Results The MRI analysis demonstrated that radial RV contraction (R2=0.77, p Conclusion FAC, an echo parameter that includes a predominant radial with a smaller part of longitudinal contraction, correlated significantly better to the invasively derived RV-PA-C-ratio than pure longitudinal RV shortening (TAPSE). Combining FAC or TAPSE with PASP did not improve the non-invasive RV-PA coupling information. However, it provided more comprehensive information on pulmonary vascular load and RV oxygen consumption, which seems to be translated into a higher prognostic power. Acknowledgement/Funding scientific grant from Boston Scientific

To determine the impact of depression, epilepsy and drug abuse during pregnancy on delivery and fetal outcome. Due to the worldwide increasing prevalence of neurological and psychiatric diseases and drug abuse, the number of affected pregnant women is increasing. A large-scale retrospective case–control analysis of pregnancies affected by depression, epilepsy or drug abuse with and without medication was conducted in two German perinatal centres between 2013 and 2017. The case group consisted of 706 pregnant women who had a diagnosis of depression, epilepsy or drug abuse vs. 12,574 pregnant women without neuropsychiatric diagnosis (control group). The analysis included the rate of intrauterine growth restriction, birth weight and length, neonatal head circumference. Significant differences in the subgroups were found in the parameters intrauterine growth restriction, birth weight, length and head circumference. Women with epilepsy were affected less often than women with depression and substance abuse. Major differences were found in the group of women with substance abuse. Negative associations were found within the non-pharmacologically managed disease group itself compared to women exposed to medication. The present results demonstrated a negative association between maternal neurological or psychiatric disease and pregnancy outcome in the examined parameters. However, the non-pharmacologically treated maternal disease was identified as a risk factor itself.