Construction and execution of experiments at the multi-purpose thermal hydraulic test facility TOPFLOW for generic investigations of two-phase flows and the development and validation of CFD codes - Final report

The works aimed at the further development and validation of models for CFD codes. For this reason, the new thermal-hydraulic test facility TOPFLOW was erected and equipped with wire-mesh sensors with high spatial and time resolution. Vertical test sections with nominal diameters of DN50 and DN200 operating with air-water as well as steam-water two-phase flows provided results on the evaluation of flow patterns, on the be¬haviour of the interfacial area as well as on interfacial momentum and heat transfer. The validation of the CFD-code for complex geometries was carried out using 3D void fraction and velocity distributions obtained in an experiment with an asymmetric obstacle in the large DN200 test section. With respect to free surface flows, stratified co- and counter-current flows as well as slug flows were studied in two horizontal test channels made from acrylic glass. Post-test calculations of these experiments succeeded in predicting the slug formation process. Corresponding to the main goal of the project, the experimental data was used for the model development. For vertical flows, the emphasis was put on lateral bubble forces (e.g. lift force). Different constitutive laws were tested using a Multi Bubble Size Class Test Solver that has been developed for this purpose. Basing on the results a generalized inhomogeneous Multiple Size Group (MUSIG) Model has been proposed and implemented into the CFD code CFX (ANSYS). Validation calculations with the new code resulted in the conclusion that particularly the models for bubble coalescence and fragmentation need further optimisation. Studies of single effects, like the assessment of turbulent dissipation in a bubbly flow and the analysis of trajectories of single bubbles near the wall, supplied other important results of the project

Long term outcome of adolescent and adult patients with pineal parenchymal tumors treated with fractionated radiotherapy between 1982 and 2003 -- a single institution's experience

Background: To evaluate the effectivity of fractionated radiotherapy in adolescent and adult patients with pineal parenchymal tumors (PPT). Methods: Between 1982 and 2003, 14 patients with PPTs were treated with fractionated radiotherapy. 4 patients had a pineocytoma (PC), one a PPT with intermediate differentiation (PPTID) and 9 patients a pineoblastoma (PB), 2 of which were recurrences. All patients underwent radiotherapy to the primary tumor site with a median total dose of 54 Gy. In 9 patients with primary PB treatment included whole brain irradiation (3 patients) or irradiation of the craniospinal axis (6 patients) with a median total dose of 35 Gy. Results: Median follow-up was 123 months in the PC patients and 109 months in the patients with primary PB. 7 patients were free from relapse at the end of follow-up. One PC patient died from spinal seeding. Among 5 PB patients treated with radiotherapy without chemotherapy, 3 developed local or spinal tumor recurrence. Both patients treated for PB recurrences died. The patient with PPTID is free of disease 7 years after radiotherapy. Conclusion: Local radiotherapy seems to be effective in patients with PC and some PPTIDs. Diagnosis and treatment of patients with more aggressive variants of PPTIDs as well as treatment of PB need to be further improved, since local and spinal failure even despite craniospinal irradiation (CSI) is common. As PPT are very rare tumors, treatment within multi-institutional trials remains necessary

MRI data-driven algorithm for the diagnosis of behavioural variant frontotemporal dementia

INTRODUCTION: Structural brain imaging is paramount for the diagnosis of behavioural variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis. METHODS: A total of 515 subjects from two different bvFTD cohorts (training and independent validation cohorts) were used to perform voxel-wise morphometric analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from deformation-based morphometry differences in isolation and together with semantic fluency. Tenfold cross validation was used to assess the performance of the classifier within the training cohort. A second held-out cohort of genetically confirmed bvFTD cases was used for additional validation. RESULTS: Average 10-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In the separate validation cohort of definite bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added semantic fluency scores. CONCLUSION: Our results show that structural MRI and semantic fluency can accurately predict bvFTD at the individual subject level within a completely independent validation cohort coming from a different and independent database

Aufbau und Durchführung von Experimenten an der Mehrzweck-Thermohydraulikversuchsanlage TOPFLOW für generische Untersuchungen von Zweiphasenströmungen und die Weiterentwicklung und Validierung von CFD-Codes - Abschlussbericht

Ziel der Arbeiten war die Weiterentwicklung und Validierung von Modellen in CFD-Codes. Hierzu wurde am FZD die thermohydraulische Versuchsanlage TOPFLOW aufgebaut und mit räumlich und zeitlich hochauflösenden Gittersensoren ausgestattet. Vertikale Teststrecken mit Nenndurchmessern von DN50 bzw. DN200 für Luft/Wasser- sowie Dampf/Wasser-Strömungen lieferten Ergebnisse zur Entwicklung von Strömungsformen, zum Verhalten der Zwischenphasengrenzfläche sowie zum Wärme- und Impulsaustausch zwischen den Phasen. Die Validierung des CFD-Codes in komplexen Geometrien erfolgte anhand von 3D Gasgehalts- und Geschwindigkeitsfeldern, die bei Umströmung eines asymmetrischen Hindernisses auftreten, das in der Teststrecke DN200 eingebaut war. Im Hinblick auf Strömungen mit freier Oberfläche untersuchte das FZD in zwei horizontalen Acrylglas-Kanälen geschichtete Zweiphasenströmungen im Gleich- bzw. Gegenstrom sowie Schwallströmungen. Bei den Nachrechnungen dieser Versuche gelang die Simulation der Schwallentstehung. Entsprechend des Projektziels wurden die experimentellen Ergebnisse zur Modellentwicklung genutzt. Bei vertikalen Strömungen stand die Wirkung der lateralen Blasenkräfte (z.B. Liftkraft) im Vordergrund. Zum Test unterschiedlicher Modellansätze wurde hierzu ein Mehrblasenklassen-Testsolver entwickelt und genutzt. Darauf aufbauend wurde ein neues Konzept für ein Mehrblasenklassenmodell, das Inhomogene MUSIG Modell erarbeitet und in den kommerziellen CFD Code CFX (ANSYS) implementiert. Bei Validierungsrechnungen zeigte sich, dass vor allem die Blasenkoaleszenz- und -zerfallsmodelle weiter optimiert werden müssen. Untersuchungen zu Einzeleffekten, wie z.B. die Abschätzung von Turbulenzkoeffizienten und die Analyse der Trajektoren von Einzelblasen in unmittelbarer Wandnähe, lieferten weitere wichtige Ergebnisse des Projekts

The multistep hypothesis of ALS revisited: The role of genetic mutations.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) incidence rates are consistent with the hypothesis that ALS is a multistep process. We tested the hypothesis that carrying a large effect mutation might account for ≥1 steps through the effect of the mutation, thus leaving fewer remaining steps before ALS begins. METHODS: We generated incidence data from an ALS population register in Italy (2007-2015) for which genetic analysis for C9orf72, SOD1, TARDBP, and FUS genes was performed in 82% of incident cases. As confirmation, we used data from ALS cases diagnosed in the Republic of Ireland (2006-2014). We regressed the log of age-specific incidence against the log of age with least-squares regression for the subpopulation carrying disease-associated variation in each separate gene. RESULTS: Of the 1,077 genetically tested cases, 74 (6.9%) carried C9orf72 mutations, 20 (1.9%) had SOD1 mutations, 15 (1.4%) had TARDBP mutations, and 3 (0.3%) carried FUS mutations. In the whole population, there was a linear relationship between log incidence and log age (r2 = 0.98) with a slope estimate of 4.65 (4.37-4.95), consistent with a 6-step process. The analysis for C9orf72-mutated patients confirmed a linear relationship (r2 = 0.94) with a slope estimate of 2.22 (1.74-2.29), suggesting a 3-step process. This estimate was confirmed by data from the Irish ALS register. The slope estimate was consistent with a 2-step process for SOD1 and with a 4-step process for TARDBP. CONCLUSION: The identification of a reduced number of steps in patients with ALS with genetic mutations compared to those without mutations supports the idea of ALS as a multistep process and is an important advance for dissecting the pathogenic process in ALS

REVEALS—a longitudinal cohort study of multifaceted respiratory assessment in ALS

Objective To systematically assess decline in respiratory measures in amyotrophic lateral sclerosis (ALS) and to examine the impact of sex, disease onset type and baseline morbidity on progression. Methods The REVEALS study (Registry of Endpoints and Validated Experiences in ALS) was conducted between April 2018 and February 2021 in six European ALS centers. Slow and forced vital capacity (S/FVC), sniff nasal inspiratory pressure (SNIP), peak cough flow, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and respiratory morbidity were collected. Data were analyzed using a Bayesian multiple outcomes random effects model. Results Two hundred and eighty participants had a median of three assessments (IQR 2.0, 5.0) over a median of 8 months (IQR 2.3, 14.1). There were 974 data collection timepoints. Differences in respiratory measures and rates of decline between disease-onset and sex subgroups were identified. Females had lower scores in all respiratory measures and females with bulbar onset ALS had faster decline compared with other sub-groups. These differences were not detected by the ALSFRS-r respiratory subscale. Dyspnea, orthopnea, and a higher King’s stage at baseline were associated with lower respiratory scores throughout follow-up, while having a regular productive cough at baseline was associated with lower peak cough flow scores. Conclusion Respiratory function declines more quickly in females with ALS compared with males when measured by FVC, SVC, SNIP, or PCF, but not the ALSFRS-R respiratory sub-score. Higher baseline King’s staging and the presence of clinical respiratory symptoms at baseline were associated with worse respiratory function. The ALSFRS-R respiratory sub-score is poorly correlated with objective respiratory measurements

Standardised Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD): study protocol for establishing a core outcome set in polycystic kidney disease

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life threatening inherited kidney disease and is responsible for 5-10% of cases of end-stage kidney disease (ESKD). Cystic kidneys may enlarge up to 20 times the weight of a normal kidney due to the growth of renal cysts, and patients with ADPKD have an increased risk of morbidity, premature mortality, and other life-time complications including renal and hepatic cyst and urinary tract infection, intracranial aneurysm, diverticulosis, and kidney pain which impair quality of life. Despite some therapeutic advances and the growing number of clinical trials in ADPKD, the outcomes that are relevant to patients and clinicians, such as symptoms and quality of life, are infrequently and inconsistently reported. This potentially limits the contribution of trials to inform evidence-based decision-making. The Standardised Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) project aims to establish a consensus-based set of core outcomes for trials in PKD (with an initial focus on ADPKD but inclusive of all stages) that patients and health professionals identify as critically important. METHODS: The five phases of SONG-PKD are: a systematic review to identify outcomes that have been reported in existing PKD trials; focus groups with nominal group technique with patients and caregivers to identify, rank, and describe reasons for their choices; qualitative stakeholder interviews with health professionals to elicit individual values and perspectives on outcomes for trials involving patients with PKD; an international three-round Delphi survey with all stakeholder groups (including patients, caregivers, healthcare providers, policy makers, researchers, and industry) to gain consensus on critically important core outcome domains; and a consensus workshop to review and establish a set of core outcome domains and measures for trials in PKD. DISCUSSION: The SONG-PKD core outcome set is aimed at improving the consistency and completeness of outcome reporting across ADPKD trials, leading to improvements in the reliability and relevance of trial-based evidence to inform decisions about treatment and ultimately improve the care and outcomes for people with ADPKD

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

\ua9 The Author(s) 2024.In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases