Numerical simulation is a vital tool for the continuous improvement of all steelmaking processes. In previous works, the authors have dedicated different approaches to optimize modeling of fluid flow ...in the ladle. This includes a sensitivity analysis of validation techniques, assembling of a validation database, and a model optimization on the water model scale. Herein, the final part of this project is presented at which the optimized model is scaled to the real process. Associated problems are identified and solutions are proposed. To achieve a tradeoff between large eddy simulation (LES) grid requirements and current computational capacities, a hybrid meshing strategy is optimized. To overcome the intrinsic drawbacks of the Euler–Lagrange model, a mapping approach for phase decoupling is implemented and made publicly available on GitHub. The upscaling of semi‐empiric submodels is discussed. Good agreement with experimental mixing time measurements is found, indicating the success of upscaling. A first time‐averaged flow field of a full‐scale 185 t ladle with the LES model is presented. Due to the extreme computing requirements, these results may currently be used as a benchmark, but the trend toward increasing computing capacities may make LES models state of the art in the future.
Histone deacetylase inhibitors have attracted considerable attention because of their ability to overcome the differentiation block in leukemic blasts, an effect achieved either alone or in ...combination with differentiating agents, such as all-trans retinoic acid. We have previously reported favorable effects of the potent histone deacetylase inhibitor valproic acid in combination with all-trans retinoic acid in patients with advanced acute myeloid leukemia leading to blast cell reduction and improvement of hemoglobin. These effects were accompanied by hypergranulocytosis most likely due to an enhancement of nonleukemic myelopoiesis and the suppression of malignant hematopoiesis rather than enforced differentiation of the leukemic cells. These data prompted us to investigate the effect of valproic acid on normal hematopoietic stem cells (HSC). Here we show that valproic acid increases both proliferation and self-renewal of HSC. It accelerates cell cycle progression of HSC accompanied by a down-regulation of p21(cip-1/waf-1). Furthermore, valproic acid inhibits GSK3beta by phosphorylation on Ser9 accompanied by an activation of the Wnt signaling pathway as well as by an up-regulation of HoxB4, a target gene of Wnt signaling. Both are known to directly stimulate the proliferation of HSC and to expand the HSC pool. In summary, we here show that valproic acid, known to induce differentiation or apoptosis in leukemic blasts, stimulates the proliferation of normal HSC, an effect with a potential effect on its future role in the treatment of acute myeloid leukemia.
The last decade has seen widespread adoption of triple quadrupole-based inductively coupled plasma–tandem mass spectrometry (ICPMS/MS) technique using a collision/reaction cell in combination with a ...precell bandpass mass analyzer to measure isotopes otherwise masked by spectral interferences. High-precision isotope ratio analysis containing such isotopes would benefit from a similar capability on a multicollector inductively coupled plasma mass spectrometry (MC-ICPMS) platform, but using a quadrupole-based precell mass analyzer for MC-ICPMS/MS has several limitations. To overcome these limitations, we developed a novel precell mass analyzer for MC-ICPMS/MS using sector field technology. The new precell mass analyzer, comprising two Wien filters and a selection aperture, and a hexapole collision/reaction cell were integrated together in a single module and added to the commercially available Thermo Scientific Neptune XT MC-ICPMS to create a prototype MC-ICPMS/MS we named Vienna. Vienna was proven to retain the same performance of the base MC-ICPMS in terms of sensitivity, accuracy, and precision. Using the Vienna mass filter to eliminate Ar-based species, the abundance sensitivity achievable was equivalent to TIMS at mass 237.05, which was used to accurately determine the low 236U/238U isotope ratio of the uranium reference material IRMM184 (certified value, 1.2446 × 10–7). The performance of Vienna was then tested for a variety of geoscience applications that were expected to benefit from MC-ICPMS/MS technique, including Ca, K, Si, and in situ Rb/Sr dating by laser ablation.
Extended-spectrum β-lactamase (ESBL) producing
pose an important threat of infection with increased morbidity and mortality, especially for immunocompromised patients. Here, we use the rise of ...multidrug-resistant
in a German neurorehabilitation center from April 2015 to April 2016 to dissect the benefit of whole genome sequencing (WGS) for outbreak analyses. In total, 53 isolates were obtained from 52 patients and examined using WGS. Two independent analysis strategies (reference-based and -free) revealed the same distinct clusters of two CTX-M-15 producing
clones (ST15,
= 31; ST405,
= 7) and one CTX-M-15 producing
strain (ST414,
= 8). Additionally, we determined sequence variations associated with antimicrobial resistance phenotypes in single isolates expressing carbapenem and colistin resistance, respectively. For rapid detection of the major
outbreak clone (ST15), a selective triplex PCR was deduced from WGS data of the major outbreak strain and
genome data deposited in central databases. Moreover, we introduce two novel open-source applications supporting reference genome selection (
; https://gitlab.com/s.fuchs/refRank) and alignment-based SNP-filtering (
; https://gitlab.com/s.fuchs/snpfilter) in NGS analyses.
In 2022, German surveillance systems observed rapidly increasing numbers of NDM-1- and NDM-1/OXA-48-producing
, which may in part reflect recurring pre-pandemic trends. Among these cases, however, a ...presence in Ukraine before diagnosis was frequently reported. Whole genome sequencing of 200 isolates showed a high prevalence of sequence types ST147, ST307, ST395 and ST23, including clusters corresponding to clonal dissemination and suggesting onward transmission in Germany. Screening and isolation of patients from Ukraine may help avoid onward transmission.
Bone-graft substitutes are commonly used for the augmentation of traumatic bone defects in tibial plateau fractures. However, their clinical performance compared with that of autologous ...bone-grafting, the gold standard in bone defect reconstruction, still remains under debate. This study investigates the differences in quality of life, pain, and radiographic outcomes in the treatment of tibial plateau fracture-associated bone defects with either autologous bone grafts or a bioresorbable hydroxyapatite and calcium sulfate cement (CERAMENT BONE VOID FILLER CBVF; BONESUPPORT).
In this study, 135 patients with acute depression and split-depression fractures of the proximal part of the tibia (OTA/AO types 41-B2 and 41-B3) were enrolled in a prospective, controlled, randomized, multicenter trial including 20 hospitals in Germany. Patients were randomized to receive either autologous iliac bone graft or CBVF for reconstruction of the bone defect. The primary outcome measures were the Short Form (SF)-12 version 2 Physical Component Summary (PCS) score at week 26 (the study was designed to show noninferiority of the CBVF with regard to the PCS with a prespecified margin of -5 points) and the pain level at 26 weeks postoperatively measured by a visual analog scale (VAS). The secondary outcomes were the SF-12 version 2 Mental Component Summary (MCS) and SF-12 PCS scores at weeks 1, 6, and 12 and bone-healing on radiographs.
Age, sex, fixation methods, and fracture pattern were comparable in both groups. There were no significant differences (p > 0.05) in the SF-12 PCS or VAS scores at postoperative week 26. There was a significant reduction of blood loss (p = 0.007) and pain levels (p = 0.008) at postoperative day 1 in the CBVF group. The rates of fracture-healing, defect remodeling, and articular subsidence were not significantly different (p > 0.05) in both groups.
Bioresorbable CBVF was noninferior to autologous bone graft with regard to both patient-reported and radiographic outcomes in tibial plateau fractures of OTA/AO types 41-B2 and 41-B3.
Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Despite recent advances in adapting the intensity of treatment for older patients with ALL, current protocols are associated with high rates of early deaths, treatment-related toxicity, and dismal ...prognosis. We evaluated inotuzumab ozogamicin and dexamethasone (Dex) as induction therapy in older patients with ALL within the German Multicenter Study Group for Adult ALL (GMALL).
The open-label, multicenter, phase II, INITIAL-1 trial enrolled 45 patients older than 55 years with newly diagnosed, CD22-positive,
-negative B-precursor ALL (B-ALL). Patients received up to three cycles of inotuzumab ozogamicin/Dex and up to six cycles of age-adapted GMALL consolidation and maintenance therapy.
Forty-three evaluable patients with common/pre-B (n = 38) and pro-B ALL (n = 5), with a median age of 64 years (range, 56-80), received at least two cycles of inotuzumab ozogamicin induction therapy. All patients achieved complete remission (CR/CR with incomplete hematologic recovery). Twenty-three (53%) and 30 (71%) patients had no evidence of molecularly assessed measurable residual disease (minimum 10e-4 threshold) after the second and third inductions, respectively. After a median follow-up of 2.7 years, event-free survival at one (primary end point) and 3 years was 88% (95% CI, 79 to 98) and 55% (95% CI, 40 to 71), while overall survival (OS) was 91% (95% CI, 82 to 99) and 73% (95% CI, 59 to 87), respectively. None of the patients died during 6 months after the start of induction. Most common adverse events having common toxicity criteria grade ≥3 during induction were leukocytopenia, neutropenia, thrombocytopenia, anemia, and elevated liver enzymes. One patient developed nonfatal veno-occlusive disease after induction II.
Inotuzumab ozogamicin-based induction followed by age-adapted chemotherapy was well tolerated and resulted in high rates of remission and OS. These data provide a rationale for integrating inotuzumab ozogamicin into first-line regimens for older patients with B-ALL.
Post-traumatic cardiac dysfunction often occurs in multiply injured patients (ISS ≥ 16). Next to direct cardiac injury, post-traumatic cardiac dysfunction is mostly induced by the release of ...inflammatory biomarkers. One of these is the heparin-binding factor Midkine, which is elevated in humans after fracture, burn injury and traumatic spinal cord injury. Midkine is associated with cardiac pathologies but the exact role of Midkine in the development of those diseases is ambiguous. The systemic profile of Midkine after multiple trauma, its effects on cardiomyocytes and the association with post-traumatic cardiac dysfunction, remain unknown.
Midkine levels were investigated in blood plasma of multiply injured humans and pigs. Furthermore, human cardiomyocytes (iPS) were cultured in presence/absence of Midkine and analyzed regarding viability, apoptosis, calcium handling, metabolic alterations, and oxidative stress. Finally, the Midkine filtration capacity of the therapeutic blood absorption column CytoSorb ®300 was tested with recombinant Midkine or plasma from multiply injured patients.
Midkine levels were significantly increased in blood plasma of multiply injured humans and pigs. Midkine acts on human cardiomyocytes, altering their mitochondrial respiration and calcium handling
. CytoSorb®300 filtration reduced Midkine concentration
and
depending on the dosage.
Midkine is elevated in human and porcine plasma after multiple trauma, affecting the functionality and metabolism of human cardiomyocytes
. Further examinations are required to determine whether the application of CytoSorb®300 filtration in patients after multiple trauma is a promising therapeutic approach to prevent post-traumatic cardiac disfunction.
In numerical computation of ladle metallurgy, multiphase models are essential. Still, these models are afflicted with great uncertainty, making a validation with experimental data mandatory. ...Validation experiments fundamentally differ from physical modeling experiments because emphasis is on a complete documentation of all boundary conditions and a detailed uncertainty assessment. For this work, the experimental design for a comprehensive accuracy assessment of numerical models and reported quantities were jointly determined with international numerical experts. The framework comprises a plume analysis and flow measurements in the single- and multiphase regions of a water model with defined conditions. All influencing factors are documented extensively and their contribution to the overall data uncertainty is quantified. Detailed data are made publicly available within a validation benchmark database for isothermal multiphase flow in metallurgical ladles. A first draft of a standardized validation procedure, including a single number validation score, is proposed. Using the available data, the accuracy of numerical models can be quantified more accurately and comparably, which helps in advancing the model’s further development. It also lays the foundation for a standardization of the validation process, which can lead to greater acceptance of the numerical results.
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