Model order reduction by means of active subspaces and dynamic mode decomposition for parametric hull shape design hydrodynamics

We present the results of the application of a parameter space reduction methodology based on active subspaces (AS) to the hull hydrodynamic design problem. Several parametric deformations of an initial hull shape are considered to assess the influence of the shape parameters on the hull wave resistance. Such problem is relevant at the preliminary stages of the ship design, when several flow simulations are carried out by the engineers to establish a certain sensibility with respect to the parameters, which might result in a high number of time consuming hydrodynamic simulations. The main idea of this work is to employ the AS to identify possible lower dimensional structures in the parameter space. The complete pipeline involves the use of free form deformation to parametrize and deform the hull shape, the high fidelity solver based on unsteady potential flow theory with fully nonlinear free surface treatment directly interfaced with CAD, the use of dynamic mode decomposition to reconstruct the final steady state given only few snapshots of the simulation, and the reduction of the parameter space by AS, and shared subspace. Response surface method is used to minimize the total drag

Efficient reduction in shape parameter space dimension for ship propeller blade design

In this work, we present the results of a ship propeller design optimization campaign carried out in the framework of the research project PRELICA, funded by the Friuli Venezia Giulia regional government. The main idea of this work is to operate on a multidisciplinary level to identify propeller shapes that lead to reduced tip vortex-induced pressure and increased efficiency without altering the thrust. First, a specific tool for the bottom-up construction of parameterized propeller blade geometries has been developed. The algorithm proposed operates with a user defined number of arbitrary shaped or NACA airfoil sections, and employs arbitrary degree NURBS to represent the chord, pitch, skew and rake distribution as a function of the blade radial coordinate. The control points of such curves have been modified to generate, in a fully automated way, a family of blade geometries depending on as many as 20 shape parameters. Such geometries have then been used to carry out potential flow simulations with the Boundary Element Method based software PROCAL. Given the high number of parameters considered, such a preliminary stage allowed for a fast evaluation of the performance of several hundreds of shapes. In addition, the data obtained from the potential flow simulation allowed for the application of a parameter space reduction methodology based on active subspaces (AS) property, which suggested that the main propeller performance indices are, at a first but rather accurate approximation, only depending on a single parameter which is a linear combination of all the original geometric ones. AS analysis has also been used to carry out a constrained optimization exploiting response surface method in the reduced parameter space, and a sensitivity analysis based on such surrogate model. The few selected shapes were finally used to set up high fidelity RANS simulations and select an optimal shape

GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia.

We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P \u3c .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P \u3c .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors. © 2019 American Society of Hematology. All rights reserved

Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes for acute myeloid leukemia (AML) patients. We evaluated 8709 AML patients from the CIBMTR database and, after selection and manual curation of cytogenetics data, 3779 patients in CR1 were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis compared to intermediate-risk patients detected an increased risk of relapse for KMT2A-rearranged and adverse-risk patients (HR 1.27, p = 0.01 and HR 1.71, p < 0.001, respectively). Leukemia-free survival (LFS) was similar for KMT2A and adverse-risk patients (HR 1.26, p = 0.002 and HR 1.47, p < 0.001), as was overall survival (OS) (HR 1.32, p < 0.001 and HR 1.45, p < 0.001). No differences in outcome could be detected when patients were stratified by KMT2A fusion partner. This is the largest study conducted to date on post-HCT outcomes in AML using manually curated cytogenetics for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A rearrangements and adverse-risk disease

Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia

The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLAmatched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P <_ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P <_ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (<_18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission

The emerging role of AMPK in the regulation of breathing and oxygen supply

Regulation of breathing is critical to our capacity to accommodate deficits in oxygen availability and demand during, for example, sleep and ascent to altitude. It is generally accepted that a fall in arterial oxygen increases afferent discharge from the carotid bodies to the brainstem and thus delivers increased ventilatory drive, which restores oxygen supply and protects against hypoventilation and apnoea. However, the precise molecular mechanisms involved remain unclear. We recently identified as critical to this process the AMP-activated protein kinase (AMPK), which is key to the cell-autonomous regulation of metabolic homoeostasis. This observation is significant for many reasons, not least because recent studies suggest that the gene for the AMPK-α1 catalytic subunit has been subjected to natural selection in high-altitude populations. It would appear, therefore, that evolutionary pressures have led to AMPK being utilized to regulate oxygen delivery and thus energy supply to the body in the short, medium and longer term. Contrary to current consensus, however, our findings suggest that AMPK regulates ventilation at the level of the caudal brainstem, even when afferent input responses from the carotid body are normal. We therefore hypothesize that AMPK integrates local hypoxic stress at defined loci within the brainstem respiratory network with an index of peripheral hypoxic status, namely afferent chemosensory inputs. Allied to this, AMPK is critical to the control of hypoxic pulmonary vasoconstriction and thus ventilation–perfusion matching at the lungs and may also determine oxygen supply to the foetus by, for example, modulating utero-placental blood flow

The Mutational Landscape in Chronic Myelomonocytic Leukemia and Its Impact on Allogeneic Hematopoietic Cell Transplantation Outcomes: A Center for Blood and Marrow Transplantation Research (CIBMTR) Analysis

Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell\u27s C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival

Computational fluid dynamics studies on spray assisted combustion of alternative energy carriers

This dissertation belongs to the research fields of computational combustion physics and chemistry, with a primary focus on the modeling and simulation of diesel spray assisted combustion of alternative energy carriers. Computational fluid dynamics and combustion modeling are utilized within an open-source software framework, to investigate complex fluid flow phenomena involving turbulence, phase change, and chemical reactions under engine-relevant conditions. The dissertation comprises four research articles, investigating the combustion characteristics of various alternative fuels (namely methane, methanol, and hydrogen) when ignited by pilot diesel spray. To cope with the ongoing worldwide decarbonization strategies, utilization of alternative fuels together with researching advanced combustion concepts are sought after. In that regard, spray assisted dual-fuel (DF) combustion is amongst the low temperature combustion (LTC) technologies which relies primarily on low reactivity fuel (LRF), or blend of different fuels, to deliver the main energy in the combustion system. The premixed LRF-air charge is then ignited by a directly injected high reactivity fuel (HRF) such as diesel spray. Due to the adopted lean-burn concept of the premixed charge, LTC is attained with better fuel economy and cleaner emissions. Moreover, early introduction of the LRF into the combustion chamber increases the mixture homogeneity, and thereby mitigates soot formation. Presently, the physicochemical characteristics of DF combustion processes are not well understood for alternative LRFs. Such aspects are further explored in this dissertation. Regarding the numerical framework, large-eddy simulation is utilized for turbulence modeling, Lagrangian-Eulerian coupling for liquid transport and phase change, and the direct integration of finite-rate chemistry for combustion modeling. The Spray A target conditions from the Engine Combustion Network are considered a baseline for simulations, whereas the mixture composition is modified to account for LRF(s) in the spray assisted DF configuration. Throughout the dissertation, the performed simulations (0D, 1D and 3D), the post-processing and analyses are all retained within an open-source software environment. While Publication I revisited the numerical framework and modeling assumptions for evaporating sprays, Publication II investigated the ignition characteristics of methanol, compared with methane, when ignited by a pilot diesel spray. The challenges identified therein, for methanol ignition under DF configuration, were further addressed in Publication III. There, hydrogen enrichment to the premixed charge was proposed as a chemical remedy to facilitate methanol ignition, while extending the operational window. Finally, in Publication IV the focus was shifted to beyond the HRF spray autoignition, wherein local numerical microscopy was conducted to investigate the combustion mode development between autoignition and premixed flame initiation and deflagration.  The main findings of the dissertation are as follows. In Publication I, the fluid dynamical setup is validated and the sensitivity of the modeling assumptions is assessed. In Publication II, for DF spray assisted ignition of methanol, the operational window to achieve smooth ignition is observed to be narrow. In Publication III, hydrogen enrichment as LRF in the previous setup is shown to extend the operational limits, by advancing ignition delay and mitigating ambient reactivity. In Publication IV, we present world's first numerical evidence on emerging deflagration fronts in dual-fuel spray assisted combustion for diesel-methane blends utilizing embedded fully resolved numerical simulations. The present dissertation pioneers high-fidelity numerical investigations on alternative fuel spray-assisted combustion problems

Numerical evidence on deflagration fronts in a methane/n-dodecane dual-fuel shear layer under engine relevant conditions

Funding Information: This study has been funded by the Academy of Finland (grant numbers 318024, 332784, and 297248). We acknowledge CSC, Finnish IT Center for Science for providing the computational resources. Funding Information: This study has been funded by the Academy of Finland (grant numbers 318024 , 332784 , and 297248 ). We acknowledge CSC, Finnish IT Center for Science for providing the computational resources. Publisher Copyright: © 2023 The Author(s)To date, high resolution spray-assisted dual-fuel (DF) studies have focused on capturing the ignition process while the subsequent post-ignition events have been largely neglected due to modeling requirements and high computational cost. Here, we use a simplified approach for studying ignition front evolution after ignition. Three-dimensional scale-resolved simulations of igniting shear layers (0≤Re≤1500) are studied to better understand reaction fronts in engine-relevant conditions. We carry out quasi-DNS in a DF combustion setup consisting of premixed n-dodecane/methane/air/EGR at 700K as a fuel stream and premixed methane/air as the oxidizer at a pressure of 60 atmospheres and an ambient temperature of 900 K. The flow solution resolution is δ/10, where δ=laminar flame thickness. The present study primarily focuses on the hypothesized flame formation and its characterization. Under these conditions, the simulations indicate two-stage ignition further leading to reaction front initiation and dual-fuel flame establishment. For Re<1500, a reaction front resembling DF deflagration is demonstrated close to the auto-ignition timescales. At Re=1500, mixing effects promote more rapid dilution and the DF deflagration front formation is slightly delayed although still observed. For the first time, at rather short timescales of 0.2−0.4 IDT (ignition delay time) after the ignition, we provide numerical evidence on DF deflagration front emergence in shear-driven DF combustion processes via 3D numerical simulations for 0<Re≤1500.Peer reviewe