An understanding of left ventricle (LV) mechanics is fundamental for designing better preventive, diagnostic, and treatment strategies for improved heart function. Because of the costs of clinical ...and experimental studies to treat and understand heart function, respectively, in-silico models play an important role. Finite element (FE) models, which have been used to create in-silico LV models for different cardiac health and disease conditions, as well as cardiac device design, are time-consuming and require powerful computational resources, which limits their use when real-time results are needed. As an alternative, we sought to use deep learning (DL) for LV in-silico modeling. We used 80 four-chamber heart FE models for feed forward, as well as recurrent neural network (RNN) with long short-term memory (LSTM) models for LV pressure and volume. We used 120 LV-only FE models for training LV stress predictions. The active material properties of the myocardium and time were features for the LV pressure and volume training, and passive material properties and element centroid coordinates were features of the LV stress prediction models. For six test FE models, the DL error for LV volume was 1.599 ± 1.227 ml, and the error for pressure was 1.257 ± 0.488 mmHg; for 20 LV FE test examples, the mean absolute errors were, respectively, 0.179 ± 0.050 for myofiber, 0.049 ± 0.017 for cross-fiber, and 0.039 ± 0.011 kPa for shear stress. After training, the DL runtime was in the order of seconds whereas equivalent FE runtime was in the order of several hours (pressure and volume) or 20 min (stress). We conclude that using DL, LV in-silico simulations can be provided for applications requiring real-time results.
The goal of this paper was to provide a real-time left ventricular (LV) mechanics simulator using machine learning (ML). Finite element (FE) simulations were conducted for the LV with different ...material properties to obtain a training set. A hyperelastic fiber-reinforced material model was used to describe the passive behavior of the myocardium during diastole. The active behavior of the heart resulting from myofiber contractions was added to the passive tissue during systole. The active and passive properties govern the LV constitutive equation. These mechanical properties were altered using optimal Latin hypercube design of experiments to obtain training FE models with varied active properties (volume and pressure predictions) and varied passive properties (stress predictions). For prediction of LV pressures, we used eXtreme Gradient Boosting (XGboost) and Cubist, and XGBoost was used for predictions of LV pressures, volumes as well as LV stresses. The LV pressure and volume results obtained from ML were similar to FE computations. The ML results could capture the shape of LV pressure as well as LV pressure-volume loops. The results predicted by Cubist were smoother than those from XGBoost. The mean absolute errors were as follows: XGBoost volume: 1.734 ± 0.584 ml, XGBoost pressure: 1.544 ± 0.298 mmHg, Cubist volume: 1.495 ± 0.260 ml, Cubist pressure: 1.623 ± 0.191 mmHg, myofiber stress: 0.334 ± 0.228 kPa, cross myofiber stress: 0.075 ± 0.024 kPa, and shear stress: 0.050 ± 0.032 kPa. The simulation results show ML can predict LV mechanics much faster than the FE method. The ML model can be used as a tool to predict LV behavior. Training of our ML model based on a large group of subjects can improve its predictability for real world applications.
Finding the best design fast Van der Velden, Alex; Soltisz, Jim
Machine Design,
05/2009, Volume:
81, Issue:
10
Magazine Article, Trade Publication Article
According to the father of the bell curve, Johann Carl Friedrich Gauss, variation is to be expected within the range of what is considered normal. Engineers who fail to account for manufacturing ...variation can make products that don't meet specifications. Problems might include high amounts of scrap and variations in the operating performance of the manufactured product. Nonlinear analyses for evaluating complex manufacturing processes such as material forming became feasible only with the advent of high-performance computing (HPC). HPC involves supercomputers and computer clusters that solve advanced computation problems. When building FEA models to simulate nonlinear behavior, engineers can modify geometry and materials, by hand, to improve performance. When building FEA models to simulate nonlinear behavior, engineers can modify geometry and materials, by hand, to improve performance. Optimized simulation can even be applied beyond product design to improve manufacturing. Material data, machine set points, and proximity sensor data can be considered as design variables for simulating machine tools.
Macrophages are innate immune cells that adopt diverse activation states in response to their microenvironment. Editing macrophage activation to dampen inflammatory diseases by promoting the ...repolarization of inflammatory (M1) macrophages to anti-inflammatory (M2) macrophages is of high interest. Here, we find that mouse and human M1 macrophages fail to convert into M2 cells upon IL-4 exposure in vitro and in vivo. In sharp contrast, M2 macrophages are more plastic and readily repolarized into an inflammatory M1 state. We identify M1-associated inhibition of mitochondrial oxidative phosphorylation as the factor responsible for preventing M1→M2 repolarization. Inhibiting nitric oxide production, a key effector molecule in M1 cells, dampens the decline in mitochondrial function to improve metabolic and phenotypic reprogramming to M2 macrophages. Thus, inflammatory macrophage activation blunts oxidative phosphorylation, thereby preventing repolarization. Therapeutically restoring mitochondrial function might be useful to improve the reprogramming of inflammatory macrophages into anti-inflammatory cells to control disease.
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•Mouse and human M1 macrophages fail to repolarize to M2 upon IL-4 restimulation•LPS + IFNγ treatment inhibits mitochondrial oxidative respiration in macrophages•Mitochondrial function is required for the repolarization to an M2 phenotype•NO blunts mitochondrial respiration and prevents plasticity in M1 macrophages
Editing macrophage polarization is an emerging concept for the treatment of inflammatory diseases. Van den Bossche et al. show that inflammatory M1 macrophage activation dampens mitochondrial function, thereby preventing the repolarization to an anti-inflammatory M2 phenotype. Inhibiting nitric oxide production improves mitochondrial function and reprogramming to M2 macrophages.
The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we ...describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study.
Univariate analysis on prognostic factors (age, white blood cell count at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI; n = 163). Bone marrow minimal residual disease (MRD) was measured in 73 patients by real-time quantitative polymerase chain reaction at various time points (EOI, n = 68; end of consolidation, n = 56; and before OCTADAD, n = 57). MRD results were classified as negative, intermediate (<5∗10−4), and high (≥5∗10−4).
The 6-year event-free and overall survival was 73.9% (standard error SE = 3.6) and 87.2% (SE = 2.7). Relapses occurred early, within 36 months from diagnosis in 28 of 31 (90%) infants. Treatment-related mortality was 3.6%. Age <6 months was a favourable prognostic factor with a 6-year disease-free survival (DFS) of 91% (SE = 9.0) compared with 71.7% (SE = 4.2) in infants >6 months of age (P = 0.04). Patients with high EOI MRD ≥5 × 10−4 had a worse outcome (6-year DFS 61.4% SE = 12.4, n = 16), compared with patients with undetectable EOI MRD (6-year DFS 87.9% SE = 6.6, n = 28) or intermediate EOI MRD <5 × 10−4 (6-year DFS 76.4% SE = 11.3, n = 24; P = 0.02).
We conclude that young age at diagnosis and low EOI MRD seem favourable prognostic factors in infants with KMT2A-germline ALL and should be considered for risk stratification in future clinical trials.
•Prognostic factors for infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) are not well known.•Characteristics of 167 uniformly treated infants with KMt2A-germline ALL were analyzed.•Young age at diagnosis (<6 months) was associated with better outcome.•End of induction minimal residual disease (MRD), rather than end of consolidation MRD, was a prognostic factor for outcome.•Combined MRD and genetic-based stratification of KMT2A-g infants should be considered.
MIR139 is a tumor suppressor and is commonly silenced in acute myeloid leukemia (AML). However, the tumor-suppressing activities of miR-139 and molecular mechanisms of MIR139-silencing remain largely ...unknown. Here, we studied the poorly prognostic MLL-AF9 fusion protein-expressing AML. We show that MLL-AF9 expression in hematopoietic precursors caused epigenetic silencing of MIR139, whereas overexpression of MIR139 inhibited in vitro and in vivo AML outgrowth. We identified novel miR-139 targets that mediate the tumor-suppressing activities of miR-139 in MLL-AF9 AML. We revealed that two enhancer regions control MIR139 expression and found that the polycomb repressive complex 2 (PRC2) downstream of MLL-AF9 epigenetically silenced MIR139 in AML. Finally, a genome-wide CRISPR-Cas9 knockout screen revealed RNA Polymerase 2 Subunit M (POLR2M) as a novel MIR139-regulatory factor. Our findings elucidate the molecular control of tumor suppressor MIR139 and reveal a role for POLR2M in the MIR139-silencing mechanism, downstream of MLL-AF9 and PRC2 in AML. In addition, we confirmed these findings in human AML cell lines with different oncogenic aberrations, suggesting that this is a more common oncogenic mechanism in AML. Our results may pave the way for new targeted therapy in AML.
Half the patients with acute myeloid leukemia (AML) who achieve complete remission (CR), ultimately relapse. Residual treatment-surviving leukemia is considered responsible for the outgrowth of AML. ...In many retrospective studies, detection of minimal residual disease (MRD) has been shown to enable identification of these poor-outcome patients by showing its independent prognostic impact. Most studies focus on molecular markers or analyze data in retrospect. This study establishes the value of immunophenotypically assessed MRD in the context of a multicenter clinical trial in adult AML with sample collection and analysis performed in a few specialized centers.
In adults (younger than age 60 years) with AML enrolled onto the Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research Acute Myeloid Leukemia 42A study, MRD was evaluated in bone marrow samples in CR (164 after induction cycle 1, 183 after cycle 2, 124 after consolidation therapy).
After all courses of therapy, low MRD values distinguished patients with relatively favorable outcome from those with high relapse rate and adverse relapse-free and overall survival. In the whole patient group and in the subgroup with intermediate-risk cytogenetics, MRD was an independent prognostic factor. Multivariate analysis after cycle 2, when decisions about consolidation treatment have to be made, confirmed that high MRD values (> 0.1% of WBC) were associated with a higher risk of relapse after adjustment for consolidation treatment time-dependent covariate risk score and early or later CR.
In future treatment studies, risk stratification should be based not only on risk estimation assessed at diagnosis but also on MRD as a therapy-dependent prognostic factor.
Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need ...for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative.
We set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs.
Here, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs.
This study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.
Objectives
Antimicrobial resistance (AMR) is a public health threat associated with antibiotic consumption. Community-acquired acute respiratory tract infections (CA-ARTIs) are a major driver of ...antibiotic consumption in primary care. We aimed to quantify the investments required for a large-scale rollout of point-of care (POC) diagnostic testing in Dutch primary care, and the impact on AMR due to reduced use of antibiotics.
Methods
We developed an individual-based model that simulates consultations for CA-ARTI at GP practices in the Netherlands and compared a scenario where GPs test all CA-ARTI patients with a hypothetical diagnostic strategy to continuing the current standard-of-care for the years 2020–2030. We estimated differences in costs and future AMR rates caused by testing all patients consulting for CA-ARTI with a hypothetical diagnostic strategy, compared to the current standard-of-care in GP practices.
Results
Compared to the current standard-of-care, the diagnostic algorithm increases the total costs of GP consultations for CA-ARTI by 9% and 19%, when priced at €5 and €10, respectively. The forecast increase in
Streptococcus pneumoniae
resistance against penicillins can be partly restrained by the hypothetical diagnostic strategy from 3.8 to 3.5% in 2030, albeit with considerable uncertainty.
Conclusions
Our results show that implementing a hypothetical diagnostic strategy for all CA-ARTI patients in primary care raises the costs of consultations, while lowering antibiotic consumption and AMR. Novel health-economic methods to assess and communicate the potential benefits related to AMR may be required for interventions with limited gains for individual patients, but considerable potential related to antibiotic consumption and AMR.
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