MRI in multiple myeloma : a pictorial review of diagnostic and post-treatment findings

Magnetic resonance imaging (MRI) is increasingly being used in the diagnostic work-up of patients with multiple myeloma. Since 2014, MRI findings are included in the new diagnostic criteria proposed by the International Myeloma Working Group. Patients with smouldering myeloma presenting with more than one unequivocal focal lesion in the bone marrow on MRI are considered having symptomatic myeloma requiring treatment, regardless of the presence of lytic bone lesions. However, bone marrow evaluation with MRI offers more than only morphological information regarding the detection of focal lesions in patients with MM. The overall performance of MRI is enhanced by applying dynamic contrast-enhanced MRI and diffusion weighted imaging sequences, providing additional functional information on bone marrow vascularization and cellularity. This pictorial review provides an overview of the most important imaging findings in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma, by performing a 'total' MRI investigation with implications for the diagnosis, staging and response assessment. Main message aEuro cent Conventional MRI diagnoses multiple myeloma by assessing the infiltration pattern. aEuro cent Dynamic contrast-enhanced MRI diagnoses multiple myeloma by assessing vascularization and perfusion. aEuro cent Diffusion weighted imaging evaluates bone marrow composition and cellularity in multiple myeloma. aEuro cent Combined morphological and functional MRI provides optimal bone marrow assessment for staging. aEuro cent Combined morphological and functional MRI is of considerable value in treatment follow-up

BetaZero: Belief-State Planning for Long-Horizon POMDPs using Learned Approximations

Real-world planning problems\unicode{x2014}including autonomous driving and sustainable energy applications like carbon storage and resource exploration\unicode{x2014}have recently been modeled as partially observable Markov decision processes (POMDPs) and solved using approximate methods. To solve high-dimensional POMDPs in practice, state-of-the-art methods use online planning with problem-specific heuristics to reduce planning horizons and make the problems tractable. Algorithms that learn approximations to replace heuristics have recently found success in large-scale problems in the fully observable domain. The key insight is the combination of online Monte Carlo tree search with offline neural network approximations of the optimal policy and value function. In this work, we bring this insight to partially observed domains and propose BetaZero, a belief-state planning algorithm for POMDPs. BetaZero learns offline approximations based on accurate belief models to enable online decision making in long-horizon problems. We address several challenges inherent in large-scale partially observable domains; namely challenges of transitioning in stochastic environments, prioritizing action branching with limited search budget, and representing beliefs as input to the network. We apply BetaZero to various well-established benchmark POMDPs found in the literature. As a real-world case study, we test BetaZero on the high-dimensional geological problem of critical mineral exploration. Experiments show that BetaZero outperforms state-of-the-art POMDP solvers on a variety of tasks.Comment: 20 page

Changing the script: a typology of Dutch theatre manuscripts in the Southern Low Countries, and the interaction between manuscript and print (Seventeenth–Eighteenth centuries)

NWO016.Veni.195.371Medieval and Early Modern Studie

Fresh-blood-free diet for rearing malaria mosquito vectors

Mosquito breeding depends on the supply of fresh vertebrate blood, a major bottleneck for large-scale production of Anopheles spp. Feeding alternatives to fresh blood are thus a priority for research, outdoor large-cage trials and control interventions. Several artificial meal compositions were tested and Anopheles oogenesis, egg laying and development into the next generation of adult mosquitoes were followed. We identified blood-substitute-diets that supported ovarian development, egg maturation and fertility as well as, low progeny larval mortality, and normal development of offspring into adult mosquitoes. The formulated diet is an effective artificial meal, free of fresh blood that mimics a vertebrate blood meal and represents an important advance for the sustainability of Anopheles mosquito rearing in captivity.Agência financiadora / Número do subsídio Bill and Melinda Gates Foundation OPP1138841 Fundacao para a Ciencia e Tecnologia GHTM - UID/Multi/04413/201 CCMAR - UID/Multi/04326/2013 UID/Multi/04326/2013 RF SFRH/BPD/89811/2012 FAPEAM, Brazil 19716.UNI472.2459.20022014info:eu-repo/semantics/publishedVersio

Modeling continental US stream water quality using long-short term memory and weighted regressions on time, discharge, and season

The temporal dynamics of solute export from catchments are challenging to quantify and model due to confounding hydrological and biogeochemical processes and sparse measurements. Conventionally, the concentration-discharge relationship (C-Q) and statistical approaches to describe it, such as the Weighted Regressions on Time, Discharge and Seasons (WRTDS), have been widely used. Recently, deep learning (DL) approaches, especially Long-Short-Term-Memory (LSTM) models, have shown predictive capability for discharge, temperature, and dissolved oxygen. However, it is not clear if such advances can be expanded to water quality variables driven by complex subsurface biogeochemical processes. This work evaluates the performance of LSTM and WRTDS for 20 water quality variables across ~500 catchments in the continental US. We find that LSTM does not markedly outperform WRTDS in our dataset, potentially limited by the current measurement capabilities of water quality across CONUS. Both models present similar performance patterns across water quality variables, with the LSTM displaying better performance for nutrients compared to weathering-derived solutes. Additionally, the LSTM does not benefit from flexibility in the inputs. For example, incorporation of climate data that constrains streamflow generation, does not significantly improve the LSTM performance. We also find that data availability is not a straightforward predictor of LSTM model performance, although higher availability tends to stabilize performance. To fully assess the potential of the LSTM model, it may be necessary to use a higher frequency dataset across the CONUS, which does not exist today. To evaluate the dynamics of C-Q patterns relative to model performance, we introduce a “simplicity index” considering both the seasonality in the concentration pattern and the linearity in the C-Q relationship, or the C-Q-t pattern. The simplicity index is strongly correlated with model performance and differentiates the underlying controls on water quality dynamics. Further DL experiments and model-intercomparison highlight the strengths and deficiencies of existing frameworks, pointing to the need for further hydrogeochemical theories that are amenable to complex basins and solutes

Optimizing Carbon Storage Operations for Long-Term Safety

To combat global warming and mitigate the risks associated with climate change, carbon capture and storage (CCS) has emerged as a crucial technology. However, safely sequestering CO2 in geological formations for long-term storage presents several challenges. In this study, we address these issues by modeling the decision-making process for carbon storage operations as a partially observable Markov decision process (POMDP). We solve the POMDP using belief state planning to optimize injector and monitoring well locations, with the goal of maximizing stored CO2 while maintaining safety. Empirical results in simulation demonstrate that our approach is effective in ensuring safe long-term carbon storage operations. We showcase the flexibility of our approach by introducing three different monitoring strategies and examining their impact on decision quality. Additionally, we introduce a neural network surrogate model for the POMDP decision-making process to handle the complex dynamics of the multi-phase flow. We also investigate the effects of different fidelity levels of the surrogate model on decision qualities

Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma

Aplidin® is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects of Aplidin in the syngeneic 5T33MM model, which is representable for the human disease. In vitro, Aplidin inhibited 5T33MMvv DNA synthesis with an IC50 of 3.87 nM. On cell-cycle progression, the drug induced an arrest in transition from G0/G1 to S phase, while Western blot showed a decreased cyclin D1 and CDK4 expression. Furthermore, Aplidin induced apoptosis by lowering the mitochondrial membrane potential, by inducing cytochrome c release and by activating caspase-9 and caspase-3. For the in vivo experiment, 5T33MM-injected C57Bl/KaLwRij mice were intraperitoneally treated with vehicle or Aplidin (90 μg kg−1 daily). Chronic treatment with Aplidin was well tolerated and reduced serum paraprotein concentration by 42% (P<0.001), while BM invasion with myeloma cells was decreased by 35% (P<0.001). Aplidin also reduced the myeloma-associated angiogenesis to basal values. This antiangiogenic effect was confirmed in vitro and explained by inhibition of endothelial cell proliferation and vessel formation. These data indicate that Aplidin is well tolerated in vivo and its antitumour and antiangiogenic effects support the use of the drug in multiple myeloma

Extramedullary disease in multiple myeloma: a systematic literature review

Extramedullary involvement (or extramedullary disease, EMD) represents an aggressive form of multiple myeloma (MM), characterized by the ability of a clone and/or subclone to thrive and grow independent of the bone marrow microenvironment. Several different definitions of EMD have been used in the published literature. We advocate that true EMD is restricted to soft-tissue plasmacytomas that arise due to hematogenous spread and have no contact with bony structures. Typical sites of EMD vary according to the phase of MM. At diagnosis, EMD is typically found in skin and soft tissues; at relapse, typical sites involved include liver, kidneys, lymph nodes, central nervous system (CNS), breast, pleura, and pericardium. The reported incidence of EMD varies considerably, and differences in diagnostic approach between studies are likely to contribute to this variability. In patients with newly diagnosed MM, the reported incidence ranges from 0.5% to 4.8%, while in relapsed/refractory MM the reported incidence is 3.4 to 14%. Available data demonstrate that the prognosis is poor, and considerably worse than for MM without soft-tissue plasmacytomas. Among patients with plasmacytomas, those with EMD have poorer outcomes than those with paraskeletal involvement. CNS involvement is rare, but prognosis is even more dismal than for EMD in other locations, particularly if there is leptomeningeal involvement. Available data on treatment outcomes for EMD are derived almost entirely from retrospective studies. Some agents and combinations have shown a degree of efficacy but, as would be expected, this is less than in MM patients with no extramedullary involvement. The paucity of prospective studies makes it difficult to justify strong recommendations for any treatment approach. Prospective data from patients with clearly defined EMD are important for the optimal evaluation of treatment outcomes

Extramedullary disease in multiple myeloma: a systematic literature review

Extramedullary involvement (or extramedullary disease, EMD) represents an aggressive form of multiple myeloma (MM), characterized by the ability of a clone and/or subclone to thrive and grow independent of the bone marrow microenvironment. Several different definitions of EMD have been used in the published literature. We advocate that true EMD is restricted to soft-tissue plasmacytomas that arise due to hematogenous spread and have no contact with bony structures. Typical sites of EMD vary according to the phase of MM. At diagnosis, EMD is typically found in skin and soft tissues; at relapse, typical sites involved include liver, kidneys, lymph nodes, central nervous system (CNS), breast, pleura, and pericardium. The reported incidence of EMD varies considerably, and differences in diagnostic approach between studies are likely to contribute to this variability. In patients with newly diagnosed MM, the reported incidence ranges from 0.5% to 4.8%, while in relapsed/refractory MM the reported incidence is 3.4 to 14%. Available data demonstrate that the prognosis is poor, and considerably worse than for MM without soft-tissue plasmacytomas. Among patients with plasmacytomas, those with EMD have poorer outcomes than those with paraskeletal involvement. CNS involvement is rare, but prognosis is even more dismal than for EMD in other locations, particularly if there is leptomeningeal involvement. Available data on treatment outcomes for EMD are derived almost entirely from retrospective studies. Some agents and combinations have shown a degree of efficacy but, as would be expected, this is less than in MM patients with no extramedullary involvement. The paucity of prospective studies makes it difficult to justify strong recommendations for any treatment approach. Prospective data from patients with clearly defined EMD are important for the optimal evaluation of treatment outcomes