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Objective: Relapsed/refractory multiple myeloma (MM) has poor outcomes, especially in heavily pretreated patients. Limited data exists on the use of novel therapies in MM patients with renal dysfunction. This case series describes the successful initiation of teclistamab in four patients with heavily pre-treated MM on hemodialysis (HD). Data Sources: The medical records of four adult MM patients on HD who received teclistamab were retrospectively reviewed. Data Summary: All patients completed teclistamab step-up dosing and received at least one full dose. HD runs were administered irrespective of teclistamab initiation. Patients tolerated therapy well, with only one patient experiencing grade 1 CRS, which was managed with supportive care. Conclusions: Due to the complexity of this patient population, close monitoring and multidisciplinary care are crucial. This approach is essential for effectively managing MM patients with renal dysfunction and for exploring novel treatment options. [ABSTRACT FROM AUTHOR]

Psychotherapy based on depth psychology (TP) and analytical psychotherapy (AP) can be understood as psychoanalytic applications which share a large number of common grounds; however, they focus on different emphases as far as the methods of treatment are concerned. The theoretical models of AP employed to understand the therapeutic process and its mode of action can therefore not simply be applied to TP, unless they are understood to be the analytical variant of "psychoanalysis light" (Rudolf 2019). Against the background of the TP setting, specific aspects of the treatment techniques which are also central to TP are described and are investigated as to what extent they might contribute to the therapeutic effectiveness of TP treatment. In addition to supportive interventions and the activation of resources the focus is on the conceptional understanding of the therapeutic relationship and the problem of how structural changes might best be achieved even though regression in the therapeutic process is limited and the analysis of the transfer is not a core aspect. By means of case studies the article demonstrates how in a mostly triangulating relationship structure emotional encounter moments (Stern 2005; Plassmann 2019) are created by intensive intersubjective presence, which are kept at eye level in a dialogic process and constantly initiate small transformative steps of development. [ABSTRACT FROM AUTHOR]

This paper investigates the mechanical properties of carbon‐based nanostructures, in particular graphene, using the FE2${\mathrm{FE}}^{2}$ method. The local boundary value problem is calculated using molecular mechanics and is therefore, in contrast to continuum mechanics, discrete. In the case of graphene as a microstructure, atomistic interactions occur with a range of up to three or more atoms. For the local boundary value problem, a representative volume element is developed that is compatible with the atomistic interactions. Boundary effects resulting from the molecular mechanical consideration are eliminated. Boundary conditions compatible with the Hill–Mandel condition are formulated for the local boundary value problem. The results are verified with fully atomistic simulations. [ABSTRACT FROM AUTHOR]

Recent years have seen a widespread integration of technology into the daily lives of families. Psychological science has recently started to focus on the use of smartphones by parents while they are engaged in parenting activities, a behavior known under the terms "phubbing," "technoference," "parental screen distraction," and various other terms. We argue that understanding the real impact of co‐present smartphone use by parents is inhibited by problems related to the conceptualization and methodology employed in empirical studies. In the present commentary, we identify the features of current research that may contribute to the theory crisis and hamper the progress of psychological research. Specifically, we discuss the implications of (a) inconsistent conceptualization of the phenomenon and (b) suboptimal operationalizations that may prevent us from understanding what is being studied and call for greater consideration of definitional clarity and valid operationalization in future research. [ABSTRACT FROM AUTHOR]

Synchrotron radiation losses are a significant cause of concern for high-temperature aneutronic fusion reactions such as proton–Boron 11. The fact that radiation losses occur primarily in the high-energy tail, where the radiation itself has a substantial impact on the electron distribution, necessitates a self-consistent approach to modeling the diffusion and drag induced by synchrotron absorption and emission. Furthermore, an accurate model must account for the fact that the radiation emission spectrum is momentum-dependent, and the plasma opacity is frequency-dependent. Here, we present a simple Fokker–Planck operator, built on a newly solved-for blackbody synchrotron diffusion operator, which captures all relevant features of the synchrotron radiation. Focusing on magnetic mirror fusion plasmas, we show that significant suppression of the electron distribution occurs for relativistic values of the perpendicular electron momentum, which therefore emit much less radiation than predicted under the assumption of a Maxwell–Jüttner distribution. [ABSTRACT FROM AUTHOR]

Charged particles interacting with electromagnetic waves have a portion of their energy tied up in wave-driven oscillations. When these waves are localized to the exhaust of linear magnetic confinement systems, this ponderomotive effect can be utilized to enhance particle confinement. The same effect can be derived for particles moving via an E × B drift into a region of a static perturbation to the electromagnetic fields which has a large wave vector component in the direction of the motion. In this work, we use a simplified slab model to self-consistently solve for the electromagnetic fields within the fluid flowing plasma of a static flute-like ( k ∥ = 0) perturbation and evaluate the resulting ponderomotive potential. We find that two types of perturbations can exist within the flowing plasma, which are an O wave and an X wave in the frame moving with the fluid. In the case of tenuous plasma, these perturbations are magnetostatic or electrostatic multipole-analog perpendicular to the guiding magnetic field in the lab frame, respectfully. For denser plasmas, the O wave-like perturbation is screened at the electron skin depth scale, and the X wave-like perturbation is a combination of a similar perpendicular electric perturbation and parallel magnetic perturbation. The ponderomotive potential generated in the X wave-like case is gyrofrequency-dependent and can be used as either potential barriers or potential wells, depending on the direction of the flow velocity. [ABSTRACT FROM AUTHOR]

Inverse opal colorimetric sensors operating on wetting transitions usually rely on physical differences of the infiltrating liquid. Here, we exploit a reactive surface chemistry that changes wettability upon binding of an analyte. Upon binding of Fe3+ to a Schiff base immobilized on the porous structure, the surface becomes more hydrophilic, triggering the infiltration of the structure and causing the structural color to disappear. [ABSTRACT FROM AUTHOR]

Circuit implementations of neuronal networks so far have been focusing on synaptic weight changes as network growth principles. Besides these weight changes, however, it is also useful to incorporate additional network growth principles such as guided axon growth and pruning. These allow for dynamical signal delays and a higher degree of self-organization, and can thus lead to novel circuit design principles. In this work we develop an ideal, bio-inspired electrical circuit mimicking growth and pruning controlled by guidance cues. The circuit is based on memristively coupled neuronal oscillators. As coupling element, we use memsensors consisting of a general sensor, two gradient sensors, and two memristors. The oscillators and memsensors are arranged in a grid structure, where oscillators and memsensors realize nodes and edges, respectively. This allows for arbitrary 2D growth scenarios with axon growth controlled by guidance cues. Simulation results show that the circuit successfully mimics a biological example in which two neurons initially grow towards two target neurons, where undesired connections are pruned later on. [ABSTRACT FROM AUTHOR]

Neurogenesis involves the precisely coordinated action of genetic programs controlling large-scale neuronal fate specification down to terminal events of neuronal differentiation. The Q neuroblasts in Caenorhabditis elegans , QL on the left and QR on the right, divide, differentiate, and migrate in a similar pattern to produce three neurons each. However, QL on the left migrates posteriorly, and QR on the right migrates anteriorly. The MAB-5 /Hox transcription factor is necessary and sufficient for posterior Q lineage migration and is normally expressed only in the QL lineage. To define genes controlled by MAB-5 in the Q cells, fluorescence-activated cell sorting was utilized to isolate populations of Q cells at a time in early L1 larvae when MAB-5 first becomes active. Sorted Q cells from wild-type, mab-5 loss-of-function (lof), and mab-5 gain-of-function (gof) mutants were subject to RNA-seq and differential expression analysis. Genes enriched in Q cells included those involved in cell division, DNA replication, and DNA repair, consist with the neuroblast stem cell identity of the Q cells at this stage. Genes affected by mab-5 included those involved in neurogenesis, neural development, and interaction with the extracellular matrix. cwn-1 , which encodes a Wnt signaling molecule, showed a paired response to mab-5 in the Q cells: cwn-1 expression was reduced in mab-5 (lof) and increased in mab-5 (gof) , suggesting that MAB-5 is required for cwn-1 expression in Q cells. MAB-5 is required to prevent anterior migration of the Q lineage while it transcriptionally reprograms the Q lineage for posterior migration. Functional genetic analysis revealed that CWN-1 is required downstream of MAB-5 to inhibit anterior migration of the QL lineage, likely in parallel to EGL-20 /Wnt in a noncanonical Wnt pathway. In sum, work here describes a Q cell transcriptome, and a set of genes regulated by MAB-5 in the QL lineage. One of these genes, cwn-1 , acts downstream of mab-5 in QL migration, indicating that this gene set includes other genes utilized by MAB-5 to facilitate posterior neuroblast migration. [ABSTRACT FROM AUTHOR]

Signal formation in a microstructured semiconductor neutron detector is more complex than in planar diode geometry. Three-dimensional microstructures are laterally smaller than the ionization cloud length, and the electric fields may be weak enough to exhibit plasma time effects. This work is the first detailed treatment of charge carrier motion in these complex semiconductor devices to replicate the time profile and signal magnitude. Simulations were performed using COMSOL Multiphysics to investigate various parameters that affect the propagation of the charge cloud. It was observed that the size of the simulated three-dimensional structure had an impact on the induced current pulse, indicating the importance of simulation geometry optimization to accurately simulate charge cloud expansion. COMSOL Multiphysics was used to replicate accurate charge creation profiles using energy deposition information imported from radiation transport codes. A detailed simulation methodology is presented to benchmark preamplifier event pulses along with complexities in modeling the charge carrier motion along the etched microstructured trenches with Si–SiO2 boundary conditions, including fixed oxide charge and interface trapping. [ABSTRACT FROM AUTHOR]

Flows and rotation, particularly E × B rotation, are critical to improving plasma performance, and waves are a primary tool of plasma control. Thus, it is paramount to understand under what conditions waves can drive E × B flows in plasmas. In this didactic review, an invited paper accompanying the 2023 Marshall N. Rosenbluth Doctoral Thesis Award, this question is answered in the context of momentum-conserving quasilinear theory. There are two primary frameworks for momentum-conserving quasilinear theories that can handle both resonant and nonresonant particles: Eulerian averaging theories and oscillation-center Hamiltonian theories. There are also two different paradigmatic wave problems: plane-wave initial value problems, and steady-state boundary value problems. Here, it is shown that each of these frameworks "naturally" works better with a different problem type. By using these theories, one finds a great difference in the behavior of time- vs space-dependent waves. A time-evolving plane wave can only drive flow if the electromagnetic momentum of the wave, given by the Poynting flux, changes. This result precludes flow drive by any planar electrostatic wave. In contrast, a steady-state spatially evolving wave can drive flow whenever there is divergence in the flux of Minkowski momentum, a completely different physical quantity. This review aims to provide a high-level, intuitive understanding of the very different behaviors observed for these two types of problem. [ABSTRACT FROM AUTHOR]

We present an analytical framework aimed at predicting the local brain activity in uncontrolled experimental conditions based on multimodal recordings of participants' behavior, and its application to a corpus of participants having conversations with another human or a conversational humanoid robot. The framework consists in extracting high-level features from the raw behavioral recordings and applying a dynamic prediction of binarized fMRI-recorded local brain activity using these behavioral features. The objective is to identify behavioral features required for this prediction, and their relative weights, depending on the brain area under investigation and the experimental condition. In order to validate our framework, we use a corpus of uncontrolled conversations of participants with a human or a robotic agent, focusing on brain regions involved in speech processing, and more generally in social interactions. The framework not only predicts local brain activity significantly better than random, it also quantifies the weights of behavioral features required for this prediction, depending on the brain area under investigation and on the nature of the conversational partner. In the left Superior Temporal Sulcus, perceived speech is the most important behavioral feature for predicting brain activity, regardless of the agent, while several features, which differ between the human and robot interlocutors, contribute to the prediction in regions involved in social cognition, such as the TemporoParietal Junction. This framework therefore allows us to study how multiple behavioral signals from different modalities are integrated in individual brain regions during complex social interactions. [ABSTRACT FROM AUTHOR]

Eukaryotic genomes are organized by loop extrusion and sister chromatid cohesion, both mediated by the multimeric cohesin protein complex. Understanding how cohesin holds sister DNAs together, and how loss of cohesion causes age-related infertility in females, requires knowledge as to cohesinÕs stoichiometry in vivo. Using quantitative super-resolution imaging, we identified two discrete populations of chromatin-bound cohesin in postreplicative human cells. Whereas most complexes appear dimeric, cohesin that localized to sites of sister chromatid cohesion and associated with sororin was exclusively monomeric. The monomeric stoichiometry of sororin:cohesin complexes demonstrates that sister chromatid cohesion is conferred by individual cohesin rings, a key prediction of the proposal that cohesion arises from the co-entrapment of sister DNAs. [ABSTRACT FROM AUTHOR]

In the limit of sufficiently fast rotation, rotating mirror traps are known to be stable against the loss-cone modes associated with conventional (non-rotating) mirrors. This paper calculates how quickly a mirror configuration must rotate in order for several of these modes to be stabilized (in particular, the high-frequency convective loss cone, drift cyclotron loss cone and Dory–Guest–Harris modes). Commonalities in the stabilization conditions for these modes then motivate a modified formulation of the Gardner free energy and diffusively accessible free energy to be used for systems in which the important modes have wavevectors that are orthogonal or nearly orthogonal to the magnetic field, as well as a modification to include the effects of a loss region in phase space. [ABSTRACT FROM AUTHOR]

Summary: We report on a systematic method for the port‐wise decomposition of electrical networks. Our method exploits the SPQR‐tree decomposition as an algorithmic way for decomposing a given circuit into a maximal set of one‐port and multiports. We provide a solution for representing multiports by suitable replacement graphs, such that they are encapsulated not decomposed or processed by the SPQR‐algorithm. Contrary to current methods, our replacement graphs are not sophisticated but rather simple, which, in general, enhances the performance of the algorithm, when it comes to decomposing large electrical networks containing multiports. Some electrical devices, such as transistors or op‐amps, are commonly described in terms of their terminals rather than their ports. Thus, we cover the application of the template‐based approach to three‐terminal devices. Lastly, we make use of the new decomposition method for the emulation of a wave digital filter. [ABSTRACT FROM AUTHOR]

Hybrid teaching (synchronous online and on-site teaching) offers many advantages (e.g., increased flexibility). However, previous research has suggested that students who join classes online suffer higher levels of distractibility, which might translate into students engaging in more off-task activities. This, in turn, can impair students' learning performance. The following quasi-experimental field study investigated this specific link between teaching mode, engagement in off-task activities, and learning performance. We collected survey data from N = 690 students in six hybrid classes (N = 254 online, N = 436 on-site). Participants reported the amount of time they spent engaging in digital and non-digital off-task activities and responded to a quiz on the course material. Results revealed that online students spent more time engaging in off-task activities than on-site students. Further, results were consistent with our hypothesis that joining the class online is associated with lower learning performance via time spent on digital off-task activities. [ABSTRACT FROM AUTHOR]

Natural gas pipelines represent a critical infrastructure for most countries and thus their safety is of paramount importance. To report potential risks along pipelines, several steps are taken such as manual inspection and helicopter flights; however, these solutions are expensive and the flights are environmentally unfriendly. Deep learning has demonstrated considerable potential in handling a number of tasks in recent years as models rely on huge datasets to learn a specific task. With the increasing number of satellites orbiting the Earth, remote sensing data have become widely available, thus paving the way for automated pipeline monitoring via deep learning. This can result in effective risk detection, thereby reducing monitoring costs while being more precise and accurate. A major hindrance here is the low resolution of images obtained from the satellites, which makes it difficult to detect smaller changes. To this end, we propose to use transformers trained with low-resolution images in a change detection setting to detect pipeline risks. We collect PlanetScope satellite imagery (3 m resolution) that captures certain risks associated with the pipelines and present how we collected the data. Furthermore, we compare various state-of-the-art models, among which ChangeFormer, a transformer architecture for change detection, achieves the best performance with a 70% F1 score. As part of our evaluation, we discuss the specific performance requirements in pipeline monitoring and show how the model's predictions can be shifted accordingly during training. [ABSTRACT FROM AUTHOR]

The synthesis and characterization of three compounds [Rh(η5‐C5Me5)Cl(N^N)]PF6 (N^N=4,4'‐disubstituted‐2,2'‐bipyridines, 1–3) are described. The cationic complexes contain the bidentate ligands N^N=4,4'‐di‐tert‐butyl‐2,2'‐bipyridine (1), N^N=4,4'‐dinonyl‐2,2'‐bipyridine (2) and N^N=4,4'‐diamino‐2,2'‐bipyridine (3). The complex salts were obtained by the bridge‐splitting reaction from the precursor [{Rh(η5‐C5Me5)(μ‐Cl)Cl}2] and subsequent salt metathesis affording their corresponding hexafluorido phosphate salts. All compounds were characterized by elemental analysis and spectroscopic means. Additionally, the molecular structure of compound 3 in the solid was determined by a single‐crystal X‐ray diffraction study. The cytotoxicity of all three compounds was examined by MTT assay against two cancer cell lines – HT‐29 (colon adenocarcinoma) and MCF‐7 (human breast adenocarcinoma) ‐ and normal human fibroblast cells (GM5657T). Compound 1 has moderate cytotoxicity against both cell lines, while compound 2 is seven to nine times more cytotoxic than cisplatin against MCF‐7 and HT‐29, respectively. In contrast to cisplatin, both compounds are more active against cancer cells than fibroblasts, thus showing some cancer selectivity. [ABSTRACT FROM AUTHOR]

Recently, it has been shown that altering the natural collisional power flow of the proton–boron 11 (pB11) fusion reaction can significantly reduce the Lawson product of ion density and confinement time required to achieve ignition. However, these products are still onerous—on the order of 7 × 10 15 cm−3 s under the most optimistic scenarios. Fortunately, a breakeven fusion power plant does not require an igniting plasma, but rather a reactor that produces more electrical power than it consumes. Here, we extend the existing 0D power balance analysis to check the conditions on power plant breakeven. We find that even for the base thermonuclear reaction, modern high-efficiency thermal engines should reduce the Lawson product to 1.2 × 10 15 cm−3 s. We then explore the impact of several potential improvements, including fast proton heating, alpha power capture, direct conversion, and efficient heating. We find that such improvements could reduce the required Lawson product by a further order of magnitude, bringing aneutronic fusion to target ITER ion densities and confinement times. [ABSTRACT FROM AUTHOR]

Background: The number of total knee replacements performed annually is steadily increasing. Parallel options for postoperative care are decreasing, which reduces patient satisfaction. External devices to support physical rehabilitation and health monitoring will improve patient satisfaction and postoperative care. Methods: In a prospective, international multicenter study, patients were asked to use an external motion sensor and a smartphone application during the postoperative course of primary total knee arthroplasty. The collected data were transferred to a data platform, allowing for the real-time evaluation of patient data. Results: In three participating centers, 98 patients were included. The general acceptance of using the sensor and app was high, with an overall compliance in study participation rate of up to 76%. The early results showed a significant improvement in the overall quality of life (p < 0.001) and significant reductions in pain (p < 0.01) and depression (p < 0.001). Conclusions: The early results of this clinical and multicenter study emphasize that there is a high interest in and acceptance of digital solutions in patients' treatment pathways. Motion sensor and smartphone applications support patients in early rehabilitation. [ABSTRACT FROM AUTHOR]

False alarm resistant smoke detectors must pass the inflight smoke-detection certification test for implementation in aircraft. Inflight certification testing uses artificial smoke generators due to health and safety. Currently, there are no objective parameters to quantify an artificial smoke generator's aerosol production for certification testing. Therefore, this study's design was to create a framework for potential guidelines for standardizing an artificial smoke generator's aerosol production. Although the aerosols created by artificial smoke generators look like real smoke, there are inconsistencies between models that could create smoke detectors not activating during certification testing. Aerosols created by artificial smoke generators must be similar to smoke for many of the false alarm resistant smoke detectors to alarm. Therefore, verifying which artificial smoke generators produce an aerosol with similar particle characteristics to smoke is essential for the implementation of false alarm resistant detectors in aircraft. Furthermore, standardizing the artificial smoke generators for the total quantity of aerosol produced, rate of aerosol production, and repeatability of aerosol production and quantifying the effects of the ambient environment is necessary to ensure the reliability and integrity of the certification test. One possible result of a non-standard aerosol production during certification testing, specifically in regards to an unexpected overabundance of aerosol production, may cause the certification of smoke detection system that would not alarm the specified threat. Conversely, insufficient aerosol production during certification testing could create the requirement of a lower smoke detection threshold than intended, creating an unfair financial burden. This study found that artificial smoke generators produce an aerosol with similar particle size distributions and light scattering characteristics to smoke created by smoldering foam, smoldering wood, and lithium-ion battery thermal runaway vent-gas. Therefore, it is reasonable to conclude that aerosols from the tested artificial smoke generators are capable of alarming most false alarm resistant smoke detectors. Furthermore, there were measurable differences in the total quantity of aerosol produced and the rate of aerosol production between smoke generators used by four major airframe manufacturers for smoke-detection certification testing. In addition, changes in ambient temperature and pressure that may occur during a typical flight profile affected an individual smoke generator's production of aerosol. Sufficiently heating the smoke generator's mineral oil before aerosol production can mitigate the effects of varying ambient temperatures. [ABSTRACT FROM AUTHOR]

There is little research in the field of problematic smartphone use, which directly enquired with users about what they find disturbing about smartphone usage behaviour. This qualitative study addressed sub-critical issues which may be a precursor to more severe problems such as problematic smartphone usage. Ninety-nine participants completed an online questionnaire with open questions regarding disturbing smartphone usage behaviour. Using the method of 'thematic analysis', we identified eight themes that we clustered into two overarching themes: reasons for use and consequences of use. Five themes related to reasons for use, including inevitability, habitual use, avoiding unpleasant circumstances, need satisfaction and fulfilling social expectations. Three themes referred to consequences of smartphone usage (i.e. life management, social life, and online life). Across all themes it appeared that the different aspects of disturbing smartphone usage were triggered and sustained by contextual factors and complex social dynamics, suggesting that participants lack control over their actual usage. Therefore, this research provides a holistic view of the sub-critical issues disturbing participants as well as identifies several mechanisms perpetuating these problems. The listing and description of such sub-critical issues and the different mechanisms are of high importance for prevention and the design of interventions. [ABSTRACT FROM AUTHOR]

Graphene is the thinnest known structure. It consists of a single layer of carbon atoms and has unique mechanical properties. The carbon atoms form bonds with neighbouring atoms that can be described by interatomic potentials. A simulation of molecular mechanical processes can be performed by applying the formalism of the finite element method to the interatomic potentials. Neglecting local effects, a continuum formulation is an efficient alternative to a discrete model. The continuum formulation requires a connection between the discrete atomic lattice and the continuum. One way of doing this is to use the Cauchy–Born rule. This paper reviews the extensions of the Cauchy–Born rule, in particular, the exponential Cauchy–Born rule, and adds an alternative approach. It is shown that all contributions dealing with the exponential Cauchy–Born rule inevitably lead to shell models with Kirchhoff–Love kinematics. The approach presented here instead uses a shell model with Reissner–Mindlin kinematics, which has the major advantage of a much simpler mesh generation and a simpler application of the boundary condition. [ABSTRACT FROM AUTHOR]

BACKGROUND: Dobutamine and adenosine stress cardiac magnetic resonance (CMR) imaging is relatively contraindicated in patients with moderate to severe aortic valve stenosis (AS). We aimed to determine the safety of dobutamine and adenosine stress CMR in patients with moderate to severe AS. METHODS: In this retrospective study patients with AS who underwent either dobutamine or adenosine stress CMR for exclusion of obstructive coronary artery disease were enrolled. We recorded clinical data, CMR and echocardiography findings, and complications as well as minor symptoms. Patients with AS were compared to matched individuals without AS. RESULTS: A total of 187 patients with AS were identified and compared to age-, gender- and body mass index-matched 187 patients without AS. No severe complications were reported in the study nor the control group. The reported frequency of non-severe complications and minor symptoms were similar between the study and the control groups. Nineteen patients with AS experienced non-severe complications or minor symptoms during dobutamine stress CMR compared to eighteen patients without AS (p = 0.855). One patient with AS and two patients without AS undergoing adenosine stress CMR experienced minor symptoms (p = 0.562). Four examinations were aborted because of chest pain, paroxysmal atrial fibrillation and third-degree atrioventricular block. Inducible ischaemia, prior coronary artery bypass grafting, prior stroke and age were associated with a higher incidence of complications and minor symptoms. CONCLUSIONS: Moderate to severe AS was not associated with complications during CMR stress test. The incidence of non-severe complications and minor symptoms was greater with dobutamine. [ABSTRACT FROM AUTHOR]

Introduction: Early afterdepolarizations (EADs) are secondary voltage depolarizations associated with reduced repolarization reserve (RRR) that can trigger lethal arrhythmias. Relating EADs to triggered activity is difficult to study, so the ability to suppress or provoke EADs would be experimentally useful. Here, we use computational simulations to assess the feasibility of subthreshold optogenetic stimulation modulating the propensity for EADs (cell-scale) and EAD-associated ectopic beats (organ-scale). Methods: We modified a ventricular ionic model by reducing rapid delayed rectifier potassium (0.25–0.1 × baseline) and increasing L-type calcium (1.0–3.5 × baseline) currents to create RRR conditions with varying severity. We ran simulations in models of single cardiomyocytes and left ventricles from post-myocardial infarction patient MRI scans. Optogenetic stimulation was simulated using either ChR2 (depolarizing) or GtACR1 (repolarizing) opsins. Results: In cell-scale simulations without illumination, EADs were seen for 164 of 416 RRR conditions. Subthreshold stimulation of GtACR1 reduced EAD incidence by up to 84.8% (25/416 RRR conditions; 0.1 μW/mm2); in contrast, subthreshold ChR2 excitation increased EAD incidence by up to 136.6% (388/416 RRR conditions; 50 μW/mm2). At the organ scale, we assumed simultaneous, uniform illumination of the epicardial and endocardial surfaces. GtACR1-mediated suppression (10–50 μW/mm2) and ChR2-mediated unmasking (50–100 μW/mm2) of EAD-associated ectopic beats were feasible in three distinct ventricular models. Conclusions: Our findings suggest that optogenetics could be used to silence or provoke both EADs and EAD-associated ectopic beats. Validation in animal models could lead to exciting new experimental regimes and potentially to novel anti-arrhythmia treatments. [ABSTRACT FROM AUTHOR]

Neuron models exist in different levels of complexity and biological modeling depth. The Hindmarsh–Rose model offers a rich repertoire of neuronal dynamics while being moderately mathematically complex. Existing circuit realizations of this neuron model, however, require a large amount of operational amplifiers due to the model's quadratic and cubic nonlinearity. In contrast to hardware realizations of simpler neuron models, this leads to a higher power consumption. In this work, the Hindmarsh–Rose model is approximated by an ideal electrical circuit that relies mostly on passive circuit elements and thus reduces the power consumption. For this purpose, we analyze the power flows of an equivalent electrical circuit of the Hindmarsh–Rose model and replace several nonlinear circuit elements by constant ones. Moreover, we approximate the cubic nonlinearity by three memristors in combination with a negative impedance converter. This negative impedance converter represents the only active circuit element required for the complete circuit, leading to an increased energy efficiency compared to the existing circuit realizations. Simulations verify the circuit's ability to generate spiking and bursting dynamics comparable to the original Hindmarsh–Rose model. [ABSTRACT FROM AUTHOR]

The synthesis and characterization of four compounds [M(η5‐C5Me5)(N^N)Cl]PF6 [N^N=4,7‐dichloro‐1,10‐phenanthroline with M=Rh, 1, and M=Ir, 2, and N^N=4'‐(4‐chlorophenyl)‐2,2':6',2''‐terpyridine in the κ2N,N'‐coordination mode with M=Rh, 3, and M=Ir, 4] are described. All compounds were characterized by spectroscopic means and their molecular structures in the crystal were confirmed by single‐crystal X‐ray diffraction studies. The cytotoxicity of all compounds was evaluated by MTT assay against the three cancer cell lines HeLa (cervical carcinoma), HT‐29 (colon adenocarcinoma) and MCF‐7 (human breast adenocarcinoma). The complexes 3 and 4 display promising activity with IC50 values of 1 μM. The rhodium(III) complex 1 also shows highly improved cytotoxicity compared to cisplatin against the cancer cell lines HT‐29 and MCF‐7. In contrast to this, the iridium(III) complex 2 is even less active against the HeLa cell line than cisplatin. [ABSTRACT FROM AUTHOR]

The study examines the impact of various types of performance-based funding (PBF) policies on institutional resources across postsecondary institution types. Although 41 states have implemented PBF over time, the design and dosage of PBF policies look very different across PBF-adopting states. We leverage multiple quasi-experimental approaches and find that high-dosage PBF policies had a negative impact on state funding for four-year historically Black colleges and universities (HBCUs) and four-year institutions serving an above-average share of racially minoritized students. We also show that sporadic positive effects of PBF policies on state funding are concentrated primarily among non-minority serving institutions (non-MSIs) and institutions serving below-average shares of racially minoritized or low-income students. Taken together, our findings reveal the unequal impacts of PBF policies and suggest that PBF policy design is an important consideration with critical implications for under-resourced institutions and the underserved students they educate. [ABSTRACT FROM AUTHOR]

DeFalco concludes I Invisible Atrocities i with a challenge for readers to reflect on exactly what constitutes an atrocity, and to consider 'the possibility that international crimes may manifest themselves in ways that may depart radically from our intuitive understandings of them.'[29] In my opinion, DeFalco's challenge is one that should be readily accepted by all readers. The presence of this aesthetic bias is especially problematic, in DeFalco's opinion, because the prosecution of the most visible crimes does not necessarily mean the prosecution of the most horrific or widespread crimes. [Extracted from the article]

Summary: The standard van Neumann computer excels at many things. However, it can be very inefficient in solving optimization problems with a large solution space. For that reason, a novel analog approach, the oscillator‐based Ising machine, has been proposed as a better alternative for dealing with such problems. In this work, we review the concept of oscillator‐based Ising machine and address how optimization problems can be mapped onto such machines when the quadratic unconstrained binary optimization (QUBO) formulation is given. Furthermore, we provide an ideal circuit that can be used in combination with the wave digital concept for real‐time simulated annealing. The functionality of this circuit is explained on the basis of a Lyapunov stability analysis. The latter also provides an answer for the decision‐making question: When has the Ising machine solved a mapped problem? At the end, we provide emulation results demonstrating the correlation between functionality and stability. Our results are based on an eigenvalue analysis of the linearized system and demonstrate that all eigenvalues converge to the left complex half plane, once an optimization problem has been optimally solved. This implies that the system enters an attractor region and is hence forced to eventually converge to the optimal solution. [ABSTRACT FROM AUTHOR]

The Tamins rock avalanche lies adjacent to the Flims rock avalanche, the largest in the Alps. Its deposit forms a ridge across the Rhine Valley just downstream of the confluence of the Vorderrhein and Hinterrhein rivers. The deposit is dominated by a 1.6-km-long longitudinal ridge, Ils Aults, and two roughly 600-m-long transverse ridges. Several extensional scarps bear witness to spreading of the deposit. A breach through the deposit, where the Rhine River presently flows, reveals a carapace and intense fragmentation. Exposure dating using cosmogenic 36Cl yields an age of 9420 ± 880 years. This suggests that the Tamins event occurred in a time frame similar to the Flims event but was slightly earlier than the Flims rock avalanche, as also required by stratigraphic relationships. 3D volume modeling reveals bulking of only 14%. The motion of the rock avalanche seems to have occurred first as a flexible block, which underwent fragmentation and simple shearing where the top moved faster than the bottom. The ensuing spreading led to the formation of extensional scarps. There is no identified weak layer along the sliding surface; nevertheless, modeling suggests a friction angle of 10°. [ABSTRACT FROM AUTHOR]

Advanced aneutronic fusion fuels such as proton-Boron11 tend to require much higher temperatures than conventional fuels like deuterium–tritium. For electrons, the bulk plasma temperature can approach a substantial fraction of the rest mass. In a mirror confinement system, where the electrons are confined by an ambipolar potential of at least five electron temperatures, the tail electrons which can escape the potential are fully relativistic, which must be taken into account in calculating their confinement. In this paper, simple estimates are employed to extend the scaling of the confinement time into the relativistic regime. By asymptotically matching this scaling to known solutions in the non-relativistic limit, accurate forms for the confinement time (and thus, the ambipolar potential) are obtained. These forms are verified using finite-element-based Fokker–Planck simulations over a wide range of parameters. Comparing relativistic and nonrelativistic mirror-confined plasmas with the same ratio of confining potential | e ϕ | to electron temperature Te and the same mirror ratio R, the net result is a decrease in the confinement time due to relativistic effects by a factor of S ≡ (1 + 15 T e / 8 m e c 2) / (1 + 2 | e ϕ | / m e c 2). [ABSTRACT FROM AUTHOR]

The noted Jewish scholar Harry Wolfson (d. 1929) claimed in youthful writings that the fifteenth‐century rabbinic thinker and physicist, Hasdai Crescas, was a pragmatist. This essay introduces evidence that there are, indeed, significant analogies between elements of Hasdai Crescas's critique of Aristotle and elements of Charles Peirce's pragmatism. The essay concludes that Crescas's primary work, Light of the Lord (Or Hashem), displays a unique analogue to classical American pragmatism, which analogue I label "rabbinic pragmatism" and classify as a subtype of "Jewish pragmatism." The essay's central hypothesis is that Crescas's scientific reasoning is correlative to his Torah‐based reasoning. A second hypothesis is that the enabling conditions of this correlativity are the inquirer's relation to God as author of Creation and of the Commandments (mitzvah). I argue that Crescas's non‐finite mathematics (a potential source for Galileo) is correlative to his account of the non‐finite meanings of each Commandment so that each command displays fresh meanings in each new context of life. [ABSTRACT FROM AUTHOR]

The synthesis and characterization of six new organometallic half‐sandwich iridium(III) compounds containing modified 4,4'‐substituted 2,2'‐bipyridines as the bidentate co‐ligands were described. Thus the compounds [Ir(η5‐C5Me5)(N^N)Cl]PF6 [N^N: 4,4'‐bpy‐Ph, 1; 4,4'‐bpy‐Me, 2; 4,4'‐bpy‐nonyl, 3; 4,4'‐bpy‐CH2OH, 4; 4,4'‐bpy‐Cl, 5; 4,4'‐bpy‐NH2, 6 were obtained by bridge‐splitting reactions from the precursor [{Ir(η5‐C5Me5)(μ‐Cl)Cl}2] with the corresponding bidentate bipyridines. The X‐ray single‐crystal structures of compounds 1, 2, 4 and 6 in the solid state were determined. To evaluate the cytotoxic properties of all six compounds, colorimetric assays (MTT assay) against two cancer cell lines, MCF‐7 and HT‐29, were performed. Most promising results were achieved for compounds 1 and 3 with nonpolar phenyl or nonyl group attached to the bipyridine ligand, while the substitution with less lipophilic groups led to the inactivation of the compound. The most remarkable biological activity showed compound 3 with an IC50 value in the low macromolecular range and >40‐fold enhanced toxicity compared to cisplatin against both cell lines. [ABSTRACT FROM AUTHOR]

The modeling of real neuronal networks by close‐to‐biology circuits can contribute to a better understanding of these networks from a circuit theoretical point of view. This can potentially lead to novel design principles for electrical circuits. This modeling process involves the mimicking of real measured neuronal activity, which is often only available as calcium imaging recordings. In this work, we develop a wave digital model as a circuit emulator capable of mimicking the calcium‐imaging‐based neuronal activity of mouse neurons. For this purpose, we design an electrical reference circuit of a mouse neuron based on an extended Morris–Lecar model in combination with an RC circuit. The circuit parameters are determined by a parameter scaling without requiring any parameter optimization. The input signal of the resulting wave digital model is designed based on estimating spike times with the spike inference software MLspike. Wave digital emulations show the successful mimicking of calcium‐based neuronal activity for mouse neurons located in the visual, motor and somatosensory cortex as well the possibility to predict ion currents occurring during this activity. This proves the suitability of the reference circuit as a model for the considered types of mouse neurons. It also implies that the circuit can act as an observer for electrical signals of mouse neurons. This is achieved despite the lack of electrophysiological measurements in most cases. Hence, the proposed wave digital model can be seen as an important step toward being able to verify close‐to‐biology electrical circuits as a model of real neuronal networks without electrophysiology. [ABSTRACT FROM AUTHOR]

Clinical Scenario: Collision sports are often at higher risk of concussion due to the physical nature and style of play. Typically, initial clinical recovery occurs within 7 to 10 days; however, even this time frame may result in significant time lost from play. Little has been done in previous research to analyze how individual game performance may be affected upon return to play postconcussion. Focused Clinical Question: Upon retum-to-play clearance, how does sport-related concussion affect game performance of professional athletes in collision sports? Summary of Key Findings: All 3 studies included found no significant change in individual performance of professional collision-sport athletes upon returning to play from concussive injury. One of the studies indicated that there was no difference in performance for NFL athletes who did not miss a single game (returned within 7 d) and those who missed at least 1 game. One study indicated that although there was no change in performance of NFL players upon returning to play from sustained concussion, there was a decline in performance in the 2 weeks before the diagnosed injury and appearing on the injury report. The final study indicated that there was no difference in performance or style of play of NHL athletes who missed time due to concussive injury when compared with athletes who missed games for a noninjury factor. Clinical Bottom Line: There was no change in performance upon return from concussive injury suggesting that players appear to be acutely recovered from the respective concussion before reluming to play. This suggests that current policies and management properly evaluate and treat concussed athletes of these professional sports. Strength of Recommendation: Grade C evidence exists that there is no change in individual game performance in professional collision-sport athletes before and after suffering a concussion. [ABSTRACT FROM AUTHOR]

When waves damp or amplify on resonant particles in a plasma, nonresonant particles experience a recoil force that conserves the total momentum between particles and electromagnetic fields. This force is important to understand, as it can completely negate current drive and rotation drive mechanisms that are predicted on the basis of only resonant particles. Here, the existing electrostatic theory of this recoil force is extended to electromagnetic waves. While the result bears close similarity to historical fluid theories of laser–plasma interactions, it now incorporates both resonant and nonresonant particles, allowing momentum conservation to be self-consistently proven. Furthermore, the result is shown to be generally valid for kinetic plasmas, which is verified through single-particle hot-plasma simulations. The new form of the force provides physical insight into the nature of the generalized Minkowski (plasmon) momentum of geometrical optics, which is shown to correspond to the momentum gained by the field and nonresonant particles as the wave is self-consistently ramped up from vanishing amplitude. [ABSTRACT FROM AUTHOR]

Initial analysis of the contents of the Laoguanshan manuscripts shows there is an emphasis on a number of healing principles and techniques that have been associated with Bian Que: puncturing the mai -channels to heal disease; diagnosis based on examining the appearance and palpating multiple sites on the body; reverence for the mantic arts, and the superior physician who can correctly "determine whether [the patient] will live or die." These characteristics have been ascribed to Bian Que across a number of domains: through non-medical texts that describe cases or anecdotes, passages in the received medical literature ascribed to a person or lineage with this name, and material evidence from Han dynasty mortuary art. Widespread references to Bian Que in medical and non-medical works indicate that citing the name constituted a recognizable and potent mode of establishing authority. Although we cannot completely reconstruct the medical practices of a person, clan, or mode of authority called "Bian Que," the traces that remain substantiate claims that a set of ideas and practices associated with Bian Que was revered as efficacious healing worthy of study and transmission. [ABSTRACT FROM AUTHOR]

Purpose: This tutorial summarizes current practices using visual--acoustic biofeedback (VAB) treatment to improve speech outcomes for individuals with speech sound difficulties. Clinical strategies will focus on residual distortions of /I/. Method: Summary evidence related to the characteristics of VAB and the populations that may benefit from this treatment are reviewed. Guidelines are provided for clinicians on how to use VAB with clients to identify and modify their productions to match an acoustic representation. The clinical application of a linear predictive coding spectrum is emphasized. Results: Successful use of VAB requires several key factors including clinician and client comprehension of the acoustic representation, appropriate acoustic target and template selection, as well as appropriate selection of articulatory strategies, practice schedules, and feedback models to scaffold acquisition of new speech sounds. Conclusion: Integrating a VAB component in clinical practice offers additional intervention options for individuals with speech sound difficulties and often facilitates improved speech sound acquisition and generalization outcomes. Supplemental Material: https://doi.org/10.23641/asha.21817722 [ABSTRACT FROM AUTHOR]

This field experiment aimed to address the issue of problematic smartphone usage (PSU) by examining the effectiveness of two frequently advised techniques to deal with PSU: moving problematic applications to a different page of the phone and changing the phone into greyscale. For one week, 97 student participants used their smartphone under one of the following three conditions: move app, greyscale, or control condition. Compared to the week before the intervention, participants significantly reduced their objective smartphone usage, but their self-reported PSU increased. These effects also emerged in the control group, which might have been due to heightened awareness of the participants of their smartphone usage. A major implication of the study is the need of using multiple outcome measures to understand the complex relationship between perceptions and behaviour. This study could be used as a blueprint for future research examining the effectiveness of interventions in the field of PSU. [ABSTRACT FROM AUTHOR]

Simple and fast dynamic model for the prediction of PV self‐consumption The widespread use of renewable energy plays a crucial role in increasing the energy efficiency of the building stock. The significantly decreased PV system prices and the high flexibility in electricity use for all loads in a building, i.e., space heating (and cooling) and domestic hot water in combination with heat pumps, auxiliary energies, household appliances, and also increasingly electric mobility leads to a wide use of PV. However, the integration of PV into the building is complex and requires the use of electrical and/or thermal energy storage and appropriate control strategies. Therefore, evaluating and optimizing the part of PV electricity that is used directly or stored in the building is a challenging task. Thus, for a detailed analysis of PV and energy storage at the building level, extensive building and system simulations were performed using reference buildings. [ABSTRACT FROM AUTHOR]

Background: Data on the prognostic value of left ventricular (LV) morphological and functional parameters including LV rotation in patients with dilated cardiomyopathy (DCM) using cardiovascular magnetic resonance (CMR) are currently scarce. In this study, we assessed the prognostic value of global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS) and LV torsion using CMR feature tracking (FT). Methods: CMR was performed in 350 DCM patients and 70 healthy subjects across 5 different European CMR Centers. Myocardial strain parameters were retrospectively assessed from conventional balanced steady-state free precession cine images applying FT. A combined primary endpoint (cardiac death, heart transplantation, aborted sudden cardiac death) was defined for the assessment of clinical outcome. Results: GLS, GCS, GRS and LV torsion were significantly lower in DCM patients than in healthy subjects (all p < 0.001). The primary endpoint occurred in 59 (18.7%) patients [median follow-up 4.2 (2.0–5.6) years]. In the univariate analyses all strain parameters showed a significant prognostic value (p < 0.05). In the multivariate model, LV strain parameters, particularly GLS provided an incremental prognostic value compared to established CMR parameters like LV ejection fraction and late gadolinium enhancement. A scoring model including six categorical variables of standard CMR and strain parameters differentiated further risk subgroups. Conclusion: LV strain assessed with CMR FT has a high prognostic value in patients with DCM, surpassing routine and dedicated functional parameters. Thus, CMR strain imaging may contribute to the improvement of risk stratification in DCM. [ABSTRACT FROM AUTHOR]

Background: Obesity disproportionately affects African American (AA) women and has been shown to increase ovarian cancer risk, with some suggestions that the association may differ by race.Methods: We evaluated body mass index (BMI) and invasive epithelial ovarian cancer (EOC) risk in a pooled study of case-control and nested case-control studies including AA and White women. We evaluated both young adult and recent BMI (within the last 5 years). Associations were estimated using multi-level and multinomial logistic regression models.Results: The sample included 1078 AA cases, 2582 AA controls, 3240 White cases and 9851 White controls. We observed a higher risk for the non-high-grade serous (NHGS) histotypes for AA women with obesity (ORBMI 30+= 1.62, 95% CI: 1.16, 2.26) and White women with obesity (ORBMI 30+= 1.20, 95% CI: 1.02, 2.42) compared to non-obese. Obesity was associated with higher NHGS risk in White women who never used HT (ORBMI 30+= 1.40, 95% CI: 1.08, 1.82). Higher NHGS ovarian cancer risk was observed for AA women who ever used HT (ORBMI 30+= 2.66, 95% CI: 1.15, 6.13), while in White women, there was an inverse association between recent BMI and risk of EOC and HGS in ever-HT users (EOC ORBMI 30+= 0.81, 95% CI: 0.69, 0.95, HGS ORBMI 30+= 0.73, 95% CI: 0.61, 0.88).Conclusion: Obesity contributes to NHGS EOC risk in AA and White women, but risk across racial groups studied differs by HT use and histotype. [ABSTRACT FROM AUTHOR]

The possibility of fusion ignition in proton–Boron11 plasma is strongly enhanced if the energy from the fusion-produced α particles is channeled to fast protons, but in an environment in which most of the protons are thermally distributed. This hybrid of thermonuclear fusion and beam-plasma fusion offers surprisingly large advantages to either purely thermonuclear or purely beam-plasma fusion, neither of which can by themselves significantly exceed the large bremsstrahlung radiation emitted by the proton–Boron11 plasma. The hybrid scheme has the potential to reduce the confinement time of the reactants that is required to achieve ignition by an order of magnitude. [ABSTRACT FROM AUTHOR]

Academic disciplines are shape-shifting zones of inquiry yet notably bounded by regimes of training, truth, genre, and aesthetics. This article journeys into liminal zones in between disciplines as an existential space to ponder matters that beg for release from disciplinary syllabi. Can one thrive or even survive in the academy while dwelling in intervals between scholarly footprints? I lay bare a life of thinking in between anthropology, linguistics, and psychology for the reader to pursue and complicate this question. Try as I might to steer clear of folly, I have thrown caution to the winds to suggest affordances that nourish transgressive thinking in ways that expand and reassemble thinkable objects of inquiry. [ABSTRACT FROM AUTHOR]

Reducing barriers to graduate and professional education may reduce racial inequities in high-status professions. In 2020, one-quarter of law schools accepted the GRE in place of the LSAT, reflecting an effort across educational domains to revisit standardized test requirements. We [End Page 109] use a generalized difference-in-differences design to investigate the impact of GRE-accepting admissions on diversity and selectivity in legal education. We find some evidence of decreased racial diversity after policies have been in place a couple of years, along with increases in applications and decreases in acceptance rates. Findings indicate GRE-accepting admissions alone are unlikely to expand access to high-status fields. [ABSTRACT FROM AUTHOR]

Advanced therapeutic medicinal products (ATMPs) have emerged as novel therapies for untreatable diseases, generating the need for large volumes of high‐quality, clinically‐compliant GMP cells to replace costly, high‐risk and limited scale manual expansion processes. We present the design of a fully automated, robot‐assisted platform incorporating the use of multiliter stirred tank bioreactors for scalable production of adherent human stem cells. The design addresses a needle‐to‐needle closed process incorporating automated bone marrow collection, cell isolation, expansion, and collection into cryovials for patient delivery. AUTOSTEM, a modular, adaptable, fully closed system ensures no direct operator interaction with biological material; all commands are performed through a graphic interface. Seeding of source material, process monitoring, feeding, sampling, harvesting and cryopreservation are automated within the closed platform, comprising two clean room levels enabling both open and closed processes. A bioprocess based on human MSCs expanded on microcarriers was used for proof of concept. Utilizing equivalent culture parameters, the AUTOSTEM robot‐assisted platform successfully performed cell expansion at the liter scale, generating results comparable to manual production, while maintaining cell quality postprocessing. [ABSTRACT FROM AUTHOR]

For decades, legal academia has been structured around a hierarchical caste system, with tenured and tenure-track doctrinal law professors--many of whom are men--occupying the highest caste, and professors of legal skills courses--who more often identify as women--relegated to the lower castes. The status of these "lower caste" professors is routinely reinforced through weaker job security, less respect, and lower pay than received by their doctrinal, "upper caste" colleagues. Given this inequality, imposter syndrome plays a pervasive role in the lives and careers of professors of legal skills courses. Relying on qualitative data obtained from teaching faculty and staff at ABA accredited and approved law schools nationwide, this Article analyzes how the law school hierarchy manifests as imposter syndrome in professors of legal skills courses, which impacts their relationships with colleagues; teaching; relationships with students; publication and promotion of scholarship; and personal health and wellbeing. Based on these findings, the Article argues that the impacts of imposter syndrome on skills professors--many of which have gendered implications--promote a recurring cycle of classism and discrimination within legal academia. The Article further identifies imposter syndrome as an institutionalized, rather than an individualized, problem within legal academia. The responsibility and capacity to address this problem therefore lies in the institution--in this case, law schools--rather than the skills professors themselves. Thus, this Article concludes that the only way to reduce the insidious presence of imposter syndrome in legal academia is to dismantle the law school caste system and level the hierarchy. [ABSTRACT FROM AUTHOR]

Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) represent a heterogeneous population and therefore there is no standard of care first salvage regimen. We conducted a multicenter, retrospective analysis to compare chemotherapy (e.g. HyperCVAD, MOAD, Larson/CALGB-9511, etc.) to novel agents (blinatumomab or inotuzumab) in first salvage. The primary endpoint, overall survival (OS), was not significantly different among treatment arms, with a median OS of 10.6 months with chemotherapy and 10.1 months with novel therapy (p =.799). Similarly, there was no difference in the CR/CRi rate, with a CR/CRi in 18 patients (41.9%) versus 16 patients (47.1%) treated with salvage chemotherapy and novel therapy, respectively (p =.817). Age significantly impacted the probability of achieving CR/CRi with novel therapy versus chemotherapy. This analysis suggests the use of chemotherapy in first salvage still represents an appropriate treatment option, particularly for young fit patients, as the median OS was roughly 10 months regardless of whether patients received novel therapy or chemotherapy in first salvage. For the reported outcomes, 100% of patients in the novel therapy arm received a novel therapy (per design), whereas only 60.5% of patients in the chemotherapy arm required a novel therapy. Thus, 40% of patients did not require a novel therapy for similar OS. This analysis demonstrates that first-line chemotherapy can achieve similar results to novel therapies, especially now that novel therapies are available for subsequent relapses. However, this study has several limitations including younger age, increased CNS involvement, and higher blast percentage in the chemotherapy arm and potential confounders, including selection of treatment sequence as 43 patients (55.8%) ultimately received both chemotherapy and novel therapy. Therefore, a larger, prospective, randomized study with adequate chemotherapy comparators and availability of novel agents upon relapse is warranted to confirm these results. [ABSTRACT FROM AUTHOR]

In recent years, an explosion of novel agents has shifted the treatment paradigm for patients with acute myeloid leukemia. The optimal place in therapy for many of these novel agents remains unknown due to limited guidance from national guidelines and the way these agents were studied prior to entering the market. A critical evaluation of the literature and incorporation of oncology stewardship principles can be helpful in determining an optimal place for these agents while being mindful of the overall cost that is associated with therapies. The purpose of this review is to critically evaluate the efficacy and safety data for five controversial agents and provide examples of the use of stewardship practices in determining their place in the treatment of acute myeloid leukemia. [ABSTRACT FROM AUTHOR]