The structural description of disordered systems has been a longstanding challenge in physical science. We propose an atomic cluster alignment method to reveal the development of three-dimensional ...topological ordering in a metallic liquid as it undercools to form a glass. By analyzing molecular dynamic (MD) simulation trajectories of a Cu(64.5)Zr(35.5) alloy, we show that medium-range order (MRO) develops in the liquid as it approaches the glass transition. Specifically, around Cu sites, we observe "Bergman triacontahedron" packing (icosahedron, dodecahedron and icosahedron) that extends out to the fourth shell, forming an interpenetrating backbone network in the glass. The discovery of Bergman-type MRO from our order-mining technique provides unique insights into the topological ordering near the glass transition and the relationship between metallic glasses and quasicrystals.
Continuous spike and wave of sleep with encephalopathy (CSWS) is a rare and severe developmental electroclinical epileptic encephalopathy characterized by seizures, abundant sleep activated ...interictal epileptiform discharges, and cognitive regression or deceleration of expected cognitive growth. The cause of the cognitive symptoms is unknown, and efforts to link epileptiform activity to cognitive function have been unrevealing. Converging lines of evidence implicate thalamocortical circuits in these disorders. Sleep spindles are generated and propagated by the same thalamocortical circuits that can generate spikes and, in healthy sleep, support memory consolidation. As such, sleep spindle deficits may provide a physiologically relevant mechanistic biomarker for cognitive dysfunction in epileptic encephalopathies.
We describe the longitudinal course of a child with CSWS with initial cognitive regression followed by dramatic cognitive improvement after treatment. Using validated automated detection algorithms, we analyzed electroencephalograms for epileptiform discharges and sleep spindles alongside contemporaneous neuropsychological evaluations over the course of the patient's disease. We found that sleep spindles increased dramatically with high-dose diazepam treatment, corresponding with marked improvements in cognitive performance. We also found that the sleep spindle rate was anticorrelated to spike rate, consistent with a competitively shared underlying thalamocortical circuitry.
Epileptic encephalopathies are challenging electroclinical syndromes characterized by combined seizures and a deceleration or regression in cognitive skills over childhood. This report identifies thalamocortical circuit dysfunction in a case of epileptic encephalopathy and motivates future investigations of sleep spindles as a biomarker of cognitive function and a potential therapeutic target in this challenging disease.
ABSTRACT
Recently, global pulsar timing arrays have released results from searching for a nano-Hertz gravitational wave background signal. Although there has not been any definite evidence of the ...presence of such a signal in residuals of pulsar timing data yet, with more and improved data in future, a statistically significant detection is expected to be made. Stochastic algorithms are used to sample a very large parameter space to infer results from data. In this paper, we attempt to rule out effects arising from the stochasticity of the sampler in the inference process. We compare different configurations of nested samplers and the more commonly used markov chain monte carlo method to sample the pulsar timing array parameter space and account for times taken by the different samplers on same data. Although we obtain consistent results on parameters from different sampling algorithms, we propose two different samplers for robustness checks on data in the future to account for cross-checks between sampling methods as well as realistic run-times.
ABSTRACT Redbacks are millisecond pulsar binaries with low-mass, irradiated companions. These systems have a rich phenomenology that can be used to probe binary evolution models, pulsar wind physics, ...and the neutron star mass distribution. A number of high-confidence redback candidates have been identified through searches for variable optical and X-ray sources within the localization regions of unidentified but pulsar-like Fermi-LAT gamma-ray sources. However, these candidates remain unconfirmed until pulsations are detected. As part of the TRAPUM project, we searched for radio pulsations from six of these redback candidates with MeerKAT. We discovered three new radio millisecond pulsars, PSRs J0838−2827, J0955−3947, and J2333−5526, confirming their redback nature. PSR J0838−2827 remained undetected for 2 yr after our discovery despite repeated observations, likely due to evaporated material absorbing the radio emission for long periods of time. While, to our knowledge, this system has not undergone a transition to an accreting state, the disappearance, likely caused by extreme eclipses, illustrates the transient nature of spider pulsars and the heavy selection bias in uncovering their radio population. Radio timing enabled the detection of gamma-ray pulsations from all three pulsars, from which we obtained 15-yr timing solutions. All of these sources exhibit complex orbital period variations consistent with gravitational quadrupole moment variations in the companion stars. These timing solutions also constrain the binary mass ratios, allowing us to narrow down the pulsar masses. We find that PSR J2333−5526 may have a neutron star mass in excess of 2 M⊙.
The reported alignment between the projected spin-axes and proper motion directions of pulsars is revisited in the light of new data from Jodrell Bank and Effelsberg. The present investigation uses ...54 pulsars, the largest to date sample of pulsars with proper motion and absolute polarization, to study this effect. Our study has found strong evidence for pulsar spin-velocity alignment, excluding that those two vectors are completely uncorrelated, with >99 per cent confidence. Although we cannot exclude the possibility of orthogonal spin-velocity configurations, comparison of the data with simulations shows that the scenario of aligned vectors is more likely than that of the orthogonal case. Moreover, we have determined the spread of velocities that a spin-aligned and spin-orthogonal distribution of kicks must have to produce the observed distribution of spin-velocity angle offsets. If the observed distribution of spin-velocity offset angles is the result of spin-aligned kicks, then we find that the distribution of kick-velocity directions must be broad with
; if the orthogonal-kick scenario is assumed, then the velocity distribution is much narrower with
. Finally, in contrast to previous studies, we have performed robustness tests on our data, in order to determine whether our conclusions are the result of a statistical and/or systematic bias. The conclusion of a correlation between the spin and velocity vectors is independent of a bias introduced by subsets in the total sample. Moreover, we estimate that the observed alignment is robust to within 10 per cent systematic uncertainties on the determination of the spin-axis direction from polarization data.
Cardiovascular magnetic resonance (CMR) stress perfusion imaging provides important diagnostic and prognostic information in coronary artery disease (CAD). Current clinical sequences have limited ...temporal and/or spatial resolution, and incomplete heart coverage. Techniques such as k-t principal component analysis (PCA) or k-t sparcity and low rank structure (SLR), which rely on the high degree of spatiotemporal correlation in first-pass perfusion data, can significantly accelerate image acquisition mitigating these problems. However, in the presence of respiratory motion, these techniques can suffer from significant degradation of image quality. A number of techniques based on non-rigid registration have been developed. However, to first approximation, breathing motion predominantly results in rigid motion of the heart. To this end, a simple robust motion correction strategy is proposed for k-t accelerated and compressed sensing (CS) perfusion imaging.
A simple respiratory motion compensation (MC) strategy for k-t accelerated and compressed-sensing CMR perfusion imaging to selectively correct respiratory motion of the heart was implemented based on linear k-space phase shifts derived from rigid motion registration of a region-of-interest (ROI) encompassing the heart. A variable density Poisson disk acquisition strategy was used to minimize coherent aliasing in the presence of respiratory motion, and images were reconstructed using k-t PCA and k-t SLR with or without motion correction. The strategy was evaluated in a CMR-extended cardiac torso digital (XCAT) phantom and in prospectively acquired first-pass perfusion studies in 12 subjects undergoing clinically ordered CMR studies. Phantom studies were assessed using the Structural Similarity Index (SSIM) and Root Mean Square Error (RMSE). In patient studies, image quality was scored in a blinded fashion by two experienced cardiologists.
In the phantom experiments, images reconstructed with the MC strategy had higher SSIM (p < 0.01) and lower RMSE (p < 0.01) in the presence of respiratory motion. For patient studies, the MC strategy improved k-t PCA and k-t SLR reconstruction image quality (p < 0.01). The performance of k-t SLR without motion correction demonstrated improved image quality as compared to k-t PCA in the setting of respiratory motion (p < 0.01), while with motion correction there is a trend of better performance in k-t SLR as compared with motion corrected k-t PCA.
Our simple and robust rigid motion compensation strategy greatly reduces motion artifacts and improves image quality for standard k-t PCA and k-t SLR techniques in setting of respiratory motion due to imperfect breath-holding.
Metastatic breast cancer is a major cause of death among women worldwide; therefore efficient therapeutic strategies are extremely needed. In this work we have developed a gene therapy- and ...bacteria-based combined neoadjuvant approach and evaluated its antitumor effect in a clinically relevant animal model of metastatic breast cancer.
2×10(8) particles of a Semliki Forest virus vector expressing interleukin-12 (SFV-IL-12) and/or 2×10(7) units of an aroC (-) Samonella Typhimurium strain (LVR01) were injected into 4T1 tumor nodules orthotopically implanted in mice. Tumors were surgically resected and long-term survival was determined. IL-12 and interferon-γ were quantified by Enzyme-Linked ImmunoSorbent Assay, bacteria was visualized by inmunohistochemistry and the number of lung metastasis was calculated with a clonogenic assay.
SFV-IL-12 and LVR01 timely inoculated and followed by surgical resection of tumors succeeded in complete inhibition of lethal lung metastasis and long-term survival in 90% of treated mice. The combined therapy was markedly synergistic compared to each treatment alone, since SFV-IL-12 monotherapy showed a potent antiangiogenic effect, being able to inhibit tumor growth and extend survival, but could not prevent establishment of distant metastasis and death of tumor-excised animals. On the other hand, LVR01 alone also showed a significant, although limited, antitumor potential, despite its ability to invade breast cancer cells and induce granulocyte recruitment. The efficacy of the combined therapy depended on the order in which both factors were administered; inasmuch the therapeutic effect was only observed when SFV-IL-12 was administered previous to LVR01, whereas administration of LVR01 before SFV-IL-12 had negligible antitumor activity. Moreover, pre-treatment with LVR01 seemed to suppress SFV-IL-12 antiangiogenic effects associated to lower IL-12 expression in this group. Re-challenged mice were unable to reject a second 4T1 tumor; however 100% of them could be totally cured by applying the same neoadjuvant combined regimen. To our knowledge, these are the most encouraging results obtained to date in a post-operatory setting using the highly aggressive 4T1 animal model.
SFV-IL-12-based gene therapy combined with Salmonella LVR01 neoadjuvant administration has a synergic antitumor effect and may be a promising therapeutic option to prevent and/or eradicate pre-operatory metastasis in locally advanced breast cancer.
Direct observation of clinical task performance plays a pivotal role in competency-based medical education. Although formal guidelines require supervisors to engage in direct observations, research ...demonstrates that trainees are infrequently observed. Supervisors may not only experience practical and socio-cultural barriers to direct observations in healthcare settings, they may also question usefulness or have low perceived self-efficacy in performing direct observations. A better understanding of how these multiple factors interact to influence supervisors' intention to perform direct observations may help us to more effectively implement the aforementioned guidelines and increase the frequency of direct observations.
We conducted an exploratory quantitative study, using the Theory of Planned Behaviour (TPB) as our theoretical framework. In applying the TPB, we transfer a psychological theory to medical education to get insight in the influence of cognitive and emotional processes on intentions to use direct observations in workplace based learning and assessment. We developed an instrument to investigate supervisors intention to perform direct observations. The relationships between the TPB measures of our questionnaire were explored by computing bivariate correlations using Pearson's R tests. Hierarchical regression analysis was performed in order to assess the impact of the respective TPB measures as predictors on the intention to perform direct observations.
In our study 82 GP supervisors completed our TPB questionnaire. We found that supervisors had a positive attitude towards direct observations. Our TPB model explained 45% of the variance in supervisors' intentions to perform them. Normative beliefs and past behaviour were significant determinants of this intention.
Our study suggests that supervisors use their past experiences to form intentions to perform direct observations in a careful, thoughtful manner and, in doing so, also take the preferences of the learner and other stakeholders potentially engaged in direct observations into consideration. These findings have potential implications for research into work-based assessments and the development of training interventions to foster a shared mental model on the use of direct observations.
The European Pulsar Timing Array (EPTA) and Indian Pulsar Timing Array (InPTA) collaborations have measured a low-frequency common signal in the combination of their second and first data releases, ...respectively, with the correlation properties of a gravitational wave background (GWB). Such a signal may have its origin in a number of physical processes including a cosmic population of inspiralling supermassive black hole binaries (SMBHBs); inflation, phase transitions, cosmic strings, and tensor mode generation by the non-linear evolution of scalar perturbations in the early Universe; and oscillations of the Galactic potential in the presence of ultra-light dark matter (ULDM). At the current stage of emerging evidence, it is impossible to discriminate among the different origins. Therefore, for this paper, we consider each process separately, and investigated the implications of the signal under the hypothesis that it is generated by that specific process. We find that the signal is consistent with a cosmic population of inspiralling SMBHBs, and its relatively high amplitude can be used to place constraints on binary merger timescales and the SMBH-host galaxy scaling relations. If this origin is confirmed, this would be the first direct evidence that SMBHBs merge in nature, adding an important observational piece to the puzzle of structure formation and galaxy evolution. As for early Universe processes, the measurement would place tight constraints on the cosmic string tension and on the level of turbulence developed by first-order phase transitions. Other processes would require non-standard scenarios, such as a blue-tilted inflationary spectrum or an excess in the primordial spectrum of scalar perturbations at large wavenumbers. Finally, a ULDM origin of the detected signal is disfavoured, which leads to direct constraints on the abundance of ULDM in our Galaxy.
In recent years, the subspecialty of neuropalliative care has emerged with the goal of improving the quality of life of patients suffering from neurological disease, though gaps remain in ...neuropalliative care education and training. E-learning has been described as a way to deliver interactive and facilitated lower-cost learning to address global gaps in medical care. We describe here the development of a novel, international, hybrid, and asynchronous curriculum with both self-paced modules and class-based lectures on neuropalliative care topics designed for the neurologist interested in palliative care, the palliative care physician interested in caring for neurological patients, and any other physician or advanced care providers interested in neuropalliative care.
The course consisted of 12 modules, one per every four weeks, beginning July 2022. Each module is based on a case and relevant topics. Course content was divided into three streams (Neurology Basics, Palliative Care Basics, and Neuropalliative Care Essentials) of which two were optional and one was mandatory, and consisted of classroom sessions, webinars, and an in-person skills session. Evaluation of learners consisted of multiple choice questions and written assignments for each module. Evaluation of the course was based on semi-structured qualitative interviews conducted with both educator and learner, the latter of which will be published separately. Audio files were transcribed and underwent thematic analysis. For the discussion of the results, Khan's e-learning framework was used.
Ten of the 12 participating educators were interviewed. Of the educators, three identified as mid-career and seven as senior faculty, ranging from six to 33 years of experience. Nine of ten reported an academic affiliation and all reported association with a teaching hospital. Themes identified from the educators' evaluations were: bridging the global gap, getting everybody on board, defining the educational scope, investing extensive hours of voluntary time and resources, benefiting within and beyond the curriculum, understanding the learner's experience, creating a community of shared learning, adapting future teaching and learning strategies, and envisioning long term sustainability.
The first year of a novel, international, hybrid, and asynchronous neuropalliative care curriculum has been completed, and its educators have described both successes and avenues for improvement. Further research is planned to assess this curriculum from the learner perspective.
PDF
