Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) ...are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.
A novel series of two zirconium- and one indium-based metal–organic frameworks (MOFs), namely, MOF-892, MOF-893, and MOF-894, constructed from the hexatopic linker, ...1′,2′,3′,4′,5′,6′-hexakis(4-carboxyphenyl)benzene, were synthesized and fully characterized. MOF-892 and MOF-893 are two new exemplars of materials with topologies previously unseen in the important family of zirconium MOFs. MOF-892, MOF-893, and MOF-894 exhibit efficient heterogeneous catalytic activity for the cycloaddition of CO2, resulting in a cyclic organic carbonate formation with high conversion, selectivity, and yield under mild conditions (1 atm CO2, 80 °C, and solvent-free). Because of the structural features provided by their building units, MOF-892 and MOF-893 are replete with accessible Lewis and Brønsted acid sites located at the metal clusters and the non-coordinating carboxylic groups of the linkers, respectively, which is found to promote the catalytic CO2 cycloaddition reaction. As a proof-of-concept, MOF-892 exhibits high catalytic activity in the one-pot synthesis of styrene carbonate from styrene and CO2 without preliminary synthesis and isolation of styrene oxide.
•Our proposed scheme yields pattern recognition systems with high generalisability.•The scheme enables fair comparison between different pattern recognition systems.•It sets up correct decision ...boundaries and avoids misclassifying training patterns.•It gives more information about the identified pattern for root cause analysis.•The pattern recognition accuracy increased when the proposed scheme was adopted.
Most applications of machine learning (ML) algorithms to control chart pattern recognition (CCPR) have focused on pattern detection and identification, rather than obtaining more detailed information about the pattern, which is important for effective assignable cause analysis. If real control chart data is not available for training purposes, synthetic patterns must be generated. Furthermore, pattern recognition accuracies achieved by different CCPR systems are usually not comparable since these were developed with different training data. How to create a diverse range of patterns for designing CCPR systems that can be compared and that are able to recognise a greater variety of patterns is an issue that needs studying.
This paper presents a scheme to generate training patterns that addresses this issue of diversity and comparability. The scheme also comprises change point detection and mean change categorisation methods that implement nonlinear models (NLMs) for estimating abnormal pattern parameters. The effect of this new pattern generation scheme on the accuracy of pattern recognition has been studied using two ML algorithms: Support Vector Machine (SVM) and Probabilistic Neural Network (PNN).
With the proposed pattern generation scheme, the mean pattern recognition accuracy was increased by 6.90% and 8.42% when SVM and PNN were used, respectively.
The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to ...identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.
The first case of COVID-19 was detected in Brazil on 25 February 2020. We report and contextualize epidemiological, demographic and clinical findings for COVID-19 cases during the first 3 months of ...the epidemic. By 31 May 2020, 514,200 COVID-19 cases, including 29,314 deaths, had been reported in 75.3% (4,196 of 5,570) of municipalities across all five administrative regions of Brazil. The R
value for Brazil was estimated at 3.1 (95% Bayesian credible interval = 2.4-5.5), with a higher median but overlapping credible intervals compared with some other seriously affected countries. A positive association between higher per-capita income and COVID-19 diagnosis was identified. Furthermore, the severe acute respiratory infection cases with unknown aetiology were associated with lower per-capita income. Co-circulation of six respiratory viruses was detected but at very low levels. These findings provide a comprehensive description of the ongoing COVID-19 epidemic in Brazil and may help to guide subsequent measures to control virus transmission.
The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally ...challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium’s target and hence gain molecular insight into BPD. By profiling the proteomics of BDP–hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The “set-point” for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such “spine-opathies,” human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium’s postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the “lithium response pathway” in BPD governs CRMP2’s phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent—even one whose mechanism-of-action is unknown—might reveal otherwise inscrutable intracellular pathogenic pathways.
The observation of hyperfine structure in atomic hydrogen by Rabi and co-workers and the measurement of the zero-field ground-state splitting at the level of seven parts in 10
are important ...achievements of mid-twentieth-century physics. The work that led to these achievements also provided the first evidence for the anomalous magnetic moment of the electron, inspired Schwinger's relativistic theory of quantum electrodynamics and gave rise to the hydrogen maser, which is a critical component of modern navigation, geo-positioning and very-long-baseline interferometry systems. Research at the Antiproton Decelerator at CERN by the ALPHA collaboration extends these enquiries into the antimatter sector. Recently, tools have been developed that enable studies of the hyperfine structure of antihydrogen-the antimatter counterpart of hydrogen. The goal of such studies is to search for any differences that might exist between this archetypal pair of atoms, and thereby to test the fundamental principles on which quantum field theory is constructed. Magnetic trapping of antihydrogen atoms provides a means of studying them by combining electromagnetic interaction with detection techniques that are unique to antimatter. Here we report the results of a microwave spectroscopy experiment in which we probe the response of antihydrogen over a controlled range of frequencies. The data reveal clear and distinct signatures of two allowed transitions, from which we obtain a direct, magnetic-field-independent measurement of the hyperfine splitting. From a set of trials involving 194 detected atoms, we determine a splitting of 1,420.4 ± 0.5 megahertz, consistent with expectations for atomic hydrogen at the level of four parts in 10
. This observation of the detailed behaviour of a quantum transition in an atom of antihydrogen exemplifies tests of fundamental symmetries such as charge-parity-time in antimatter, and the techniques developed here will enable more-precise such tests.
Objectives
Sarcopenia, defined as an age-associated loss of skeletal muscle function and muscle mass, occurs in approximately 6 - 22 % of older adults. This paper presents evidence-based clinical ...practice guidelines for screening, diagnosis and management of sarcopenia from the task force of the International Conference on Sarcopenia and Frailty Research (ICSFR).
Methods
To develop the guidelines, we drew upon the best available evidence from two systematic reviews paired with consensus statements by international working groups on sarcopenia. Eight topics were selected for the recommendations: (i) defining sarcopenia; (ii) screening and diagnosis; (iii) physical activity prescription; (iv) protein supplementation; (v) vitamin D supplementation; (vi) anabolic hormone prescription; (vii) medications under development; and (viii) research. The ICSFR task force evaluated the evidence behind each topic including the quality of evidence, the benefitharm balance of treatment, patient preferences/values, and cost-effectiveness. Recommendations were graded as either strong or conditional (weak) as per the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Consensus was achieved via one face-to-face workshop and a modified Delphi process.
Recommendations
We make a conditional recommendation for the use of an internationally accepted measurement tool for the diagnosis of sarcopenia including the EWGSOP and FNIH definitions, and advocate for rapid screening using gait speed or the SARC-F. To treat sarcopenia, we strongly recommend the prescription of resistance-based physical activity, and conditionally recommend protein supplementation/a protein-rich diet. No recommendation is given for Vitamin D supplementation or for anabolic hormone prescription. There is a lack of robust evidence to assess the strength of other treatment options.
This paper focuses on formulas for the
ε
-subdifferential of the optimal value function of scalar and vector convex optimization problems. These formulas can be applied when the set of solutions of ...the problem is empty. In the scalar case, both unconstrained problems and problems with an inclusion constraint are considered. For the last ones, limiting results are derived, in such a way that no qualification conditions are required. The main mathematical tool is a limiting calculus rule for the
ε
-subdifferential of the sum of convex and lower semicontinuous functions defined on a (non necessarily reflexive) Banach space. In the vector case, unconstrained problems are studied and exact formulas are derived by linear scalarizations. These results are based on a concept of infimal set, the notion of cone proper set and an
ε
-subdifferential for convex vector functions due to Taa.
Abstract
We present multiwavelength photometry and spectroscopy of SN 2022jli, an unprecedented Type Ic supernova discovered in the galaxy NGC 157 at a distance of ≈ 23 Mpc. The multiband light ...curves reveal many remarkable characteristics. Peaking at a magnitude of
g
= 15.11 ± 0.02, the high-cadence photometry reveals periodic undulations of 12.5 ± 0.2 days superimposed on the 200-day supernova decline. This periodicity is observed in the light curves from nine separate filter and instrument configurations with peak-to-peak amplitudes of ≃ 0.1 mag. This is the first time that repeated periodic oscillations, over many cycles, have been detected in a supernova light curve. SN 2022jli also displays an extreme early excess that fades over ≈25 days, followed by a rise to a peak luminosity of
L
opt
= 10
42.1
erg s
−1
. Although the exact explosion epoch is not constrained by data, the time from explosion to maximum light is ≳ 59 days. The luminosity can be explained by a large ejecta mass (
M
ej
≈ 12 ± 6
M
⊙
) powered by
56
Ni, but we find it difficult to quantitatively model the early excess with circumstellar interaction and cooling. Collision between the supernova ejecta and a binary companion is a possible source of this emission. We discuss the origin of the periodic variability in the light curve, including interaction of the SN ejecta with nested shells of circumstellar matter and neutron stars colliding with binary companions.
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