Validation of a classification system for treatment-related mortality in children with cancer

Background Death not directly due to cancer has been termed 'treatment-related mortality' (TRM). Appreciating the differences between TRM and disease-related death is critical in directing strategies to improve supportive care, interventions delivered or disease progression. Recently, a global collaboration developed and validated a consensus-based classification tool and attribution system.Objectives To evaluate the reliability of the newly developed consensus-based definition of TRM and explore the use of the cause-of-death attribution system outside the centre it was initially validated (Toronto, Canada). In the initial study, reviewers listed multiple causes of death. In this study, reviewers identified a primary cause for simplicity.Setting The paediatric haematology and oncology department at Leeds Teaching Hospital in Leeds, UK.Participants Two consultants and two clinical research associates (CRAs).Methods Thirty medical records of the most recent deaths in children with cancer, 2 and 4 weeks prior to death, were anonymised and presented to the participants. Reviewers independently classified deaths as 'treatment related mortality' or 'not treatment related' according to the algorithm developed. When TRM occurred, reviewers applied the cause-of-death attribution system to identify the primary cause of death. Inter-relater reliability was assessed using the kappa statistic (k).Main outcome Inter-relater reliability between CRA and consultants.Results Reliability of the classification was deemed 'very good' between CRA and consultants (k=0.86, 95% CI 0.72 to 0.97). Ten deaths were classified as TRM, of which infection was the most frequent cause identified. Reviewers disagreed on the primary cause of death (eg, respiratory vs infection) when applying the cause-of-death attribution system in six cases and probable and possible causes in four cases. The study identified how the algorithm may not detect TRM in patients receiving non-curative therapy.Conclusions The classification and cause of death attribution system could be implemented in different healthcare settings. Adaptation of the classification tool in patients receiving non-curative interventions and the cause of death attribution system should be considered

Spatial Curvature Falsifies Eternal Inflation

Inflation creates large-scale cosmological density perturbations that are characterized by an isotropic, homogeneous, and Gaussian random distribution about a locally flat background. Even in a flat universe, the spatial curvature measured within one Hubble volume receives contributions from long wavelength perturbations, and will not in general be zero. These same perturbations determine the Cosmic Microwave Background (CMB) temperature fluctuations, which are O(10^-5). Consequently, the low-l multipole moments in the CMB temperature map predict the value of the measured spatial curvature \Omega_k. On this basis we argue that a measurement of |\Omega_k| > 10^-4 would rule out slow-roll eternal inflation in our past with high confidence, while a measurement of \Omega_k < -10^-4 (which is positive curvature, a locally closed universe) rules out false-vacuum eternal inflation as well, at the same confidence level. In other words, negative curvature (a locally open universe) is consistent with false-vacuum eternal inflation but not with slow-roll eternal inflation, and positive curvature falsifies both. Near-future experiments will dramatically extend the sensitivity of \Omega_k measurements and constitute a sharp test of these predictions.Comment: 16+2 pages, 2 figure

Human bony labyrinth is an indicator of population history and dispersal from Africa.

The dispersal of modern humans from Africa is now well documented with genetic data that track population history, as well as gene flow between populations. Phenetic skeletal data, such as cranial and pelvic morphologies, also exhibit a dispersal-from-Africa signal, which, however, tends to be blurred by the effects of local adaptation and in vivo phenotypic plasticity, and that is often deteriorated by postmortem damage to skeletal remains. These complexities raise the question of which skeletal structures most effectively track neutral population history. The cavity system of the inner ear (the so-called bony labyrinth) is a good candidate structure for such analyses. It is already fully formed by birth, which minimizes postnatal phenotypic plasticity, and it is generally well preserved in archaeological samples. Here we use morphometric data of the bony labyrinth to show that it is a surprisingly good marker of the global dispersal of modern humans from Africa. Labyrinthine morphology tracks genetic distances and geography in accordance with an isolation-by-distance model with dispersal from Africa. Our data further indicate that the neutral-like pattern of variation is compatible with stabilizing selection on labyrinth morphology. Given the increasingly important role of the petrous bone for ancient DNA recovery from archaeological specimens, we encourage researchers to acquire 3D morphological data of the inner ear structures before any invasive sampling. Such data will constitute an important archive of phenotypic variation in present and past populations, and will permit individual-based genotype-phenotype comparisons

Differential Proteoglycan Expression in Atherosclerosis Alters Platelet Adhesion and Activation

\ua9 2024 by the authors.Proteoglycans are differentially expressed in different atherosclerotic plaque phenotypes, with biglycan and decorin characteristic of ruptured plaques and versican and hyaluronan more prominent in eroded plaques. Following plaque disruption, the exposure of extracellular matrix (ECM) proteins triggers platelet adhesion and thrombus formation. In this study, the impact of differential plaque composition on platelet function and thrombus formation was investigated. Platelet adhesion, activation and thrombus formation under different shear stress conditions were assessed in response to individual proteoglycans and composites representing different plaque phenotypes. The results demonstrated that all the proteoglycans tested mediated platelet adhesion but not platelet activation, and the extent of adhesion observed was significantly lower than that observed with type I and type III collagens. Thrombus formation upon the rupture and erosion ECM composites was significantly reduced (p &lt; 0.05) compared to relevant collagen alone, indicating that proteoglycans negatively regulate platelet collagen responses. This was supported by results demonstrating that the addition of soluble biglycan or decorin to whole blood markedly reduced thrombus formation on type I collagen (p &lt; 0.05). Interestingly, thrombus formation upon the erosion composite displayed aspirin sensitivity, whereas the rupture composite was intensive to aspirin, having implications for current antiplatelet therapy regimes. In conclusion, differential platelet responses and antiplatelet efficacy are observed on ECM composites phenotypic of plaque rupture and erosion. Proteoglycans inhibit thrombus formation and may offer a novel plaque-specific approach to limit arterial thrombosis

Limits on dark matter annihilation in prompt cusps from the isotropic gamma-ray background

Recent studies indicate that thermally produced dark matter will form highly concentrated, low-mass cusps in the early universe that often survive until the present. While these cusps contain a small fraction of the dark matter, their high density significantly increases the expected gamma-ray flux from dark matter annihilation, particularly in searches of large angular regions. We utilize 14 years of Fermi-LAT data to set strong constraints on dark matter annihilation through a detailed study of the isotropic gamma-ray background, excluding with 95% confidence dark matter annihilation to $b\bar{b}$ final states for dark matter masses below 120 GeV.Comment: 11 pages, 10 figure

Positron scattering from the group IIB metals zinc and cadmium: recommended cross sections and transport simulations

Results from the application of our optical potential and relativistic optical potential models to positron scattering from gas-phase zinc (Zn) and cadmium (Cd) are presented. In particular, integral cross sections (ICSs) for elastic scattering, positronium formation, summed discrete electronic-state excitation, and ionization scattering processes are reported for both species and over an extended incident positron energy range. From those ICSs, the total cross section is subsequently constructed by taking their sum. We note that there are currently no experimental data available for any of these scattering processes for either species, with earlier computational results being limited to the elastic channel and restricted to relatively narrow incident positron energy regimes. Nonetheless, we construct recommended positron cross section datasets for both zinc and cadmium over the incident positron energy range of 0-10 000 eV. The recommended positron cross section data are subsequently employed in a multi-term Boltzmann equation analysis to simulate the transport of positrons, under the influence of an applied (external) electric field, through the background Zn and Cd gases. Qualitatively similar behavior in the calculated transport coefficients was observed between both species. Finally, for the case of zinc, the present positron transport coefficients are compared against corresponding results from electron transport with some significant differences now being observed

MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

Rationale: The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology

ROSAT X-ray sources in the field of the LMC I.Total LMC gas from the background AGN spectral fits

We analyzed a sample of 26 background X-ray sources in a ~60 square degree field of the Large Magellanic Cloud observed with the ROSAT PSPC. The sample has been selected from previously classified and optically identified X-ray sources. In addition pointlike and spectrally hard sources with at least 100 to 200 observed counts have been used for the analysis. We performed X-ray spectral fitting and derived total hydrogen absorbing column densities due to LMC gas in the range 10^20 - 2. 10^21 cm^-2. We compared these columns with the HI columns derived from a 21-cm Parkes survey of the LMC. For 7 optically identified sources we find, within the uncertainties derived from the X-ray spectral fit, agreement for both columns. For further 19 sources we constrain the LMC columns from the X-ray spectral fit assuming that the powerlaw photon index is that of AGN type spectra. We derive for 20 sources gas columns which are within the uncertainties in agreement with the HI columns. We derive for two background sources (RX J0536.9-6913 and RX J0547.0-7040) hydrogen absorbing column densities due to LMC gas, which are in excess to the HI columns. These sources - located in regions of large (~3. 10^21 cm^-2) LMC HI column densities - could be seen through additional gas which may be warm and diffuse, cold or molecular. For 10 sources we derive upper limits for the gas columns additional to HI and constrain the molecular mass fraction to <(30-140)%.Comment: Accepted by A&

Human bony labyrinth is an indicator of population history and dispersal from Africa.

The dispersal of modern humans from Africa is now well documented with genetic data that track population history, as well as gene flow between populations. Phenetic skeletal data, such as cranial and pelvic morphologies, also exhibit a dispersal-from-Africa signal, which, however, tends to be blurred by the effects of local adaptation and in vivo phenotypic plasticity, and that is often deteriorated by postmortem damage to skeletal remains. These complexities raise the question of which skeletal structures most effectively track neutral population history. The cavity system of the inner ear (the so-called bony labyrinth) is a good candidate structure for such analyses. It is already fully formed by birth, which minimizes postnatal phenotypic plasticity, and it is generally well preserved in archaeological samples. Here we use morphometric data of the bony labyrinth to show that it is a surprisingly good marker of the global dispersal of modern humans from Africa. Labyrinthine morphology tracks genetic distances and geography in accordance with an isolation-by-distance model with dispersal from Africa. Our data further indicate that the neutral-like pattern of variation is compatible with stabilizing selection on labyrinth morphology. Given the increasingly important role of the petrous bone for ancient DNA recovery from archaeological specimens, we encourage researchers to acquire 3D morphological data of the inner ear structures before any invasive sampling. Such data will constitute an important archive of phenotypic variation in present and past populations, and will permit individual-based genotype-phenotype comparisons

Credit spreads: An empirical analysis on the informational content of stocks, bonds, and CDS.

This paper explores the dynamic relationship between stock market implied credit spreads, CDS spreads, and bond spreads. A general VECM representation is proposed for changes in the three credit spread measures which accounts for zero, one, or two independent cointegration equations, depending on the evidence provided by any particular company. Empirical analysis on price discovery, based on a proprietary sample of North American and European firms, and tailored to the specific VECM at hand, indicates that stocks lead CDS and bonds more frequently than the other way round. It likewise confirms the leading role of CDS with respect to bonds.Publicad