Development of a Consensus Statement for the Definition, Diagnosis, and Treatment of Acute Exacerbations of Idiopathic Pulmonary Fibrosis Using the Delphi Technique.

© 2015, The Author(s).Introduction: There is a lack of agreed and established guidelines for the treatment of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). This reflects, in part, the limited evidence-base underpinning the management of AE-IPF. In the absence of high-quality evidence, the aim of this research was to develop a clinician-led consensus statement for the definition, diagnosis and treatment of AE-IPF. Methods: A literature review was conducted to obtain published material on the definition and treatment of AE-IPF. The results of this review were circulated to an online panel of clinicians for review. Statements were then shared with ten expert respiratory clinicians who regularly treat patients with IPF. A Delphi technique was then used to develop a consensus statement for the definition, diagnosis and treatment of AE-IPF. During the first round of review, clinicians rated the clarity of each statement, the extent to which the statement should be included and provided comments. In two subsequent rounds of review, clinicians were provided with the group median inclusion rating for each statement, and any revised wording of statements to aid clarity. Clinicians were asked to repeat the clarity and inclusion ratings for the revised statements. Results: The literature review, online panel discussion, and face-to-face meeting generated 65 statements covering the definition, diagnosis, and management of AE-IPF. Following three rounds of blind review, 90% of clinicians agreed 39 final statements. These final statements included a definition of AE-IPF, approach to diagnosis, and treatment options, specifically: supportive measures, use of anti-microbials, immunosuppressants, anti-coagulants, anti-fibrotic therapy, escalation, transplant management, and long-term management including discharge planning. Conclusion: This clinician-led consensus statement establishes the ‘best practice’ for the management and treatment of AE-IPF based on current knowledge, evidence, and available treatments. Funding: Boehringer Ingelheim Ltd., Bracknell, West Berkshire, UK

Differentiating dark energy and modified gravity with galaxy redshift surveys

The observed cosmic acceleration today could be due to an unknown energy component (dark energy), or a modification to general relativity (modified gravity). If dark energy models and modified gravity models are required to predict the same cosmic expansion history H(z), they will predict different growth rate for cosmic large scale structure, f_g(z)=d\ln \delta/d\ln a (\delta=(\rho_m-\bar{\rho_m})/\bar{\rho_m}), a is the cosmic scale factor). If gravity is not modified, the measured H(z) leads to a unique prediction for f_g(z), f_g^H(z). Comparing f_g^H(z) with the measured f_g(z) provides a transparent and straightforward test of gravity. We show that a simple \chi^2 test provides a general figure-of-merit for our ability to distinguish between dark energy and modified gravity given the measured H(z) and f_g(z). We study a magnitude-limited NIR galaxy redshift survey covering >10,000 (deg)^2 and the redshift range of 0.5<z<2. The resultant data can be divided into 7 redshift bins, and yield the measurement of H(z) to the accuracy of 1-2% via baryon acoustic oscillation measurements, and f_g(z) to the accuracy of a few percent via the measurement of redshift space distortions and the bias factor which describes how light traces mass. We find that if the H(z) data are fit by both a DGP gravity model and an equivalent dark energy model that predict the same expansion history, a survey area of 11,931 (deg)^2 is required to rule out the DGP gravity model at the 99.99% confidence level. It is feasible for such a galaxy redshift survey to be carried out by the next generation space missions from NASA and ESA, and it will revolutionize our understanding of the universe by differentiating between dark energy and modified gravity.Comment: 6 pages, 2 color figures. Expanded version accepted by JCA

An Anti-Glitch in a Magnetar

Magnetars are neutron stars showing dramatic X-ray and soft $\gamma$-ray outbursting behaviour that is thought to be powered by intense internal magnetic fields. Like conventional young neutron stars in the form of radio pulsars, magnetars exhibit "glitches" during which angular momentum is believed to be transferred between the solid outer crust and the superfluid component of the inner crust. Hitherto, the several hundred observed glitches in radio pulsars and magnetars have involved a sudden spin-up of the star, due presumably to the interior superfluid rotating faster than the crust. Here we report on X-ray timing observations of the magnetar 1E 2259+586 which we show exhibited a clear "anti-glitch" -- a sudden spin down. We show that this event, like some previous magnetar spin-up glitches, was accompanied by multiple X-ray radiative changes and a significant spin-down rate change. This event, if of origin internal to the star, is unpredicted in models of neutron star spin-down and is suggestive of differential rotation in the neutron star, further supporting the need for a rethinking of glitch theory for all neutron stars

The influence of circumnuclear environment on the radio emission from TDE jets

Dozens of stellar tidal disruption events (TDEs) have been identified at optical, UV and X-ray wavelengths. A small fraction of these, most notably Swift J1644+57, produce radio synchrotron emission, consistent with a powerful, relativistic jet shocking the surrounding circumnuclear gas. The dearth of similar non-thermal radio emission in the majority of TDEs may imply that powerful jet formation is intrinsically rare, or that the conditions in galactic nuclei are typically unfavourable for producing a detectable signal. Here we explore the latter possibility by constraining the radial profile of the gas density encountered by a TDE jet using a one-dimensional model for the circumnuclear medium which includes mass and energy input from a stellar population. Near the jet Sedov radius of radius of 10^18 cm, we find gas densities in the range of n18 ∼ 0.1-1000 cm^−3 across a wide range of plausible star formation histories. Using one- and two-dimensional relativistic hydrodynamical simulations, we calculate the synchrotron radio light curves of TDE jets (as viewed both on and off-axis) across the allowed range of density profiles. We find that bright radio emission would be produced across the plausible range of nuclear gas densities by jets as powerful as Swift J1644+57, and we quantify the relationship between the radio luminosity and jet energy. We use existing radio detections and upper limits to constrain the energy distribution of TDE jets. Radio follow-up observations several months to several years after the TDE candidate will strongly constrain the energetics of any relativistic flow

Penetrance of HNPCC-related cancers in a retrolective cohort of 12 large Newfoundland families carrying a MSH2 founder mutation: an evaluation using modified segregation models

<p>Abstract</p> <p>Background</p> <p>Accurate risk (penetrance) estimates for associated phenotypes in carriers of a major disease gene are important for genetic counselling of at-risk individuals. Population-specific estimates of penetrance are often needed as well. Families ascertained from high-risk disease clinics provide substantial data to estimate penetrance of a disease gene, but these estimates must be adjusted for possible specific sources of bias.</p> <p>Methods</p> <p>A cohort of 12 independently ascertained HNPCC families harbouring a founder MSH2 mutation was identified from a cancer genetics clinic in St. John's, Newfoundland, Canada. Carrier status was known for 247 family members but phenotype information on up to 85 additional relatives with unknown carrier status was available; using modified segregation models these additional individuals could be included in the analyses. Three HNPCC-related phenotypes were evaluated as age at diagnosis of: any HNPCC cancer (first cancer), colorectal cancer (CRC), and endometrial cancer (EC) for females.</p> <p>Results</p> <p>Lifetime (age 70) risk estimates for male and female carriers were similar for developing any HNPCC cancer (Males = 98.2%, 95% Confidence Interval (CI) = (93.8%, 99.9%); Females = 92.8%, 95% CI = (82.4%, 99.1%)) but female carriers experienced substantially reduced lifetime risk for developing CRC compared to male carriers (Females = 38.9%, 95% CI = (24.2%, 62.1%); Males = 84.5%, 95% CI = (67.3%, 91.3%)). Female non-carriers had very low lifetime risk for these two outcomes while male non-carriers had lifetime risks intermediate to the female carriers and non-carriers. Female carriers had a lifetime risk of developing EC of 82.4%. Relative risks for developing any HNPCC cancer (carriers relative to non-carriers) were substantially greater for females compared to their male counterparts (Females = 54.8, 95%CI = (4.4, 379.8); Males = 9.7, 95% CI = (0.3, 23.8)). Relative risks for developing CRC at age 70 were substantially greater for females compared to their male counterparts (Females = 23.7, 95%CI = (5.6, 137.9); Males = 6.8%, 95% CI = (2.3, 66.2)). However, the risk of developing CRC decreased with age among both genders.</p> <p>Conclusion</p> <p>The proposed modified segregation-based models used to estimate age-specific risks for HNPCC phenotypes can reduce bias due to ascertainment and missing genotype information as well as provide estimates of absolute and relative risks.</p

Strongly magnetized pulsars: explosive events and evolution

Well before the radio discovery of pulsars offered the first observational confirmation for their existence (Hewish et al., 1968), it had been suggested that neutron stars might be endowed with very strong magnetic fields of $10^{10}$-$10^{14}$G (Hoyle et al., 1964; Pacini, 1967). It is because of their magnetic fields that these otherwise small ed inert, cooling dead stars emit radio pulses and shine in various part of the electromagnetic spectrum. But the presence of a strong magnetic field has more subtle and sometimes dramatic consequences: In the last decades of observations indeed, evidence mounted that it is likely the magnetic field that makes of an isolated neutron star what it is among the different observational manifestations in which they come. The contribution of the magnetic field to the energy budget of the neutron star can be comparable or even exceed the available kinetic energy. The most magnetised neutron stars in particular, the magnetars, exhibit an amazing assortment of explosive events, underlining the importance of their magnetic field in their lives. In this chapter we review the recent observational and theoretical achievements, which not only confirmed the importance of the magnetic field in the evolution of neutron stars, but also provide a promising unification scheme for the different observational manifestations in which they appear. We focus on the role of their magnetic field as an energy source behind their persistent emission, but also its critical role in explosive events.Comment: Review commissioned for publication in the White Book of "NewCompStar" European COST Action MP1304, 43 pages, 8 figure

Stunted children display ectopic small intestinal colonization by oral bacteria, which cause lipid malabsorption in experimental models

Environmental enteric dysfunction (EED) is an inflammatory syndrome postulated to contribute to stunted child growth and to be associated with intestinal dysbiosis and nutrient malabsorption. However, the small intestinal contributions to EED remain poorly understood. This study aimed to assess changes in the proximal and distal intestinal microbiota in the context of stunting and EED and to test for a causal role of these bacterial isolates in the underlying pathophysiology. We performed a cross-sectional study in two African countries recruiting roughly 1,000 children aged 2 to 5 years and assessed the microbiota in the stomach, duodenum, and feces. Upper gastrointestinal samples were obtained from stunted children and stratified according to stunting severity. Fecal samples were collected. We then investigated the role of clinical isolates in EED pathophysiology using tissue culture and animal models. We find that small intestinal bacterial overgrowth (SIBO) is extremely common (>80%) in stunted children. SIBO is frequently characterized by an overgrowth of oral bacteria, leading to increased permeability and inflammation and to replacement of classical small intestinal strains. These duodenal bacterial isolates decrease lipid absorption in both cultured enterocytes and mice, providing a mechanism by which they may exacerbate EED and stunting. Further, we find a specific fecal signature associated with the EED markers fecal calprotectin and alpha-antitrypsin. Our study shows a causal implication of ectopic colonization of oral bacterial isolated from the small intestine in nutrient malabsorption and gut leakiness in vitro. These findings have important therapeutic implications for modulating the microbiota through microbiota-targeted interventions

Inter-Cellular Variation in DNA Content of Entamoeba histolytica Originates from Temporal and Spatial Uncoupling of Cytokinesis from the Nuclear Cycle

Accumulation of multiple copies of the genome in a single nucleus and several nuclei in a single cell has previously been noted in Entamoeba histolytica, contributing to the genetic heterogeneity of this unicellular eukaryote. In this study, we demonstrate that this genetic heterogeneity is an inherent feature of the cell cycle of this organism. Chromosome segregation occurs on a variety of novel microtubular assemblies including multi-polar spindles. Cytokinesis in E. histolytica is completed by the mechanical severing of a thin cytoplasmic bridge, either independently or with the help of neighboring cells. Importantly, cytokinesis is uncoupled from the nuclear division cycle, both temporally and spatially, leading to the formation of unequal daughter cells. Sorting of euploid and polyploid cells showed that each of these sub-populations acquired heterogeneous DNA content upon further growth. Our study conclusively demonstrates that genetic heterogeneity originates from the unique mode of cell division events in this protist

An evolving jet from a strongly magnetized accreting X-ray pulsar

© 2018, Springer Nature Limited. Relativistic jets are observed throughout the Universe and strongly affect their surrounding environments on a range of physical scales, from Galactic binary systems1 to galaxies and clusters of galaxies2. All types of accreting black hole and neutron star have been observed to launch jets3, with the exception of neutron stars with strong magnetic fields4,5 (higher than 1012 gauss), leading to the conclusion that their magnetic field strength inhibits jet formation6. However, radio emission recently detected from two such objects could have a jet origin, among other possible explanations7,8, indicating that this long-standing idea might need to be reconsidered. But definitive observational evidence of such jets is still lacking. Here we report observations of an evolving jet launched by a strongly magnetized neutron star accreting above the theoretical maximum rate given by the Eddington limit. The radio luminosity of the jet is two orders of magnitude fainter than those seen in other neutron stars with similar X-ray luminosities9, implying an important role for the properties of the neutron star in regulating jet power. Our result also shows that the strong magnetic fields of ultra-luminous X-ray pulsars do not prevent such sources from launching jets