Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy ...number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10
), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10
) and 1.68 (P=2.18 × 10
), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10
) for all patients and 3.19 (P=1.23 × 10
) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10
), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.
Background. Marked increases in Clostridium difficile infection (CDI) incidence, driven by epidemic strain spread, is a global phenomenon. Methods. The Clostridium difficile Ribotyping Network (CDRN) ...was established in 2007 as part of enhanced CDI surveillance in England, to facilitate the recognition and control of epidemic strains. We report on changes in CDI epidemiology in England in the first 3 years of CDRN. Results. CDRN received 12 603 fecal specimens, comprising significantly (P < .05) increasing numbers and proportions of national CDI cases in 2007–2008 (n = 2109, 3.8%), 2008–2009 (n = 4774, 13.2%), and 2009–2010 (n = 5720, 22.3%). The C. difficile recovery rate was 90%, yielding 11 294 isolates for ribotyping. Rates of 9 of the 10 most common ribotypes changed significantly (P < .05) during 2007–2010. Clostridium difficile ribotype 027 predominated, but decreased markedly from 55% to 36% and 21% in 2007–2008, 2008–2009, and 2009–2010, respectively. The largest regional variations in prevalence occurred for ribotypes 027, 002, 015, and 078. Cephalosporin and fluoroquinolone use in CDI cases was reported significantly (P < .05) less frequently during 2007–2010. Mortality data were subject to potential reporting bias, but there was a significant decrease in CDI-associated deaths during 2007–2010, which may have been due to multiple factors, including reduced prevalence of ribotype 027. Conclusions. Access to C. difficile ribotyping was associated with significant changes in the prevalence of epidemic strains, especially ribotype 027. These changes coincided with markedly reduced CDI incidence and related mortality in England. CDI control programs should include prospective access to C. difficile typing and analysis of risk factors for CDI and outcomes.
Abstract
Stimulated Brillouin scattering experiments in the ionospheric plasma using a single electromagnetic pump wave have previously been observed to generate an electromagnetic sideband wave, ...emitted by the plasma, together with an ion- acoustic wave. Here we report results of a controlled, pump and probe beat-wave driven Brillouin scattering experiment, in which an ion-acoustic wave generated by the beating of electromagnetic pump and probe waves, results in electromagnetic sideband waves that are recorded on the ground. The experiment used the EISCAT facility in northern Norway, which has several high power electromagnetic wave transmitters and receivers in the radio frequency range. An electromagnetic pump consisting of large amplitude radio waves with ordinary (O) or extraordinary (X) mode polarization was injected into the overhead ionosphere, along with a less powerful probe wave, and radio sideband emissions observed on the ground clearly show stimulated Brillouin emissions at frequencies agreeing with, and changing with, the pump and probe frequencies. The experiment was simulated using a numerical full-scale model which clearly supports the interpretation of the experimental results. Such controlled beat-wave experiments demonstrate a way of remotely investigating the ionospheric plasma parameters.
Large-scale disturbances generated by the Sun’s dynamics first propagate through the heliosphere, influence the heliosphere’s outer boundaries, and then traverse and modify the very local ...interstellar medium (VLISM). The existence of shocks in the VLISM was initially suggested by Voyager observations of the 2-3 kHz radio emissions in the heliosphere. A couple of decades later, both Voyagers crossed the definitive edge of our heliosphere and became the first ever spacecraft to sample interstellar space. Since Voyager 1’s entrance into the VLISM, it sampled electron plasma oscillation events that indirectly measure the medium’s density, increasing as it moves further away from the heliopause. Some of the observed electron oscillation events in the VLISM were associated with the local heliospheric shock waves. The observed VLISM shocks were very different than heliospheric shocks. They were very weak and broad, and the usual dissipation via wave-particle interactions could not explain their structure. Estimates of the dissipation associated with the collisionality show that collisions can determine the VLISM shock structure. According to theory and models, the existence of a bow shock or wave in front of our heliosphere is still an open question as there are no direct observations yet. This paper reviews the outstanding observations recently made by the Voyager 1 and 2 spacecraft, and our current understanding of the properties of shocks/waves in the VLISM. We present some of the most exciting open questions related to the VLISM and shock waves that should be addressed in the future.
ABSTRACT
We present SCUBA-2 850 $\mathrm{ \mu}$m observations of 13 candidate starbursting protoclusters selected using Planck and Herschel data. The cumulative number counts of the 850 $\mathrm{ ...\mu}$m sources in 9 of 13 of these candidate protoclusters show significant overdensities compared to the field, with the probability <10−2 assuming the sources are randomly distributed in the sky. Using the 250, 350, 500, and 850 $\mathrm{ \mu}$m flux densities, we estimate the photometric redshifts of individual SCUBA-2 sources by fitting spectral energy distribution templates with an MCMC method. The photometric redshift distribution, peaking at 2 < z < 3, is consistent with that of known z > 2 protoclusters and the peak of the cosmic star formation rate density (SFRD). We find that the 850 $\mathrm{ \mu}$m sources in our candidate protoclusters have infrared luminosities of $L_{\mathrm{IR}}\gtrsim 10^{12}\, \mathrm{L}_{\odot }$ and star formation rates of SFR = (500–1500) M⊙ yr−1. By comparing with results in the literature considering only Herschel photometry, we conclude that our 13 candidate protoclusters can be categorized into four groups: six of them being high-redshift starbursting protoclusters, one being a lower redshift cluster or protocluster, three being protoclusters that contain lensed dusty star-forming galaxies or are rich in 850 $\mathrm{ \mu}$m sources, and three regions without significant Herschel or SCUBA-2 source overdensities. The total SFRs of the candidate protoclusters are found to be comparable or higher than those of known protoclusters, suggesting our sample contains some of the most extreme protocluster population. We infer that cross-matching Planck and Herschel data is a robust method for selecting candidate protoclusters with overdensities of 850 $\mathrm{ \mu}$m sources.
We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its ...impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.
Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate ...exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.
This paper describes a durable carbon nanotube (CNT) film for flexible devices and its mechanical properties. Films as thin as 10
nm thick have properties approaching those of existing electrodes ...based on indium tin oxide (ITO) but with significantly improved mechanical properties. In uniaxial tension, strains as high as 25% are required for permanent damage and at lower strains resistance changes are slight and consistent with elastic deformation of the individual CNTs. A simple model confirms that changes in electrical resistance are described by a Poisson's ratio of 0.22. These films are also durable to cyclic loading, and even at peak strains of 10% no significant damage occurs after 250
cycles. The scratch resistance is also high as measured by nanoscratch, and for a 50
μm tip a load of 140
mN is required to cause initial failure. This is more than 5 times higher than is required to cause cracking in ITO. The robustness of the transparent conductive coating leads to significant improvement in device performance. In touch screen devices fabricated using CNT no failure occurs after a million actuations while for devices based on ITO electrodes 400,000
cycles are needed to cause failure.
These durable electrodes hold the key to developing robust, large-area, lightweight, optoelectronic devices such as lighting, displays, electronic-paper, and printable solar cells. Such devices could hold the key to producing inexpensive green energy, providing reliable solid-state lighting, and significantly reducing our dependence on paper.
Evidence for active DNA demethylation in vertebrates is accumulating, but the mechanisms and enzymes remain unclear. Using zebrafish embryos we provide evidence for 5-methylcytosine (5-meC) removal ...in vivo via the coupling of a 5-meC deaminase (AID, which converts 5-meC to thymine) and a G:T mismatch-specific thymine glycosylase (Mbd4). The injection of methylated DNA into embryos induced a potent DNA demethylation activity, which was attenuated by depletion of AID or the non enzymatic factor Gadd45. Remarkably, overexpression of the deaminase/glycosylase pair AID/Mbd4 in vivo caused demethylation of the bulk genome and injected methylated DNA fragments, likely involving a G:T intermediate. Furthermore, AID or Mbd4 knockdown caused the remethylation of a set of common genes. Finally, Gadd45 promoted demethylation and enhanced functional interactions between deaminase/glycosylase pairs. Our results provide evidence for a coupled mechanism of 5-meC demethylation, whereby AID deaminates 5-meC, followed by thymine base excision by Mbd4, promoted by Gadd45.
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