Dynamics of interferon-gamma release assay and cytokine profiles in blood and respiratory tract specimens from mice with tuberculosis and the effect of therapy

There are limitations on diagnostic methods to differentiate between active and latent tuberculosis (TB), and the prediction of latent progression to TB disease is yet complex. Traditionally, tuberculosis-specific host immune response was visualized using the tuberculin skin test. Nowadays, IFN-γ release assays (IGRA) provide a more specific and sensitive tool, by which exposure to Mtb could be determined. However, the merit of IGRA aids in diagnosing active TB is yet unclear. We adapted IGRA for use in mice, and quantifying bead-based flow cytometry techniques were used to assess cytokine profiles during the course of untreated infection and to investigate the value of IGRA and cytokines as biomarkers for therapy response. High variability of IGRA results during progression of active TB infection related to various phases of infection was obtained. However, a significant decrease in IGRA results and in levels of IFN-γ, IL-17, IP-10 or MIG was observed and appeared to be associated with successful therapy. This outcome does not support the value of IGRA to accurately diagnose active TB or to monitor infection progression. However, IGRA proved to be a useful biomarker to monitor therapy success. In addition, different cytokines might serve as biomarkers

Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences

BACKGROUND: Elevated urinary excretion of orotic acid is associated with treatable disorders of the urea cycle and pyrimidine metabolism. Establishing the correct and timely diagnosis in a patient with orotic aciduria is key to effective treatment. Uridine monophosphate synthase is involved in de novo pyrimidine synthesis. Uridine monophosphate synthase deficiency (or hereditary orotic aciduria), due to biallelic mutations in UMPS, is a rare condition presenting with megaloblastic anemia in the first months of life. If not treated with the pyrimidine precursor uridine, neutropenia, failure to thrive, growth retardation, developmental delay, and intellectual disability may ensue. METHODS AND RESULTS: We identified mild and isolated orotic aciduria in 11 unrelated individuals with diverse clinical signs and symptoms, the most common denominator being intellectual disability/developmental delay. Of note, none had blood count abnormalities, relevant hyperammonemia or altered plasma amino acid profile. All individuals were found to have heterozygous alterations in UMPS. Four of these variants were predicted to be null alleles with complete loss of function. The remaining variants were missense changes and predicted to be damaging to the normal encoded protein. Interestingly, family screening revealed heterozygous UMPS variants in combination with mild orotic aciduria in 19 clinically asymptomatic family members. CONCLUSIONS: We therefore conclude that heterozygous UMPS-mutations can lead to mild and isolated orotic aciduria without clinical consequence. Partial UMPS-deficiency should be included in the differential diagnosis of mild orotic aciduria. The discovery of heterozygotes manifesting clinical symptoms such as hypotonia and developmental delay are likely due to ascertainment bias

Diagnosis of latent tuberculosis infection among HIV discordant partners using interferon gamma release assays

<p>Abstract</p> <p>Background</p> <p>There is limited data on the effect of HIV status and CD4 counts on performance of Interferon-<b>g </b>Release assays (IGRAs) for diagnosis of latent tuberculosis infection (LTBI).</p> <p>Methods</p> <p>A cross sectional study was conducted to assess the prevalence of and risk factors for a positive diagnostic test for LTBI, using tuberculin skin test (TST) and IGRAs among HIV-discordant couples in Zambia.</p> <p>Results</p> <p>A total of 596 subjects (298 couples) were enrolled. Median CD4 count among HIV positive persons was 388 cells/μl, (range 51-1330). HIV negative persons were more likely than their HIV positive partner, to have a positive diagnostic test for LTBI with TST (203 vs 128), QFT (171 vs 109) and TSPOT (156 vs. 109). On multivariate analysis, HIV negative status was an independent predictor for a positive QFT (OR = 2.22, 95% CI 1.42- 3.46) and TSPOT (OR = 1.79, 95% CI 1.16-2.77). Among HIV positive subjects a CD4 count ≥ 388 cells/μl was associated with a positive TST (OR = 1.76 95% CI 1.10-2.82) and QFT (OR = 1.71 95% CI 1.06-2.77) but not TSPOT (OR = 1.20 95% CI 0.74-1.94).</p> <p>Conclusions</p> <p>Persons with HIV had significantly fewer positive diagnostic tests for LTBI with TST, QFT and TSPOT. Persons with a CD4 count < 388 cells/μl were less likely to have a positive TST or QFT, but not less likely to have a positive TSPOT. TSPOT may perform better than TST or QFT in HIV positive individuals.</p

Constraints on cosmic strings using data from the first Advanced LIGO observing run

Cosmic strings are topological defects which can be formed in grand unified theory scale phase transitions in the early universe. They are also predicted to form in the context of string theory. The main mechanism for a network of Nambu-Goto cosmic strings to lose energy is through the production of loops and the subsequent emission of gravitational waves, thus offering an experimental signature for the existence of cosmic strings. Here we report on the analysis conducted to specifically search for gravitational-wave bursts from cosmic string loops in the data of Advanced LIGO 2015-2016 observing run (O1). No evidence of such signals was found in the data, and as a result we set upper limits on the cosmic string parameters for three recent loop distribution models. In this paper, we initially derive constraints on the string tension Gμ and the intercommutation probability, using not only the burst analysis performed on the O1 data set but also results from the previously published LIGO stochastic O1 analysis, pulsar timing arrays, cosmic microwave background and big-bang nucleosynthesis experiments. We show that these data sets are complementary in that they probe gravitational waves produced by cosmic string loops during very different epochs. Finally, we show that the data sets exclude large parts of the parameter space of the three loop distribution models we consider

Directional Limits on Persistent Gravitational Waves from Advanced LIGO’s First Observing Run

We employ gravitational-wave radiometry to map the stochastic gravitational wave background expected from a variety of contributing mechanisms and test the assumption of isotropy using data from the Advanced Laser Interferometer Gravitational Wave Observatory’s (aLIGO) first observing run. We also search for persistent gravitational waves from point sources with only minimal assumptions over the 20–1726 Hz frequency band. Finding no evidence of gravitational waves from either point sources or a stochastic background, we set limits at 90% confidence. For broadband point sources, we report upper limits on the gravitational wave energy flux per unit frequency in the range Fα;ΘðfÞ < ð0.1–56Þ × 10−8 erg cm−2 s−1 Hz−1ðf=25 HzÞα−1 depending on the sky location Θ and the spectral power index α. For extended sources, we report upper limits on the fractional gravitational wave energy density required to close the Universe of Ωðf; ΘÞ < ð0.39–7.6Þ × 10−8 sr−1ðf=25 HzÞα depending on Θ and α. Directed searches for narrowband gravitational waves from astrophysically interesting objects (Scorpius X-1, Supernova 1987 A, and the Galactic Center) yield median frequency-dependent limits on strain amplitude of h0 < ð6.7; 5.5; and 7.0Þ × 10−25, respectively, at the most sensitive detector frequencies between 130–175 Hz. This represents a mean improvement of a factor of 2 across the band compared to previous searches of this kind for these sky locations, considering the different quantities of strain constrained in each case

Full band all-sky search for periodic gravitational waves in the O1 LIGO data

We report on a new all-sky search for periodic gravitational waves in the frequency band 475–2000 Hz and with a frequency time derivative in the range of ½−1.0; þ0.1 × 10−8 Hz=s. Potential signals could be produced by a nearby spinning and slightly nonaxisymmetric isolated neutron star in our Galaxy. This search uses the data from Advanced LIGO’s first observational run O1. No gravitational-wave signals were observed, and upper limits were placed on their strengths. For completeness, results from the separately published low-frequency search 20–475 Hz are included as well. Our lowest upper limit on worst-case (linearly polarized) strain amplitude h0 is ∼4 × 10−25 near 170 Hz, while at the high end of our frequency range, we achieve a worst-case upper limit of 1.3 × 10−24. For a circularly polarized source (most favorable orientation), the smallest upper limit obtained is ∼1.5 × 10−25

Prospects for observing and localizing gravitational-wave transients with Advanced LIGO, Advanced Virgo and KAGRA

We present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron star systems, which are the most promising targets for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and 90% credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5– 20 deg2 requires at least three detectors of sensitivity within a factor of ∼2 of each other and with a broad frequency bandwidth. When all detectors, including KAGRA and the third LIGO detector in India, reach design sensitivity, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone

Hyper-precarious lives : Migrants, work and forced labour in the Global North

This paper unpacks the contested inter-connections between neoliberal work and welfare regimes, asylum and immigration controls, and the exploitation of migrant workers. The concept of precarity is explored as a way of understanding intensifying and insecure post-Fordist work in late capitalism. Migrants are centrally implicated in highly precarious work experiences at the bottom end of labour markets in Global North countries, including becoming trapped in forced labour. Building on existing research on the working experiences of migrants in the Global North, the main part of the article considers three questions. First, what is precarity and how does the concept relate to working lives? Second, how might we understand the causes of extreme forms of migrant labour exploitation in precarious lifeworlds? Third, how can we adequately theorize these particular experiences using the conceptual tools of forced labour, slavery, unfreedom and precarity? We use the concept of ‘hyper-precarity’ alongside notions of a ‘continuum of unfreedom’ as a way of furthering human geographical inquiry into the intersections between various terrains of social action and conceptual debate concerning migrants’ precarious working experiences

Strange particle production in proton-proton collisions at s=0.9\sqrt{s}=0.9 TeV with ALICE at the LHC

The production of mesons containing strange quarks (K$^0_s$, $\phi$) and both singly and doubly strange baryons ($\Lambda$, Anti-$\Lambda$, and $\Xi$+Anti-$\Xi$) are measured at central rapidity in pp collisions at $\sqrt{s}$ = 0.9 TeV with the ALICE experiment at the LHC. The results are obtained from the analysis of about 250 k minimum bias events recorded in 2009. Measurements of yields (dN/dy) and transverse momentum spectra at central rapidities for inelastic pp collisions are presented. For mesons, we report yields () of 0.184 $\pm$ 0.002 stat. $\pm$ 0.006 syst. for K$^0_s$ and 0.021 $\pm$ 0.004 stat. $\pm$ 0.003 syst. for $\phi$. For baryons, we find = 0.048 $\pm$ 0.001 stat. $\pm$ 0.004 syst. for $\Lambda$, 0.047 $\pm$ 0.002 stat. $\pm$ 0.005 syst. for Anti-$\Lambda$ and 0.0101 $\pm$ 0.0020 stat. $\pm$ 0.0009 syst. for $\Xi$+Anti-$\Xi$. The results are also compared with predictions for identified particle spectra from QCD-inspired models and provide a baseline for comparisons with both future pp measurements at higher energies and heavy-ion collisions.Comment: 33 pages, 21 captioned figures, 10 tables, authors from page 28, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/387