Background Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease may lead to interventions that impact the epidemic. Methods Healthy, M. tuberculosis infected South African adolescents were followed for 2 years; blood was collected every 6 months. A prospective signature of risk was derived from whole blood RNA-Sequencing data by comparing participants who ultimately developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex qRT-PCR, the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. The latter participants were household contacts of adults with active pulmonary tuberculosis disease. Findings Of 6,363 adolescents screened, 46 progressors and 107 matched controls were identified. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% confidence interval, 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA-Seq and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6–64·3) and a specificity of 82·8% (76·7–86) in 12 months preceding tuberculosis. Interpretation The whole blood tuberculosis risk signature prospectively identified persons at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. Funding Bill and Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union and the South African Medical Research Council (detail at end of text).

Our understanding of mechanisms underlying progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease in humans remains limited. To define such mechanisms, we followed M. tuberculosis-infected adolescents longitudinally. Blood samples from forty-four adolescents who ultimately developed tuberculosis disease (“progressors”) were compared with those from 106 matched controls, who remained healthy during two years of follow up. We performed longitudinal whole blood transcriptomic analyses by RNA sequencing and plasma proteome analyses using multiplexed slow off-rate modified DNA aptamers. Tuberculosis progression was associated with sequential modulation of immunological processes. Type I/II interferon signalling and complement cascade were elevated 18 months before tuberculosis disease diagnosis, while changes in myeloid inflammation, lymphoid, monocyte and neutrophil gene modules occurred more proximally to tuberculosis disease. Analysis of gene expression in purified T cells also revealed early suppression of Th17 responses in progressors, relative to M. tuberculosis-infected controls. This was confirmed in an independent adult cohort who received BCG re-vaccination; transcript expression of interferon response genes in blood prior to BCG administration was associated with suppression of IL-17 expression by BCG-specific CD4 T cells 3 weeks post-vaccination. Our findings provide a timeline to the different immunological stages of disease progression which comprise sequential inflammatory dynamics and immune alterations that precede disease manifestations and diagnosis of tuberculosis disease. These findings have important implications for developing diagnostics, vaccination and host-directed therapies for tuberculosis.Trial registrationClincialtrials.gov, NCT01119521

Rationale: Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with Mycobacterium tuberculosis and progression to disease.Objectives: We investigated biosignatures with predictive ability for incident TB.Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated. Measurements and Main Results:A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. Post hoc meta-analysis identified a single gene pair, C1QC/TRAV27 (complement C1q C-chain / T-cell receptor-a variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events.Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs.

Biomarkers for tuberculosis treatment outcome will assist in guiding individualized treatment and evaluation of new therapies. To identify candidate biomarkers, RNA sequencing of whole blood from a well-characterized TB treatment cohort was performed. Application of a validated transcriptional correlate of risk for TB revealed symmetry in host gene expression during progression from latent TB infection to active TB disease and resolution of disease during treatment, including return to control levels after drug therapy. The symmetry was also seen in a TB disease signature, constructed from the TB treatment cohort, that also functioned as a strong correlate of risk. Both signatures identified patients at risk of treatment failure 1–4 weeks after start of therapy. Further mining of the transcriptomes revealed an association between treatment failure and suppressed expression of mitochondrial genes before treatment initiation, leading to development of a novel baseline (pre-treatment) signature of treatment failure. These novel host responses to TB treatment were integrated into a five-gene real-time PCR-based signature that captures the clinically relevant responses to TB treatment and provides a convenient platform for stratifying patients according to their risk of treatment failure. Furthermore, this 5-gene signature is shown to correlate with the pulmonary inflammatory state (as measured by PET-CT) and can complement sputum-based Gene Xpert for patient stratification, providing a rapid and accurate alternative to current methods.

We use the holographic proposal for calculating entanglement entropies to determine the boundary entropy of defects in strongly coupled two-dimensional conformal field theories. We study several examples including the Janus solution and show that the boundary entropy extracted from the entanglement entropy as well as its more conventional definition via the free energy agree with each other. Maybe somewhat surprisingly we find that, unlike in the case of a conformal field theory with boundary, the entanglement entropy for a generic region in a theory with defect carries detailed information about the microscopic details of the theory. We also argue that the g-theorem for the boundary entropy is closely related to the strong subadditivity of the entanglement entropy. 1

We find the first example of a quantum Berenzinskii-Kosterlitz-Thouless (BKT) phase transition in two spatial dimensions via holography. This transition occurs in the D3/D5 system at nonzero density and magnetic field. At any nonzero temperature, the BKT scaling is destroyed and the transition becomes second order with mean-field exponents. We go on to conjecture about the generality of quantum BKT transitions in two spatial dimensions.PACS numbers: 11.25.TqIntroduction.-Holography [1-3] has become an important tool in the investigation of strongly-coupled systems. Despite being restricted to a special class of theoriesthose with simple gravitational duals-the technique has found interesting applications to the physics of the quarkgluon plasma [4]. Recently, there have been attempts to use holographic models to approach condensed matter systems-like the Fermi gas at unitarity [5,6], superfluids [7] and non-Fermi liquids [8][9][10][11]-with various degrees of success.Phase transitions are one central physical concept that can be studied holographically. They are present in many holographic models and frequently allow simple geometric interpretations. However, most holographic phase transitions are either first-order [12][13][14] or second-order with mean-field exponents. The reason for the meanfield behavior is the large N parameter which suppresses quantum fluctuations in the gravity theory and allows the latter to be treated semiclassically. On the other hand, the most interesting questions are usually beyond the mean-field approximation [15], or beyond the LandauGinzburg-Wilson paradigm altogether [16]. It is very important to investigate whether the holographic method can be used to study these non-mean-field phase transitions.In this Letter, we show that, even within the confines of large-N field theories, another type of phase transition is possible-namely, those with the scaling behavior of the Berezinskii-Kosterlitz-Thouless (BKT) phase transition [17,18]. Recall that in the BKT phase transition, the order parameter scales as exp(−c/ √ T c − T ) near the critical temperature T c [19]. In our case, interestingly, the phase transition is a quantum phase transition, occurring at zero temperature in 2+1 spacetime dimensions. The explicit example we consider is a 2+1 dimensional theory at a finite density d of a conserved charge and a magnetic field B. At a particular value of the "filling fraction" ν = d/B, the system suffers a transition to a broken symmetry state, and the scaling of the order parameter is the same as in a BKT phase transition, σ ∼ exp(−c/ √ ν c − ν). We shall call this phase transition the "holographic BKT phase transition," although

Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts. Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.

We show that the recently constructed holographic duals of conformal non-relativistic theories behave hydrodynamically at long distances, and construct the gravitational dual of fluid flows in a long-wavelength approximation. We compute the thermal conductivity of the holographic conformal non-relativistic fluid. The corresponding Prandtl number is equal to one.