AbstractTuberculosis (TB) continues to cause more deaths worldwide than any other infectious disease. Even though global TB incidence has been decreasing for some time, the proportion of drug ...resistance is increasing, contributing to greater complexity, morbidity, mortality, and cost. Since the advent of rifampicin in the 1960s, and the implementation of the standard quadruple anti-tuberculosis regimen in the late 1970s, no new drugs have changed the first line regimen. This regimen while effective, has a long duration and pill burden, which has received little investment and innovation. Drug-resistant regimens are lengthy and frequently poorly tolerated due to significant toxicity. Fortunately, many significant advances have taken place in this field in recent years with the WHO shorter multidrug-resistant tuberculosis regimen and availability of new drugs like bedaquiline, delamanid and repurposed drugs like clofazimine, carbapenems, and linezolid. These drugs pose unique challenges relating to their rational use to prevent selection of resistant strains of Mycobacterium tuberculosis even before a new regimen has been studied. The availability of these new drugs offers hope and new possibilities to patients with limited or no treatment options. Their use and combination into effective regimens need to be studied; trials are in progress. It is hoped that soon we will be able to treat sensitive and drug-resistant cases with a universal regimen, this would revolutionise treatment and take us another step closer towards elimination. This review is an update on the new drugs and perspectives for the treatment of drug-susceptible and drug-resistant tuberculosis.
We present the first extensive radio to γ-ray observations of a fast-rising blue optical transient, AT 2018cow, over its first ∼100 days. AT 2018cow rose over a few days to a peak luminosity Lpk ∼ 4 ...× 1044 erg s−1, exceeding that of superluminous supernovae (SNe), before declining as L ∝ t−2. Initial spectra at δt 15 days were mostly featureless and indicated large expansion velocities v ∼ 0.1c and temperatures reaching T ∼ 3 × 104 K. Later spectra revealed a persistent optically thick photosphere and the emergence of H and He emission features with v ∼ 4000 km s−1 with no evidence for ejecta cooling. Our broadband monitoring revealed a hard X-ray spectral component at E ≥ 10 keV, in addition to luminous and highly variable soft X-rays, with properties unprecedented among astronomical transients. An abrupt change in the X-ray decay rate and variability appears to accompany the change in optical spectral properties. AT 2018cow showed bright radio emission consistent with the interaction of a blast wave with vsh ∼ 0.1c with a dense environment ( for vw = 1000 km s−1). While these properties exclude 56Ni-powered transients, our multiwavelength analysis instead indicates that AT 2018cow harbored a "central engine," either a compact object (magnetar or black hole) or an embedded internal shock produced by interaction with a compact, dense circumstellar medium. The engine released ∼1050-1051.5 erg over ∼103-105 s and resides within low-mass fast-moving material with equatorial-polar density asymmetry (Mej,fast 0.3 M☉). Successful SNe from low-mass H-rich stars (like electron-capture SNe) or failed explosions from blue supergiants satisfy these constraints. Intermediate-mass black holes are disfavored by the large environmental density probed by the radio observations.
Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent ...tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-gamma release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection. In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.
Extensively drug-resistant tuberculosis is a burgeoning global health crisis mainly affecting economically active young adults, and has high mortality irrespective of HIV status. In some countries ...such as South Africa, drug-resistant tuberculosis represents less than 3% of all cases but consumes more than a third of the total national budget for tuberculosis, which is unsustainable and threatens to destabilise national tuberculosis programmes. However, concern about drug-resistant tuberculosis has been eclipsed by that of totally and extremely drug-resistant tuberculosis--ie, resistance to all or nearly all conventional first-line and second-line antituberculosis drugs. In this Review, we discuss the epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medicolegal aspects of extensively drug-resistant tuberculosis and other resistant strains. Finally, we discuss the emerging problem of functionally untreatable tuberculosis, and the issues and challenges that it poses to public health and clinical practice. The emergence and growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis--and increased funding to strengthen global control efforts, research, and advocacy--even more pressing.
Context.
We present a systematic X-ray spectral-timing study of the recently discovered, exceptionally bright black hole X-ray binary system MAXI J1820+070. Our analysis focuses on the first part of ...the 2018 outburst, covering the rise throughout the hard state, the bright hard and hard-intermediate states, and the transition to the soft-intermediate state.
Aims.
We address the issue of constraining the geometry of the innermost accretion flow and its evolution throughout an outburst.
Methods.
We employed two independent X-ray spectral-timing methods applied to archival NICER data of MAXI J1820+070. We first identified and tracked the evolution of a characteristic frequency of soft X-ray thermal reverberation lags (lags of the thermally reprocessed disc emission after the irradiation of variable hard X-ray photons). This frequency is sensitive to intrinsic changes in the relative distance between the X-ray source and the disc. Then, we studied the spectral evolution of the quasi-thermal component responsible for the observed thermal reverberation lags. We did so by analysing high-frequency covariance spectra, which single out spectral components that vary in a linearly correlated way on the shortest sampled timescales and are thus produced in the innermost regions of the accretion flow.
Results.
The frequency of thermal reverberation lags steadily increases throughout most of the outburst, implying that the relative distance between the X-ray source and the disc decreases as the source softens. However, near transition this evolution breaks, showing a sudden increase (decrease) in lag amplitude (frequency). On the other hand, the temperature of the quasi-thermal component in covariance spectra, due to disc irradiation and responsible for the observed soft reverberation lags, consistently increases throughout all the analysed observations.
Conclusions.
This study proposes an alternative interpretation to the recently proposed contracting corona scenario. Assuming a constant height for the X-ray source, the steady increase in the reverberation lag frequency and in the irradiated disc temperature in high-frequency covariance spectra can be explained in terms of a decrease in the disc inner radius as the source softens. The behaviour of thermal reverberation lags near transition might be related to the relativistic plasma ejections detected at radio wavelengths, suggesting a causal connection between the two phenomena. Throughout most of the hard and hard-intermediate state, the disc is consistent with being truncated (with an inner radius
R
in
≳ 10
R
g
), reaching close to the innermost stable circular orbit only near transition.
Little is known about the relationship between the COVID-19 and tuberculosis (TB). The aim of this study is to describe a group of patients who died with TB (active disease or sequelae) and COVID-19 ...in two cohorts.
Data from 49 consecutive cases in 8 countries (cohort A) and 20 hospitalised patients with TB and COVID-19 (cohort B) were analysed and patients who died were described. Demographic and clinical variables were retrospectively collected, including co-morbidities and risk factors for TB and COVID-19 mortality.
Overall, 8 out of 69 (11.6%) patients died, 7 from cohort A (14.3%) and one from cohort B (5%).
Out of 69 patients 43 were migrants, 26/49 (53.1%) in cohort A and 17/20 (85.0%) in cohort B.
Migrants: (1) were younger than natives; in cohort A the median (IQR) age was 40 (27–49) VS. 66 (46–70) years, whereas in cohort B 37 (27–46) VS. 48 (47–60) years; (2) had a lower mortality rate than natives (1/43, 2.3% versus 7/26, 26.9%; p-value: 0.002); (3) had fewer co-morbidities than natives (23/43, 53.5% versus 5/26–19.2%) natives; p-value: 0.005).
The study findings show that: (1) mortality is likely to occur in elderly patients with co-morbidities; (2) TB might not be a major determinant of mortality and (3) migrants had lower mortality, probably because of their younger age and lower number of co-morbidities. However, in settings where advanced forms of TB frequently occur and are caused by drug-resistant strains of M. tuberculosis, higher mortality rates can be expected in young individuals.
Contact investigation to identify individuals with tuberculosis and latent infection with Mycobacterium tuberculosis is an important component of tuberculosis control in low tuberculosis incidence ...countries. This document provides evidence-based and best-practice policy recommendations for contact tracing among high- and medium-priority contacts in a variety of settings. It provides a basis for national guidelines on contact investigation and tuberculosis outbreak management, and should support countries and tuberculosis control managers in evaluating and revising national policies. A review of existing guidelines, a literature search, several meetings and consultation with experts were used to formulate and grade recommendations for action during contact investigation. Available tests to identify individuals with latent infection with M. tuberculosis are designed to identify immune response against mycobacterial antigens and have variable predictive value for the likelihood to develop active tuberculosis in different populations. Contact investigation should therefore be limited to situations with a clear likelihood of transmission or to those with a higher probability of developing active tuberculosis, for instance, young children and immunocompromised persons. A risk assessment-based approach is recommended, where the need to screen contacts is prioritised on the basis of the infectiousness of the index case, intensity of exposure and susceptibility of contacts.
We conducted a systematic review and meta-analysis to compare the accuracy of the QuantiFERON-TB® Gold In-Tube (QFT-G-IT) and the T-SPOT®.TB assays with the tuberculin skin test (TST) for the ...diagnosis of latent Mycobacterium tuberculosis infection (LTBI). The Medline, Embase and Cochrane databases were explored for relevant articles in November 2009. Specificities, and negative (NPV) and positive (PPV) predictive values of interferon-γ release assays (IGRAs) and the TST, and the exposure gradient influences on test results among bacille Calmette-Guérin (BCG) vaccinees were evaluated. Specificity of IGRAs varied 98-100%. In immunocompetent adults, NPV for progression to tuberculosis within 2 yrs were 97.8% for T-SPOT®.TB and 99.8% for QFT-G-IT. When test performance of an immunodiagnostic test was not restricted to prior positivity of another test, progression rates to tuberculosis among IGRA-positive individuals followed for 19-24 months varied 8-15%, exceeding those reported for the TST (2-3%). In multivariate analyses, the odd ratios for TST positivity following BCG vaccination varied 3-25, whereas IGRA results remained uninfluenced and IGRA positivity was clearly associated with exposure to contagious tuberculosis cases. IGRAs may have a relative advantage over the TST in detecting LTBI and allow the exclusion of M. tuberculosis infection with higher reliability.
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