A central pillar of global tuberculosis (TB) control programs is early antimicrobial treatment of paucibacillary infection to prevent its progression to multibacillary disease (1). The rationale is ...self-evident. This approach is expected to reduce incident disease, both in the infected individual and by reducing risk of onward transmission of infection. It also offers the advantage of shorter treatment with fewer drugs and mitigates against the risk of antimicrobial resistance. The gold standard to identify prevalent disease necessitating antimicrobial treatment has been microbiological diagnosis of Mycobacterium tuberculosis (Mtb) infection by microscopy, culture, PCR, or antigen detection in clinical samples, but the sensitivity of all of these tests is inevitably proportional to the bacillary burden. The accessibility of omics technologies has fueled the search for new biomarkers of TB (5). Among these, quantitation of circulating host mRNA molecules either individually or in combination as a transcriptional signature has gained the most traction-at least one candidate has already been developed into a cartridge-based PCR test.
OBJECTIVES:Tuberculosis (TB) is estimated to be the leading cause of HIV-related deaths globally. However, since HIV-associated TB frequently remains unascertained, we systematically reviewed autopsy ...studies to determine the true burden of TB at death.
METHODS:We systematically searched Medline and Embase databases (to end 2013) for literature reporting on health facility-based autopsy studies of HIV-infected adults and/or children in resource-limited settings. Using forest plots and random-effects meta-analysis, we summarized the TB prevalence found at autopsy and used meta-regression to explore variables associated with autopsy TB prevalence.
RESULTS:We included 36 eligible studies, reporting on 3237 autopsies. Autopsy TB prevalence was extremely heterogeneous (range 0–64.4%), but was markedly higher in adults pooled prevalence 39.7%, 95% confidence interval (CI) 32.4–47.0% compared to children (pooled prevalence 4.5%, 95% CI 1.7–7.4%). Post-mortem TB prevalence varied by world region, with pooled estimates in adults of 63.2% (95% CI 57.7–68.7%) in South Asia (n = 2 studies); 43.2% (95% CI 38.0–48.3) in sub-Saharan Africa (n = 9 studies); and 27.1% (95% CI 16.0–38.1%) in the Americas (n = 5 studies). Autopsy prevalence positively correlated with contemporary estimates of national TB prevalence. TB in adults was disseminated in 87.9% (82.2–93.7%) of cases and was considered the cause of death in 91.4% (95% CI 85.8–97.0%) of TB cases. Overall, TB was the cause of death in 37.2% (95% CI 25.7–48.7%) of adult HIV/AIDS-related deaths. TB remained undiagnosed at death in 45.8% (95% CI 32.6–59.1%) of TB cases.
CONCLUSIONS:In resource-limited settings, TB accounts for approximately 40% of facility-based HIV/AIDS-related adult deaths. Almost half of this disease remains undiagnosed at the time of death. These findings highlight the critical need to improve the prevention, diagnosis and treatment of HIV-associated TB globally.
To use mathematical models to predict the epidemiological impact of lifting the lockdown in London, UK, and alternative strategies to help inform policy in the UK.
A mathematical model for the ...transmission of SARS-CoV2 in London. The model was parametrised using data on notified cases, deaths, contacts, and mobility to analyse the epidemic in the UK capital. We investigated the impact of multiple non pharmaceutical interventions (NPIs) and combinations of these measures on future incidence of COVID-19.
Immediate action at the early stages of an epidemic in the affected districts would have tackled spread. While an extended lockdown is highly effective, other measures such as shielding older populations, universal testing and facemasks can all potentially contribute to a reduction of infections and deaths. However, based on current evidence it seems unlikely they will be as effective as continued lockdown. In order to achieve elimination and lift lockdown within 5 months, the best strategy seems to be a combination of weekly universal testing, contact tracing and use of facemasks, with concurrent lockdown. This approach could potentially reduce deaths by 48% compared with continued lockdown alone.
A combination of NPIs such as universal testing, contact tracing and mask use while under lockdown would be associated with least deaths and infections. This approach would require high uptake and sustained local effort but it is potentially feasible as may lead to elimination in a relatively short time scale.
The immune system interacts with cancer cells in multiple intricate ways that can shield the host against hyper-proliferation but can also contribute to malignancy. Understanding the protective roles ...of the immune system in its interaction with cancer cells can help device new and alternate therapeutic strategies. Many immunotherapeutic methodologies, including adaptive cancer therapy, cancer peptide vaccines, monoclonal antibodies, and immune checkpoint treatment, have transformed the traditional cancer treatment landscape. However, many questions remain unaddressed. The development of personalized combination therapy and neoantigen-based cancer vaccines would be the avant-garde approach to cancer treatment. Desirable chemotherapy should be durable, safe, and target-specific. Managing both tumor (intrinsic factors) and its microenvironment (extrinsic factors) are critical for successful immunotherapy. This review describes current approaches and their advancement related to monoclonal antibody-related clinical trials, new cytokine therapy, a checkpoint inhibitor, adoptive T cell therapy, cancer vaccine, and oncolytic virus.
The use of robots has significantly increased to fight highly contagious diseases like SARS-COV-2, Ebola, MERS, and others. One of the important applications of robots to fight such infectious ...diseases is disinfection. Manual disinfection can be a time-consuming, risky, labor-intensive, and mundane, and humans may fail to disinfect critical areas due to the resulting fatigue. Autonomous or semi-autonomous mobile manipulators mounted with a spray nozzle at the end-effector can be very effective in spraying disinfectant liquid for deep disinfection of objects and surfaces. In this paper, we present an area-coverage planning algorithm to compute a path that the nozzle follows to disinfect surfaces represented by their point clouds. We project the point cloud on a plane and produce a polygon on which we generate multiple spray paths using our branch and bound-based tree search area-coverage algorithm such that the spray paths cover the entire area of the polygon. An appropriate spray path is chosen using a robot capability map-based selection criterion. We generate mobile manipulator trajectories using successive refinement-based parametric optimization so that the paths for the nozzle are followed accurately. Thereafter, we need to make sure that the joint velocities of the mobile manipulator are regulated appropriately such that each point on the surface receives enough disinfectant spray. To this end, we compute the time intervals between the robot path waypoints such that enough disinfectant liquid is sprayed on all points of the point cloud that results in thorough disinfection of the surface, and the particular robot path is executed in the minimum possible time. We have implemented the area-coverage planning and mobile manipulator motion planning on five test scenarios in simulation using our ADAMMS-SD (Agile Dexterous Autonomous Mobile Manipulation System for Surface Disinfection) robot. We benchmark our spray path generation algorithm with three competing methods by showing that the generated paths are significantly more efficient in terms of area coverage and reducing disinfectant wastage. We also show the time interval computation between successive waypoints results in thorough disinfection of surfaces.
•Covid-19 and similar viral diseases can spread via surfaces, hence disinfection is important, especially with robots as it reduces human risk and effort.•Mobile manipulators mounted with a spray nozzle can be used autonomously or semi-autonomously to disinfect surfaces.•A branch and bound-based algorithm is presented to determine spray paths on a point cloud of the surfae being disinfected.•A spline-based representation of the robot degrees of freedom and successive refinement-based optimization are used for generating robot motion.•A linear programming-based formulation is used to find the time taken between successive waypoints to guarantee thorough disinfection of surfaces.
Multiple blood transcriptional signatures have been proposed for identification of active and incipient tuberculosis. We aimed to compare the performance of systematically identified candidate ...signatures for incipient tuberculosis and to benchmark these against WHO targets.
We did a systematic review and individual participant data meta-analysis. We searched Medline and Embase for candidate whole blood mRNA signatures discovered with the primary objective of diagnosis of active or incipient tuberculosis, compared with controls who were healthy or had latent tuberculosis infection. We tested the performance of eligible signatures in whole blood transcriptomic datasets, in which sampling before tuberculosis diagnosis was done and time to disease was available. Culture-confirmed and clinically or radiologically diagnosed pulmonary or extrapulmonary tuberculosis cases were included. Non-progressor (individuals who remained tuberculosis-free during follow-up) samples with less than 6 months of follow-up from the date of sample collection were excluded, as were participants with prevalent tuberculosis and those who received preventive therapy. Scores were calculated for candidate signatures for each participant in the pooled dataset. Receiver operating characteristic curves, sensitivities, and specificities were examined using prespecified intervals to tuberculosis (<3 months, <6 months, <1 year, and <2 years) from sample collection. This study is registered with PROSPERO, number CRD42019135618.
We tested 17 candidate mRNA signatures in a pooled dataset from four eligible studies comprising 1126 samples. This dataset included 183 samples from 127 incipient tuberculosis cases in South Africa, Ethiopia, The Gambia, and the UK. Eight signatures (comprising 1–25 transcripts) that predominantly reflect interferon and tumour necrosis factor-inducible gene expression, had equivalent diagnostic accuracy for incipient tuberculosis over a 2-year period with areas under the receiver operating characteristic curves ranging from 0·70 (95% CI 0·64–0·76) to 0·77 (0·71–0·82). The sensitivity of all eight signatures declined with increasing disease-free time interval. Using a threshold derived from two SDs above the mean of uninfected controls to prioritise specificity and positive-predictive value, the eight signatures achieved sensitivities of 24·7–39·9% over 24 months and of 47·1–81·0% over 3 months, with corresponding specificities of more than 90%. Based on pre-test probability of 2%, the eight signatures achieved positive-predictive values ranging from 6·8–9·4% over 24 months and 11·2–14·4% over 3 months. When using biomarker thresholds maximising sensitivity and specificity with equal weighting to both, no signature met the minimum WHO target product profile parameters for incipient tuberculosis biomarkers over a 2-year period.
Blood transcriptional biomarkers reflect short-term risk of tuberculosis and only exceed WHO benchmarks if applied to 3–6-month intervals. Serial testing among carefully selected target groups might be required for optimal implementation of these biomarkers.
Wellcome Trust and National Institute for Health Research.
...major advances in the understanding of TB pathogenesis (including vaccine development) and transmission, together with new tools for the diagnosis and treatment of both active TB disease and ...latent infection, are needed. Diagnosis and Treatment of Active TB Disease In the Journal, Lessells and colleagues reported the results of a cluster randomized controlled trial examining the impact of point-of-care compared with hospital laboratory implementation of Xpert MTB/RIF (Cepheid), a molecular test for TB and rifampicin resistance (10), on TB treatment initiation among individuals who were HIV positive (92.5%) and/or had risk factors for multidrug-resistant (MDR)-TB (45%) (11). In the Journal, Ganmaa and colleagues reported their randomized controlled trial in which they assessed the impact of high-dose vitamin D3 on response to antimicrobial therapy in adults with drugsensitive pulmonary TB in Mongolia, with the primary outcome of time to sputum culture conversion (30). Four of these regions were subsequently confirmed in an independent strain cohort and functionally validated to demonstrate that mutations in the targets affected in vitro monocyte and T-cell cytokine production, neutrophil reactive oxygen species release, and apoptosis.
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