Host-response profiles can discriminate different infections. A new 8-gene blood RNA signature to discriminate bacterial and viral infections extends our focus hitherto on the case mix from the US ...and Europe to include that of low- and middle-income countries.1 Challenges remain.
Host-response profiles can discriminate different infections. A new 8-gene blood RNA signature to discriminate bacterial and viral infections extends our focus hitherto on the case mix from the US and Europe to include that of low- and middle-income countries.1 Challenges remain.
BACKGROUNDAn estimated one fourth of the world's population is infected with Mycobacterium tuberculosis, and 5-10% of those infected develop tuberculosis in their lifetime. Preventing tuberculosis is ...one of the most underutilized but essential components of curtailing the tuberculosis epidemic. Moreover, current evidence illustrates that tuberculosis manifestations occur along a dynamic spectrum from infection to disease rather than a binary state as historically conceptualized. Elucidating determinants of transition between these states is crucial to decreasing the tuberculosis burden and reaching the END-TB Strategy goals as defined by the WHO. Vaccination, detection of infection, and provision of preventive treatment are key elements of tuberculosis prevention.OBJECTIVESThis review provides a comprehensive summary of recent evidence and state-of-the-art updates on advancements to prevent tuberculosis in various settings and high-risk populations.SOURCESWe identified relevant studies in the literature and synthesized the findings to provide an overview of the current state of tuberculosis prevention strategies and latest research developments.CONTENTWe present the current knowledge and recommendations regarding tuberculosis prevention, with a focus on M. bovis Bacille-Calmette-Guérin vaccination and novel vaccine candidates, tests for latent infection with M. tuberculosis, regimens available for tuberculosis preventive treatment and recommendations in low- and high-burden settings.IMPLICATIONSEffective tuberculosis prevention worldwide requires a multipronged approach that addresses social determinants, and improves access to tuberculosis detection and to new short tuberculosis preventive treatment regimens. Robust collaboration and innovative research are needed to reduce the global burden of tuberculosis and develop new detection tools, vaccines, and preventive treatments that serve all populations and ages.
We present an approach to generate path-constrained synchronous motion for the coupled ensemble of robots. In this article, we refer to serial-link manipulators and mobile bases as robots. We assume ...that the relative motion constraints among the objects in the environment are given. We represent the motion constraints as path constraints and pose the problem of path-constrained synchronous trajectory generation as a non-linear optimization problem. Our approach generates configuration space trajectories for the robots to manipulate the objects such that the given motion constraints among the objects are satisfied. We present a method that formulates the problem as a discrete parameter optimization problem and solves it using successive constraint refinement techniques. The method adaptively selects the parametric representation of the configuration variables for a given scenario. It also generates an approximate solution as the starting point for the successive constraint refinement stages to reduce the computation time. We discuss in detail why successive constraint refinement strategies are useful for solving this class of problems. We demonstrate the effectiveness of the proposed method on challenging test cases in simulation and physical environments with high-degree-of-freedom robotic systems.
Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority.
We evaluated whether implementing higher diagnostic thresholds than currently ...recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB, and the tuberculin skin test (TST) might improve prediction of incident TB.
Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by relinkage to national TB surveillance records (median follow-up 4.7 yr). Incidence rates and rate ratios, sensitivities, specificities, and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB, and TST (with adjustment for prior bacillus Calmette-Guérin BCG vaccination).
For all tests, incidence rates and rate ratios increased with the magnitude of the test result (
< 0.0001). Over 3 years' follow-up, there was a modest increase in positive predictive value with the higher thresholds (3.0% for QFT-GIT ≥0.35 IU/ml vs. 3.6% for ≥4.00 IU/ml; 3.4% for T-SPOT.TB ≥5 spots vs. 5.0% for ≥50 spots; and 3.1% for BCG-adjusted TST ≥5 mm vs. 4.3% for ≥15 mm). As thresholds increased, sensitivity to detect incident TB waned for all tests (61.0% for QFT-GIT ≥0.35 IU/ml vs. 23.2% for ≥4.00 IU/ml; 65.4% for T-SPOT.TB ≥5 spots vs. 27.2% for ≥50 spots; 69.7% for BCG-adjusted TST ≥5 mm vs. 28.1% for ≥15 mm).
Implementation of higher thresholds for QFT-GIT, T-SPOT.TB, and TST modestly increases positive predictive value for incident TB, but markedly reduces sensitivity. Novel biomarkers or validated multivariable risk algorithms are required to improve prediction of incident TB.
The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 ...systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI, 3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8% (95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide.
•CRP has good diagnostic accuracy for pulmonary TB among symptomatic adults.•At ≥10 mg/L CRP approaches, but fails to meet, WHO benchmarks for a TB triage test.•CRP may still offer clinical utility ...to prioritize use of confirmatory tests.•Performance is similar across key risk groups for TB including people living with HIV.•Clinical utility of CRP is dependent on target population TB prevalence.
Identification of an accurate, low-cost triage test for pulmonary TB among people presenting to healthcare facilities is an urgent global research priority. We assessed the diagnostic accuracy and clinical utility of C-reactive protein (CRP) for TB triage among symptomatic adult outpatients, irrespective of HIV status.
We prospectively enrolled adults reporting at least one (for people with HIV) or two (for people without HIV) symptoms of cough, fever, night sweats, or weight loss at two TB clinics in Cape Town, South Africa. Participants provided sputum for culture and Xpert MTB/RIF Ultra. We evaluated the diagnostic accuracy of CRP (measured using a laboratory-based assay) against a TB-culture reference standard as the area under the receiver operating characteristic curve (AUROC), and sensitivity and specificity at pre-specified thresholds. We assessed clinical utility using decision curve analysis and benchmarked against WHO recommendations.
Of 932 included individuals, 255 (27%) had culture-confirmed pulmonary TB and 389 (42%) were living with HIV. CRP demonstrated an AUROC of 0·80 (95% confidence interval 0·77–0·83), with sensitivity 93% (89–95%) and specificity 54% (50–58%) using a primary cut-off of ≥10 mg/L. Performance was similar among people with HIV to those without. In decision curve analysis, CRP-based triage offered greater clinical utility than confirmatory testing for all up to a number willing to test threshold of 20 confirmatory tests per true positive pulmonary TB case diagnosed (threshold probability 5%). If it is possible to perform more confirmatory tests than this, a ‘confirmatory test for all’ strategy performed better.
CRP achieved the WHO-defined sensitivity, but not specificity, targets for a triage test for pulmonary TB and showed evidence of clinical utility among symptomatic outpatients, irrespective of HIV status.
South African Medical Research Council, EDCTP2, Royal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, Royal College of Physicians.
SARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody ...levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity.
Healthcare workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16–21 weeks. Serological analysis (n =12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to pseudovirus neutralizing antibody measurements.
A total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated (r = 0.57, p<0.0001) but only anti-S1 measurements correlated with near-contemporary pseudovirus neutralising antibody titres (measured at 16–18 weeks, r = 0.57, p<0.0001). By 21 weeks’ follow-up, 31/143 (21.7%) anti-S1 and 6/150 (4.0%) anti-NP measurements reverted to negative. Mathematical modelling revealed faster clearance of anti-S1 compared to anti-NP (median half-life of 2.5 weeks versus 4.0 weeks), earlier transition to lower levels of antibody production (median of 8 versus 13 weeks), and greater reductions in relative antibody production rate after the transition (median of 35% versus 50%).
Mild SARS-CoV-2 infection is associated with heterogeneous serological responses in Euroimmun anti-S1 and Roche anti-NP assays. Anti-S1 responses showed faster rates of clearance, more rapid transition from high to low level production rate and greater reduction in production rate after this transition. In mild infection, anti-S1 serology alone may underestimate incident infections. The mechanisms that underpin faster clearance and lower rates of sustained anti-S1 production may impact on the longevity of humoral immunity.
Charitable donations via Barts Charity, Wellcome Trust, NIHR.
PDF
