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Purpose To investigate the incremental value of enhanced CT-based radiomics in discriminating between pulmonary tuberculosis (PTB) and pulmonary adenocarcinoma (PAC) presenting as solid nodules or masses and to develop an optimal radiomics model. Methods A total of 128 lesions (from 123 patients) from three hospitals were retrospectively analyzed and were randomly divided into training and test datasets at a ratio of 7:3. Independent predictors in subjective image features were used to develop the subjective image model (SIM). The plain CT-based and enhanced CT-based radiomics features were screened by the correlation coefficient method, univariate analysis, and the least absolute shrinkage and selection operator, then used to build the plain CT radiomics model (PRM) and enhanced CT radiomics model (ERM), respectively. Finally, the combined model (CM) combining PRM and ERM was established. In addition, the performance of three radiologists and one respiratory physician was evaluated. The areas under the receiver operating characteristic curve (AUCs) were used to assess the performance of each model. Results The differential diagnostic capability of the ERM (training: AUC = 0.933; test: AUC = 0.881) was better than that of the PRM (training: AUC = 0.861; test: AUC = 0.756) and the SIM (training: AUC = 0.760; test: AUC = 0.611). The CM was optimal (training: AUC = 0.948; test: AUC = 0.917) and outperformed the respiratory physician and most radiologists. Conclusions The ERM was more helpful than the PRM for identifying PTB and PAC that present as solid nodules or masses, and the CM was the best.

Administration of tuberculosis (TB) vaccines in participants with previous or current pulmonary TB may have the potential for causing harmful postvaccination immunologic (Koch-type) reactions. To assess the safety and immunogenicity of three dose levels of the AERAS-402 live, replication-deficient adenovirus 35-vectored TB candidate vaccine, containing three mycobacterial antigens, in individuals with current or previous pulmonary TB. We performed a phase II randomized, placebo-controlled, double-blinded dose-escalation study in an HIV-negative adult South African cohort (n = 72) with active pulmonary TB (on treatment for 1-4 mo) or pulmonary TB treated at least 12 months before study entry and considered cured. Safety endpoints included clinical assessment, flow volume curves, diffusing capacity of the lung for carbon monoxide, pulse oximetry, chest radiograph, and high-resolution thoracic computerized tomography scans. Cytokine expression by CD4 and CD8 T cells, after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools, was examined by intracellular cytokine staining. No apparent temporal or dose-related changes in clinical status (specifically acute, Koch phenomenon-like reactions), lung function, or radiology attributable to vaccine were observed. Injection site reactions were mild or moderate. Hematuria (by dipstick only) occurred in 25 (41%) of 61 AERAS-402 recipients and 3 (27%) of 11 placebo recipients, although no gross hematuria was reported. AERAS-402 induced robust CD8 and moderate CD4 T-cell responses, mainly to Ag85B in both vaccine groups. Administration of the AERAS-402 candidate TB vaccine to participants with current or previous pulmonary TB induced a robust immune response and is not associated with clinically significant pulmonary complications. Clinical trial registered with www.clinicaltrials.gov (NCT 02414828) and in the South African National Clinical Trials Register ( www.sanctr.gov.za DOH 27-0808-2060).

Adjunctive rosuvastatin for rifampicin-susceptible pulmonary tuberculosis (rs-PTB) shows no effect on microbiological or radiological outcomes in a phase IIb randomised, controlled trial (NCT04504851). We explore the impact of adjunctive rosuvastatin on 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) imaging in a sub-study of 24 participants. Changes in standardised uptake value (SUVmax, SUVmean), Total Metabolic Volume, (TMV), Total Lesion Glycolysis (TLG), cavity diameter and volume, between week 0 and week 8 post-randomisation, are evaluated. Here we show no evidence of difference in the reduction in TLG [median 65.8% for the rosuvastatin group (Q1, Q3 38.6, 94.5) vs 64.3% for standard tuberculosis treatment group (Q1, Q3 −20.0, 81.7), P  = 0.32], reduction in cavity volume on CT [median 3.2 cm 3 (IQR 11.1, 0.5) for rosuvastatin, 2.2 cm 3 (IQR 4.6, 0.7) for control ( p  = 0.72)], or any other PET-CT parameter measured. We show that the first 8-weeks of standard tuberculosis treatment results in a reduction in the volumetric indices (TLG and TMV), but had little change in SUVmax or SUVmean. Change in TLG and TMV holds promise as biomarkers of tuberculosis treatment response: future PET-CT studies should evaluate their role in predicting relapse-free cure, and the overall role of 18F-FDG-PET-CT as a tool for early-phase tuberculosis clinical trials. In this work, authors report on the PET-CT outcomes from the use of adjunctive statin therapy, rosuvastatin, in the intensive phase of tuberculosis (TB) treatment. Rosuvastatin had no impact on PET-CT changes when used as an adjunct to TB treatment. 8-weeks of TB treatment resulted in ~50% reduction in total lesion glycolysis (TLG), a metric that combines the volume of lung affected and metabolic activity.

Background Diabetes mellitus type 2 (DM) may impede immune responses in tuberculosis (TB) and thus contribute to enhanced disease severity. In this study, we aimed to evaluate DM-mediated alterations in clinical, radiological and immunological outcomes in TB disease. Methods Newly diagnosed pulmonary TB patients with or without DM (TB n  = 40; TB-DM n = 40) were recruited in Dhaka, Bangladesh. Clinical symptoms, sputum smear and culture conversion as well as chest radiography were assessed. Peripheral blood and sputum samples were collected at the time of diagnosis (baseline) and after 1, 2 and 6 months of standard anti-TB treatment. Blood samples were also obtained from healthy controls ( n  = 20). mRNA expression of inflammatory markers in blood and sputum samples were quantified using real-time PCR. Results The majority of TB-DM patients had poor glycemic control (HbA1c > 8%) and displayed elevated pulmonary pathology ( P  = 0.039) particularly in the middle ( P  < 0.004) and lower lung zones ( P  < 0.02) throughout the treatment period. However, reduction of clinical symptoms and time to sputum smear and culture conversion did not differ between the groups. Transcripts levels of the pro-inflammatory cytokines IL-1β ( P  = 0.003 at month-1 and P  = 0.045 at month-2) and TNF-α ( P  = 0.005 at month-1) and the anti-inflammatory cytokine IL-10 ( P  = 0.005 at month-2) were higher in peripheral blood after anti-TB treatment in TB-DM compared to TB patients. Conversely in sputum, TB-DM patients had reduced CD4 ( P  < 0.009 at month-1) and IL-10 ( P  = 0.005 at month-1 and P  = 0.006 at month-2) transcripts, whereas CD8 was elevated ( P  = 0.016 at month-2). At 1- and 2-month post-treatment, sputum IL-10 transcripts were inversely correlated with fasting blood glucose and HbA1c levels in all patients. Conclusion Insufficient up-regulation of IL-10 in the lung may fuel persistent local inflammation thereby promoting lung pathology in TB-DM patients with poorly controlled DM.

Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week. We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drugsusceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat. 1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9·2%) in those on rifapentine once a week, and 28/502 (5·6%) in those given rifampicin twice a week (relative risk 1·64, 95% CI 1·04–2·58, p=0·04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2·8, 95% CI 1·7–4·6); cavitation on chest radiography (3·0, 1·6–5·9); being underweight (3·0, 1·8–4·9); bilateral pulmonary involvement (1·8, 1·0–3·1); and being a non-Hispanic white person (1·8, 1·1–3·0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1·34; 0·83–2·18; p=0·23). Of participants without cavitation, rates of failure/relapse were 6/210 (2·9%) in the once a week group and 6/241 (2·5%) in the twice a week group (relative risk 1·15; 95% CI 0·38–3·50; p=0·81). Rates of adverse events and death were similar in the two treatment groups. Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.

Background In 2012, as a pilot for Botswana’s national Xpert MTB/RIF (Xpert) rollout plans, intensified tuberculosis (TB) case finding (ICF) activities were strengthened at 22 HIV treatment clinics prior to phased activation of 13 Xpert instruments. Together, the strengthened ICF intervention and Xpert activation are referred to as the “Xpert package”. Methods The evaluation, called the Xpert Package Rollout Evaluation using a Stepped-wedge design (XPRES), has two key objectives: (1) to compare sensitivity of microscopy-based and Xpert-based pulmonary TB diagnostic algorithms in diagnosing sputum culture-positive TB; and (2) to evaluate impact of the “Xpert package” on all-cause, 6-month, adult antiretroviral therapy (ART) mortality. A pragmatic, stepped-wedge cluster-randomized trial design was chosen. The design involves enrollment of three cohorts: (1) cohort R, a retrospective cohort of all study clinic ART enrollees in the 24 months before study initiation (July 31, 2012); (2) cohort A, a prospective cohort of all consenting patients presenting to study clinics after study initiation, who received the ICF intervention and the microscopy-based TB diagnostic algorithm; and (3) cohort B, a prospective cohort of all consenting patients presenting to study clinics after Xpert activation, who received the ICF intervention and the Xpert-based TB diagnostic algorithm. TB diagnostic sensitivity will be compared between TB culture-positive enrollees in cohorts A and B. All-cause, 6-month ART-mortality will be compared between cohorts R and B. With anticipated cohort R, A, and B sample sizes of about 10,131, 1,878, and 4,258, respectively, the study is estimated to have >80 % power to detect differences in pre-versus post-Xpert TB diagnostic sensitivity if pre-Xpert sensitivity is ≤52.5 % and post-Xpert sensitivity ≥82.5 %, and >80 % power to detect a 40 % reduction in all-cause, 6-month, ART mortality between cohorts R and B if cohort R mortality is ≥13/100 person-years. Discussion Only one small previous trial ( N  = 424) among ART enrolees in Zimbabwe evaluated, in a secondary analysis, Xpert impact on all-cause 6-month ART mortality. No mortality impact was observed. This Botswana trial, with its larger sample size and powered specifically to detect differences in all-cause 6-month ART mortality, remains well-positioned to contribute understanding of Xpert impact. Trial registration Retrospectively registered at ClinicalTrials.gov: NCT02538952 .

BackgroundThe incidence of tuberculosis has increased among South African gold miners despite comprehensive control programmes, including a radiological screening programme. No data are available as to the optimal frequency of screening. The aim of this study was to compare 6-monthly and 12-monthly radiological screening for active tuberculosis case-finding.MethodsEmployees of a gold mining company were randomly assigned to the control arm (screening at baseline, 12 and 24 months) or the intervention arm (additional ‘intervention’ radiographs at 6 and 18 months after baseline). Study outcomes included proportion of tuberculosis cases detected by screening, proportion smear-positive, extent of disease and mortality.Results22 634 miners were randomised. Compared with 12-monthly screening, 6-monthly screening detected more tuberculosis suspects but not more cases, partly due to greater attrition between screening and further investigation after ‘intervention’ compared with routine radiographs. Tuberculosis cases detected in the 6-monthly versus the 12-monthly screening arm had less extensive disease (p=0.05) and a lower tuberculosis-specific mortality (death on tuberculosis treatment) (2.1 and 2.8 per 1000 person-years respectively, HR 0.73, 95% CI 0.50 to 1.08, p=0.1), which was most marked in the first 2 months of treatment (HR 0.48, 95% CI 0.23 to 0.98, p=0.04) when death from tuberculosis is most likely.DiscussionIn settings with a high prevalence of HIV and tuberculosis despite standard tuberculosis control measures, more frequent case-finding may reduce the extent of disease, tuberculosis mortality and tuberculosis transmission through earlier detection of active tuberculosis cases. To be effective, however, all tuberculosis suspects identified through screening must be investigated for tuberculosis.

Trial designCluster randomised controlled trial.ObjectiveTo compare current practice for encouraging homeless people to be screened for tuberculosis on a mobile digital X-ray unit in London, UK, with the additional use of volunteer peer educators who have direct experience of tuberculosis, homelessness or both.Participants46 hostels took part in the study, with a total of 2342 residents eligible for screening. The study took place between February 2012 and October 2013 at homeless hostels in London, UK.InterventionAt intervention sites, volunteer peer educators agreed to a work plan that involved moving around the hostel in conjunction with the hostel staff, and speaking to residents in order to encourage them to attend the screening.RandomisationCluster randomisation (by hostel) was performed using an internet-based service to ensure allocation concealment, with minimisation by hostel size and historical screening uptake.BlindingOnly the study statistician was blinded to the allocation of intervention or control arms.Primary outcomeThe primary outcome was the number of eligible clients at a hostel venue screened for active pulmonary tuberculosis by the mobile X-ray unit.ResultsA total of 59 hostels were considered for eligibility and 46 were randomised. Control sites had a total of 1192 residents, with a median uptake of 45% (IQR 33–55). Intervention sites had 1150 eligible residents with a median uptake of 40% (IQR 25–61). Using Poisson regression to account for the clustered study design, hostel size and historical screening levels, there was no evidence that peer educators increased uptake (adjusted risk ratio 0.98; 95% CIs 0.80 to 1.20). The study team noted no adverse events.ConclusionsThis study found no evidence that volunteer peer educators increased client uptake of mobile X-ray unit screening for tuberculosis. Further qualitative work should be undertaken to explore the possible ancillary benefits to peer volunteers.Trial registration numberISRCTN17270334.

BackgroundPost-tuberculosis lung damage (PTLD) is a recognised consequence of pulmonary TB (pTB). However, little is known about its prevalence, patterns and associated outcomes, especially in sub-Saharan Africa and HIV-positive adults.MethodsAdult (≥15 years) survivors of a first episode of pTB in Blantyre, Malawi, completed the St George’s Respiratory Questionnaire, 6-minute walk test, spirometry and high-resolution CT (HRCT) chest imaging at TB treatment completion. Symptom, spirometry, health seeking, TB-retreatment and mortality data were collected prospectively to 1 year. Risk factors for persistent symptoms, pulmonary function decline and respiratory-related health-seeking were identified through multivariable regression modelling.ResultsBetween February 2016 and April 2017, 405 participants were recruited. Median age was 35 years (IQR: 28 to 41), 77.3% (313/405) had had microbiologically proven pTB, and 60.3% (244/403) were HIV-positive. At pTB treatment completion, 60.7% (246/405) reported respiratory symptoms, 34.2% (125/365) had abnormal spirometry, 44.2% (170/385) had bronchiectasis ≥1 lobe and 9.4% (36/385) had ≥1 destroyed lobe on HRCT imaging. At 1 year, 30.7% (113/368) reported respiratory symptoms, 19.3% (59/305) and 14.1% (43/305) of patients had experienced declines in FEV1 or FVC of ≥100 mL, 16.3% (62/380) had reported ≥1 acute respiratory event and 12.2% (45/368) had symptoms affecting their ability to work.ConclusionsPTLD is a common and under-recognised consequence of pTB that is disabling for patients and associated with adverse outcomes beyond pTB treatment completion. Increased efforts to prevent PTLD and guidelines for management of established disease are urgently needed. Low-cost clinical interventions to improve patient outcomes must be evaluated.

By using combined positron emission and computed tomography (PET–CT), Esmail et al. show that some patients with latent tuberculosis have signs of subclinical, active disease in the lungs and a greater likelihood of progression, suggesting a spectrum of disease rather than discrete latent and active disease states. Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.