Combining host-derived biomarkers with patient characteristics improves signature performance in predicting tuberculosis treatment outcomes

CITATION: Sivakumaran, Dhanasekaran et al. 2020. Combining host-derived biomarkers with patient characteristics improves signature performance in predicting tuberculosis treatment outcomes. Communications Biology, 3(1):359, doi:10.1038/s42003-020-1087-x.The original publication is available at: https://pubmed.ncbi.nlm.nih.gov/Tuberculosis (TB) is a global health concern. Treatment is prolonged, and patients on anti-TB therapy (ATT) often experience treatment failure for various reasons. There is an urgent need to identify signatures for early detection of failure and initiation of a treatment switch.We investigated how gene biomarkers and/or basic patient characteristics could be used to define signatures for treatment outcomes in Indian adult pulmonary-TB patients treated with standard ATT. Using blood samples at baseline, a 12-gene signature combined with information on gender, previously-diagnosed TB, severe thinness, smoking and alcohol consumption was highly predictive of treatment failure at 6 months. Likewise a 4-protein biomarker signature combined with the same patient characteristics was almost as highly predictive of treatment failure. Combining biomarkers and basic patient characteristics may be useful for predicting and hence identification of treatment failure at an early stage of TB therapy.Publlisher's versio

Autorregulación y trabajo autónomo del estudiante en una actividad de aprendizaje basada en TIC

Este estudio analiza las estrategias de autorregulación en una práctica basada en las TIC con trabajo autónomo del estudiante (TAE). Participaron 53 estudiantes del primer curso de psicología de la Universidad Autónoma de Barcelona que realizaron prácticas de atención y percepción. Los objetivos, contenidos, materiales y evaluación de la práctica se diseñaron y desarrollaron en un entorno en línea. Posteriormente, se aplicaron varios cuestionarios con la finalidad de identificar las autovaloraciones que sobre la actividad autorregulatoria y el nivel de participación manifestaron los estudiantes. Los resultados muestran que los componentes de la dimensión cognitiva de la autorregulación (concepciones de aprendizaje y estrategias metacognitivas) se relacionan significativamente entre sí; sin embargo, no explican las diferencias encontradas en la valoración que los estudiantes realizan de su participación activa. Los factores del componente motivacional (orientación y autoeficacia) se encuentran, igualmente, relacionados entre sí, pero sólo la autoeficacia explica las diferencias observadas en la valoración de la participación activaThis work analyses a self-regulation strategies in autonomous task in an ICT-based learning activity. Participants were 53 psychology undergraduates at the Universidad Autónoma de Barcelona who made a practice in Attention and Perception Psychology. The aims, contents, materials and assessment of the practice were implemented in a virtual environment. We applied several questionnaires in order to identify the students' self-assessments about their self-regulatory activity and participation level. The results showed that cognitive dimension components in the self-regulation construct (conception of learning and metacognitive strategies) are significantly interrelated. However, this dimension does not account for the differences found in self-assessments students' active participation. With regard to motivational dimension factors (goal orientation and self-efficacy), a significant relation between them is observed, but only self-efficacy explains the differences found in self-assessments' active participatio

Determinants of antibody persistence across doses and continents after single-dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study.

BACKGROUND: The recombinant vesicular stomatitis virus (rVSV) vaccine expressing the Zaire Ebola virus (ZEBOV) glycoprotein is efficacious in the weeks following single-dose injection, but duration of immunity is unknown. We aimed to assess antibody persistence at 1 and 2 years in volunteers who received single-dose rVSV-ZEBOV in three previous trials. METHODS: In this observational cohort study, we prospectively followed-up participants from the African and European phase 1 rVSV-ZEBOV trials, who were vaccinated once in 2014-15 with 300 000 (low dose) or 10-50 million (high dose) plaque-forming units (pfu) of rVSV-ZEBOV vaccine to assess ZEBOV glycoprotein (IgG) antibody persistence. The primary outcome was ZEBOV glycoprotein-specific IgG geometric mean concentrations (GMCs) measured yearly by ELISA compared with 1 month (ie, 28 days) after immunisation. We report GMCs up to 2 years (Geneva, Switzerland, including neutralising antibodies up to 6 months) and 1 year (Lambaréné, Gabon; Kilifi, Kenya) after vaccination and factors associated with higher antibody persistence beyond 6 months, according to multivariable analyses. Trials and the observational study were registered at ClinicalTrials.gov (Geneva: NCT02287480 and NCT02933931; Kilifi: NCT02296983) and the Pan-African Clinical Trials Registry (Lambaréné PACTR201411000919191). FINDINGS: Of 217 vaccinees from the original studies (102 from the Geneva study, 75 from the Lambaréné study, and 40 from the Kilifi study), 197 returned and provided samples at 1 year (95 from the Geneva study, 63 from the Lambaréné, and 39 from the Kilifi study) and 90 at 2 years (all from the Geneva study). In the Geneva group, 44 (100%) of 44 participants who had been given a high dose (ie, 10-50 million pfu) of vaccine and who were seropositive at day 28 remained seropositive at 2 years, whereas 33 (89%) of 37 who had been given the low dose (ie, 300 000 pfu) remained seropositive for 2 years (p=0·042). In participants who had received a high dose, ZEBOV glycoprotein IgG GMCs decreased significantly between their peak (at 1-3 months) and month 6 after vaccination in Geneva (p0·05). Neutralising antibodies seem to be less durable, with seropositivity dropping from 64-71% at 28 days to 27-31% at 6 months in participants from the Geneva study. INTERPRETATION: Antibody responses to single-dose rVSV-ZEBOV vaccination are sustained across dose ranges and settings, a key criterion in countries where booster vaccinations would be impractical. FUNDING: The Wellcome Trust and Innovative Medicines Initiative 2 Joint Undertaking

Identification of probable early-onset biomarkers for tuberculosis disease progression.

Determining what constitutes protective immunity to TB is critical for the development of improved diagnostics and vaccines. The comparison of the immune system between contacts of TB patients, who later develop TB disease (progressors), versus contacts who remain healthy (non-progressors), allows for identification of predictive markers of TB disease. This study provides the first comprehensive analysis of the immune system of progressors and non-progressors using a well-characterised TB case-contact (TBCC) platform in The Gambia, West Africa. 22 progressors and 31 non-progressors were analysed at recruitment, 3 months and 18 months (time to progression: median[IQR] of 507[187-714] days). Immunophenotyping of PBMC, plasma cytokine levels and RT-MLPA analysis of whole blood-derived RNA was performed to capture key immune system parameters. At recruitment, progressors had lower PBMC proportions of CD4+ T cells, NKT cells and B cells relative to non-progressors. Analysis of the plasma showed higher levels of IL-18 in progressors compared to non-progressors and analysis of the RNA showed significantly lower gene expression of Bcl2 but higher CCR7 in progressors compared to non-progressors. This study shows several markers that may predict the onset of active TB at a very early stage after infection. Once these markers have been validated in larger studies, they provide avenues to prospectively identify people at risk of developing TB, a key issue in the testing of new TB vaccines

Novel transcriptional signatures for sputum-independent diagnostics of tuberculosis in children

Pediatric tuberculosis (TB) is challenging to diagnose, confirmed by growth of Mycobacterium tuberculosis at best in 40% of cases. The WHO has assigned high priority to the development of non-sputum diagnostic tools. We therefore sought to identify transcriptional signatures in whole blood of Indian children, capable of discriminating intra-thoracic TB disease from other symptomatic illnesses. We investigated the expression of 198 genes in a training set, comprising 47 TB cases (19 definite/28 probable) and 36 asymptomatic household controls, and identified a 7- and a 10-transcript signature, both including NOD2, GBP5, IFITM1/3, KIF1B and TNIP1. The discriminatory abilities of the signatures were evaluated in a test set comprising 24 TB cases (17 definite/7 probable) and 26 symptomatic non-TB cases. In separating TB-cases from symptomatic non-TB cases, both signatures provided an AUC of 0.94 (95%CI, 0.88–1.00), a sensitivity of 91.7% (95%CI, 71.5–98.5) regardless of culture status, and 100% sensitivity for definite TB. The 7-transcript signature provided a specificity of 80.8% (95%CI, 60.0–92.7), and the 10-transcript signature a specificity of 88.5% (95%CI, 68.7–96.9%). Although warranting exploration and validation in other populations, our findings are promising and potentially relevant for future non-sputum based POC diagnostic tools for pediatric TB

BLR1 and FCGR1A transcripts in peripheral blood associate with the extent of intrathoracic tuberculosis in children and predict treatment outcome

Biomarkers reflecting the extent of Mycobacterium tuberculosis-induced pathology and normalization during anti-tuberculosis treatment (ATT) would considerably facilitate trials of new treatment regimens and the identification of patients with treatment failure. Therefore, in a cohort of 99 Indian children with intrathoracic tuberculosis (TB), we performed blood transcriptome kinetic analysis during ATT to explore 1) the association between transcriptional biomarkers in whole blood (WB) and the extent of TB disease at diagnosis and treatment outcomes at 2 and 6 months, and 2) the potential of the biomarkers to predict treatment response at 2 and 6 months. We present the first data on the association between transcriptional biomarkers and the extent of TB disease as well as outcome of ATT in children: Expression of three genes down-regulated on ATT (FCGR1A, FPR1 and MMP9) exhibited a positive correlation with the extent of TB disease, whereas expression of eight up-regulated genes (BCL, BLR1, CASP8, CD3E, CD4, CD19, IL7R and TGFBR2) exhibited a negative correlation with the extent of disease. Baseline levels of these transcripts displayed an individual capacity >70% to predict the six-month treatment outcome. In particular, BLR1 and FCGR1A seem to have a potential in monitoring and perhaps tailoring future antituberculosis therapy

Human Transcriptomic Response to the VSV-Vectored Ebola Vaccine

Ebolavirus Disease (EVD) is a severe haemorrhagic fever that occurs in epidemic outbreaks, with a high fatality rate and no specific therapies available. rVSVΔG-ZEBOV-GP (Ervebo®), a live-attenuated recombinant vesicular stomatitis virus vector expressing the glycoprotein G of Zaire Ebolavirus, is the first vaccine approved for prevention of EVD. Both innate and adaptive responses are deemed to be involved in vaccine-induced protection, yet the mechanisms are not fully elucidated. A global transcriptomic approach was used to profile the blood host-response in 51 healthy volunteers enrolled in a phase 1/2 clinical trial. Signatures of the host responses were investigated assessing the enrichment in differentially expressed genes (DEGs) of specific "blood transcription modules" (BTM). Comparison of gene-expression levels showed that vaccination produces a peak of 5469 DEGs at day one, representing 38.6% of the expressed genes. Out of 346 BTMs, 144 were significantly affected by vaccination. Innate immunity pathways were induced from day 1 to day 14. At days 2 and 3, neutrophil modules were downregulated and complement-related modules upregulated. T-cell and cell-cycle associated modules were upregulated at days 7 and 14, while at day 28, no modules remained activated. At day 14, a direct correlation was observed between ZEBOV glycoprotein-specific antibody titres and activation of seven BTMs, including two related to B-cell activation and B cell receptor signalling. Transcriptomic analysis identified an rVSVΔG-ZEBOV-GP-induced signature and demonstrated a direct correlation of blood transcriptomic changes with ZEBOV glycoprotein-specific antibody titres

Differences in RT-MLPA gene expression levels in progressors and non-progressors.

<p>Data expressed as median[interquartile range]. Fold difference is shown as expression in progressors compared to non-progressors. BPI showed the highest fold increase and FCGR1A the lowest.</p

Analysis of hematological parameters in progressors versus non-progressors.

<p>Hemoglobin (A) and MCV (B) levels, Total white blood cell (WBC) (C), and platelet (D) counts, were obtained from the Hematology lab at MRC, Fajara. Bar indicates median of 13 progressors and 28 non-progressors at recruitment (0), 9 progressors and 30 non-progressors at 3-months (3) and 7 progressors and 19 non-progressors at 18 months (18). Data were analysed using a Kruskal-Wallis test followed by Dunn's post-test comparison. Significant differences are indicated.</p