Summary Background We aimed to assess whether interferon-γ release assays (IGRAs) can predict the development of active tuberculosis and whether the predictive ability of these tests is better than ...that of the tuberculin skin test (TST). Methods Longitudinal studies of the predictive value for active tuberculosis of in-house or commercial IGRAs were identified through searches of PubMed, Embase, Biosis, and Web of Science and complementary manual searches up to June 30, 2011. Eligible studies included adults or children, with or without HIV, who were free of active tuberculosis at study baseline. We summarised incidence rates in forest plots and pooled data with random-effects models when appropriate. We calculated incidence rate ratios (IRR) for rates of disease progression in IGRA-positive versus IGRA-negative individuals. Findings 15 studies had a combined sample size of 26 680 participants. Incidence of tuberculosis during a median follow-up of 4 years (IQR 2–6), even in IGRA-positive individuals, was 4–48 cases per 1000 person-years. Seven studies with no possibility of incorporation bias and reporting baseline stratification on the basis of IGRA results showed a moderate association between positive results and subsequent tuberculosis (pooled unadjusted IRR 2·10, 95% CI 1·42–3·08). Compared with test-negative results, IGRA-positive and TST-positive results were much the same with regard to the risk of tuberculosis (pooled IRR in the five studies that used both was 2·11 95% CI 1·29–3·46 for IGRA vs 1·60 0·94–2·72 for TST at the 10 mm cutoff). However, the proportion of IGRA-positive individuals in seven of 11 studies that assessed both IGRAs and TST was generally lower than TST-positive individuals. Interpretation Neither IGRAs nor the TST have high accuracy for the prediction of active tuberculosis, although use of IGRAs in some populations might reduce the number of people considered for preventive treatment. Until more predictive biomarkers are identified, existing tests for latent tuberculosis infection should be chosen on the basis of relative specificity in different populations, logistics, cost, and patients' preferences rather than on predictive ability alone. Funding Special Programme for Research and Training in Tropical Diseases (WHO), Wellcome Trust, Canadian Institutes of Health Research, UK Medical Research Council, and the European and Developing Countries Clinical Trials Partnership.
Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the ...molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.
Early initiation of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected patients who have tuberculosis reduces mortality among patients with low CD4 counts, but it increases ...the risk of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS).
We conducted this randomized, double-blind, placebo-controlled trial to assess whether prophylactic prednisone can safely reduce the incidence of paradoxical tuberculosis-associated IRIS in patients at high risk for the syndrome. We enrolled HIV-infected patients who were initiating ART (and had not previously received ART), had started tuberculosis treatment within 30 days before initiating ART, and had a CD4 count of 100 cells or fewer per microliter. Patients received either prednisone (at a dose of 40 mg per day for 14 days, then 20 mg per day for 14 days) or placebo. The primary end point was the development of tuberculosis-associated IRIS within 12 weeks after initiating ART, as adjudicated by an independent committee.
Among the 240 patients who were enrolled, the median age was 36 (interquartile range, 30 to 42), 60% were men, and 73% had microbiologically confirmed tuberculosis; the median CD4 count was 49 cells per microliter (interquartile range, 24 to 86), and the median HIV type 1 RNA viral load was 5.5 log
copies per milliliter (interquartile range, 5.2 to 5.9). A total of 120 patients were assigned to each group, and 18 patients were lost to follow-up or withdrew. Tuberculosis-associated IRIS was diagnosed in 39 patients (32.5%) in the prednisone group and in 56 (46.7%) in the placebo group (relative risk, 0.70; 95% confidence interval CI, 0.51 to 0.96; P=0.03). Open-label glucocorticoids were prescribed to treat tuberculosis-associated IRIS in 16 patients (13.3%) in the prednisone group and in 34 (28.3%) in the placebo group (relative risk, 0.47; 95% CI, 0.27 to 0.81). There were five deaths in the prednisone group and four in the placebo group (P=1.00). Severe infections (acquired immunodeficiency syndrome-defining illnesses or invasive bacterial infections) occurred in 11 patients in the prednisone group and in 18 patients in the placebo group (P=0.23). One case of Kaposi's sarcoma occurred in the placebo group.
Prednisone treatment during the first 4 weeks after the initiation of ART for HIV infection resulted in a lower incidence of tuberculosis-associated IRIS than placebo, without evidence of an increased risk of severe infections or cancers. (Funded by the European and Developing Countries Clinical Trials Partnership and others; PredART ClinicalTrials.gov number, NCT01924286 .).
Interactions between dark matter (DM) and radiation (photons or neutrinos) in the early Universe suppress density fluctuations on small mass scales. Here, we perform a thorough analysis of structure ...formation in the fully non-linear regime using N-body simulations for models with DM–radiation interactions and compare the results to a traditional calculation in which DM only interacts gravitationally. Significant differences arise due to the presence of interactions, in terms of the number of low-mass DM haloes and their properties, such as their spin and density profile. These differences are clearly seen even for haloes more massive than the scale on which density fluctuations are suppressed. We also show that semi-analytical descriptions of the matter distribution in the non-linear regime fail to reproduce our numerical results, emphasizing the challenge of predicting structure formation in models with physics beyond collisionless DM.
The cold dark matter (CDM) model faces persistent challenges on small scales. In particular, taken at face value, the model significantly overestimates the number of satellite galaxies around the ...Milky Way. Attempts to solve this problem remain open to debate and have even led some to abandon CDM altogether. However, current simulations are limited by the assumption that dark matter feels only gravity. Here, we show that including interactions between CDM and radiation (photons or neutrinos) leads to a dramatic reduction in the number of satellite galaxies, alleviating the Milky Way satellite problem and indicating that physics beyond gravity may be essential to make accurate predictions of structure formation on small scales. The methodology introduced here gives constraints on dark matter interactions that are significantly improved over those from the cosmic microwave background.
Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess ...whether a 4-week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events.
A randomized, double-blind, placebo-controlled trial of prednisone (1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 weeks). Patients with immediately life-threatening TB-IRIS manifestations were excluded.
The primary combined endpoint was days of hospitalization and outpatient therapeutic procedures, which were counted as one hospital day.
One hundred and ten participants were enrolled (55 to each arm). The primary combined endpoint was more frequent in the placebo than the prednisone arm {median hospital days 3 interquartile range (IQR) 0-9 and 0 (IQR 0-3), respectively; P = 0.04}. There were significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone vs. the placebo arm at 2 and 4 weeks, but not at later time points. Chest radiographs improved significantly more in the prednisone arm at weeks 2 (P = 0.002) and 4 (P = 0.02). Infections on study medication occurred in more participants in prednisone than in placebo arm (27 vs. 17, respectively; P = 0.05), but there was no difference in severe infections (2 vs. 4, respectively; P = 0.40). Isolates from 10 participants were found to be resistant to rifampicin after enrolment.
Prednisone reduced the need for hospitalization and therapeutic procedures and hastened improvements in symptoms, performance, and quality of life. It is important to investigate for drug-resistant tuberculosis and other causes for deterioration before administering glucocorticoids.
Vitamin D was used to treat tuberculosis (TB) in the preantibiotic era. Prospective studies to evaluate the effect of vitamin D supplementation on antimycobacterial immunity have not previously been ...performed.
To determine the effect of vitamin D supplementation on antimycobacterial immunity and vitamin D status.
A double-blind randomized controlled trial was conducted in 192 healthy adult TB contacts in London, United Kingdom. Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks.
The primary outcome measure was assessed with a functional whole blood assay (BCG-lux assay), which measures the ability of whole blood to restrict luminescence, and thus growth, of recombinant reporter mycobacteria in vitro; the readout is expressed as a luminescence ratio (luminescence postinfection/baseline luminescence). IFN-gamma responses to the Mycobacterium tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay. Vitamin D supplementation significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro compared with placebo (mean luminescence ratio at follow-up, 0.57, vs. 0.71, respectively; 95% confidence interval for difference, 0.01-0.25; p=0.03) but did not affect antigen-stimulated IFN-gamma secretion.
A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses. Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent TB infection. Clinical trial registered with www.clinicaltrials.gov (NCT 00157066).
The increasing use of nanomaterials in consumer products has led to increased concerns about their potential environmental and health impacts. To better understand the transport, fate, and behavior ...of nanoparticles in aquatic systems, it is essential to understand their interactions with different components of natural waters including natural organic matter over a broad range of physicochemical conditions. Fluorescence correlation spectroscopy was used to determine the diffusion coefficients of TiO2 nanoparticles having a nominal size of 5 nm. The effects of a various concentrations of the Suwannee River Fulvic Acid (SRFA) and the roles of pH and ionic strength were evaluated. Aggregation of the bare TiO2 nanoparticles increased for pH values near the zero point of charge. At any given pH, an increase in ionic strength generally resulted in increased aggregation. Furthermore, conditions which favored adsorption of the SRFA resulted in less aggregation of the TiO2 nanoparticles, presumably due to increased steric repulsion. Under the conditions studied here, nanoparticle dispersions were often stable for environmentally relevant conditions of SRFA, pH, and ionic strength, suggesting that in the natural environment, TiO2 dispersion might occur to a greater extent than expected.
The ongoing challenge of latent tuberculosis Esmail, H.; Barry, C. E.; Young, D. B. ...
Philosophical transactions - Royal Society. Biological sciences,
06/2014, Letnik:
369, Številka:
1645
Journal Article
Recenzirano
Odprti dostop
The global health community has set itself the task of eliminating tuberculosis (TB) as a public health problem by 2050. Although progress has been made in global TB control, the current decline in ...incidence of 2% yr−1 is far from the rate needed to achieve this. If we are to succeed in this endeavour, new strategies to reduce the reservoir of latently infected persons (from which new cases arise) would be advantageous. However, ascertainment of the extent and risk posed by this group is poor. The current diagnostics tests (tuberculin skin test and interferon-gamma release assays) poorly predict who will develop active disease and the therapeutic options available are not optimal for the scale of the intervention that may be required. In this article, we outline a basis for our current understanding of latent TB and highlight areas where innovation leading to development of novel diagnostic tests, drug regimens and vaccines may assist progress. We argue that the pool of individuals at high risk of progression may be significantly smaller than the 2.33 billion thought to be immune sensitized by Mycobacterium tuberculosis and that identifying and targeting this group will be an important strategy in the road to elimination.
Summary Background Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid ...preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy. Methods For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov , number NCT00463086. Findings 1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6–3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8–4·7; hazard ratio HR 0·63, 95% CI 0·41–0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90–4·09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0·43 0·21–0·86 and 0·43 0·20–0·96; for positive tests 0·86 0·37–2·00 and 0·55 0·26–1·24, respectively). Interpretation Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status. Funding Department of Health of South Africa, the Wellcome Trust, Médecins Sans Frontières, European and Developing Countries Clinical Trials Partnership, Foundation for Innovation and New Diagnostics, the European Union, and Hasso Plattner (Institute of Infectious Diseases and Molecular Medicine, University of Cape Town).
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