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When the Planets first spun into orbit, Plasma helped create a space-sea of electric particles for them to float in. She did this by spending most of her time shooting through the tortuous hallways of the Sun, her radiant train of electrons and ions flowing behind her

Rev Variation during Persistent Lentivirus Infection

The ability of lentiviruses to continually evolve and escape immune control is the central impediment in developing an effective vaccine for HIV-1 and other lentiviruses. Equine infectious anemia virus (EIAV) is considered a useful model for immune control of lentivirus infection. Virus-specific cytotoxic T lymphocytes (CTL) and broadly neutralizing antibody effectively control EIAV replication during inapparent stages of disease, but after years of low-level replication, the virus is still able to produce evasion genotypes that lead to late re-emergence of disease. There is a high rate of genetic variation in the EIAV surface envelope glycoprotein (SU) and in the region of the transmembrane protein (TM) overlapped by the major exon of Rev. This review examines genetic and phenotypic variation in Rev during EIAV disease and a possible role for Rev in immune evasion and virus persistence

QuantiFERON-TB gold in-tube implementation for latent tuberculosis diagnosis in a public health clinic: a cost-effectiveness analysis

BACKGROUND: The tuberculin skin test (TST) has limitations for latent tuberculosis infection (LTBI) diagnosis in low-prevalence settings. Previously, all TST-positive individuals referred from the community to Baltimore City Health Department (BCHD) were offered LTBI treatment, after active TB was excluded. In 2010, BCHD introduced adjunctive QuantiFERON-TB Gold In-Tube (QFT-GIT) testing for TST-positive referrals. We evaluated costs and cost-effectiveness of this new diagnostic algorithm. METHODS: A decision-analysis model compared the strategy of treating all TST-positive referrals versus only those with positive results on adjunctive QFT-GIT testing. Costs were collected at BCHD, and Incremental Cost-Effectiveness Ratios (ICERs) were utilized to report on cost-effectiveness. RESULTS: QFT-GIT testing at BCHD cost $43.51 per test. Implementation of QFT-GIT testing was associated with an ICER of$1,202 per quality-adjusted life-year gained and was considered highly cost-effective. In sensitivity analysis, the QFT-GIT strategy became cost-saving if QFT-GIT sensitivity increased above 92% or if less than 3.5% of individuals with LTBI progress to active TB disease. CONCLUSIONS: LTBI screening with TST in low-prevalence settings may lead to overtreatment and increased expenditures. In this public health clinic, additional QFT-GIT testing of individuals referred for a positive TST was cost-effective

Interleukin (IL)–12 and IL-23 Are Key Cytokines for Immunity against Salmonella in Humans

Patients with inherited deficiency of the interleukin (IL)–12/IL-23–interferon (IFN)–g axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23–component deficiency had a history of salmonella disease than did those with IFN-g–component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN-g–independent pathways. Investigation of the IL-12/IL-23–IFN-g axis should be considered in patients with invasive salmonella disease

Ultraviolet Imaging of the Globular Cluster 47 Tucanae

We have used the Ultraviolet Imaging Telescope to obtain deep far-UV (1620 Angstrom), 40' diameter images of the prototypical metal-rich globular cluster 47 Tucanae. We find a population of about 20 hot (Teff > 9000 K) objects near or above the predicted UV luminosity of the hot horizontal branch (HB) and lying within two half-light radii of the cluster center. We believe these are normal hot HB or post-HB objects rather than interacting binaries or blue stragglers. IUE spectra of two are consistent with post-HB phases. These observations, and recent HST photometry of two other metal-rich clusters, demonstrate that populations with rich, cool HB's can nonetheless produce hot HB and post-HB stars. The cluster center also contains an unusual diffuse far-UV source which is more extended than its V-band light. It is possible that this is associated with an intracluster medium, for which there was earlier infrared and X-ray evidence, and is produced by C IV emission or scattered light from grains.Comment: 13 pages AASLaTeX including one postscript figure and one bitmapped image, JPEG format. Submitted to the Astronomical Jorunal. Full Postscript version available at http://www.astro.virginia.edu/~bd4r

Longitudinal Analysis of QuantiFERON-TB Gold In-Tube in Children with Adult Household Tuberculosis Contact in South Africa: A Prospective Cohort Study

QuantiFERON-TB Gold In Tube (QFT-GIT) is a tool for detecting M. tuberculosis infection. However, interpretation and utility of serial QFT-GIT testing of pediatric tuberculosis (TB) contacts is not well understood. We compared TB prevalence between baseline and 6 months follow-up using QFT-GIT and tuberculin skin testing (TST) in children who were household contacts of adults with pulmonary TB in South Africa, and explored factors associated with QFT-GIT conversions and reversions.Prospective study with six month longitudinal follow-up.Among 270 enrolled pediatric contacts, 196 (73%) underwent 6-month follow-up testing. The 6-month prevalence estimate of MTB infection in pediatric contacts increased significantly from a baseline of 29% (79/270, 95%CI [24-35]) to 38% (103/270, 95% CI [32-44], p<0.001) using QFT-GIT; prevalence increased from a baseline of 28% (71/254, 95%CI [23-34]) to 33% (88/263, 95%CI [21-32], p = 0.002) using TST. Prevalence estimates were influenced by thresholds for positivity for TST, but not for QFT-GIT. Among 134 children with a negative or indeterminate baseline QFT-GIT, 24 (18%) converted to positive at follow-up; conversion rates did not differ significantly when using more stringent thresholds to define QFT-GIT conversion. Older age >10 years (AOR 8.9 95%CI [1.1-72]) and baseline TST positivity ≥5 mm (AOR 5.2 95%CI [1.2-23]) were associated with QFT-GIT conversion. Among 62 children with a positive baseline QFT-GIT, 9 (15%) reverted to negative; female gender (AOR 18.5 95%CI [1.1-321]; p = 0.04] was associated with reversion, while children with baseline positive TST were less likely to have QFT-GIT reversion (AOR 0.01 95%CI [0.001-0.24]).Among pediatric contacts of adult household TB cases in South Africa, prevalence estimates of TB infection increased significantly from baseline to 6 months. Conversions and reversions occurred among pediatric TB contacts using QFT-GIT, but QFT-GIT conversion rates were less influenced by thresholds used for conversions than were TST conversion rates

Evaluation of a point-of-care tuberculosis test-and-treat algorithm on early mortality in people with HIV accessing antiretroviral therapy (TB Fast Track study): study protocol for a cluster randomised controlled trial.

BACKGROUND: Early mortality for HIV-positive people starting antiretroviral therapy (ART) remains high in resource-limited settings, with tuberculosis the most important cause. Existing rapid diagnostic tests for tuberculosis lack sensitivity among HIV-positive people, and consequently, tuberculosis treatment is either delayed or started empirically (without bacteriological confirmation). We developed a management algorithm for ambulatory HIV-positive people, based on body mass index and point-of-care tests for haemoglobin and urine lipoarabinomannan (LAM), to identify those at high risk of tuberculosis and mortality. We designed a clinical trial to test whether implementation of this algorithm reduces six-month mortality among HIV-positive people with advanced immunosuppression. METHODS/DESIGN: The TB Fast Track study is an open, pragmatic, cluster randomised superiority trial, with 24 primary health clinics randomised to implement the intervention or standard of care. Adults (aged ≥18 years) with a CD4 count of 150 cells/μL or less, who have not received any tuberculosis treatment in the last three months, or ART in the last six months, are eligible. In intervention clinics, the study algorithm is used to classify individuals as at high, medium or low probability of tuberculosis. Those classified as high probability start tuberculosis treatment immediately, followed by ART after two weeks. Medium-probability patients follow the South African guidelines for test-negative tuberculosis and are reviewed within a week, to be re-categorised as low or high probability. Low-probability patients start ART as soon as possible. The primary outcome is all-cause mortality at six months. Secondary outcomes include severe morbidity, time to ART start and cost-effectiveness. DISCUSSION: This trial will test whether a primary care-friendly management algorithm will enable nurses to identify HIV-positive patients at the highest risk of tuberculosis, to facilitate prompt treatment and reduce early mortality. There remains an urgent need for better diagnostic tests for tuberculosis, especially for people with advanced HIV disease, which may render empirical treatment unnecessary. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN35344604 ) on 12 September 2012

Geographic Differences in Time to Culture Conversion in Liquid Media: Tuberculosis Trials Consortium Study 28. Culture Conversion Is Delayed in Africa

Tuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding.In TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites.African TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found.Compared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved.ClinicalTrials.gov NCT00144417

Rifapentine Population Pharmacokinetics and Dosing Recommendations for Latent Tuberculosis Infection.

RATIONALE: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms but clarity on the optimal dosing approach is lacking. OBJECTIVES: In this individual participant data meta-analysis of rifapentine pharmacokinetics, we characterize rifapentine population pharmacokinetics, including autoinduction, and determine optimal dosing strategies for short-course rifapentine-based regimens for latent tuberculosis infection. METHODS: Rifapentine pharmacokinetic studies were identified though a systematic review of literature. Individual plasma concentrations were pooled, and non-linear mixed effects modeling was performed. A subset of data was reserved for external validation. Simulations were performed under various dosing conditions including current weight-based methods and alternative methods driven by identified covariates. MEASUREMENTS AND MAIN RESULTS: We identified 9 clinical studies with a total of 863 participants with pharmacokinetic data (n=4301 plasma samples). Rifapentine population pharmacokinetics were described successfully with a one-compartment distribution model. Autoinduction of clearance was driven by rifapentine plasma concentration. The maximum effect was a 72% increase in clearance and was reached after 21 days. Drug bioavailability decreased by 27% with HIV infection, decreased by 28% with fasting, and increased by 49% with a high-fat meal. Body weight was not a clinically relevant predictor of clearance. Pharmacokinetic simulations showed that current weight-based dosing leads to lower exposures in low weight individuals, which can be overcome with flat dosing. In HIV-positive patients, 30% higher doses are required to match drug exposure in HIV-negative patients. CONCLUSIONS: Weight-based dosing of rifapentine should be removed from clinical guidelines and higher doses for HIV-positive patients should be considered to provide equivalent efficacy