An evaluation of tuberculosis contact investigations against national standards.

BACKGROUND: Contact tracing is a key element in England's 2015 collaborative TB strategy, although proposed indicators of successful contact tracing remain undescribed. METHODS: We conducted descriptive and multivariable analyses of contact tracing of TB cases in London between 1 July 2012 and 31 December 2015 using cohort review data from London's TB Register, identifying characteristics associated with improved indicators and yield. RESULTS: Of the pulmonary TB cases notified, 60% (2716/4561) had sufficient information for inclusion. Of these, 91% (2481/2716) had at least 1 contact (median: 4/case (IQR: 2-6)) identified, with 86% (10 251/11 981) of these contacts evaluated. 4.1% (177/4328), 1.3% (45/3421) and 0.70% (51/7264) of evaluated contacts of pulmonary smear-positive, pulmonary smear-negative and non-pulmonary cases, respectively, had active disease. Cases who were former prisoners or male were less likely to have at least one contact identified than those never imprisoned or female, respectively. Cases diagnosed at clinics with more directly observed therapy or social workers were more likely to have one or more contacts identified. Contacts screened at a different clinic to their index case or of male index cases were less likely to be evaluated than those screened at the same clinic or of women, respectively; yield of active disease was similar by sex. 10% (490/4850) of evaluated child contacts had latent TB infection. CONCLUSIONS: These are the first London-wide estimates of TB contact tracing indicators which are important for monitoring the strategy's success and informing risk assessment of index cases. Understanding why differences in indicators occur between groups could improve contact tracing outcomes

Should NICE reconsider the 2016 UK guidelines on TB contact tracing? A cost-effectiveness analysis of contact investigations in London.

BACKGROUND: In January 2016, clinical TB guidance in the UK changed to no longer recommend screening contacts of non-pulmonary, non-laryngeal (ETB) index cases. However, no new evidence was cited for this change, and there is evidence that screening these contacts may be worthwhile. The objective of this study was to estimate the cost-effectiveness of screening contacts of adult ETB cases and adult pulmonary or laryngeal TB (PTB) cases in London, UK. METHODS: We carried out a cross-sectional analysis of data collected on TB index cases and contacts in the London TB register and an economic evaluation using a static model describing contact tracing outcomes. Incremental cost-effectiveness ratios (ICERs) were calculated using no screening as the baseline comparator. All adult TB cases (≥15 years old) in London from 2012 to 2015, and their contacts, were eligible (2465/5084 PTB and 2559/6090 ETB index cases were included). RESULTS: Assuming each contact with PTB infects one person/month, the ICER of screening contacts of ETB cases was £78 000/quality-adjusted life-years (QALY) (95% CI 39 000 to 140 000), and screening contacts of PTB cases was £30 000/QALY (95% CI 18 000 to 50 000). The ICER of screening contacts of ETB cases was £30 000/QALY if each contact with PTB infects 3.4 people/month. Limitations of this study include the use of self-reported symptomatic periods and lack of knowledge about onward transmission from PTB contacts. CONCLUSIONS: Screening contacts of ETB cases in London was almost certainly not cost-effective at any conventional willingness-to-pay threshold in England, supporting recent changes to National Institute for Health and Care Excellence national guidelines

FIRST J102347.6+003841: The First Radio-Selected Cataclysmic Variable

We have identified the 1.4 GHz radio source FIRST J102347.6+003841 (hereafter FIRST J1023+0038) with a previously unknown 17th-mag Galactic cataclysmic variable (CV). The optical spectrum resembles that of a magnetic (AM Herculis- or DQ Herculis-type) CV. Five nights of optical CCD photometry showed variations on timescales of minutes to hours, along with rapid flickering. A re-examination of the FIRST radio survey data reveals that the radio detection was based on a single 6.6 mJy flare; on two other occasions the source was below the ~1 mJy survey limit. Several other magnetic CVs are known to be variable radio sources, suggesting that FIRST J1023+0038 is a new member of this class (and the first CV to be discovered on the basis of radio emission). However, FIRST J1023+0038 is several optical magnitudes fainter than the other radio-detected magnetic CVs. It remains unclear whether the source simply had a very rare and extraordinarily intense radio flare at the time of the FIRST observation, or is really an unusually radio-luminous CV; thus further observations are urged.Comment: 4 pages, 3 figures; accepted for December 2002 issue of Publications of the Astronomical Society of the Pacifi

Intrauterine Candida albicans infection causes systemic fetal candidiasis with progressive cardiac dysfunction in a sheep model of early pregnancy

Introduction: Several recent studies have identified a potential role for intrauterine Candida albicans in adverse pregnancy outcomes, including preterm birth. There is, however, a limited understanding of the impact of intrauterine candida infection on fetal well-being in early pregnancy. Using a sheep model of early pregnancy, the aims of this study were to determine (1) the ability of experimentally induced intrauterine C albicans to infect the fetus and (2) whether C albicans exposure in early pregnancy is associated with alterations in fetal cardiac function, as measured by spectral tissue Doppler imaging analysis of fetal cardiac function. Methods: Merino ewes carrying singleton pregnancies at 89 days’ gestation (term is ∼150 days) received C albicans (n = 8) via ultrasound-guided intra-amniotic injection. Saline-exposed fetuses served as controls (n = 6). Spectral tissue Doppler imaging echocardiography and amniotic fluid collection were performed at baseline and 24 and 72 hours after intrauterine C albicans injection. Fetal tissues were collected at postmortem for analysis of infection and inflammation. Results: Relative to saline control, intrauterine C albicans infection resulted in pronounced increases in amniotic fluid tumor necrosis factor α (TNF-α; P < .05) and cytokine/chemokine messenger RNA (interleukin [IL] 1β, IL-6, TNF-α, and monocyte chemoattractant protein 1; P < .05) in the fetal myocardium, lung, skin, and liver at 72 and 96 hours postinfection. Spectral tissue Doppler imaging showed diastolic dysfunction at 24 hours and severe biventricular diastolic dysfunction 72 hours postinfection. Conclusion: Intrauterine C albicans infection in a sheep model of early pregnancy causes systemic fetal candidiasis, which is associated with a robust systemic inflammatory response and progressive cardiac dysfunction detectable by spectral tissue Doppler imaging

Group cognitive behavioural therapy for stroke survivors with depression and their carers

Background: Depression in stroke survivors is common, leads to poorer outcomes and often not treated. A group cognitive behavioural therapy (CBT) program (Brainstorm) for stroke survivors with depression, and their carers has been running as part of usual care since 2007. Objective: To evaluate the implementation and acceptability of Brainstorm, a closed group intervention consisting of up to 10 sessions of education, activity planning, problem solving and thought challenging. Methods: Participating stroke survivors and their carers complete assessment measures at baseline, post-treatment and 1-month and 6-months follow-up. A mixed models for repeated measures data was conducted with depression and anxiety scores for stroke survivors (Beck Depression Inventory-II; Hospital Anxiety and Depression Scale) and the assessment of depression, anxiety and carer burden for carers. Acceptability was assessed by session attendance and written and open participant feedback upon completion of the program. Results: Forty-eight community dwelling stroke survivors and 34 carers attended Brainstorm, with a median attendance of 88% of sessions. Follow-up assessments were completed by 77% (post-treatment), 46% (1-month) and 38% (6-month) of stroke survivors. Stroke survivors’ depression scores decreased from baseline to post-treatment (p<.001); maintained at 1-month (p<.001) but not at 6-month (p=.056). Anxiety scores decreased between baseline and 1-month (p=.013). Carer burden, depression and anxiety scores at 1-month and 6-month follow-up, for carers, were all reduced when compared with baseline (p<.05). Conclusion: The Brainstorm group intervention for depression in stroke survivors appears to have been effectively implemented and is acceptable to stroke survivors and carers

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

High precision astrometry mission for the detection and characterization of nearby habitable planetary systems with the Nearby Earth Astrometric Telescope (NEAT)

(abridged) A complete census of planetary systems around a volume-limited sample of solar-type stars (FGK dwarfs) in the Solar neighborhood with uniform sensitivity down to Earth-mass planets within their Habitable Zones out to several AUs would be a major milestone in extrasolar planets astrophysics. This fundamental goal can be achieved with a mission concept such as NEAT - the Nearby Earth Astrometric Telescope. NEAT is designed to carry out space-borne extremely-high-precision astrometric measurements sufficient to detect dynamical effects due to orbiting planets of mass even lower than Earth's around the nearest stars. Such a survey mission would provide the actual planetary masses and the full orbital geometry for all the components of the detected planetary systems down to the Earth-mass limit. The NEAT performance limits can be achieved by carrying out differential astrometry between the targets and a set of suitable reference stars in the field. The NEAT instrument design consists of an off-axis parabola single-mirror telescope, a detector with a large field of view made of small movable CCDs located around a fixed central CCD, and an interferometric calibration system originating from metrology fibers located at the primary mirror. The proposed mission architecture relies on the use of two satellites operating at L2 for 5 years, flying in formation and offering a capability of more than 20,000 reconfigurations (alternative option uses deployable boom). The NEAT primary science program will encompass an astrometric survey of our 200 closest F-, G- and K-type stellar neighbors, with an average of 50 visits. The remaining time might be allocated to improve the characterization of the architecture of selected planetary systems around nearby targets of specific interest (low-mass stars, young stars, etc.) discovered by Gaia, ground-based high-precision radial-velocity surveys.Comment: Accepted for publication in Experimental Astronomy. The full member list of the NEAT proposal and the news about the project are available at http://neat.obs.ujf-grenoble.fr. The final publication is available at http://www.springerlink.co

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Interaction between the microbiome and TP53 in human lung cancer.

BACKGROUND: Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort. RESULTS: Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which Acidovorax is enriched in smokers. Acidovorax temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas. CONCLUSIONS: The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection