The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling.

BACKGROUND: The existing estimate of the global burden of latent TB infection (LTBI) as "one-third" of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI. METHODS AND FINDINGS: We constructed trends in annual risk in infection (ARI) for countries between 1934 and 2014 using a combination of direct estimates of ARI from LTBI surveys (131 surveys from 1950 to 2011) and indirect estimates of ARI calculated from World Health Organisation (WHO) estimates of smear positive TB prevalence from 1990 to 2014. Gaussian process regression was used to generate ARIs for country-years without data and to represent uncertainty. Estimated ARI time-series were applied to the demography in each country to calculate the number and proportions of individuals infected, recently infected (infected within 2 y), and recently infected with isoniazid (INH)-resistant strains. Resulting estimates were aggregated by WHO region. We estimated the contribution of existing infections to TB incidence in 2035 and 2050. In 2014, the global burden of LTBI was 23.0% (95% uncertainty interval [UI]: 20.4%-26.4%), amounting to approximately 1.7 billion people. WHO South-East Asia, Western-Pacific, and Africa regions had the highest prevalence and accounted for around 80% of those with LTBI. Prevalence of recent infection was 0.8% (95% UI: 0.7%-0.9%) of the global population, amounting to 55.5 (95% UI: 48.2-63.8) million individuals currently at high risk of TB disease, of which 10.9% (95% UI:10.2%-11.8%) was isoniazid-resistant. Current LTBI alone, assuming no additional infections from 2015 onwards, would be expected to generate TB incidences in the region of 16.5 per 100,000 per year in 2035 and 8.3 per 100,000 per year in 2050. Limitations included the quantity and methodological heterogeneity of direct ARI data, and limited evidence to inform on potential clearance of LTBI. CONCLUSIONS: We estimate that approximately 1.7 billion individuals were latently infected with Mycobacterium tuberculosis (M.tb) globally in 2014, just under a quarter of the global population. Investment in new tools to improve diagnosis and treatment of those with LTBI at risk of progressing to disease is urgently needed to address this latent reservoir if the 2050 target of eliminating TB is to be reached

DNA models of trinucleotide frameshift deletions: the formation of loops and bulges at the primer–template junction

Although mechanisms of single-nucleotide residue deletion have been investigated, processes involved in the loss of longer nucleotide sequences during DNA replication are poorly understood. Previous reports have shown that in vitro replication of a 3′-TGC TGC template sequence can result in the deletion of one 3′-TGC. We have used low-energy circular dichroism (CD) and fluorescence spectroscopy to investigate the conformations and stabilities of DNA models of the replication intermediates that may be implicated in this frameshift. Pyrrolocytosine or 2-aminopurine residues, site-specifically substituted for cytosine or adenine in the vicinity of extruded base sequences, were used as spectroscopic probes to examine local DNA conformations. An equilibrium mixture of four hybridization conformations was observed when template bases looped-out as a bulge, i.e. a structure flanked on both sides by duplex DNA. In contrast, a single-loop structure with an unusual unstacked DNA conformation at its downstream edge was observed when the extruded bases were positioned at the primer–template junction, showing that misalignments can be modified by neighboring DNA secondary structure. These results must be taken into account in considering the genetic and biochemical mechanisms of frameshift mutagenesis in polymerase-driven DNA replication

LGMD2I in a North American population

<p>Abstract</p> <p>Background</p> <p>There is a marked variation in clinical phenotypes that have been associated with mutations in <it>FKRP</it>, ranging from severe congenital muscular dystrophies to limb-girdle muscular dystrophy type 2I (LGMD2I).</p> <p>Methods</p> <p>We screened the <it>FKRP </it>gene in two cohorts totaling 87 patients with the LGMD phenotype.</p> <p>Results</p> <p>The c.826C>A, p.L276I mutation was present in six patients and a compound heterozygote mutation in a seventh patient. Six patients had a mild LGMD2I phenotype, which resembles that of Becker muscular dystrophy. The other patient had onset before the age of 3 years, and thus may follow a more severe course.</p> <p>Conclusion</p> <p>These findings suggest that LGMD2I may be common in certain North American populations. This diagnosis should be considered early in the evaluation of LGMD.</p

Exploring Halo Substructure with Giant Stars XI: The Tidal Tails of the Carina Dwarf Spheroidal and the Discovery of Magellanic Cloud Stars in the Carina Foreground

A new large-area Washington M,T_2+DDO51 filter survey of more than 10 deg^2 around the Carina dSph galaxy reveals a spectroscopically confirmed power law radial density "break" population of Carina giant stars extending several degrees beyond the central King profile. Magellan telescope MIKE spectroscopy establishes the existence of Carina stars to at least 4.5 times its central King limiting radius, r_lim and primarily along Carina's major axis. To keep these stars bound to the dSph would require a global Carina mass-to-light ratio of M/L > 6,300 M/L_sun. The MIKE velocities, supplemented with ~950 additional Carina field velocities from archived VLT+GIRAFFE spectra with r<=r_lim, demonstrate a nearly constant Carina velocity dispersion to just beyond r = r_lim, and both a rising velocity dispersion and a velocity shear at still larger radii. Together, the observational evidence suggests that the discovered extended Carina population represents tidal debris from the dSph. Of 65 giant candidates at large angular radii from the Carina center for which MIKE spectra have been obtained 94% are associated either with Carina or a second, newly discovered diffuse, but strongly radial velocity-coherent (velocity dispersion of 9.8 km s^-1), foreground halo system. The fifteen stars in this second, retrograde velocity population have (1) a mean metallicity ~1 dex higher than that of Carina, and (2) colors and magnitudes consistent with the red clump of the Large Magellanic Cloud (LMC). Additional spectroscopy of giant star candidates in fields linking Carina and the LMC shows a smooth velocity gradient between the LMC and the retrograde Carina moving group. We conclude that we have found Magellanic stars almost twice as far (22 deg) from the LMC center than previously known.Comment: ApJ, in pres

An Acidic Motif Retains Vesicular Monoamine Transporter 2 on Large Dense Core Vesicles

The release of biogenic amines from large dense core vesicles (LDCVs) depends on localization of the vesicular monoamine transporter VMAT2 to LDCVs. We now find that a cluster of acidic residues including two serines phosphorylated by casein kinase 2 is required for the localization of VMAT2 to LDCVs. Deletion of the acidic cluster promotes the removal of VMAT2 from LDCVs during their maturation. The motif thus acts as a signal for retention on LDCVs. In addition, replacement of the serines by glutamate to mimic phosphorylation promotes the removal of VMAT2 from LDCVs, whereas replacement by alanine to prevent phosphorylation decreases removal. Phosphorylation of the acidic cluster thus appears to reduce the localization of VMAT2 to LDCVs by inactivating a retention mechanism

Scripts of Sexual Desire and Danger in US and Dutch Teen Girl Magazines: A Cross-National Content Analysis

The aim of this comparative quantitative content analysis was to investigate how US and Dutch teen girl magazines cover sexual desire (i.e., sexual wanting, and pleasure) and sexual danger (i.e., sexual risk, and negative physical/health consequences of sex). Relying on the sexual scripts framework and Hofstede’s cultural dimension of masculinity/femininity, we examined (a) how the coverage varied for boys and girls, (b) how it differed between the United States and the Netherlands, and (c) how gender differences varied by country. The sample comprised 627 sex-related feature stories from all 2006–2008 issues of three US (i.e., Seventeen, CosmoGirl! United States edition, and Teen) and three Dutch teen girl magazines (i.e., Fancy, CosmoGirl! Netherlands edition, and Girlz!). Overall, sexual wanting occurred more frequently in the US magazines than in the Dutch magazines. In the US coverage, boys’ sexual wanting received more attention than girls’ sexual wanting, whereas in the Dutch coverage sexual wanting was depicted equally often for boys and girls. The depiction of sexual pleasure did not vary by gender in either country, but was generally more visible in the Dutch magazines than in the US magazines. Sexual risks and the negative consequences of sex were associated with girls more than with boys, and were primarily depicted in the US magazines rather than in the Dutch magazines

Comparison of cisplatin sensitivity and the 18F fluoro-2-deoxy 2 glucose uptake with proliferation parameters and gene expression in squamous cell carcinoma cell lines of the head and neck

<p>Abstract</p> <p>Background</p> <p>The survival of patients with locally advanced head and neck cancer is still poor, with 5-year survival rates of 24–35%. The identification of prognostic and predictive markers at the molecular and cellular level could make it possible to find new therapeutic targets and provide "taylor made" treatments. Established cell lines of human squamous cell carcinoma (HNSCC) are valuable models for identifying such markers.</p> <p>The aim of this study was to establish and characterize a series of cell lines and to compare the cisplatin sensitivity and 18F fluoro-2 deoxy 2 glucose (18F-FDG) uptake of these cell lines with other cellular characteristics, such as proliferation parameters and TP53 and CCND1 status.</p> <p>Methods</p> <p>Explant cultures of fresh tumour tissue were cultivated, and six new permanent cell lines were established from 18 HNSCC cases. Successfully grown cell lines were analysed regarding clinical parameters, histological grade, karyotype, DNA ploidy, and index and S-phase fraction (Spf). The cell lines were further characterized with regard to their uptake of 18F-FDG, their sensitivity to cisplatin, as measured by a viability test (crystal violet), and their TP53 and CCND1 status, by fluorescence in situ hybridization (FISH), polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) with DNA sequencing and, for cyclin D1, by immunohistochemistry.</p> <p>Results</p> <p>Patients with tumours that could be cultured in vitro had shorter disease-free periods and overall survival time than those whose tumours did not grow in vitro, when analysed with the Kaplan-Meier method and the log-rank test. Their tumours also showed more complex karyotypes than tumours from which cell lines could not be established. No correlation was found between TP53 or CCND1 status and 18F-FDG uptake or cisplatin sensitivity. However, there was an inverse correlation between tumour cell doubling time and 18F-FDG uptake.</p> <p>Conclusion</p> <p>In vitro growth of HNSCC cells seem to be an independent prognostic factor, with cell lines being more readily established from aggressive tumours, a phenomenon more dependent on the molecular genetic characteristics of the tumour cells than on tumour location or TNM status.</p

“Shake It Baby, Shake It”: Media Preferences, Sexual Attitudes and Gender Stereotypes Among Adolescents

In this study exposure to and preferences for three important youth media (TV, music styles/music TV, internet) were examined in relation to adolescents’ permissive sexual attitudes and gender stereotypes (i.e., views of men as sex-driven and tough, and of women as sex objects). Multivariate structural analysis of data from a school-based sample of 480 13 to 16-year-old Dutch students revealed that preferences, rather than exposure were associated with attitudes and stereotypes. For both girls and boys, preferences for hip-hop and hard-house music were associated positively with gender stereotypes and preference for classical music was negatively associated with gender stereotypes. Particularly for boys, using internet to find explicit sexual content emerged as a powerful indicator of all attitudes and stereotypes