Interim modelling analysis to validate reported increases in condom use and assess HIV infections averted among female sex workers and clients in southern India following a targeted HIV prevention programme.

OBJECTIVES: This study assesses whether the observed declines in HIV prevalence since the beginning of the 'Avahan' India HIV/AIDS prevention initiative are consistent with self-reported increases in condom use by female sex workers (FSWs) in two districts of southern India, and provides estimates of the fraction of new infections averted among FSWs and clients due to increases in condom use in commercial sex after 2004. METHODS: A deterministic compartmental model of HIV/sexually transmitted infection (STI) transmission incorporating heterogeneous sexual behaviour was developed, parameterised and fitted using data from two districts in Karnataka, India. Three hypotheses of condom use among FSWs were tested: (H(0)), that condom use increased in line with reported FSW survey data prior to the Avahan initiative but remained constant afterwards; (H(1)) that condom use increased following the Avahan initiative, in accordance with survey data; (H(2)) that condom use increased according to estimates derived from condom distribution data. The proportion of fits to HIV/STI prevalence data was examined to determine which hypothesis was most consistent. RESULTS: For Mysore 0/36/82.7 fits were identified per million parameter sets explored under hypothesis H(0)/H(1)/H(2), respectively, while for Belgaum 9.7/8.3/0 fits were identified. The HIV epidemics in Belgaum and Mysore are both declining. In Mysore, increases in condom use during commercial sex between 2004 and 2009 may have averted 31.2% to 47.4% of new HIV infections in FSWs, while in Belgaum it may have averted 24.8% to 43.2%, if there was an increase in condom use. DISCUSSION: Increased condom use following the Avahan intervention is likely to have played a role in curbing the HIV epidemic in Mysore. In Belgaum, given the limitations in available data, this method cannot be used alone to decide if there has been an increase in condom use

Dust mass-loss rates from AGB stars in the Fornax and Sagittarius dwarf Spheroidal galaxies

To study the effect of metallicity on the mass-loss rate of asymptotic giant branch (AGB) stars, we have conducted mid-infrared photometric measurements of such stars in the Sagittarius (Sgr dSph) and Fornax dwarf spheroidal galaxies with the 10-$\mu$m camera VISIR at the VLT. We derive mass-loss rates for 29 AGB stars in Sgr dSph and 2 in Fornax. The dust mass-loss rates are estimated from the $K-[9]$ and $K-[11]$ colours. Radiative transfer models are used to check the consistency of the method. Published IRAS and Spitzer data confirm that the same tight correlation between $K-[12]$ colour and dust mass-loss rates is observed for AGB stars from galaxies with different metallicities, i.e. the Galaxy, the LMC and the SMC. The derived dust mass-loss rates are in the range 5$\times10^{-10}$ to 3$\times10^{-8}$ M$_{\odot}$yr$^{-1}$ for the observed AGB stars in Sgr dSph and around 5$\times10^{-9}$ M$_{\odot}$yr$^{-1}$ for those in Fornax; while values obtained with the two different methods are of the same order of magnitude. The mass-loss rates for these stars are higher than the nuclear burning rates, so they will terminate their AGB phase by the depletion of their stellar mantles before their core can grow significantly. Some observed stars have lower mass-loss rates than the minimum value predicted by theoretical models.Comment: 12 pages, 9 figures, accepted for publication in MNRA

The impacts of discriminatory experiences on lesbian, gay and bisexual people in sport

This study examines the nature and impact of sexist and homophobic discrimination experienced by lesbians, gays and bisexuals (LGB) in Australian sporting settings. A mixed methods online survey was utilized to collate participant experiences. The findings suggest that, in sport, participants experienced sexism directly and systemically, and homophobia explicitly and implicitly. Women experienced sexism and homophobia, whilst men reported more homophobic events. The most mentioned impacts of discrimination were negative emotions such as sadness, anger, distress and shame, followed by negative engagement with sport such as disliking sport, or avoiding or leaving sport. The well-recognized benefits of sport such as physical and mental well-being, social connections, enjoyment, positive identity and achievement may be more difficult to realize within this context of significant social stress

Regulatory modules function in a non-autonomous manner to control transcription of the mbp gene

Multiple regulatory modules contribute to the complex expression programs realized by many loci. Although long thought of as isolated components, recent studies demonstrate that such regulatory sequences can physically associate with promoters and with each other and may localize to specific sub-nuclear transcription factories. These associations provide a substrate for putative interactions and have led to the suggested existence of a transcriptional interactome. Here, using a controlled strategy of transgenesis, we analyzed the functional consequences of regulatory sequence interaction within the myelin basic protein (mbp) locus. Interactions were revealed through comparisons of the qualitative and quantitative expression programs conferred by an allelic series of 11 different enhancer/inter-enhancer combinations ligated to a common promoter/reporter gene. In a developmentally contextual manner, the regulatory output of all modules changed markedly in the presence of other sequences. Predicted by transgene expression programs, deletion of one such module from the endogenous locus reduced oligodendrocyte expression levels but unexpectedly, also attenuated expression of the overlapping golli transcriptional unit. These observations support a regulatory architecture that extends beyond a combinatorial model to include frequent interactions capable of significantly modulating the functions conferred through regulatory modules in isolation

Accuracy of Xpert Ultra in Diagnosis of Pulmonary Tuberculosis among Children in Uganda: a Substudy from the SHINE Trial.

Childhood tuberculosis (TB) presents significant diagnostic challenges associated with paucibacillary disease and requires a more sensitive test. We evaluated the diagnostic accuracy of Xpert MTB/RIF Ultra (Ultra) compared to other microbiological tests using respiratory samples from Ugandan children in the SHINE trial. SHINE is a randomized trial evaluating shorter treatment in 1,204 children with minimal TB disease in Africa and India. Among 352 samples and one cervical lymph node fine needle aspirate, one sample was randomly selected per patient and tested with the Xpert MTB/RIF assay (Xpert) and with Lowenstein-Jensen medium (LJ) and liquid mycobacterial growth indicator tube (MGIT) cultures. We selected only uncontaminated stored sample pellets for Ultra testing. We estimated the sensitivity of Xpert and Ultra against culture and a composite microbiological reference standard (any positive result). Of 398 children, 353 (89%) had culture, Xpert, and Ultra results. The median age was 2.8 years (interquartile range [IQR], 1.3 to 5.3); 8.5% (30/353) were HIV infected, and 54.4% (192/353) were male. Of the 353, 31 (9%) were positive by LJ and/or MGIT culture, 36 (10%) by Ultra, and 16 (5%) by Xpert. Sensitivities (95% confidence intervals [CI]) were 58% (39 to 65% [18/31]) for Ultra and 45% (27 to 64% [14/31]) for Xpert against any culture-positive result, with false positives of <1% and 5.5% for Xpert and Ultra. Against a composite microbiological reference, sensitivities were 72% (58 to 84% [36/50]) for Ultra and 32% (20 to 47% [16/50]) for Xpert. However, there were 17 samples that were positive only with Ultra (majority trace). Among children screened for minimal TB in Uganda, Ultra has higher sensitivity than Xpert. This represents an important advance for a condition which has posed a diagnostic challenge for decades

Differential requirement of a distal regulatory region for pre-initiation complex formation at globin gene promoters

Although distal regulatory regions are frequent throughout the genome, the molecular mechanisms by which they act in a promoter-specific manner remain to be elucidated. The human β-globin locus constitutes an extremely well-established multigenic model to investigate this issue. In erythroid cells, the β-globin locus control region (LCR) exerts distal regulatory function by influencing local chromatin organization and inducing high-level expression of individual β-like globin genes. Moreover, in transgenic mice expressing the entire human β-globin locus, deletion of LCR-hypersensitive site 2 (HS2) can alter β-like globin gene expression. Here, we show that abnormal expression of human β-like globin genes in the absence of HS2 is associated with decreased efficacy of pre-initiation complex formation at the human ɛ- and γ-promoters, but not at the β-promoter. This promoter-specific phenomenon is associated with reduced long-range interactions between the HS2-deleted LCR and human γ-promoters. We also find that HS2 is dispensable for high-level human β-gene transcription, whereas deletion of this hypersensitive site can alter locus chromatin organization; therefore the functions exerted by HS2 in transcriptional enhancement and locus chromatin organization are distinct. Overall, our data delineate one mechanism whereby a distal regulatory region provides promoter-specific transcriptional enhancement

Shorter treatment for minimal tuberculosis (TB) in children (SHINE): a study protocol for a randomised controlled trial

Background: Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed. Methods/design: SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations. Discussion: Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smearnegative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB. Recruitment to the SHINE trial begun in July 2016; results are expected in 2020. Trial registration: International Standard Randomised Controlled Trials Number: ISRCTN63579542, 14 October 2014. Pan African Clinical Trials Registry Number: PACTR201505001141379, 14 May 2015. Clinical Trial Registry-India, registration number: CTRI/2017/07/009119, 27 July 2017

Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans

The study of Drosophila neurodegenerative mutants combined with genetic and biochemical analyses lead to the identification of multiple complex mutations in 60 patients with a novel form of ataxia/leukoencephalopathy