Microscopic-observation drug-susceptibility assay for the diagnosis of TB.

BACKGROUND: New diagnostic tools are urgently needed to interrupt the transmission of tuberculosis and multidrug-resistant tuberculosis. Rapid, sensitive detection of tuberculosis and multidrug-resistant tuberculosis in sputum has been demonstrated in proof-of-principle studies of the microscopic-observation drug-susceptibility (MODS) assay, in which broth cultures are examined microscopically to detect characteristic growth. METHODS: In an operational setting in Peru, we investigated the performance of the MODS assay for culture and drug-susceptibility testing in three target groups: unselected patients with suspected tuberculosis, prescreened patients at high risk for tuberculosis or multidrug-resistant tuberculosis, and unselected hospitalized patients infected with the human immunodeficiency virus. We compared the MODS assay head-to-head with two reference methods: automated mycobacterial culture and culture on Löwenstein-Jensen medium with the proportion method. RESULTS: Of 3760 sputum samples, 401 (10.7%) yielded cultures positive for Mycobacterium tuberculosis. Sensitivity of detection was 97.8% for MODS culture, 89.0% for automated mycobacterial culture, and 84.0% for Löwenstein-Jensen culture (P<0.001); the median time to culture positivity was 7 days, 13 days, and 26 days, respectively (P<0.001), and the median time to the results of susceptibility tests was 7 days, 22 days, and 68 days, respectively. The incremental benefit of a second MODS culture was minimal, particularly in patients at high risk for tuberculosis or multidrug-resistant tuberculosis. Agreement between MODS and the reference standard for susceptibility was 100% for rifampin, 97% for isoniazid, 99% for rifampin and isoniazid (combined results for multidrug resistance), 95% for ethambutol, and 92% for streptomycin (kappa values, 1.0, 0.89, 0.93, 0.71, and 0.72, respectively). CONCLUSIONS: A single MODS culture of a sputum sample offers more rapid and sensitive detection of tuberculosis and multidrug-resistant tuberculosis than the existing gold-standard methods used

Prioritized Sweeping Neural DynaQ with Multiple Predecessors, and Hippocampal Replays

During sleep and awake rest, the hippocampus replays sequences of place cells that have been activated during prior experiences. These have been interpreted as a memory consolidation process, but recent results suggest a possible interpretation in terms of reinforcement learning. The Dyna reinforcement learning algorithms use off-line replays to improve learning. Under limited replay budget, a prioritized sweeping approach, which requires a model of the transitions to the predecessors, can be used to improve performance. We investigate whether such algorithms can explain the experimentally observed replays. We propose a neural network version of prioritized sweeping Q-learning, for which we developed a growing multiple expert algorithm, able to cope with multiple predecessors. The resulting architecture is able to improve the learning of simulated agents confronted to a navigation task. We predict that, in animals, learning the world model should occur during rest periods, and that the corresponding replays should be shuffled.Comment: Living Machines 2018 (Paris, France

Expression and functional profiling reveal distinct gene classes involved in fatty acid metabolism

Cells respond to fatty acid exposure by metabolic reorganization and proliferation of peroxisomes. Described here is the development and application of a genome-wide screen to identify nonessential yeast genes necessary for efficient metabolism of myristic and oleic acids. Comparison of the resultant fitness data set with an integrated data set of genes transcriptionally responsive to fatty acids revealed very little overlap between the data sets. Furthermore, the fitness data set enriched for genes involved in peroxisome biogenesis and other processes related to cell morphology, whereas the expression data set enriched for genes related to metabolism. These data suggest that in response to fatty acid exposure, transcriptional control is biased towards metabolic reorganization, and structural changes tend to be controlled post-transcriptionally. They also suggest that fatty acid responsive metabolic networks are more robust than those related to cell structure. Statistical analyses of these and other global data sets suggest that the utilization of distinct control mechanisms for the execution of morphological versus metabolic responses is widespread

Head Position in Stroke Trial (HeadPoST)- sitting-up vs lying-flat positioning of patients with acute stroke: study protocol for a cluster randomised controlled trial

Background Positioning a patient lying-flat in the acute phase of ischaemic stroke may improve recovery and reduce disability, but such a possibility has not been formally tested in a randomised trial. We therefore initiated the Head Position in Stroke Trial (HeadPoST) to determine the effects of lying-flat (0°) compared with sitting-up (≥30°) head positioning in the first 24 hours of hospital admission for patients with acute stroke. Methods/Design We plan to conduct an international, cluster randomised, crossover, open, blinded outcome-assessed clinical trial involving 140 study hospitals (clusters) with established acute stroke care programs. Each hospital will be randomly assigned to sequential policies of lying-flat (0°) or sitting-up (≥30°) head position as a ‘business as usual’ stroke care policy during the first 24 hours of admittance. Each hospital is required to recruit 60 consecutive patients with acute ischaemic stroke (AIS), and all patients with acute intracerebral haemorrhage (ICH) (an estimated average of 10), in the first randomised head position policy before crossing over to the second head position policy with a similar recruitment target. After collection of in-hospital clinical and management data and 7-day outcomes, central trained blinded assessors will conduct a telephone disability assessment with the modified Rankin Scale at 90 days. The primary outcome for analysis is a shift (defined as improvement) in death or disability on this scale. For a cluster size of 60 patients with AIS per intervention and with various assumptions including an intracluster correlation coefficient of 0.03, a sample size of 16,800 patients at 140 centres will provide 90 % power (α 0.05) to detect at least a 16 % relative improvement (shift) in an ordinal logistic regression analysis of the primary outcome. The treatment effect will also be assessed in all patients with ICH who are recruited during each treatment study period. Discussion HeadPoST is a large international clinical trial in which we will rigorously evaluate the effects of different head positioning in patients with acute stroke. Trial registration ClinicalTrials.gov identifier: NCT02162017 (date of registration: 27 April 2014); ANZCTR identifier: ACTRN12614000483651 (date of registration: 9 May 2014). Protocol version and date: version 2.2, 19 June 2014

Limiting distributions for explosive PAR(1) time series with strongly mixing innovation

This work deals with the limiting distribution of the least squares estimators of the coefficients a r of an explosive periodic autoregressive of order 1 (PAR(1)) time series X r = a r X r--1 +u r when the innovation {u k } is strongly mixing. More precisely {a r } is a periodic sequence of real numbers with period P \textgreater{} 0 and such that P r=1 |a r | \textgreater{} 1. The time series {u r } is periodically distributed with the same period P and satisfies the strong mixing property, so the random variables u r can be correlated

Normal levels of p27Xic1 are necessary for somite segmentation and determining pronephric organ size

The Xenopus laevis cyclin dependent kinase inhibitor p27Xic1 has been shown to be involved in exit from the cell cycle and differentiation of cells into a quiescent state in the nervous system, muscle tissue, heart and retina. We show that p27Xic1 is expressed in the developing kidney in the nephrostomal regions. Using over-expression and morpholino oligonucleotide (MO) knock-down approaches we show normal levels of p27Xic1 regulate pronephros organ size by regulating cell cycle exit. Knock-down of p27Xic1 expression using a MO prevented myogenesis, as previously reported; an effect that subsequently inhibits pronephrogenesis. Furthermore, we show that normal levels of p27Xic1 are required for somite segmentation also through its cell cycle control function. Finally, we provide evidence to suggest correct paraxial mesoderm segmentation is not necessary for pronephric induction in the intermediate mesoderm. These results indicate novel developmental roles for p27Xic1, and reveal its differentiation function is not universally utilised in all developing tissues

Differential effects of pre and post-payment on neurologists' response rates to a postal survey

<p>Abstract</p> <p>Background</p> <p>Monetary incentives are an effective way of increasing response rates to surveys, though they are generally less effective in physicians, and are more effective when the incentive is paid up-front rather than when made conditional on completion.</p> <p>Methods</p> <p>In this study we examine the effectiveness of pre- and post-completion incentives on the response rates of all the neurologists in the UK to a survey about conversion disorder, using a cluster randomised controlled design. A postal survey was sent to all practicing consultant neurologists, in two rounds, including either a book token, the promise of a book token, or nothing at all.</p> <p>Results</p> <p>Three hundred and fifty-one of 591 eligible neurologists completed the survey, for a response rate of 59%. While the post-completion incentive exerted no discernible influence on response rates, a pre-completion incentive did, with an odds-ratio of 2.1 (95% confidence interval 1.5 - 3.0).</p> <p>Conclusions</p> <p>We conclude that neurologists, in the UK at least, may be influenced to respond to a postal survey by a pre-payment incentive but are unaffected by a promised reward.</p

Knowledge and care seeking practices for ear infections among parents of under five children in Kigali, Rwanda : a cross-sectional study

Background: Infections affecting the middle ear are a common childhood occurrence. Some cases may present with ear discharge through a tympanic membrane perforation which may heal spontaneously. However, up to 5% or more cases of those affected have persistent ear discharge. A number of barriers contribute towards delayed presentation at health facilities for treatment of ear infections. We conducted a study to evaluate parents’ and caregivers’ knowledge and care seeking practices for ear infections in children under five in Gasabo district in Kigali, Rwanda. Methods: Parents/guardians (n = 810) were interviewed using a structured questionnaire to elicit their knowledge of ear infections in children under five and their attitude to seeking care for their children. Results: The mean age of the respondents was 31.27 years (SD = 7.88, range 17–83). Considering an average of knowledge parameters which included causes, symptoms, prevention, treatment and consequences of ear infections, we found that 76.6% (622) of respondents were knowledgeable about ear infections. We defined a positive practice as seeking medical treatment (community health workers or health facility) and this was found in 89.1% (722) respondents. Correlating knowledge with choice of seeking treatment, respondents were 33% less likely to practice medical pluralism (OR = 0.33, CI 0.11–0.97, P = 0.043) if they were familiar with infections. Moreover, urban dweller were 1.7 times more likely to know ear infections compared to rural dwellers (OR = 1.70, CI 1.22–2.38, P = 0.002). Conclusion: The majority of respondents had good knowledge and positive attitudes and practices about ear infection. However, medical pluralism was common. There is need to improve the community’s awareness and access to primary health care facilities for the care of ear infections especially in rural areas of Rwanda

A combinatorial TIR1/AFB–Aux/IAA co-receptor system for differential sensing of auxin

The plant hormone auxin regulates virtually every aspect of plant growth and development. Auxin acts by binding the F-box protein transport inhibitor response 1 (TIR1) and promotes the degradation of the AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) transcriptional repressors. Here we show that efficient auxin binding requires assembly of an auxin co-receptor complex consisting of TIR1 and an Aux/IAA protein. Heterologous experiments in yeast and quantitative IAA binding assays using purified proteins showed that different combinations of TIR1 and Aux/IAA proteins form co-receptor complexes with a wide range of auxin-binding affinities. Auxin affinity seems to be largely determined by the Aux/IAA. As there are 6 TIR1/AUXIN SIGNALING F-BOX proteins (AFBs) and 29 Aux/IAA proteins in Arabidopsis thaliana, combinatorial interactions may result in many co-receptors with distinct auxin-sensing properties. We also demonstrate that the AFB5–Aux/IAA co-receptor selectively binds the auxinic herbicide picloram. This co-receptor system broadens the effective concentration range of the hormone and may contribute to the complexity of auxin response