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Characterizing the Diverse Mutational Pathways Associated with R5-Tropic Maraviroc Resistance::HIV-1 That Uses the Drug-Bound CCR5 Coreceptor
No full textEntry inhibitors represent a potent class of antiretroviral drugs that target a host cell protein, CCR5, an HIV-1 entry coreceptor, and not viral protein. Lack of sensitivity can occur due to preexisting virus that uses the CXCR4 coreceptor, while true resistance occurs through viral adaptation to use a drug-bound CCR5 coreceptor. To understand this R5 resistance pathway, we analyzed >500 envelope protein sequences and phenotypes from viruses of 20 patients from the clinical trials MOTIVATE 1 and 2, in which treatment-experienced patients received maraviroc plus optimized background therapy. The resistant viral population was phylogenetically distinct and associated with a genetic bottleneck in each patient, consistent with de novo emergence of resistance. Recombination analysis showed that the C2-V3-C3 region tends to genotypically correspond to the recombinant's phenotype, indicating its primary importance in conferring resistance. Between patients, there was a notable lack of commonality in the specific sites conferring resistance, confirming the unusual nature of R5-tropic resistance. We used coevolutionary and positive-selection analyses to characterize the genotypic determinants of resistance and found that (i) there are complicated covariation networks, indicating frequent coevolutionary/compensatory changes in the context of protein structure; (ii) covarying sites under positive selection are enriched in resistant viruses; (iii) CD4 binding sites form part of a unique covariation network independent of the V3 loop; and (iv) the covariation network formed between the V3 loop and other regions of gp120 and gp41 intersects sites involved in glycosylation and protein secretion. These results demonstrate that while envelope sequence mutations are the key to conferring maraviroc resistance, the specific changes involved are context dependent and thus inherently unpredictable. IMPORTANCE: The entry inhibitor drug maraviroc makes the cell coreceptor CCR5 unavailable for use by HIV-1 and is now used in combination antiretroviral therapy. Treatment failure with drug-resistant virus is particularly interesting because it tends to be rare, with lack of sensitivity usually associated with the presence of CXCR4-using virus (CXCR4 is the main alternative coreceptor HIV-1 uses, in addition to CD4). We analyzed envelope sequences from HIV-1, obtained from 20 patients who enrolled in maraviroc clinical trials and experienced treatment failure, without detection of CXCR4-using virus. Evolutionary analysis was employed to identify molecular changes that confer maraviroc resistance. We found that in these individuals, resistant viruses form a distinct population that evolved once and was successful as a result of drug pressure. Further evolutionary analysis placed the complex network of interdependent mutational changes into functional groups that help explain the impediments to the emergence of maraviroc-associated R5 drug resistance
Interventions for the cessation of non-nutritive sucking habits in children
No full textBACKGROUND: Comforting behaviours, such as the use of pacifiers (dummies, soothers), blankets and finger or thumb sucking, are common in babies and young children. These comforting habits, which can be referred to collectively as 'non-nutritive sucking habits' (NNSHs), tend to stop as children get older, under their own impetus or with support from parents and carers. However, if the habit continues whilst the permanent dentition is becoming established, it can contribute to, or cause, development of a malocclusion (abnormal bite). A diverse variety of approaches has been used to help children with stopping a NNSH. These include advice, removal of the comforting object, fitting an orthodontic appliance to interfere with the habit, application of an aversive taste to the digit or behaviour modification techniques. Some of these interventions are easier to apply than others and less disturbing for the child and their parent; some are more applicable to a particular type of habit. OBJECTIVES: The primary objective of the review was to evaluate the effects of different interventions for cessation of NNSHs in children. The secondary objectives were to determine which interventions work most quickly and are the most effective in terms of child and parent- or carer-centred outcomes of least discomfort and psychological distress from the intervention, as well as the dental measures of malocclusion (reduction in anterior open bite, overjet and correction of posterior crossbite) and cost-effectiveness.SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group Trials Register (to 8 October 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 9), MEDLINE via OVID (1946 to 8 October 2014), EMBASE via OVID (1980 to 8 October 2014), PsycINFO via OVID (1980 to 8 October 2014) and CINAHL via EBSCO (1937 to 8 October 2014), the US National Institutes of Health Trials Register (Clinical Trials.gov) (to 8 October 2014) and the WHO International Clinical Trials Registry Platform (to 8 October 2014). There were no restrictions regarding language or date of publication in the searches of the electronic databases. We screened reference lists from relevant articles and contacted authors of eligible studies for further information where necessary.SELECTION CRITERIA: Randomised or quasi-randomised controlled trials in children with a non-nutritive sucking habit that compared one intervention with another intervention or a no-intervention control group. The primary outcome of interest was cessation of the habit.DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Three review authors were involved in screening the records identified; two undertook data extraction, two assessed risk of bias and two assessed overall quality of the evidence base. Most of the data could not be combined and only one meta-analysis could be carried out.MAIN RESULTS: We included six trials, which recruited 252 children (aged two and a half to 18 years), but presented follow-up data on only 246 children. Digit sucking was the only NNSH assessed in the studies. Five studies compared single or multiple interventions with a no-intervention or waiting list control group and one study made a head-to-head comparison. All the studies were at high risk of bias due to major limitations in methodology and reporting. There were small numbers of participants in the studies (20 to 38 participants per study) and follow-up times ranged from one to 36 months. Short-term outcomes were observed under one year post intervention and long-term outcomes were observed at one year or more post intervention. Orthodontics appliance (with or without psychological intervention) versus no treatmentTwo trials that assessed this comparison evaluated our primary outcome of cessation of habit. One of the trials evaluated palatal crib and one used a mix of palatal cribs and arches. Both trials were at high risk of bias. The orthodontic appliance was more likely to stop digit sucking than no treatment, whether it was used over the short term (risk ratio (RR) 6.53, 95% confidence interval (CI) 1.67 to 25.53; two trials, 70 participants) or long term (RR 5.81, 95% CI 1.49 to 22.66; one trial, 37 participants) or used in combination with a psychological intervention (RR 6.36, 95% CI 0.97 to 41.96; one trial, 32 participants). Psychological intervention versus no treatmentTwo trials (78 participants) at high risk of bias evaluated positive reinforcement (alone or in combination with gaining the child's co-operation) or negative reinforcement compared with no treatment. Pooling of data showed a statistically significant difference in favour of the psychological interventions in the short term (RR 6.16, 95% CI 1.18 to 32.10; I(2) = 0%). One study, with data from 57 participants, reported on the long-term effect of positive and negative reinforcement on sucking cessation and found a statistically significant difference in favour of the psychological interventions (RR 6.25, 95% CI 1.65 to 23.65). Head-to-head comparisonsOnly one trial demonstrated a clear difference in effectiveness between different active interventions. This trial, which had only 22 participants, found a higher likelihood of cessation of habit with palatal crib than palatal arch (RR 0.13, 95% CI 0.03 to 0.59).AUTHORS' CONCLUSIONS: This review found low quality evidence that orthodontic appliances (palatal arch and palatal crib) and psychological interventions (including positive and negative reinforcement) are effective at improving sucking cessation in children. There is very low quality evidence that palatal crib is more effective than palatal arch. This review has highlighted the need for high quality trials evaluating interventions to stop non-nutritive sucking habits to be conducted and the need for a consolidated, standardised approach to reporting outcomes in these trials.</p
Kinematics and energetics of swimming performance during acute warming in brown trout (Salmo trutta)
No full textThis study examined how acute warming of water temperature affects the mechanical efficiency of swimming and aerobic capabilities of the brown trout Salmo trutta. Swimming efficiency was assessed using the relationship between swimming kinematics and forward speed (U), which is thought to converge upon an optimum range of a dimensionless parameter, the Strouhal number (St). Swim-tunnel intermittent stopped-flow respirometry was used to record kinematics and measure oxygen consumption ( ˙M O2) of S. trutta during warming and swimming challenges. Salmo trutta maintained St between 0⋅2 and 0⋅3 at any given U over a range of temperatures, irrespective of body size. The maintenance of St within the range for maximum efficiency for oscillatory propulsion was achieved through an increase in tail-beat frequency (f tail) and a decrease in tail-beat amplitude (A) as temperature increased. Maintenance of efficient steady-state swimming was fuelled by aerobic metabolism, which increased as temperature increased up to 18∘ C but declined above this temperature, decreasing the apparent metabolic scope. As St was maintained over the full range of temperatures whilst metabolic scope was not, the results may suggest energetic trade-offs at any given U at temperatures above thermal optima
'Displaced responsibilities in the pedagogical state: early intervention, ‘resilience' and the schooling of social inequalities',
No full textCharacterization and understanding of residual stresses in a NiCoCrAlY bond coat for thermal barrier coating application
No full textThe residual stresses in a NiCoCrAlY bond coat deposited on a Ni-base superalloy substrate after oxidation at 1150 degrees C were studied by X-ray diffraction using the sin(2)psi technique. The stresses were found to be tensile; they first increased and then decreased with oxidation time. High temperature stress measurement indicated that the stress developed and built up upon cooling, predominantly within the temperature range from 1150 degrees C to 600 degrees C. Microstructural examination suggested that, due to the limited penetration depth into the bond coat, the X-ray only probed the stress in a thin surface layer consisting of the single gamma-phase formed through Al depletion during oxidation. Quantitative high temperature X-ray diffraction analysis revealed that, above 600 degrees C, the volume fraction of the beta-phase in the bond coat increased with decreasing temperature. The mechanisms of stress generation in the bond coat were examined and are discussed based on the experiments designed to isolate the contribution of possible stress generation factors. It was found that the measured bond coat stresses were mainly induced by the volume change of the bond coat associated with the precipitation of the beta-phase upon cooling
Embedding Quantitative Skills into the Social Science Curriculum: Case studies from Manchester
No full textThose aiming to respond to the recognised shortage in quantitative skills within the UK social sciences have increasingly focused on the content of undergraduate degree programmes. Problems occur when ‘quantitative methods (QM)’ are generally confined to a dedicated module, detached from substantive topics. This model makes it hard for students to understand or engage with the contribution of quantitative research to their discipline and can perpetuate negative perceptions of quantitative training. We suggest a solution to this problem is ‘quantitative embedding’, in which quantitative evidence and methods are incorporated into substantive teaching in the social sciences. We illustrate quantitative embedding with case studies from an ESRC funded project based in The University of Manchester, where teaching partnerships have developed curriculum innovations in Sociology and Politics. The paper then discusses the challenges of disseminating quantitative embedding, highlighting the need to bridge separate ‘communities of practice’ that can isolate quantitative specialists
Measurement of the charge asymmetry in top-quark pair production in the lepton-plus-jets final state in collision data at TeV with the ATLAS detector
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In Situ Grazing Incidence X-ray Diffraction of Sweet Corrosion Scaling on Carbon Steel
No full textAn electrochemical cell for in situ grazing incidence x-ray diffraction is described, along with its implementation for characterization of corrosion in a model sweet oilfield environment. In order to mimic reservoir fluids, the cell has been designed to facilitate measurements from substrates immersed in solutions with low concentrations of dissolved oxygen. In addition, the temperature of the solution can be varied from room temperature up to ~ 80°C. Diffraction patterns acquired with synchrotron radiation from X65 pipeline steel immersed in CO2-saturated aqueous NaCl solution (pH = 6.8, T = 80°C) are presented. These data demonstrate the formation and temporal evolution of a multicomponent corrosion scale, which includes siderite (FeCO3) and chukanovite (Fe2(OH)2CO3)
