How antimalarial drug resistance affects post-treatment prophylaxis

Slowly eliminated antimalarial drugs suppress malaria reinfections for a period of time determined by the dose, the pharmacokinetic properties of the drug, and the susceptibility of the infecting parasites. This effect is called post-treatment prophylaxis (PTP). The clinical benefits of preventing recrudescence (reflecting treatment efficacy) compared with preventing reinfection (reflecting PTP) need further assessment. Antimalarial drug resistance shortens PTP. While blood concentrations are in the terminal elimination phase, the degree of shortening may be estimated from measurements of in-vitro susceptibility and the terminal elimination half-life. More information is needed on PTP following intermittent preventive treatments, and on the relationship between the duration of PTP and immunity, so that policy recommendations can have a firmer evidence base

Working memory updating training reduces state repetitive negative thinking: proof-of-concept for a novel cognitive control training (article)

This is the final version. Available on open access from Elsevier via the DOI in this record.The research data supporting this publication are openly available from the University of Exeter's institutional repository at https://doi.org/10.24378/exe.3283Repetitive negative thinking (RNT) is a proximal risk factor implicated in the onset and maintenance of common mental health problems such as depression and anxiety. Adolescence may be a key developmental window in which to target RNT and prevent the emergence of such disorders. Impairments in updating the contents of working memory are hypothesised to causally contribute to RNT, and some theorists have suggested these difficulties may be specific to the manipulation of negative information. The present study compared the effects of computerised adaptive working memory updating training (in which the task becomes more difficult as performance improves) to a non-adaptive control task in reducing levels of RNT. 124 healthy young people were randomised to 20 sessions of (i) working memory updating training using neutral stimuli, (ii) working memory updating training using negative stimuli, or (iii) non-adaptive working memory updating training. Adaptive working memory updating training using neutral, but not negative, stimuli resulted in significant improvements to working memory updating for negative material, as assessed using an unpractised task, and significant reductions in susceptibility to state RNT. These findings demonstrate proof-of-concept that working memory updating training has the potential to reduce susceptibility to episodes of state RNT.Wellcome Trus

Seroprevalence of SARS-CoV-2 among Blood Donors and Changes after Introduction of Public Health and Social Measures, London, UK

We describe results of testing blood donors in London, UK, for severe acute respiratory disease coronavirus 2 (SARS-CoV-2) IgG before and after lockdown measures. Anonymized samples from donors 17–69 years of age were tested using 3 assays: Euroimmun IgG, Abbott IgG, and an immunoglobulin receptor-binding domain assay developed by Public Health England. Seroprevalence increased from 3.0% prelockdown (week 13, beginning March 23, 2020) to 10.4% during lockdown (weeks 15–16) and 12.3% postlockdown (week 18) by the Abbott assay. Estimates were 2.9% prelockdown, 9.9% during lockdown, and 13.0% postlockdown by the Euroimmun assay and 3.5% prelockdown, 11.8% during lockdown, and 14.1% postlockdown by the receptor-binding domain assay. By early May 2020, nearly 1 in 7 donors had evidence of past SARS-CoV-2 infection. Combining results from the Abbott and Euroimmun assays increased seroprevalence by 1.6%, 2.3%, and 0.6% at the 3 timepoints compared with Euroimmun alone, demonstrating the value of using multiple assays

Laser Forming of Aerospace Alloys

Non-contact forming by application of a thermal source has been known for some time. Recently, it has been shown that much greater controllability can be introduced by replacing the thermal source with a laser. This yields a process with strong potential for application in aerospace, including the rapid manufacture of prototypes and the adjustment of misaligned components. This paper briefly reviews the mechanisms involved in laser forming and then summarises experimental work carried out on aluminium alloys and titanium alloys that led to the development of a prototype system for the forming of 2-D sheet materials. Emphasis is placed on the process advantages, including the high accuracy (arising from the progressive nature of the process) that can be achieved in forming or adjustment of misalignment. Future work in a new collaborative programme to develop 3-D laser forming is summarised. Copyright © 2001 Society of Automotive Engineers, Inc

Duration of Protection against Malaria and Anaemia Provided by Intermittent Preventive Treatment in Infants in Navrongo, Ghana

BACKGROUND: Intermittent preventive treatment for malaria in Infants (IPTi) has been shown to give effective and safe protection against malaria. It has been suggested that IPTi might have long-lasting beneficial effects but, in most settings, the protection provided by IPTi appears to be short-lived. Knowledge of the duration of protection given by IPTi would help interpret the results of existing trials and suggest optimal delivery schedules for IPTi. This study investigated how the protective efficacy of IPTi against malaria and anaemia changes over time. METHODS AND FINDINGS: A secondary analysis of data from a cluster-randomised, placebo-controlled trial of IPTi using sulfadoxine-pyrimethamine (SP) in Ghana was conducted. In this trial IPTi was given to 2485 infants at 3, 4, 9 and 12 months of age; children remained in follow-up until two years of age. Poisson regression with a random effect to adjust for the cluster-randomised design was used to determine protective efficacy of IPTi against clinical malaria and anaemia in defined time strata following administration of IPTi. Analysis of first-or-only clinical malaria episode following the individual IPTi doses showed that some protection against malaria lasted between 4 to 6 weeks. A similar pattern was seen when the incidence of all malaria episodes up to 2 years of age was analysed in relation to the most recent IPT, by pooling the incidence of malaria after the individual IPTi doses. Protective efficacy within four weeks of IPTi was 75.2% (95% CI: 66-82) against malaria, 78.9% (95% CI: 69-86) against high parasite density malaria, and 93.8% (95% CI: 73-99) against anaemia. Protection against these outcomes was short-lived, with evidence of any effect lasting for only 6, 6 and 4 weeks respectively. Protection in children who were parasitaemic when receiving IPTi appeared to be of shorter duration than in uninfected children. There was no evidence of any benefit of IPTi after the immediate period following the IPTi doses. CONCLUSIONS: Intermittent preventive treatment provides considerable protection against malaria and anaemia for short periods, even in an area of intense seasonal transmission. Due to the relatively short duration of protection provided by each dose of IPTi, this treatment will be of most benefit when delivered at the time of peak malaria incidence

Emerging ecophenotype: reward anticipation is linked to high-risk behaviours after sexual abuse.

This is the final version. Available from Oxford University Press via the DOI in this record. Adolescents frequently engage in high-risk behaviours (HRB) following childhood sexual abuse (CSA). Aberrant reward processes are implicated in HRB, and their underlying fronto-striatal networks are vulnerable to neurodevelopmental changes during adversity representing a promising candidate for understanding links between CSA and HRB. We examined whether fronto-striatal responses during reward anticipation and feedback (i) are altered in depressed adolescents with CSA compared to depressed, non-abused peers and (ii) moderate the relationship between CSA and HRB irrespective of depression. Forty-eight female adolescents {14 with CSA and depression [CSA +  major depressive disorder (MDD)]; 17 with MDD but no CSA (MDD); 17 healthy, non-abused controls} completed a monetary reward task during functional magnetic resonance imaging. No differences in fronto-striatal response to reward emerged between CSA + MDD and MDD. Critically, high left nucleus accumbens activation during reward anticipation was associated with greater HRB in CSA + MDD compared to MDD and controls. Low left putamen activation during reward feedback was associated with the absence of HRB in CSA + MDD compared to MDD. Striatal reward responses appear to play a key role in HRB for adolescents with CSA irrespective of depression, providing initial support for a CSA ecophenotype. Such information is pivotal to identify at-risk youth and prevent HRB in adolescents after CSA.Brain and Behaviour Research FoundationWellcome TrustNational Institute of Mental HealthNational Institute of Mental Healt

Frequency-dependent selection in vaccine-associated pneumococcal population dynamics

Many bacterial species are composed of multiple lineages distinguished by extensive variation in gene content. These often cocirculate in the same habitat, but the evolutionary and ecological processes that shape these complex populations are poorly understood. Addressing these questions is particularly important for Streptococcus pneumoniae, a nasopharyngeal commensal and respiratory pathogen, because the changes in population structure associated with the recent introduction of partial-coverage vaccines have substantially reduced pneumococcal disease. Here we show that pneumococcal lineages from multiple populations each have a distinct combination of intermediate-frequency genes. Functional analysis suggested that these loci may be subject to negative frequency-dependent selection (NFDS) through interactions with other bacteria, hosts or mobile elements. Correspondingly, these genes had similar frequencies in four populations with dissimilar lineage compositions. These frequencies were maintained following substantial alterations in lineage prevalences once vaccination programmes began. Fitting a multilocus NFDS model of post-vaccine population dynamics to three genomic datasets using Approximate Bayesian Computation generated reproducible estimates of the influence of NFDS on pneumococcal evolution, the strength of which varied between loci. Simulations replicated the stable frequency of lineages unperturbed by vaccination, patterns of serotype switching and clonal replacement. This framework highlights how bacterial ecology affects the impact of clinical interventions.Accessory loci are shown to have similar frequencies in diverse Streptococcus pneumoniae populations, suggesting negative frequency-dependent selection drives post-vaccination population restructuring

Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing