Interferon lambda is required for interferon gamma-expressing NK cell responses but does not afford antiviral protection during acute and persistent murine cytomegalovirus infection

Interferon lambda (IFNλ) is a group of cytokines that belong to the IL-10 family. They exhibit antiviral activities against certain viruses during infection of the liver and mucosal tissues. Here we report that IFNλ restricts in vitro replication of the β-herpesvirus murine cytomegalovirus (mCMV). However, IFNλR1-deficient (Ifnλr1-/-) mice were not preferentially susceptible to mCMV infection in vivo during acute infection after systemic or mucosal challenge, or during virus persistence in the mucosa. Instead, our studies revealed that IFNλ influences NK cell responses during mCMV infection. Ifnλr1-/- mice exhibited defective development of conventional interferon-gamma (IFNγ)-expressing NK cells in the spleen during mCMV infection whereas accumulation of granzyme B-expressing NK cells was unaltered. In vitro, development of splenic IFNγ+ NK cells following stimulation with IL-12 or, to a lesser extent, IL-18 was abrogated by IFNλR1-deficiency. Thus, IFNλ regulates NK cell responses during mCMV infection and restricts virus replication in vitro but is redundant in the control of acute and persistent mCMV replication within mucosal and non-mucosal tissues

S06-5 The Walking In ScHools (WISH) study: Development and evaluation of a peer-led school-based walking intervention in adolescent girls from pilot to fully-powered trial

BACKGROUND: Walking interventions, delivered within the school setting, have the potential to increase physical activity (PA) in adolescents. Previous research has shown that walking is an acceptable form of PA for adolescent girls, and that walking interventions may be effective at increasing PA in this group. Findings from the Walking In ScHools (WISH) pilot study (n199 female participants) found the intervention was effective in increasing light intensity PA in adolescent girls, but further research is needed to examine the effects of walking on overall PA and the role of peer leaders in delivering school-based interventions. The present study aims to build upon this pilot work and evaluate the effectiveness of a novel, low-cost, peer-led school-based walking intervention, delivered across the school year, at increasing accelerometer-measured PA levels of adolescent girls. METHODS: The WISH study is a school-based cluster randomised controlled trial targeting adolescent girls (aged 12-14 years) within the post-primary school setting. Data will be collected at four timepoints, baseline, mid-intervention, post-intervention, and 13 months post-baseline. Following baseline data collection, schools were randomly allocated to intervention (n = 9) or control (n = 9). In intervention schools, older pupils (aged 15-18 years) were trained as walk leaders and led the younger girls in 10-15min walks before school, at break, and during lunch, across the school year (20-22 weeks). The primary outcome measure is accelerometer-measured total PA (post-intervention) and secondary outcomes include anthropometry measures, and wellbeing. RESULTS: Some 590 participants (mean(SD) age 12.6(0.64)years) were recruited from 18 schools across Northern Ireland (n = 9) and the Border region of the Republic of Ireland (n9). Within the intervention schools, 149 walk leaders were trained. At baseline (n = 535), mean(SD) time spent in moderate to vigorous PA (MVPA) was 39.2(17.07)mins/day and 66 (12%) girls achieved PA guidelines of 60 minutes MVPA per day. Data collection and analysis is ongoing. CONCLUSIONS: This research has outlined the development of a novel, peer-led walking intervention and demonstrated its effectiveness at increasing light intensity PA in adolescent girls. The ongoing fully powered trial will build upon this pilot work and further evaluate the effects of the WISH study on increasing PA in adolescent girls

Correction: Signatures of Adaptation in Human Invasive Salmonella Typhimurium ST313 Populations from Sub-Saharan Africa.

Correction to: 7 Aug 2015: The PLOS Neglected Tropical Diseases Staff (2015) Correction: Correction: Signatures of Adaptation in Human Invasive Salmonella Typhimurium ST313 Populations from Sub-Saharan Africa. PLoS Negl Trop Dis 9(8): e0003970. doi: 10.1371/journal.pntd.0003970

FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele.

FBXO7 encodes an F box containing protein that interacts with multiple partners to facilitate numerous cellular processes and has a canonical role as part of an SCF E3 ubiquitin ligase complex. Mutation of FBXO7 is responsible for an early onset Parkinsonian pyramidal syndrome and genome-wide association studies have linked variants in FBXO7 to erythroid traits. A putative orthologue in Drosophila, nutcracker, has been shown to regulate the proteasome, and deficiency of nutcracker results in male infertility. Therefore, we reasoned that modulating Fbxo7 levels in a murine model could provide insights into the role of this protein in mammals. We used a targeted gene trap model which retained 4-16% residual gene expression and assessed the sensitivity of phenotypic traits to gene dosage. Fbxo7 hypomorphs showed regenerative anaemia associated with a shorter erythrocyte half-life, and male mice were infertile. Alterations to T cell phenotypes were also observed, which intriguingly were both T cell intrinsic and extrinsic. Hypomorphic mice were also sensitive to infection with Salmonella, succumbing to a normally sublethal challenge. Despite these phenotypes, Fbxo7 hypomorphs were produced at a normal Mendelian ratio with a normal lifespan and no evidence of neurological symptoms. These data suggest that erythrocyte survival, T cell development and spermatogenesis are particularly sensitive to Fbxo7 gene dosage

The history, genome and biology of NCTC 30: a non-pandemic Vibrio cholerae isolate from World War One.

The sixth global cholera pandemic lasted from 1899 to 1923. However, despite widespread fear of the disease and of its negative effects on troop morale, very few soldiers in the British Expeditionary Forces contracted cholera between 1914 and 1918. Here, we have revived and sequenced the genome of NCTC 30, a 102-year-old Vibrio cholerae isolate, which we believe is the oldest publicly available live V. cholerae strain in existence. NCTC 30 was isolated in 1916 from a British soldier convalescent in Egypt. We found that this strain does not encode cholera toxin, thought to be necessary to cause cholera, and is not part of V. cholerae lineages responsible for the pandemic disease. We also show that NCTC 30, which predates the introduction of penicillin-based antibiotics, harbours a functional β-lactamase antibiotic resistance gene. Our data corroborate and provide molecular explanations for previous phenotypic studies of NCTC 30 and provide a new high-quality genome sequence for historical, non-pandemic V. cholerae

Genomics of the Argentinian cholera epidemic elucidate the contrasting dynamics of epidemic and endemic Vibrio cholerae

Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Abstract: In order to control and eradicate epidemic cholera, we need to understand how epidemics begin, how they spread, and how they decline and eventually end. This requires extensive sampling of epidemic disease over time, alongside the background of endemic disease that may exist concurrently with the epidemic. The unique circumstances surrounding the Argentinian cholera epidemic of 1992–1998 presented an opportunity to do this. Here, we use 490 Argentinian V. cholerae genome sequences to characterise the variation within, and between, epidemic and endemic V. cholerae. We show that, during the 1992–1998 cholera epidemic, the invariant epidemic clone co-existed alongside highly diverse members of the Vibrio cholerae species in Argentina, and we contrast the clonality of epidemic V. cholerae with the background diversity of local endemic bacteria. Our findings refine and add nuance to our genomic definitions of epidemic and endemic cholera, and are of direct relevance to controlling current and future cholera epidemics

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Organizational change and everyday health system resilience: Lessons from Cape Town, South Africa

This paper reports a study from Cape Town, South Africa, that tested an existing framework of everyday health system resilience (EHSR) in examining how a local health system responded to the chronic stress of large-scale organizational change. Over two years (2017–18), through cycles of action-learning involving local managers and researchers, the authorial team tracked the stress experienced, the response strategies implemented and their consequences. The paper considers how a set of micro-governance interventions and mid-level leadership practices supported responses to stress whilst nurturing organizational resilience capacities. Data collection involved observation, in-depth interviews and analysis of meeting minutes and secondary data. Data analysis included iterative synthesis and validation processes