Influenza virus protecting RNA : an effective prophylactic and therapeutic antiviral

Another influenza pandemic is inevitable, and new measures to combat this and seasonal influenza are urgently needed. Here we describe a new concept in antivirals based on a defined, naturally occurring defective influenza RNA that has the potential to protect against any influenza A virus in any animal host. This protecting RNA (244 RNA) is incorporated into virions which although non-infectious, deliver the RNA to those cells of the respiratory tract that are naturally targeted by infectious influenza virus. A small intranasal dose of this 244 protecting virus (120 ng) completely protected mice against a simultaneous lethal (10 LD50) challenge with influenza A/WSN (H1N1) virus. 244 virus also protected mice against a strong challenge dose of all other subtypes tested (H2N2, H3N2, H3N8). This prophylactic activity was maintained in the animal for at least 1 week prior to challenge. 244 virus was 10 to 100-fold more active than previously characterised influenza A defective viruses, and the protecting activity was confirmed to reside in the 244 RNA molecule by recovering a protecting virus entirely from cloned cDNA. There was clear therapeutic benefit when protecting 244 virus was administered 24-48 h after lethal challenge, an effect which has not been previously observed with any defective virus. Protecting virus reduced, but did not abolish, replication of challenge virus in mouse lungs during both prophylactic and therapeutic treatments. Protecting virus is a novel antiviral which has the potential to combat influenza infections in humans, particularly when the infecting strain is not known, or is resistant to antiviral drugs

Trigeneration in food retail: An energetic, economic and environmental evaluation for a supermarket application; Applied Thermal Engineering

This paper presents results on the evaluation of energy utilisation efficiency and economic and environmental performance of a micro-gas turbine (MGT) based trigeneration system for supermarket applications. A spreadsheet energy model has been developed for the analysis of trigeneration systems and a 2800 m2 sales area supermarket was selected for the feasibility study. Historical energy demand data were used for the analysis, which considered factors such as the fraction of the heat output used to drive the absorption chillers, the chiller COP and the difference between electricity and gas prices. The results showed that energy and environmental benefits can be obtained from the application of trigeneration systems to supermarkets compared to conventional systems. The payback period of natural gas driven trigeneration systems and greenhouse gas emissions savings will depend on the relative gas and electricity prices and the COP of the vapour compression and absorption systems. It was also shown that operation at full electrical output gives a better performance than a heat load-following strategy due to the reduction of the electrical generation efficiency of the MGT unit at part load conditions

Cloned defective interfering influenza virus protects ferrets from pandemic 2009 influenza A virus and allows protective immunity to be established

Influenza A viruses are a major cause of morbidity and mortality in the human population, causing epidemics in the winter, and occasional worldwide pandemics. In addition there are periodic outbreaks in domestic poultry, horses, pigs, dogs, and cats. Infections of domestic birds can be fatal for the birds and their human contacts. Control in man operates through vaccines and antivirals, but both have their limitations. In the search for an alternative treatment we have focussed on defective interfering (DI) influenza A virus. Such a DI virus is superficially indistinguishable from a normal virus but has a large deletion in one of the eight RNAs that make up the viral genome. Antiviral activity resides in the deleted RNA. We have cloned one such highly active DI RNA derived from segment 1 (244 DI virus) and shown earlier that intranasal administration protects mice from lethal disease caused by a number of different influenza A viruses. A more cogent model of human influenza is the ferret. Here we found that intranasal treatment with a single dose of 2 or 0.2 µg 244 RNA delivered as A/PR/8/34 virus particles protected ferrets from disease caused by pandemic virus A/California/04/09 (A/Cal; H1N1). Specifically, 244 DI virus significantly reduced fever, weight loss, respiratory symptoms, and infectious load. 244 DI RNA, the active principle, was amplified in nasal washes following infection with A/Cal, consistent with its amelioration of clinical disease. Animals that were treated with 244 DI RNA cleared infectious and DI viruses without delay. Despite the attenuation of infection and disease by DI virus, ferrets formed high levels of A/Cal-specific serum haemagglutination-inhibiting antibodies and were solidly immune to rechallenge with A/Cal. Together with earlier data from mouse studies, we conclude that 244 DI virus is a highly effective antiviral with activity potentially against all influenza A subtypes

Breastfeeding, the use of docosahexaenoic acid-fortified formulas in infancy and neuropsychological function in childhood

OBJECTIVE: To investigate the relation between breastfeeding, use of docosahexaenoic acid (DHA)-fortified formula and neuropsychological function in children. DESIGN: Prospective cohort study. SETTING: Southampton, UK. SUBJECTS: 241 children aged 4 years followed up from birth. MAIN OUTCOME MEASURES: IQ measured by the Wechsler Pre-School and Primary Scale of Intelligence (3rd edn), visual attention, visuomotor precision, sentence repetition and verbal fluency measured by the NEPSY, and visual form-constancy measured by the Test of Visual-Perceptual Skills (Non-Motor). RESULTS: In unadjusted analyses, children for whom breast milk or DHA-fortified formula was the main method of feeding throughout the first 6 months of life had higher mean full-scale and verbal IQ scores at age 4 years than those fed mainly unfortified formula. After adjustment for potential confounding factors, particularly maternal IQ and educational attainment, the differences in IQ between children in the breast milk and unfortified formula groups were severely attenuated, but children who were fed DHA-fortified formula had full-scale and verbal IQ scores that were respectively 5.62 (0.98 to 10.2) and 7.02 (1.56 to 12.4) points higher than children fed unfortified formula. However, estimated total intake of DHA in milk up to age 6 months was not associated with subsequent IQ or with score on any other test. CONCLUSIONS: Differences in children's intelligence according to type of milk fed in infancy may be due more to confounding by maternal or family characteristics than to the amount of long-chain polyunsaturated fatty acids they receive in milk

Analysis of the profile, characteristics, patient experience and community value of community hospitals : a multimethod study

Background: Community hospitals have been part of England’s health-care landscape since the mid-nineteenth century. Evidence on them has not kept pace with their development. Aim: To provide a comprehensive analysis of the profile, characteristics, patient experience and community value of community hospitals. Design: A multimethod study with three phases. Phase one involved national mapping and the construction of a new database of community hospitals through data set reconciliation and verification. Phase two involved nine case studies, including interviews and focus groups with patients (n = 60), carers (n = 28), staff (n = 132), volunteers (n = 68), community stakeholders (n = 74) and managers and commissioners (n = 9). Phase three involved analysis of Charity Commission data on voluntary support. Setting: Community hospitals in England. Results: The study identified 296 community hospitals with beds in England. Typically, the hospitals were small (<30 beds), in rural communities, led by doctors/general practitioners (GPs) and nurses, without 24/7 on-site medical cover, providing step-down and step-up inpatient care, with an average length of stay of <30 days and a variable range of intermediate care services. Key to patients’ and carers’ experiences of community hospitals was their closeness to ‘home’ through their physical location, environment and atmosphere and the relationships that they support; their provision of personalised, holistic care; and their role in supporting patients through difficult psychological transitions. Communities engage with and support their hospitals through giving time (average = 24 volunteers), raising money (median voluntary income = £15,632), providing services (voluntary and community groups) and giving voice (e.g. communication and consultation). This can contribute to hospital utilisation and sustainability, patient experience, staff morale and volunteer well-being. Engagement varies between and within communities and over time. Community hospitals are important community assets, representing direct and indirect value: instrumental (e.g. health care), economic (e.g. employment), human (e.g. skills development), social (e.g. networks), cultural (e.g. identity and belonging) and symbolic (e.g. vitality and security). Value varies depending on place and time. Limitations: There were limitations to the secondary data available for mapping community hospitals and tracking charitable funds and to our sample of case study respondents, which concentrated on people with a connection to the hospitals. Conclusions: Community hospitals are diverse but are united by a set of common characteristics. Patients and carers experience community hospitals as qualitatively different from other settings. Their accounts highlight the importance of considering the functional, interpersonal, social and psychological dimensions of experience. Community hospitals are highly valued by their local communities, as demonstrated through their active involvement as volunteers and donors. Community hospitals enable the provision of local intermediate care services, delivered through an embedded, relational model of care, which generates deep feelings of reassurance. However, current developments, including the withdrawal of GPs, shifts towards step-down care for non-local patients and changing configurations of services, providers and ownership may undermine this. Future work: Comparative studies of patient experience in different settings, longitudinal studies of community support and value, studies into the implications of changes in community hospital function, GP involvement, provider-mix and ownership and international comparative studies could all be undertaken

Indigenous Resilience in Australia: A Scoping Review Using a Reflective Decolonizing Collective Dialogue

Contemporary definitions and understandings of resilience refer to an individual's positive adaptation to the experience of adversity. One of the challenges of this extant body of work is that the central concept of resilience is rarely questioned. Current understandings of these concepts, largely framed in Western understandings, are unquestioningly accepted, reframed for, yet not by, Indigenous peoples, and then are unchallenged when imposed on Indigenous peoples. A scoping review was conducted and reported in line with the PRISMA-ScR guidelines. The review involved the participation of local Aboriginal Research Cultural Advisory Groups who participated and approved the analysis of the findings and collaborated on the design and writing of the paper. Eight publications drew on Aboriginal constructs of resilience in examining the effectiveness of programs, processes, and practices to promote individual and/or collective resilience and well-being. Most studies emphasized the need for strategies to strengthen individual or community connection to culture to foster resilience. Six studies used culturally validated strength-based tools to measure resilience, while two relied on Western constructs. This review reveals both the distinctive colonial characteristics of adversity experienced by Aboriginal people and the range of coping strategies and protective resources that support the development of resilience within different Aboriginal communities in diverse research sites across Australia. Importantly, many studies confirm adversity is linked to the enduring legacies of colonization, continuous and cumulative transgenerational grief and loss, structural inequities, racism, and discrimination. These external factors of adversity are unique to Aboriginal populations, as are the protective factors that entail strengthening connection to culture (including language reclamation), community, ancestry and land (including management and economic development) which contribute to individual and collective resilience. These findings suggest that Aboriginal community resilience is strengthened through the collective experience of adversity, such as transgenerational grief and loss, and the resulting support structures and shared resources that are developed and maintained through cultural practices to strengthen the bonds and mutual reciprocity to participate in transformative strategies to address adversity. This review highlights that strategies such as building on community strengths, capacities, and resources is critical when strengthening resilience within Indigenous communities across Australia

A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

Please mind the gap: students’ perspectives of the transition in academic skills between A-level and degree level geography

This paper explores first-year undergraduates’ perceptions of the transition from studying geography at pre-university level to studying for a degree. This move is the largest step students make in their education, and the debate about it in the UK has been reignited due to the government’s planned changes to A-level geography. However, missing from most of this debate is an appreciation of the way in which geography students themselves perceive their transition to university. This paper begins to rectify this absence. Using student insights, we show that their main concern is acquiring the higher level skills required for university learning

History-sensitive accumulation rules for life-time prediction under variable loading

This is the post-print version of the article. The official published version can be obtained from the link below - Copyright @ 2011 SpringerA general form of temporal strength conditions under variable creep loading is employed to formulate several new phenomenological accumulation rules based on the constant-loading durability diagram. Unlike the well-known Robinson rule of linear accumulation of partial life-times, the new rules allow to describe the life-time sensibility to the load sequence, observed in experiments. Comparison of the new rules with experimental data shows that they fit the data much more accurately than the Robinson rule