The Specificity of Rabies Virus RNA Encapsidation by Nucleoprotein

AbstractRabies virus nucleoprotein (N) encapsidates negative-strand genomic RNAin vivo,and this RNA–N complex, together with the nominal viral phosphoprotein (P) and RNA polymerase (L), forms the active cytoplasmic ribonucleoprotein (RNP) complex in virus-infected cells and the RNP core in virus particles. The RNP complex is capable of initiating viral RNA transcription and replicationin vivoandin vitro.To obtain insight into the events leading to the formation of the RNA–N complex, we have investigated the interaction between rabies virus N and the positive-strand leader RNA transcript. Binding studies revealed that recombinant N binds preferentially to rabies virus leader RNA and that N binding to leader RNA was 5 to 10 times stronger than to nonleader RNA. Encapsidation of leader RNA by N could be competetively inhibited by unlabeled leader RNA but not by nonleader RNA. Furthermore, N protein encapsidation of nonleader RNA but not the leader RNA was inhibited when P was simultaneously added into the encapsidation reaction, indicating that P helps confer the specificity of leader RNA encapsidation by N. The initiation signal for leader RNA encapsidation by N has been mapped to nucleotides 20–30 of the RNA sequence which is A rich. Studies with N-deletion mutants indicate that the intact N is required to encapsidate RNA, since deletion of amino acid residues from either the N- or the C-terminus of N abolishes the ability of N to encapsidate leader RNA

Developing standards for reporting implementation studies of complex interventions (StaRI): a systematic review and e-Delphi

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Use of Medicare claims to rank hospitals by surgical site infection risk following coronary artery bypass graft surgery

ObjectiveTo evaluate whether longitudinal insurer claims data allow reliable identification of elevated hospital surgical site infection (SSI) rates.DesignWe conducted a retrospective cohort study of Medicare beneficiaries who underwent coronary artery bypass grafting (CABG) in US hospitals performing at least 80 procedures in 2005. Hospitals were assigned to deciles by using case mix-adjusted probabilities of having an SSI-related inpatient or outpatient claim code within 60 days of surgery. We then reviewed medical records of randomly selected patients to assess whether chart-confirmed SSI risk was higher in hospitals in the worst deciles compared with the best deciles.ParticipantsFee-for-service Medicare beneficiaries who underwent CABG in these hospitals in 2005.ResultsWe evaluated 114,673 patients who underwent CABG in 671 hospitals. In the best decile, 7.8% (958/12,307) of patients had an SSI-related code, compared with 24.8% (2,747/11,068) in the worst decile ([Formula: see text]). Medical record review confirmed SSI in 40% (388/980) of those with SSI-related codes. In the best decile, the chart-confirmed annual SSI rate was 3.2%, compared with 9.4% in the worst decile, with an adjusted odds ratio of SSI of 2.7 (confidence interval, 2.2-3.3; [Formula: see text]) for CABG performed in a worst-decile hospital compared with a best-decile hospital.ConclusionsClaims data can identify groups of hospitals with unusually high or low post-CABG SSI rates. Assessment of claims is more reproducible and efficient than current surveillance methods. This example of secondary use of routinely recorded electronic health information to assess quality of care can identify hospitals that may benefit from prevention programs

Negative regulation of autoimmune demyelination by the inhibitory receptor CLM-1

Multiple sclerosis and its preclinical model, experimental autoimmune encephalomyelitis, are marked by perivascular inflammation and demyelination. Myeloid cells, derived from circulating progenitors, are a prominent component of the inflammatory infiltrate and are believed to directly contribute to demyelination and axonal damage. How the cytotoxic activity of these myeloid cells is regulated is poorly understood. We identify CMRF-35–like molecule-1 (CLM-1) as a negative regulator of autoimmune demyelination. CLM-1 is expressed on inflammatory myeloid cells present in demyelinating areas of the spinal cord after immunization of mice with MOG35-55 (myelin oligodendrocyte glycoprotein) peptide. Absence of CLM-1 resulted in significantly increased nitric oxide and proinflammatory cytokine production, along with increased demyelination and worsened clinical scores, whereas T cell responses in the periphery or in the spinal cord remained unaffected. This study thus identifies CLM-1 as a negative regulator of myeloid effector cells in autoimmune demyelination

Older women's reduced contact with food in the Changes Around Food Experience (CAFE) study: choices, adaptations and dynamism

Many older women reduce the amount of cooking and food preparation they do in later life. While cooking may be seen as traditionally associated with women's family roles, little is known about the impact of such reduced engagement with food on their lives. This paper presents the findings from a one-year qualitative study (Changes Around Food Experience, CAFE) of the impact of reduced contact with preparing and cooking meals from scratch for 40 women, aged 65–95 years, living in Norfolk, United Kingdom. Data were collected through semi-structured interviews, focus groups and observations. Women's reasons for reducing food-related activities included changes in health, loss of a partner or a caring role, and new patterns of socialising. Disengagement from cooking and shopping was not found to entail predominantly negative feelings, passive acceptance or searching for forms of support to re-enable more cooking from scratch. Accounts evidenced the dynamic adaptability of older women in actively managing changed relationships with food. In exploring new meal options, older women were not simply disengaging from their environments. CAFE findings linked women's engagement with their environments to how they were using formal services and, even more, to the value they placed on social engagement and being out and about. Through the connections they fostered with friends, family and community, older women actively enabled their continued involvement in their social, public and family spheres. Reduced contact with preparing and cooking meals from scratch, therefore, did not induce or imply passivity or debility in the CAFE cohort. By contrast, it involved their exploring new means of retaining what was important to them about food in the context of their lived situation and social connections with friends, family, the community and public spheres

The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies.

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting

Supporting young women to have smokefree pregnancies - BabyBe Smokefree

Background and challenges to implementation Given the damage that tobacco smoke can have on the unborn child and the high associated costs, it is critical that rates of smoking in pregnancy are reduced. Current pathways for supporting pregnant smokers are not meeting the needs of some of the youngest and most vulnerable women as evidenced by the low rate of uptake of support and the high rate of young women who smoke throughout their pregnancy. Intervention or response Two insight-driven projects were undertaken in three diverse areas across England. The intervention was to facilitate a better understanding of young women drivers and barriers to changing behaviour and develop asset-based approaches which encourage and enable young women aged between 16 and 24 to have pregnancies that are free from tobacco use. Results and lessons learnt The projects provided a better understanding of: · Their experiences of being pregnant and of smoking during pregnancy. · The real barriers to quitting. · What or who they would turn to if they wanted support and how they want to quit. · Their expectations of health professionals. · What information they want, how and from whom. · Trusted messengers - who they want to trust and when/why they can't · Influences on choice. · View to risk and how it's measured. · Clear thoughts on what would work and outline of the delivered intervention. Conclusions and key recommendations An insights driven approach can: · Positively impact on the commissioning and provision of evidence based support for young vulnerable women · Influence the design of interventions and professional practice to better meet the needs of target populations

Proxy purchasing - a project to determine the awareness of the public in England of a new offence and improve practice

Background and challenges to implementation The introduction of an offence for proxy purchasing of tobacco in England in 2015 was well received as a means of tackling the supply of tobacco to young people. The offence of a proxy purchase is committed by the adult that buys the tobacco product on behalf of the young person under 18 years, not the retailer that sells the product. It is not a straightforward matter for Regulatory Services to investigate or to take enforcement action on. Little data was available to indicate the scale of the problem or how aware adults were of the offence. Intervention or response The project gathered insights around knowledge of the law regarding proxy purchasing; how behaviours had changed; how awareness and compliance could be improved and how communities can be encouraged to support compliance. Insight gathering was carried out systematically in two geographic areas among selected groups of the population. This method was positively received and generated additional information on other related issues. Results and lessons learnt The results revealed that the term a proxy purchase was not recognised by the great majority of participants; the majority of participants had experienced young people asking an adult to purchase cigarettes; proxy purchasing was seen very negatively but legislation was generally not the reason why people would not proxy purchase. It was widely recognised that proxy purchasing was only one way young people obtain tobacco. There was discussion with those interviewed about the relative risks of the ways young people obtain tobacco. Participants identified a variety of ways of informing local communities. Including targeting specific groups to ensure that individuals received relevant information in appropriate formats. Conclusions and key recommendations When planning future actions to ensure compliance with the proxy purchasing legislation, consideration must be given to the likelihood of any unintended consequences