Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing

Homology-dependent RNA silencing occurs in many eukaryotic cells. We reported recently that nodaviral infection triggers an RNA silencing-based antiviral response (RSAR) in Drosophila, which is capable of a rapid virus clearance in the absence of expression of a virus-encoded suppressor. Here, we present further evidence to show that the Drosophila RSAR is mediated by the RNA interference (RNAi) pathway, as the viral suppressor of RSAR inhibits experimental RNAi initiated by exogenous double-stranded RNA and RSAR requires the RNAi machinery. We demonstrate that RNAi also functions as a natural antiviral immunity in mosquito cells. We further show that vaccinia virus and human influenza A, B, and C viruses each encode an essential protein that suppresses RSAR in Drosophila. The vaccinia and influenza viral suppressors, E3L and NS1, are distinct double-stranded RNA-binding proteins and essential for pathogenesis by inhibiting the mammalian IFN-regulated innate antiviral response. We found that the double-stranded RNA-binding domain of NS1, implicated in innate immunity suppression, is both essential and sufficient for RSAR suppression. These findings provide evidence that mammalian virus proteins can inhibit RNA silencing, implicating this mechanism as a nucleic acid-based antiviral immunity in mammalian cells

Mapping Pediatric Oncology Clinical Trial Collaborative Groups on the Global Stage

The global pediatric oncology clinical research landscape, particularly in Central and South America, Africa, and Asia, which bear the highest burden of global childhood cancer cases, is less characterized in the literature. Review of how existing pediatric cancer clinical trial groups internationally have been formed and how their research goals have been pursued is critical for building global collaborative research and data-sharing efforts, in line with the WHO Global Initiative for Childhood Cancer. METHODS: A narrative literature review of collaborative groups performing pediatric cancer clinical research in each continent was conducted. An inventory of research groups was assembled and reviewed by current pediatric cancer regional and continental leaders. Each group was narratively described with identification of common structural and research themes among consortia. RESULTS: There is wide variability in the structure, history, and goals of pediatric cancer clinical trial collaborative groups internationally. Several continental regions have longstanding endogenously-formed clinical trial groups that have developed and published numerous adapted treatment regimens to improve outcomes, whereas other regions have consortia focused on developing foundational database registry infrastructure supported by large multinational organizations or twinning relationships. CONCLUSION: There cannot be a one-size-fits-all approach to increasing collaboration between international pediatric cancer clinical trial groups, as this requires a nuanced understanding of local stakeholders and resources necessary to form partnerships. Needs assessments, performed either by local consortia or in conjunction with international partners, have generated productive clinical trial infrastructure. To achieve the goals of the Global Initiative for Childhood Cancer, global partnerships must be sufficiently granular to account for the distinct needs of each collaborating group and should incorporate grassroots approaches, robust twinning relationships, and implementation science

Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial.

BackgroundInfluenza viruses cause substantial annual morbidity and mortality globally. Current vaccines protect against influenza only when well matched to the circulating strains. However, antigenic drift can cause considerable mismatches between vaccine and circulating strains, substantially reducing vaccine effectiveness. Moreover, current seasonal vaccines are ineffective against pandemic influenza, and production of a vaccine matched to a newly emerging virus strain takes months. Therefore, there is an unmet medical need for a broadly protective influenza virus vaccine. We aimed to test the ability of chimeric H1 haemagglutinin-based universal influenza virus vaccine candidates to induce broadly cross-reactive antibodies targeting the stalk domain of group 1 haemagglutinin-expressing influenza viruses.MethodsWe did a randomised, observer-blinded, phase 1 study in healthy adults in two centres in the USA. Participants were randomly assigned to one of three prime-boost, chimeric haemagglutinin-based vaccine regimens or one of two placebo groups. The vaccine regimens included a chimeric H8/1, intranasal, live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine on day 85; the same regimen but with the inactivated vaccine being adjuvanted with AS03; and an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine. In this planned interim analysis, the primary endpoints of reactogenicity and safety were assessed by blinded study group. We also assessed anti-H1 haemagglutinin stalk, anti-H2, anti-H9, and anti-H18 IgG antibody titres and plasmablast and memory B-cell responses in peripheral blood. This trial is registered with ClinicalTrials.gov, number NCT03300050.FindingsBetween Oct 10, 2017, and Nov 27, 2017, 65 participants were enrolled and randomly assigned. The adjuvanted inactivated vaccine, but not the live-attenuated vaccine, induced a substantial serum IgG antibody response after the prime immunisation, with a seven times increase in anti-H1 stalk antibody titres on day 29. After boost immunisation, all vaccine regimens induced detectable anti-H1 stalk antibody (2·2-5·6 times induction over baseline), cross-reactive serum IgG antibody, and peripheral blood plasmablast responses. An unsolicited adverse event was reported for 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 (48%) of 25 participants following prime vaccination with intramuscular study product or placebo, in 12 (33%) of 36 after prime immunisation with intranasal study product or placebo, and in 18 (32%) of 56 following booster doses of study product or placebo. Solicited systemic adverse events were reported in 14 (56%) of 25 after prime immunisation with intramuscular study product or placebo, in 22 (61%) of 36 after immunisation with intranasal study product or placebo, and in 21 (38%) of 56 after booster doses of study product or placebo. Disaggregated safety data were not available at the time of this interim analysis.InterpretationThe tested chimeric haemagglutinin-based, universal influenza virus vaccine regimens elicited cross-reactive serum IgG antibodies that targeted the conserved haemagglutinin stalk domain. This is the first proof-of-principle study to show that high anti-stalk titres can be induced by a rationally designed vaccine in humans and opens up avenues for further development of universal influenza virus vaccines. On the basis of the blinded study group, the vaccine regimens were tolerable and no safety concerns were observed.FundingBill & Melinda Gates Foundation

Fatal Cases of Influenza A(H3N2) in Children: Insights from Whole Genome Sequence Analysis

During the Northern Hemisphere winter of 2003–2004 the emergence of a novel influenza antigenic variant, A/Fujian/411/2002-like(H3N2), was associated with an unusually high number of fatalities in children. Seventeen fatal cases in the UK were laboratory confirmed for Fujian/411-like viruses. To look for phylogenetic patterns and genetic markers that might be associated with increased virulence, sequencing and phylogenetic analysis of the whole genomes of 63 viruses isolated from fatal cases and non fatal “control” cases was undertaken. The analysis revealed the circulation of two main genetic groups, I and II, both of which contained viruses from fatal cases. No associated amino acid substitutions could be linked with an exclusive or higher occurrence in fatal cases. The Fujian/411-like viruses in genetic groups I and II completely displaced other A(H3N2) viruses, but they disappeared after 2004. This study shows that two A(H3N2) virus genotypes circulated exclusively during the winter of 2003–2004 in the UK and caused an unusually high number of deaths in children. Host factors related to immune state and differences in genetic background between patients may also play important roles in determining the outcome of an influenza infection

The Self-Rating Scale of Self-Directed Learning tool: findings from a Confirmatory Factor Analysis

4Introduction: Healthcare students and professionals possess self-directed learning abilities at different levels of development. For educators, measuring these abilities allow to tailor teaching and mentoring interventions. The aim of this study was to validate the structure of the Self-Rating Scale of Self-Directed Learning, Italian version (SRSSDL-Ita). Methods: A cross-sectional study design was adopted involving a convenience sample of 593 healthcare students and professionals. A Confirmatory Factor Analysis was performed to confirm the validity of the measurement model of the original structure of the SRSSDL-Ita. Results: The Maximum Likelihood Meand-and-Variance (MLMV) to confirmatory factor analysis was used to examine the underlying latent variable structure of the SRSSDL-Ita, which was composed of 40 items. All standardized factor loadings were > 0.42. Latent dimensions were all positively correlated, ranging in magnitude between 0.28 and 0.78. The Chi-square value for the overall model was χ2 (712) = 1,104.273 with p < .001, Root Mean Square Error of Approximation (RMSEA) (90% confidence interval (CI)) = 0.031 (lower bound 0.027; upper bound 0.054) with p = 1.00, and Standardized Root Mean Square Residual (SRMR) = 0.055. The overall interpretation of the fit indices suggests a more than acceptable fit between the hypothesized model and the data. The emerged structure confirms the original structure of the instrument composed of eight factors: “Awareness”, “Attitudes”, “Motivation”, “Learning Strategies”, “Learning Methods”, “Learning Activities”, “Interpersonal Skills” and “Constructing Knowledge”. Conclusions: The SRSSDL-Ita structure was confirmed. Therefore, SRSSDL-Ita is a valid and practical tool that may contribute to determining learning needs among students and healthcare professionals; helping educators in identifying and implementing strategies to enhance SDL abilities in both groups.reservedmixedCadorin,Lucia; Ghezzi,Valerio; Camillo,Monica; Palese, AlvisaCadorin, Lucia; Ghezzi, Valerio; Camillo, Monica; Palese, Alvis

The concept of caring in nursing: results from a pilot research study

Background: International literature identifies many gaps in the concept of caring. Investigation is needed in order to understand how nurses and patients perceive caring. Aim: To examine and compare the concept of caring and individualized caring as perceived by patients and nurses, and to assess the levels of patient satisfaction with nursing care in 6 European countries. Method: In this study, which was the pilot phase of a larger project, 369 persons participated, 182 nurses and 187 patients, recruited by the convenience sampling process, in 6 European countries, Cyprus, Greece, Finland, Hungary, Italy and the Czech Republic. The response rate was 78.11% for nurses and 83.11% for patients. Data were collected from surgical units during May 2009. For the purpose of this study, three instruments were used: (a) the Caring Behaviors Inventory (CBI) which measures the frequency of the provided caring as perceived by both nurses and patients, (b) the Individualized Care Scale (ICS) which examines the support and provision of individualized care in two dimensions, ICS-A support, ICS-B provision, and (c) the Patient Satisfaction Scale (PSS) which examines the patients' satisfaction with the nursing care received. Descriptive statistics, t-test, chi-square and ANOVA were performed for analysis of the responses. The level of statistical significance was set at p<0.05. Results: Statistically significant difference between the views of patients and nurses was observed only for ICS-A (p=0.001), with nurses scoring higher than patients. The concept of individualized care was not supported by the nurses, although they reported that they offered it to the patients. The patients' satisfaction with the nursing care they received was reported high. Satisfaction with nursing care was significantly correlated with the frequency of the provision of nursing care (r=0.764, p<0.001), with the support of the idea of individualized care (r=0.674, p<0.001), and with receipt of individualized care (r=0.701, p<0.001). Conclusions: The study findings partially support reports in the relevant literature of differences between the perceptions of nurses and patients about care, general and individualised. They fully support previous findings that nursing caring behavior is highly correlated with patient satisfaction. The lack of such studies at the European and international level demonstrates the need for further analysis of this concept using larger samples

Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure

Despite the great effort of the scientific community in the field, the pathogenesis of frontotemporal dementia (FTD) remains elusive. Recently, a role for autoimmunity and altered glutamatergic neurotransmission in triggering disease onset has been put forward. We reported the presence of autoantibodies recognizing the GluA3 subunit of \u3b1-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in about 25% of FTD cases. In this study, we evaluated the mechanisms involved in anti-GluA3 autoimmunity, through molecular/neurochemical analyses conducted on patients' brain specimens with frontotemporal lobar degeneration-tau neuropathology. We then corroborated these results in&nbsp;vivo in FTD patients with transcranial magnetic stimulation and glutamate, D-serine, and L-serine dosages in the cerebrospinal fluid and serum. We observed that GluA3 autoantibodies affect glutamatergic neurotransmission, decreasing glutamate release and altering GluA3-containing \u3b1-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor levels. These alterations were accompanied by changes of scaffolding proteins involved in receptor synaptic retention/internalization. The above results were confirmed by transcranial magnetic stimulation, suggesting a significant impairment of indirect measures of glutamatergic neurotransmission in FTD patients compared with controls, with further add-on harmful effect in those FTD patients with anti-GluA3 antibodies. Finally, FTD patients showed a significant increase of glutamate, D-serine, and L-serine levels in the cerebrospinal fluid

Lo sciopero degli infermieri nel Regno Unito: le ragioni, il dibattito e le implicazioni

Unlabelled: . The nurses' strike in the United Kingdom: an overview of the reasons, debate and implications. Introduction: In the UK, where the National Health Service (NHS) was founded, one of the most important and long-lasting strikes in nursing is taking place. Aim: To understand the historical, professional, political/social reasons for the UK nurse's strike. Method: Historical, scientific literature and data from key informant interviews have been analysed. Data has been summarized narratively. Results: On 15th December 2022, more than 100,000 NHS nurses went on strike in England, Northern Ireland, and Wales asking for an increased salary; on the 6th and 7th of February and 1st of March the protest has continued. By improving pay, nurses believe the attractiveness of the profession can increase and counteract the loss of nurses who are leaving the public for the private sector, and the lack of attractiveness of the profession towards young people. The strike is organized by the Royal College of Nursing in a structured form which gives nurses precise information on how it should be explained to patients: according to a survey, 79% of the population supports the nurses' strike. However, not all agree with this strike action. Discussion: The media, social media and professional debate is passionate with some polarization between who is in favor and who is against. Nurses strike not only for better wages but also to increase patient safety. What we see in the UK today is the result of years of austerity, lack of investment and health priorities: a similar situation experienced in several countries as well