Communicating Uncertainty During Public Health Emergency Events:A Systematic Review

To answer the question, "What are the best ways to communicate uncertainties to public audiences, at-risk communities, and stakeholders during public health emergency events?" we conducted a systematic review of published studies, grey literature, and media reports in English and other United Nations (UN) languages: Arabic, Chinese, French, Russian, and Spanish. Almost 11,500 titles and abstracts were scanned of which 46 data-based primary studies were selected, which were classified into four methodological streams: Quantitative-comparison groups; Quantitative-descriptive survey; Qualitative; and Mixed-method and case-study. Study characteristics (study method, country, emergency type, emergency phase, at-risk population) and study findings (in narrative form) were extracted from individual studies. The findings were synthesized within methodological streams and evaluated for certainty and confidence. These within-method findings were next synthesized across methodological streams to develop an overarching synthesis of findings. The findings showed that country coverage focused on high and middle-income countries in Asia, Europe, North America, and Oceania, and the event most covered was infectious disease followed by flood and earthquake. The findings also showed that uncertainty during public health emergency events is a multi-faceted concept with multiple components (e.g., event occurrence, personal and family safety, recovery efforts). There is universal agreement, with some exceptions, that communication to the public should include explicit information about event uncertainties, and this information must be consistent and presented in an easy to understand format. Additionally, uncertainty related to events requires a distinction between uncertainty information and uncertainty experience. At-risk populations experience event uncertainty in the context of many other uncertainties they are already experiencing in their lives due to poverty. Experts, policymakers, healthcare workers, and other stakeholders experience event uncertainty and misunderstand some uncertainty information (e.g., event probabilities) similar to the public. Media professionals provide event coverage under conditions of contradictory and inconsistent event information that can heighten uncertainty experience for all

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Functional analysis of germ cell less during germ cell formation and specification in Drosophila melanogaster embryos

Transcriptional quiescence is an evolutionarily conserved trait that distinguishes the embryonic Primordial Germ Cells (PGCs) from their somatic neighbors. In Drosophila melanogaster embryos, Germ cell less (Gcl) protein is required for proper pole cell formation and the establishment and maintenance of transcriptional quiescence in PGCs. Thus, PGCs from germ cell less (gcl) embryos ectopically express several somatic genes including two x-linked numerator elements, sisterless-A (sisA) and sisterless-B (sisB). These two proteins are shown to activate transcription of Sex-lethal (Sxl), a sex-determination gene that orchestrates female identity in the somatic nuclei. Importantly, wild type (WT) pole cells from blastoderm stage embryos do not express Sxl and are naïve with respect to their sexual identity. Here, we have examined Sxl expression in gcl PGCs. Consistent with precocious activation of numerator elements, Sxl is inappropriately activated on a transcriptional level and in a sex-nonspecific manner in gcl PGCs. Reciprocally, ectopic expression of gcl in the soma is sufficient to inhibit Sxl expression. Precocious expression of Sxl in PGCs results in consistent reduction in the number of PGCs in early embryos and disrupts their migration during mid-embryogenesis. Supporting the conclusion that Sxl is a critical target of Gcl, simultaneous removal of Sxl and gcl mitigates the loss of PGCs observed in gcl embryos. These observations underscore the biological relevance of transcriptional quiescence in the embryonic PGCs and establish Sxl, the master determinant of female somatic fate, as a critical target of silencing mechanisms in PGCs. Finally, considering the findings of two recent papers, we propose two possible models for the activity initiated by Gcl

Functional analysis of germ cell less during germ cell formation and specification in Drosophila melanogaster embryos

Transcriptional quiescence is an evolutionarily conserved trait that distinguishes the embryonic Primordial Germ Cells (PGCs) from their somatic neighbors. In Drosophila melanogaster embryos, Germ cell less (Gcl) protein is required for proper pole cell formation and the establishment and maintenance of transcriptional quiescence in PGCs. Thus, PGCs from germ cell less (gcl) embryos ectopically express several somatic genes including two x-linked numerator elements, sisterless-A (sisA) and sisterless-B (sisB). These two proteins are shown to activate transcription of Sex-lethal (Sxl), a sex-determination gene that orchestrates female identity in the somatic nuclei. Importantly, wild type (WT) pole cells from blastoderm stage embryos do not express Sxl and are naïve with respect to their sexual identity. Here, we have examined Sxl expression in gcl PGCs. Consistent with precocious activation of numerator elements, Sxl is inappropriately activated on a transcriptional level and in a sex-nonspecific manner in gcl PGCs. Reciprocally, ectopic expression of gcl in the soma is sufficient to inhibit Sxl expression. Precocious expression of Sxl in PGCs results in consistent reduction in the number of PGCs in early embryos and disrupts their migration during mid-embryogenesis. Supporting the conclusion that Sxl is a critical target of Gcl, simultaneous removal of Sxl and gcl mitigates the loss of PGCs observed in gcl embryos. These observations underscore the biological relevance of transcriptional quiescence in the embryonic PGCs and establish Sxl, the master determinant of female somatic fate, as a critical target of silencing mechanisms in PGCs. Finally, considering the findings of two recent papers, we propose two possible models for the activity initiated by Gcl