Overcoming barriers in viral vector manufacturing: Small molecule targeting of antiviral defences

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Direct comparison of distinct naive pluripotent states in human embryonic stem cells

Until recently, human embryonic stem cells (hESCs) were shown to exist in a state of primed pluripotency, while mouse embryonic stem cells (mESCs) display a naive or primed pluripotent state. Here we show the rapid conversion of in-house-derived primed hESCs on mouse embryonic feeder layer (MEF) to a naive state within 5-6 days in naive conversion media (NCM-MEF), 6-10 days in naive human stem cell media (NHSM-MEF) and 14-20 days using the reverse-toggle protocol (RT-MEF). We further observe enhanced unbiased lineage-specific differentiation potential of naive hESCs converted in NCM-MEF, however, all naive hESCs fail to differentiate towards functional cell types. RNA-seq analysis reveals a divergent role of PI3K/AKT/mTORC signalling, specifically of the mTORC2 subunit, in the different naive hESCs. Overall, we demonstrate a direct evaluation of several naive culture conditions performed in the same laboratory, thereby contributing to an unbiased, more in-depth understanding of different naive hESCs

Personality judgments from everyday images of faces

The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: an ESRC studentship [ES/I900748/1] and postdoctoral research support from the Australian Research Council Centre of Excellence in Cognition and its Disorders, University of Western Australia (CE110001021), to the first author. The work was completed while the first author was at the University of York, UK. We thank Richard Vernon for calculating the attributes used in Study 2.Peer reviewedPublisher PD

Chronic testicular Chlamydia muridarum infection impairs mouse fertility and offspring development

With approximately 131 million new genital tract infections occurring each year, Chlamydia is the most common sexually transmitted bacterial pathogen worldwide. Male and female infections occur at similar rates and both cause serious pathological sequelae. Despite this, the impact of chlamydial infection on male fertility has long been debated, and the effects of paternal chlamydial infection on offspring development are unknown. Using a male mouse chronic infection model, we show that chlamydial infection persists in the testes, adversely affecting the testicular environment. Infection increased leukocyte infiltration, disrupted the blood:testis barrier and reduced spermiogenic cell numbers and seminiferous tubule volume. Sperm from infected mice had decreased motility, increased abnormal morphology, decreased zona-binding capacity, and increased DNA damage. Serum anti-sperm antibodies were also increased. When both acutely and chronically infected male mice were bred with healthy female mice, 16.7% of pups displayed developmental abnormalities. Female offspring of chronically infected sires had smaller reproductive tracts than offspring of noninfected sires. The male pups of infected sires displayed delayed testicular development, with abnormalities in sperm vitality, motility, and sperm-oocyte binding evident at sexual maturity. These data suggest that chronic testicular Chlamydia infection can contribute to male infertility, which may have an intergenerational impact on sperm quality

What influences people’s responses to public health messages for managing risks and preventing infectious diseases? A rapid systematic review of the evidence and recommendations

Background: Individual behaviour changes, such as hand hygiene and physical distancing, are required on a population scale to reduce transmission of infectious diseases such as COVID-19. However, little is known about effective methods of communicating risk reducing information, and how populations might respond. Objective: To synthesise evidence relating to what (1) characterises effective public health messages for managing risk and preventing infectious disease and (2) influences people’s responses to messages. Design: A rapid systematic review was conducted. Protocol is published on Prospero CRD42020188704. Data sources: Electronic databases were searched: Ovid Medline, Ovid PsycINFO and Healthevidence. org, and grey literature (PsyarXiv, OSF Preprints) up to May 2020. Study selection: All study designs that (1) evaluated public health messaging interventions targeted at adults and (2) concerned a communicable disease spread via primary route of transmission of respiratory and/or touch were included. Outcomes included preventative behaviours, perceptions/awareness and intentions. Non-English language papers were excluded. Synthesis: Due to high heterogeneity studies were synthesised narratively focusing on determinants of intentions in the absence of measured adherence/ preventative behaviours. Themes were developed independently by two researchers and discussed within team to reach consensus. Recommendations were translated from narrative synthesis to provide evidence-based methods in providing effective messaging. Results: Sixty-eight eligible papers were identified. Characteristics of effective messaging include delivery by credible sources, community engagement, increasing awareness/knowledge, mapping to stage of epidemic/ pandemic. To influence intent effectively, public health messages need to be acceptable, increase understanding/perceptions of health threat and perceived susceptibility. Discussion: There are four key recommendations: (1) engage communities in development of messaging, (2) address uncertainty immediately and with transparency, (3) focus on unifying messages from sources and (4) frame messages aimed at increasing understanding, social responsibility and personal control. Embedding principles of behavioural science into public health messaging is an important step towards more effective health-risk communication during epidemics/pandemics

A rapid systematic review of public responses to health messages encouraging vaccination against infectious diseases in a pandemic or epidemic

Public health teams need to understand how the public responds to vaccination messages in a pandemic or epidemic to inform successful campaigns encouraging the uptake of new vaccines as they become available. A rapid systematic review was performed by searching PsycINFO, MED-LINE, healthevidence.org, OSF Preprints and PsyArXiv Preprints in May 2020 for studies including at least one health message promoting vaccine uptake of airborne-, droplet-and fomite-spread vi-ruses. Included studies were assessed for quality using the Mixed Methods Appraisal Tool (MMAT) or the Assessment of Multiple Systematic Reviews (AMSTAR), and for patient and public involvement (PPI) in the research. Thirty-five articles were included. Most reported messages for seasonal influenza (n = 11; 31%) or H1N1 (n = 11; 31%). Evidence from moderate to high quality studies for improving vaccine uptake included providing information about virus risks and vaccination safety, as well as addressing vaccine misunderstandings, offering vaccination reminders, including vaccination clinic details, and delivering mixed media campaigns across hospitals or communities. Behavioural influences (beliefs and intentions) were improved when: shorter, risk-reducing or relative risk framing messages were used; the benefits of vaccination to society were emphasised; and beliefs about capability and concerns among target populations (e.g., vaccine safety) were addressed. Clear, credible, messages in a language target groups can understand were associated with higher accept-ability. Two studies (6%) described PPI in the research process. Future campaigns should consider the beliefs and information needs of target populations in their design, including ensuring that vaccine eligibility and availability is clear, and messages are accessible. More high quality research is needed to demonstrate the effects of messaging interventions on actual vaccine uptake

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Alien Registration- Leavitt, Ella W. (Eastport, Washington County)

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