Hesitancy for receiving regular SARS-CoV-2 vaccination in UK healthcare workers: a cross-sectional analysis from the UK-REACH study

BACKGROUND: Regular vaccination against SARS-CoV-2 may be needed to maintain immunity in 'at-risk' populations, which include healthcare workers (HCWs). However, little is known about the proportion of HCWs who might be hesitant about receiving a hypothetical regular SARS-CoV-2 vaccination or the factors associated with this hesitancy. METHODS: Cross-sectional analysis of questionnaire data collected as part of UK-REACH, a nationwide, longitudinal cohort study of HCWs. The outcome measure was binary, either a participant indicated they would definitely accept regular SARS-CoV-2 vaccination if recommended or they indicated some degree of hesitancy regarding acceptance (probably accept or less likely). We used logistic regression to identify factors associated with hesitancy for receiving regular vaccination. RESULTS: A total of 5454 HCWs were included in the analysed cohort, 23.5% of whom were hesitant about regular SARS-CoV-2 vaccination. Black HCWs were more likely to be hesitant than White HCWs (aOR 2.60, 95%CI 1.80-3.72) as were those who reported a previous episode of COVID-19 (1.33, 1.13-1.57 [vs those who tested negative]). Those who received influenza vaccination in the previous two seasons were over five times less likely to report hesitancy for regular SARS-CoV-2 vaccination than those not vaccinated against influenza in either season (0.18, 0.14-0.21). HCWs who trusted official sources of vaccine information (such as NHS or government adverts or websites) were less likely to report hesitancy for a regular vaccination programme. Those who had been exposed to information advocating against vaccination from friends and family were more likely to be hesitant. CONCLUSIONS: In this study, nearly a quarter of UK HCWs were hesitant about receiving a regular SARS-CoV-2 vaccination. We have identified key factors associated with hesitancy for regular SARS-CoV-2 vaccination, which can be used to identify groups of HCWs at the highest risk of vaccine hesitancy and tailor interventions accordingly. Family and friends of HCWs may influence decisions about regular vaccination. This implies that working with HCWs and their social networks to allay concerns about SARS-CoV-2 vaccination could improve uptake in a regular vaccination programme. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN11811602

Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2

Congenital hereditary endothelial dystrophy 1 (CHED1) and posterior polymorphous corneal dystrophy 1 (PPCD1) are autosomal-dominant corneal endothelial dystrophies that have been genetically mapped to overlapping loci on the short arm of chromosome 20. We combined genetic and genomic approaches to identify the cause of disease in extensive pedigrees comprising over 100 affected individuals. After exclusion of pathogenic coding, splice-site, and copy-number variations, a parallel approach using targeted and whole-genome sequencing facilitated the identification of pathogenic variants in a conserved region of the OVOL2 proximal promoter sequence in the index families (c.−339_361dup for CHED1 and c.−370T>C for PPCD1). Direct sequencing of the OVOL2 promoter in other unrelated affected individuals identified two additional mutations within the conserved proximal promoter sequence (c.−274T>G and c.−307T>C). OVOL2 encodes ovo-like zinc finger 2, a C2H2 zinc-finger transcription factor that regulates mesenchymal-to-epithelial transition and acts as a direct transcriptional repressor of the established PPCD-associated gene ZEB1. Interestingly, we did not detect OVOL2 expression in the normal corneal endothelium. Our in vitro data demonstrate that all four mutated OVOL2 promoters exhibited more transcriptional activity than the corresponding wild-type promoter, and we postulate that the mutations identified create cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during endothelial cell development. Our data establish CHED1 and PPCD1 as allelic conditions and show that CHED1 represents the extreme of what can be considered a disease spectrum. They also implicate transcriptional dysregulation of OVOL2 as a common cause of dominantly inherited corneal endothelial dystrophies

Evaluation of<em> Galleria mellonella</em> larvae for measuring the efficacy and pharmacokinetics of antibiotic therapies versus <em>Pseudomonas aeruginosa</em> infection.

The aim of the study was to determine if Galleria mellonella larvae can be used: (i) as an in vivo infection model for Pseudomonas aeruginosa, and (ii) for evaluating the pharmacokinetics and efficacy of anti-pseudomonal antibiotics. Two strains of P. aeruginosa were employed, NCTC10662 (antibiotic susceptible) and NCTC13437 (multi-drug resistant). Larvae were infected with increasing doses of either P. aeruginosa strain to investigate the effect of inoculum size on survival. Subsequently, infected larvae were treated with a range of antibiotics to examine whether these agents were effective against P. aeruginosa infections in vivo and if the efficacy of these drugs matched the known susceptibilities of each bacterial strain. Larval burden of P. aeruginosa was also determined after infection and treatment with cefotaxime. Pharmacokinetic properties of the antibiotics tested were measured using a well-diffusion assay to determine the concentration of antibiotics in larval haemolymph over time. G. mellonella larvae were sensitive to P. aeruginosa infection and increasing inoculum doses of live cells resulted in greater larval mortality. Heat-killed bacteria had no detrimental effect on survival. Antibiotic efficacy versus P. aeruginosa-infected G. mellonella correlated with the measured in vitro sensitivities of the two strains tested. The therapeutic benefit arising from administration of cefotaxime correlated with reduced burden of bacteria present in the haemolymph. There was clear correlation between the measured antibiotic pharmacokinetics and the therapeutic effect. This study strongly supports the future application of the G. mellonella infection model to initial studies of novel anti-pseudomonal treatments