Dimensions of equality in uptake of COVID-19 vaccination in Wales, UK: A multivariable linked data population analysis.

Vaccination has proven to be effective at preventing severe outcomes of COVID-19 infection, and uptake in the population has been high in Wales. However, there is a risk that high-level vaccination coverage statistics may mask hidden inequalities in under-served populations, many of whom may be at increased risk of severe outcomes of COVID-19 infection. The study population included 1,436,229 individuals aged 18 years and over, alive and residence in Wales as at 31st July 2022, and excluded immunosuppressed or care home residents. We compared people who had received one or more vaccinations to those with no vaccination using linked data from nine datasets within the Secure Anonymised Information Linkage (SAIL) databank. Multivariable analysis was undertaken to determine the impact of a range of sociodemographic characteristics on vaccination uptake, including ethnicity, country of birth, severe mental illness, homelessness and substance use. We found that overall uptake of first dose of COVID-19 vaccination was high in Wales (92.1 %), with the highest among those aged 80 years and over and females. Those aged under 40 years, household composition (aOR 0.38 95 %CI 0.35-0.41 for 10+ size household compared to two adult household) and being born outside the UK (aOR 0.44 95 %CI 0.43-0.46) had the strongest negative associations with vaccination uptake. This was followed by a history of substance misuse (aOR 0.45 95 %CI 0.44-0.46). Despite high-level population coverage in Wales, significant inequalities remain across several underserved groups. Factors associated with vaccination uptake should not be considered in isolation, to avoid drawing incorrect conclusions. Ensuring equitable access to vaccination is essential to protecting under-served groups from COVID-19 and further work needs to be done to address these gaps in coverage, with focus on tailored vaccination pathways and advocacy, using trusted partners and communities.

Household Composition and Inequalities in COVID-19 Vaccination in Wales, UK.

The uptake of COVID-19 vaccination in Wales is high at a population level but many inequalities exist. Household composition may be an important factor in COVID-19 vaccination uptake due to the practical, social, and psychological implications associated with different living arrangements. In this study, the role of household composition in the uptake of COVID-19 vaccination in Wales was examined with the aim of identifying areas for intervention to address inequalities. Records within the Wales Immunisation System (WIS) COVID-19 vaccination register were linked to the Welsh Demographic Service Dataset (WDSD; a population register for Wales) held within the Secure Anonymised Information Linkage (SAIL) databank. Eight household types were defined based on household size, the presence or absence of children, and the presence of single or multiple generations. Uptake of the second dose of any COVID-19 vaccine was analysed using logistic regression. Gender, age group, health board, rural/urban residential classification, ethnic group, and deprivation quintile were included as covariates for multivariable regression. Compared to two-adult households, all other household types were associated with lower uptake. The most significantly reduced uptake was observed for large, multigenerational, adult group households (aOR 0.45, 95%CI 0.43-0.46). Comparing multivariable regression with and without incorporation of household composition as a variable produced significant differences in odds of vaccination for health board, age group, and ethnic group categories. These results indicate that household composition is an important factor for the uptake of COVID-19 vaccination and consideration of differences in household composition is necessary to mitigate vaccination inequalities.

Maternal SARS-CoV-2 sero-surveillance using newborn dried blood spot (DBS) screening specimens highlights extent of low vaccine uptake in pregnant women.

SARS-CoV-2 vaccine uptake in pregnant women is believed to be low and lags behind the general population contributing to increased hospital admissions, and poor maternal and fetal outcomes. However, there is a paucity of information on the SARS-CoV-2 serostatus of pregnant women to help inform policy planning and assess impact of interventions to improve vaccine uptake in this at-risk group. We analyzed 8,683 residual, anonymized newborn screening dried bloodspot (DBS) specimens during a 15-month period (October 2020 to December 2021) in Wales (UK) for SARS-CoV-2 IgG-antibodies. We compared newborn DBS antibody-positive rates to the percentage number of pregnant women vaccinated and the percentage number of antibody-positive adults. In December 2021, 47.8% of women in Wales had received two doses of the vaccine by their delivery date; however, only 41.1% of DBS specimens had high antibody concentrations. Results indicate that a proportion of pregnant women remain at higher-risk of COVID complications, particularly given the reduction in antibody neutralization of Omicron versus the Delta variant. Our study demonstrates the utility of newborn screening DBS specimens to monitor SARS-CoV-2 serostatus in pregnant women representing maternal vaccination and natural infection in almost real-time, defining the immunity gap and impact of any interventions.

Differential Effects of D-Cycloserine and ACBC at NMDA Receptors in the Rat Entorhinal Cortex Are Related to Efficacy at the Co-Agonist Binding Site.

Partial agonists at the NMDA receptor co-agonist binding site may have potential therapeutic efficacy in a number of cognitive and neurological conditions. The entorhinal cortex is a key brain area in spatial memory and cognitive processing. At synapses in the entorhinal cortex, NMDA receptors not only mediate postsynaptic excitation but are expressed in presynaptic terminals where they tonically facilitate glutamate release. In a previous study we showed that the co-agonist binding site of the presynaptic NMDA receptor is endogenously and tonically activated by D-serine released from astrocytes. In this study we determined the effects of two co-agonist site partial agonists on both presynaptic and postsynaptic NMDA receptors in layer II of the entorhinal cortex. The high efficacy partial agonist, D-cycloserine, decreased the decay time of postsynaptic NMDA receptor mediated currents evoked by electrical stimulation, but had no effect on amplitude or other kinetic parameters. In contrast, a lower efficacy partial agonist, 1-aminocyclobutane-1-carboxylic acid, decreased decay time to a greater extent than D-cycloserine, and also reduced the peak amplitude of the evoked NMDA receptor mediated postsynaptic responses. Presynaptic NMDA receptors, (monitored indirectly by effects on the frequency of AMPA receptor mediated spontaneous excitatory currents) were unaffected by D-cycloserine, but were reduced in effectiveness by 1-aminocyclobutane-1-carboxylic acid. We discuss these results in the context of the effect of endogenous regulation of the NMDA receptor co-agonist site on receptor gating and the potential therapeutic implications for cognitive disorders.

Experimental and mathematical analysis of in vitro Pitavastatin hepatic uptake across species.

1. To investigate the non-linear kinetics of in vitro hepatocyte uptake across species, the OATP substrate Pitavastatin was used as a probe. 2. Experiments were conducted at AstraZeneca (Alderley Park, Macclesfield) using freshly isolated rat, dog and human hepatocytes, utilising the "oil spin" methodology described by Hassen et al. (1996). Very few mechanistic models have previously been used to characterise the uptake process. 3. Here two candidate pharmacokinetic non-linear compartmental models are proposed. Both models have been shown to be structurally identifiable and distinghishable previously, which establishes that all unknown parameters could be identified from the experimental observations available and that input/output relationships for both the candidate models were structurally different. 4. A kinetic modelling software package, FACSIMILE (MCPA Software, Faringdon, UK), was used to obtain numerical solutions for the system equations and for parameter estimation. Model fits gave good agreement with the in vitro data and suggest the current widely accepted assumption that the rate of diffusion across the hepatocyte cell membrane is the same at both 4 °C and 37 °C is not valid, at least for Pitavastatin. Although this finding has already been proposed, this is the first time it is comprehensively debunked using statistical testing.

Astroglial d-serine is the endogenous co-agonist at the presynaptic NMDA receptor in rat entorhinal cortex.

Presynaptic NMDA receptors facilitate the release of glutamate at excitatory cortical synapses and are involved in regulation of synaptic dynamics and plasticity. At synapses in the entorhinal cortex these receptors are tonically activated and provide a positive feedback modulation of the level of background excitation. NMDA receptor activation requires obligatory occupation of a co-agonist binding site, and in the present investigation we have examined whether this site on the presynaptic receptor is activated by endogenous glycine or d-serine. We used whole-cell patch clamp recordings of spontaneous AMPA receptor-mediated synaptic currents from rat entorhinal cortex neurones in vitro as a monitor of presynaptic glutamate release. Addition of exogenous glycine or d-serine had minimal effects on spontaneous release, suggesting that the co-agonist site was endogenously activated and likely to be saturated in our slices. This was supported by the observation that a co-agonist site antagonist reduced the frequency of spontaneous currents. Depletion of endogenous glycine by enzymatic breakdown with a bacterial glycine oxidase had little effect on glutamate release, whereas d-serine depletion with a yeast d-amino acid oxidase significantly reduced glutamate release, suggesting that d-serine is the endogenous agonist. Finally, the effects of d-serine depletion were mimicked by compromising astroglial cell function, and this was rescued by exogenous d-serine, indicating that astroglial cells are the provider of the d-serine that tonically activates the presynaptic NMDA receptor. We discuss the significance of these observations for the aetiology of epilepsy and possible targeting of the presynaptic NMDA receptor in anticonvulsant therapy.

Background synaptic activity in rat entorhinal cortex shows a progressively greater dominance of inhibition over excitation from deep to superficial layers.

The entorhinal cortex (EC) controls hippocampal input and output, playing major roles in memory and spatial navigation. Different layers of the EC subserve different functions and a number of studies have compared properties of neurones across layers. We have studied synaptic inhibition and excitation in EC neurones, and we have previously compared spontaneous synaptic release of glutamate and GABA using patch clamp recordings of synaptic currents in principal neurones of layers II (L2) and V (L5). Here, we add comparative studies in layer III (L3). Such studies essentially look at neuronal activity from a presynaptic viewpoint. To correlate this with the postsynaptic consequences of spontaneous transmitter release, we have determined global postsynaptic conductances mediated by the two transmitters, using a method to estimate conductances from membrane potential fluctuations. We have previously presented some of this data for L3 and now extend to L2 and L5. Inhibition dominates excitation in all layers but the ratio follows a clear rank order (highest to lowest) of L2>L3>L5. The variance of the background conductances was markedly higher for excitation and inhibition in L2 compared to L3 or L5. We also show that induction of synchronized network epileptiform activity by blockade of GABA inhibition reveals a relative reluctance of L2 to participate in such activity. This was associated with maintenance of a dominant background inhibition in L2, whereas in L3 and L5 the absolute level of inhibition fell below that of excitation, coincident with the appearance of synchronized discharges. Further experiments identified potential roles for competition for bicuculline by ambient GABA at the GABAA receptor, and strychnine-sensitive glycine receptors in residual inhibition in L2. We discuss our results in terms of control of excitability in neuronal subpopulations of EC neurones and what these may suggest for their functional roles.