Static Socio-Ecological COVID-19 Vulnerability Index and Vaccine Hesitancy Index for England

Background: Population characteristics can be used to infer vulnerability of communities to COVID-19, or to the likelihood of high levels of vaccine hesitancy. Communities harder hit by the virus, or at risk of being so, stand to benefit from greater resource allocation than their population size alone would suggest. This study reports a simple but efficacious method of ranking small areas of England by relative characteristics that are linked with COVID-19 vulnerability and vaccine hesitancy. Methods: Publicly available data on a range of characteristics previously linked with either poor COVID-19 outcomes or vaccine hesitancy were collated for all Middle Super Output Areas of England (MSOA, n=6790, excluding Isles of Scilly), scaled and combined into two numeric indices. Multivariable linear regression was used to build a parsimonious model of vulnerability (static socio-ecological vulnerability index, SEVI) in 60% of MSOAs, and retained variables were used to construct two simple indices. Assuming a monotonic relationship between indices and outcomes, Spearman correlation coefficients were calculated between the SEVI and cumulative COVID-19 case rates at MSOA level in the remaining 40% of MSOAs over periods both during and out with national lockdowns. Similarly, a novel vaccine hesitancy index (VHI) was constructed using population characteristics aligned with factors identified by an Office for National Statistics (ONS) survey analysis. The relationship between the VHI and vaccine coverage in people aged 12+years (as of 2021-06-24) was determined using Spearman correlation. The indices were split into quintiles, and MSOAs within the highest vulnerability and vaccine hesitancy quintiles were mapped. Findings: The SEVI showed a moderate to strong relationship with case rates in the validation dataset across the whole study period, and for every intervening period studied except early in the pandemic when testing was highly selective. The SEVI was more strongly correlated with case rates than any of its domains (rs 0·59 95% CI 0.57-0.62) and outperformed an existing MSOA-level vulnerability index. The VHI was significantly negatively correlated with COVID-19 vaccine coverage in the validation data at the time of writing (rs -0·43 95% CI -0·46 to -0·41). London had the largest number and proportion of MSOAs in quintile 5 (most vulnerable/hesitant) of SEVI and VHI concurrently. Interpretation: The indices presented offer an efficacious way of identifying geographical disparities in COVID-19 risk, thus helping focus resources according to need. Funding: Funder: Integrated Covid Hub North East Award number: n/a Grant recipient: Fiona Matthew

Can vaccination roll-out be more equitable if population risk is taken into account?

Background COVID-19 vaccination in many countries, including England, has been prioritised primarily by age. However, people of the same age can have very different health statuses. Frailty is a commonly used metric of health and has been found to be more strongly associated with mortality than age among COVID-19 inpatients. Methods We compared the number of first vaccine doses administered across the 135 NHS Clinical Commissioning Groups (CCGs) of England to both the over 50 population and the estimated frail population in each area. Area-based frailty estimates were generated using the English Longitudinal Survey of Ageing (ELSA), a national survey of older people. We also compared the number of doses to the number of people with other risk factors associated with COVID- 19: Atrial fibrillation, chronic kidney disease, diabetes, learning disabilities, obesity and smoking status. Results We estimate that after 79 days of the vaccine program, across all Clinical Commissioning Group areas, the number of people who received a first vaccine per frail person ranged from 4.4 (95% CI 4.0-4.8) and 20.1 (95% CI 18.3-21.9). The prevalences of other risk factors were also poorly associated with the prevalence of vaccination across England. Conclusions Vaccination with age-based priority created area-based inequities in the number of doses administered relative to the number of people who are frail or have other risk factors associated with COVID-19. As frailty has previously been found to be more strongly associated with mortality than age for COVID-19 inpatients, an age-based priority system may increase the risk of mortality in some areas during the vaccine roll-out period. Authorities planning COVID-19 vaccination programmes should consider the disadvantages of an age-based priority system

Recruiting participants to walking intervention studies: a systematic review

Most researchers who are conducting physical activity trials face difficulties in recruiting participants who are representative of the population or from specific population groups. Participants who are often the hardest to recruit are often those who stand to benefit most (the least active, from ethnic and other minority groups, from neighbourhoods with high levels of deprivation, or have poor health). The aim of our study was to conduct a systematic review of published literature of walking interventions, in order to identify the impact, characteristics, and differential effects of recruitment strategies among particular population groups. We conducted standard searches for studies from four sources, (i) electronic literature databases and websites, (ii) grey literature from internet sources, (iii) contact with experts to identify additional "grey" and other literature, and (iv) snowballing from reference lists of retrieved articles. Included studies were randomised controlled trials, controlled before-and-after experimental or observational qualitative studies, examining the effects of an intervention to encourage people to walk independently or in a group setting, and detailing methods of recruitment. Forty seven studies met the inclusion criteria. The overall quality of the descriptions of recruitment in the studies was poor with little detail reported on who undertook recruitment, or how long was spent planning/preparing and implementing the recruitment phase. Recruitment was conducted at locations that either matched where the intervention was delivered, or where the potential participants were asked to attend for the screening and signing up process. We identified a lack of conceptual clarity about the recruitment process and no standard metric to evaluate the effectiveness of recruitment. Recruitment concepts, methods, and reporting in walking intervention trials are poorly developed, adding to other limitations in the literature, such as limited generalisability. The lack of understanding of optimal and equitable recruitment strategies evident from this review limits the impact of interventions to promote walking to particular social groups. To improve the delivery of walking interventions to groups which can benefit most, specific attention to developing and evaluating targeted recruitment approaches is recommended

Living well with dementia: An exploratory matched analysis of minority ethnic and white people with dementia and carers participating in the IDEAL programme

Objectives: The increasing heterogeneity of the population of older people is reflected in an increasing number of people with dementia and carers drawn from minority ethnic groups. Data from the IDEAL study are used to compare indices of ‘living well’ among people with dementia and carers from ethnic minority groups with matched white peers. Methods: We used an exploratory cross-sectional case-control design to compare ‘living well’ for people with dementia and carers from minority ethnic and white groups. Measures for both groups were quality of life, life satisfaction, wellbeing, loneliness, and social isolation and, for carers, stress, relationship quality, role captivity and caring competence. Results: The sample of people with dementia consisted of 20 minority ethnic and 60 white participants and for carers 15 and 45 respectively. People with dementia from minority ethnic groups had poorer quality of life (−4.74, 95% CI: −7.98 to −1.50) and higher loneliness (1.72, 95% CI: 0.78–2.66) whilst minority ethnic carers had higher stress (8.17, 95% CI: 1.72–14.63) and role captivity (2.00, 95% CI: 0.43–3.57) and lower relationship quality (−9.86, 95% CI: −14.24 to −5.48) than their white peers. Conclusion: Our exploratory study suggests that people with dementia from minority ethnic groups experience lower quality of life and carers experience higher stress and role captivity and lower relationship quality than their white peers. Confirmatory research with larger samples is required to facilitate analysis of the experiences of specific minority ethnic groups and examine the factors contributing to these disadvantages

Epstein-Barr Virus as a Trigger of Autoimmune Liver Diseases

The pathogenesis of autoimmune diseases includes a combination of genetic factors and environmental exposures including infectious agents. Infectious triggers are commonly indicated as being involved in the induction of autoimmune disease, with Epstein-Barr virus (EBV) being implicated in several autoimmune disorders. EBV is appealing in the pathogenesis of autoimmune disease, due to its high prevalence worldwide, its persistency throughout life in the host's B lymphocytes, and its ability to alter the host's immune response and to inhibit apoptosis. However, the evidence in support of EBV in the pathogenesis varies among diseases. Autoimmune liver diseases (AiLDs), including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), have a potential causative link with EBV. The data surrounding EBV and AiLD are scarce. The lack of evidence surrounding EBV in AiLD may also be reflective of the rarity of these conditions. EBV infection has also been linked to other autoimmune conditions, which are often found to be concomitant with AiLD. This paper will critically examine the literature surrounding the link between EBV infection and AiLD development. The current evidence is far from being conclusive of the theory of a link between EBV and AiLD

Trajectories of cognitive and perceived functional decline in people with dementia: Findings from the IDEAL programme

INTRODUCTION: Impaired cognition and instrumental activities of daily living (iADL) are key diagnostic features of dementia; however, few studies have compared trajectories of cognition and iADL. METHODS: Participants from the IDEAL study comprised 1537, 1183, and 851 people with dementia, and 1277, 977, and 749 caregivers at baseline, 12 and 24 months, respectively. Addenbrooke's Cognitive Examination-III and Functional Activities Questionnaire were used to measure cognition and iADL, respectively. Scores were converted to deciles. RESULTS: Self-rated iADL declined on average by -0.08 (-0.25, 0.08) decile points per timepoint more than cognition. Informant-rated iADL declined on average by -0.31 (-0.43, -0.18) decile points per timepoint more than cognition. DISCUSSION: Cognition and self-rated iADL declined at a similar rate. Informant-rated iADL declined at a significantly greater rate than cognition. Therefore, either cognition and perceived iADL decline at different rates or informants overestimate increasing iADL difficulties compared to both cognition and self-ratings. Highlights: Self-ratings of the degree of functional difficulties were consistent with cognition Decline in self-rated everyday activities was consistent with cognitive decline Informant-ratings of everyday activities declined more than cognition

NDRG2 Expression Correlates with Neurofibrillary Tangles and Microglial Pathology in the Ageing Brain.

Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer's disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific phenotype markers to identify astrocyte subtypes, changes in function and their relation to pathology. This study aimed to characterise expression of the astrocyte marker N-myc downstream regulated gene 2 (NDRG2) in the ageing brain, investigate the relationship between NDRG2 and a panel of astrocyte markers, and relate NDRG2 expression to pathology. NDRG2 specifically immunolabelled the cell body and radiating processes of astrocytes in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) neuropathology cohort. Expression of NDRG2 did not correlate with other astrocyte markers, including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). NDRG2 showed a relationship to AT8+ neurofibrillary tangles (p = 0.001) and CD68+ microglia (p = 0.047), but not β-amyloid plaques or astrocyte nuclear γH2AX immunoreactivity, a marker of DNA damage response. These findings provide new insight into the astrocyte response to pathology in the ageing brain, and suggest NDRG2 may be a potential target to modulate this response

Metallothionein-I/II expression associates with the astrocyte DNA damage response and not Alzheimer-type pathology in the ageing brain

Oxidative stress and oxidative DNA damage are early features of mild cognitive impairment and Alzheimer’s disease (AD), occurring before the formation of classical AD neuropathology, and resulting from an imbalance between pro- and anti-oxidants. Astrocytes play a major neuroprotective role, producing high levels of anti-oxidants including metallothionein-I and –II (MT-I/II). In the present study we characterized the immunoreactive profile of MT-I/II in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) aging population-representative neuropathology cohort, and examined H2O2-modulation of MT transcription by human astrocytes. MT-I/II is primarily expressed by astrocytes in the aging brain, but is also associated with pyramidal neurons in a small proportion of cases. Astrocyte expression of MT-I/II does not correlate with Alzheimer-type pathology (Aβ plaques and neurofibrillary tangles) but does relate to astrocyte oxidative DNA damage (rs= 0.312, p= 0.006) and the astrocyte response to oxidative DNA damage in vivo (rs= 0.238, p= 0.04), and MT gene expression is significantly induced in human astrocytes response to oxidative stress in vitro (p=0.01). In contrast, neuronal MT-I/II does not relate to oxidative DNA damage or the neuronal DNA damage response, but is significantly higher in cases with high levels of local tangle pathology (p=0.007). As MT-I/II is neuroprotective against oxidative stress, modulation of MT-I/II expression is a potential therapeutic target to treat the onset and progression of cognitive impairment