Vitamin D and the brain: key questions for future research

Over the last decade a convergent body of evidence has emerged from epidemiology, animal experiments and clinical trials which links low vitamin D status with a range of adverse neuropsychiatric outcomes. This research demonstrates that the timing of exposure to low vitamin D influences the nature of brain phenotypes, as exposures during gestation versus adulthood result in different phenotypes. With respect to early life exposures, there is robust evidence from rodent experiments indicating that transient developmental vitamin D (DVD) deficiency is associated with changes in brain structure, neurochemistry, gene and protein expression and behavior. In particular, DVD deficiency is associated with alterations in the dopaminergic neurotransmitter systems. In contrast, recently published animal experiments indicate that adult vitamin D (AVD) deficiency is associated with more subtle neurochemical and behavioral phenotypes. This paper explores key issues that need to be addressed in future research. There is a need to define the timing and duration of the ‘critical window’ during which low vitamin D status is associated with differential and adverse brain outcomes. We discuss the role for ‘two-hit hypotheses’, which propose that adult vitamin D deficiency leaves the brain more vulnerable to secondary adverse exposures, and thus may exacerbate disease progression. Finally, we explore the evidence implicating a role for vitamin D in rapid, non-genomic mechanisms that may involve L-type calcium channels and brain functio

Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice

Epidemiological evidence suggests that low levels of vitamin D may predispose people to develop depression and cognitive impairment. While rodent studies have demonstrated that prenatal vitamin D deficiency is associated with altered brain development, there is a lack of research examining adult vitamin D (AVD) deficiency. The aim of this study was to examine the impact of AVD deficiency on behaviour and brain function in the mouse. Ten-week old male C57BL/6J and BALB/c mice were fed a control or vitamin D deficient diet for 10 weeks prior to, and during behavioural testing. We assessed a broad range of behavioural domains, excitatory and inhibitory neurotransmission in brain tissue, and, in separate groups of mice, locomotor response to d-amphetamine and MK-801. Overall, AVD deficiency resulted in hyperlocomotion in a novel open field and reduced GAD65/67 levels in brain tissue. AVD-deficient BALB/c mice had altered behaviour on the elevated plus maze, altered responses to heat, sound and shock, and decreased levels of glutamate and glutamine, and increased levels of GABA and glycine. By contrast C57BL/6J mice had a more subtle phenotype with no further behavioural changes but significant elevations in serine, homovanillic acid and 5-hydroxyindoleacetic acid. Although the behavioural phenotype of AVD did not seem to model a specific disorder, the overall reduction in GAD65/67 levels associated with AVD deficiency may be relevant to a number of neuropsychiatric conditions. This is the first study to show an association between AVD deficiency and prominent changes in behaviour and brain neurochemistry in the mouse

The Genomics of Streptococcus Pneumoniae Carriage Isolates from UK Children and Their Household Contacts, Pre-PCV7 to Post-PCV13.

We used whole genome sequencing (WGS) analysis to investigate the population structure of 877 Streptococcus pneumoniae isolates from five carriage studies from 2002 (N = 346), 2010 (N = 127), 2013 (N = 153), 2016 (N = 187) and 2018 (N = 64) in UK households which covers the period pre-PCV7 to post-PCV13 implementation. The genomic lineages seen in the population were determined using multi-locus sequence typing (MLST) and PopPUNK (Population Partitioning Using Nucleotide K-mers) which was used for local and global comparisons. A Roary core genome alignment of all the carriage genomes was used to investigate phylogenetic relationships between the lineages. The results showed an influx of previously undetected sequence types after vaccination associated with non-vaccine serotypes. A small number of lineages persisted throughout, associated with both non-vaccine and vaccine types (such as ST199), or that could be an example of serotype switching from vaccine to non-vaccine types (ST177). Serotype 3 persisted throughout the study years, represented by ST180 and Global Pneumococcal Sequencing Cluster (GPSC) 12; the local PopPUNK analysis and core genome maximum likelihood phylogeny separated them into two clades, one of which is only seen in later study years. The genomic data showed that serotype replacement in the carriage studies was mostly due to a change in genotype as well as serotype, but that some important genetic lineages, previously associated with vaccine types, persisted

Adult vitamin D deficiency exacerbates impairments caused by social stress in BALB/c and C57BL/6 mice

Vitamin D deficiency is prevalent in adults throughout the world. Epidemiological studies have shown significant associations between vitamin D deficiency and an increased risk of various neuropsychiatric and neurodegenerative disorders, such as schizophrenia, depression, Alzheimer's disease and cognitive impairment. However, studies based on observational epidemiology cannot address questions of causality; they cannot determine if vitamin D deficiency is a causal factor leading to the adverse health outcome. The main aim of this study was to determine if AVD deficiency would exacerbate the effects of a secondary exposure, in this case social stress, in BALE/c mice and in the more resilient C57BL/6 mice. Ten-week old male BALB/c and C57BL/6 mice were fed a control or vitamin D deficient diet for 10 weeks, and the mice were further separated into one of two groups for social treatment, either Separated (SEP) or Social Defeat (DEF). SEP mice were placed two per cage with a perforated Plexiglas divider, whereas the DEF mice underwent 10 days of social defeat prior to behavioural testing. We found that AVD-deficient mice were more vulnerable to the effects of social stress using a social avoidance test, and this was dependent on strain. These results support the hypothesis that vitamin D deficiency may exacerbate behavioural outcomes in mice vulnerable to stress, a finding that can help guide future studies. Importantly, these discoveries support the epidemiological link between vitamin D deficiency and neuropsychiatric and neurodegenerative disorders; and has provided clues that can guide future studies related to unravelling the mechanisms of action linking adult vitamin D deficiency and adverse brain related outcomes

Worry about crime in Europe: A model-based small area estimation from the European Social Survey

© The Author(s) 2019. Worry about crime is known to be higher in some European regions than others. However, cross-national surveys, which are the main source of information to map worry about crime across Europe, are designed to be representative of large areas (countries), and regions often suffer from small and unrepresentative sample sizes. This research produces reliable model-based small area estimates of worry about crime at regional level from European Social Survey data, in order to map the phenomenon and examine its macro-level predictors. Model-based small area estimation techniques borrow strength across areas to produce reliable estimates of parameters of interest. Estimates of worry about crime are higher in most South and East European regions, in contrast to Northern and Central Europe

APOBEC3 deaminase editing in mpox virus as evidence for sustained human transmission since at least 2016

Historically, mpox has been characterized as an endemic zoonotic disease that transmits through contact with the reservoir rodent host in West and Central Africa. However, in May 2022, human cases of mpox were detected spreading internationally beyond countries with known endemic reservoirs. When the first cases from 2022 were sequenced, they shared 42 nucleotide differences from the closest mpox virus (MPXV) previously sampled. Nearly all these mutations are characteristic of the action of APOBEC3 deaminases, host enzymes with antiviral function. Assuming APOBEC3 editing is characteristic of human MPXV infection, we developed a dual-process phylogenetic molecular clock that-inferring a rate of ~6 APOBEC3 mutations per year-estimates that MPXV has been circulating in humans since 2016. These observations of sustained MPXV transmission present a fundamental shift to the perceived paradigm of MPXV epidemiology as a zoonosis and highlight the need for revising public health messaging around MPXV as well as outbreak management and control.Editor’s summary: In March 2022, an international epidemic of human Mpox was detected, showing that it was not solely a zoonotic infection. A hallmark of the approximately 88,000 cases that have been reported were TC>TT and GA>AA mutations in Mpox viruses, which were acquired at a surprisingly high evolutionary rate for a pox virus. Knowing that these types of mutation are a sign of activity by a host antiviral enzyme called APOBEC3, O’Toole et al. investigated whether the mutations reflected human-to-human transmission rather than repeated zoonotic spillover. Bayesian evolutionary analysis showed that Mpox virus recently diversified into several lineages in humans that display elevated numbers of mutations, signaling APOBEC exposure and sustained human-to-human transmission rather than zoonosis as the source of new cases. —Caroline AshWellcome Trust ARTIC (Collaborators Award 206298/Z/17/Z, ARTIC network) (Á.O.T., P.L., M.A.S., A.R.); European Research Council (grant agreement no. 725422 – ReservoirDOCS) (P.L., M.A.S., A.R.); National Institutes of Health (R01 AI153044) (P.L., M.A.S., A.R.); David and Lucile Packard Foundation (M.W.); Research Foundation, Flanders– Fonds voor Wetenschappelijk Onderzoek–Vlaanderen, G066215N, G0D5117N and G0B9317N (P.L.); HORIZON 2020 EU grant 874850 MOOD (P.L.); HERA project (grant/2021/PHF/23776) supported by the European Commission through the European Centre for Disease Control and Prevention (V.B. and J.P.G.). The Nigeria Centre for Disease Control and Prevention receives core funding from the Nigerian government.info:eu-repo/semantics/publishedVersio

Generation of SARS-CoV-2 escape mutations by monoclonal antibody therapy

COVID-19 patients at risk of severe disease may be treated with neutralising monoclonal antibodies (mAbs). To minimise virus escape from neutralisation these are administered as combinations e.g. casirivimab+imdevimab or, for antibodies targeting relatively conserved regions, individually e.g. sotrovimab. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to detect emerging drug resistance in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the antibody epitopes and for casirivimab+imdevimab multiple mutations are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum

Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16-20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement

Comparative transmission of SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) variants and the impact of vaccination: national cohort study, England

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) rapidly replaced Delta (B.1.617.2) to become dominant in England. Our study assessed differences in transmission between Omicron and Delta using two independent data sources and methods. Omicron and Delta cases were identified through genomic sequencing, genotyping and S-gene target failure in England from 5-11 December 2021. Secondary attack rates for named contacts were calculated in household and non-household settings using contact tracing data, while household clustering was identified using national surveillance data. Logistic regression models were applied to control for factors associated with transmission for both methods. For contact tracing data, higher secondary attack rates for Omicron vs. Delta were identified in households (15.0% vs. 10.8%) and non-households (8.2% vs. 3.7%). For both variants, in household settings, onward transmission was reduced from cases and named contacts who had three doses of vaccine compared to two, but this effect was less pronounced for Omicron (adjusted risk ratio, aRR 0.78 and 0.88) than Delta (aRR 0.62 and 0.68). In non-household settings, a similar reduction was observed only in contacts who had three doses vs. two doses for both Delta (aRR 0.51) and Omicron (aRR 0.76). For national surveillance data, the risk of household clustering, was increased 3.5-fold for Omicron compared to Delta (aRR 3.54 (3.29-3.81)). Our study identified increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta. We identified a reduced effectiveness of vaccination in lowering risk of transmission, a likely contributor for the rapid propagation of Omicron