GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

NHS CHECK: protocol for a cohort study investigating the psychosocial impact of the COVID-19 pandemic on healthcare workers

INTRODUCTION: The COVID-19 pandemic has had profound effects on the working lives of healthcare workers (HCWs), but the extent to which their well-being and mental health have been affected remains unclear. This longitudinal cohort study aims to recruit a cohort of National Health Service (NHS) HCWs, conducting surveys at regular intervals to provide evidence about the prevalence of symptoms of mental disorders, and investigate associated factors such as occupational contexts and support interventions available. METHODS AND ANALYSIS: All staff, students and volunteers working in the 18 participating NHS Trusts in England will be sent emails inviting them to complete a survey at baseline, with email invitations for the follow-up surveys sent 6 months and 12 months later. Opening in late April 2020, the baseline survey collects data on demographics, occupational/organisational factors, experiences of COVID-19, validated measures of symptoms of poor mental health (eg, depression, anxiety, post-traumatic stress disorder), and constructs such as resilience and moral injury. These surveys will be complemented by in-depth psychiatric interviews with a sample of HCWs. Qualitative interviews will also be conducted, to gain deeper understanding of the support programmes used or desired by staff, and facilitators and barriers to accessing such programmes. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the Health Research Authority (reference: 20/HRA/210, IRAS: 282686) and local Trust Research and Development approval. Cohort data are collected via Qualtrics online survey software, pseudonymised and held on secure university servers. Participants are aware that they can withdraw from the study at any time, and there is signposting to support services if participants feel they need it. Only those consenting to be contacted about further research will be invited to participate in further components. Findings will be rapidly shared with NHS Trusts, and via academic publications in due course

Prevalence of at-risk drinking recognition: A systematic review and meta-analysis

Background: There is a prominent “treatment gap” in relation to at-risk drinking (ARD), whereby a minority of at-risk drinkers ever access treatment. Research suggests that recognition of problem drinking is a necessary precursor for help-seeking and treatment. Objective: This systematic review and meta-analysis aimed to estimate the prevalence of ARD recognition within those meeting criteria for ARD. Method: PsycINFO, Web of Science, Scopus, and MEDLINE were searched using the terms: problem* AND (recogni* OR perceive* OR perception OR self-identif*) AND alcohol - to identify studies published in English between 2000 and 2022. Studies reported the frequency (weighted or unweighted) of participants meeting ARD criteria that also directly identified ARD, perceived a need for help, or endorsed a readiness to change. The prevalence of ARD recognition was estimated using a random-effects meta-analysis with 95% confidence intervals (CIs). Results: 17 studies were included which provided data for 33,349 participants with ARD. Most (n = 14) were US studies. ARD was self-identified via a single indicator in 7 studies, whereas recognition was assessed via stages of change in 4 studies and need for help in 6 studies. The pooled prevalence of ARD recognition was 31% (95% CI: 25%−36%), and subgroup analyses indicated alcohol use severity, measure of recognition, and population type to be significant sources of heterogeneity. Conclusions: Most individuals with ARD fail to recognise their drinking problem so preventive approaches that promote recognition may be helpful. However, we must be cautious of how inconsistency in question framing affects self-reported problem recognition

'You get looked at like you're failing': A reflexive thematic analysis of experiences of mental health and wellbeing support for NHS staff

Staff in the National Health Service (NHS) are under considerable strain, exacerbated by the COVID-19 pandemic; whilst NHS Trusts provide a variety of health and wellbeing support services, there has been little research investigating staff perceptions of these services. We interviewed 48 healthcare workers from 18 NHS Trusts in England about their experiences of workplace health and wellbeing support during the pandemic. Reflexive thematic analysis identified that perceived stigma around help-seeking, and staffing shortages due to wider socio-political contexts such as austerity, were barriers to using support services. Visible, caring leadership at all levels (CEO to line managers), peer support, easily accessible services, and clear communication about support offers were enablers. Our evidence suggests Trusts should have active strategies to improve help-seeking, such as manager training and peer support facilitated by building in time for this during working hours, but this will require long-term strategic planning to address workforce shortages

Assessing the genetic association between vitamin B6 metabolism and genetic generalized epilepsy

Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication

Cardiovascular and lifestyle risk factors of mild cognitive impairment in UK veterans and non-veterans

Acknowledgement: We thank all volunteers who participated in the PROTECT study.Key learning points: What is already known about this subject: · Previous evidence in the general population has shown exposure to cardiovascular health, or lifestyle choices, are modifiable risk factors for mild cognitive impairment. · This is concerning as veterans are at an increased risk of cardiovascular health or lifestyle factors. This could potentially have a negative consequence on their cognitive function with age. What this study adds: · This is the first study to quantify the risk of mild cognitive impairment in UK veterans exposed to nine key cardiovascular health and lifestyle risk factors compared to the non-veteran population using longitudinal data. · Obesity, alcohol consumption and physical inactivity reduced the risk of mild cognitive impairment in veterans compared to non-veterans. · Within the veteran sample, diabetes and high cholesterol increased the risk of mild cognitive impairment. What impact this may have on practice or policy: · Early diagnosis and intervention of modifiable risk factors may reduce the risk of mild cognitive impairment and subsequently dementia in both veterans and non-veterans.Background: The link between poor cardiovascular health (CVH), lifestyle and mild cognitive impairment (MCI) has been well established in the general population. However, there is limited research exploring these associations in ageing UK veterans. Aims: This study explored the risk of MCI and its association with nine CVH and lifestyle risk factors (including diabetes, heart disease, high cholesterol, high blood pressure, obesity, stroke, physical inactivity, the frequency of alcohol consumption and smoking) in UK veterans and non-veterans. Methods: This prospective cohort study comprised data from the PROTECT study between 2014 and 2022. Participants comprised of UK military veterans and non-veterans aged ≥50 years at baseline. Veteran status was defined using the Military Service History Questionnaire. CVH and lifestyle risk factors were defined using a combination of self-report measures, medication history or physical measurements. MCI was defined as the presence of subjective and objective cognitive impairment. Results: Based on a sample of 9378 veterans (n = 488) and non-veterans (n = 8890), the findings showed the risk of MCI significantly reduced in veterans with obesity, those who frequently consumed alcohol and were physically inactive compared to non-veterans. The risk of MCI significantly increased in veterans with diabetes (hazards ratio [HR] = 2.22, 95% confidence interval [CI] 1.04–4.75, P ≤ 0.05) or high cholesterol (HR = 3.11, 95% CI 1.64–5.87, P ≤ 0.05) compared to veterans without. Conclusions: This study identified CVH and lifestyle factors of MCI in UK veterans and non-veterans. Further work is needed to understand these associations and the underpinning mechanisms which could determine intervention strategies to reduce the risk of MCI.This study was funded as part of a PhD studentship by Alzheimer’s Society (award no. 475 [AS-PhD-18b-002]). The PROTECT study was externally funded/supported by the National Institute of Health and Care Research Exeter Biomedical Research Centre. The Family History of Neurological Disease Questionnaire was funded in part by the Alzheimer’s Research UK South West Network

Is lifetime traumatic brain injury a risk factor for mild cognitive impairment in veterans compared to non-veterans?

Data availability statement: Owing to the nature of the research, for ethical reasons supporting data are not available.Supplemental data for this article can be accessed online at: https://doi.org/10.1080/20008066.2023.2291965 .Copyright . Background: Traumatic brain injury (TBI) is prevalent in veterans and may occur at any stages of their life (before, during, or after military service). This is of particular concern, as previous evidence in the general population has identified TBI as a strong risk factor for mild cognitive impairment (MCI), a known precursor of dementia. Objectives: This study aimed to investigate whether exposure to at least one TBI across the lifetime was a risk factor for MCI in ageing UK veterans compared to non-veterans. Method: This cross-sectional study comprised of data from PROTECT, a cohort study comprising UK veterans and non-veterans aged ≥ 50 years at baseline. Veteran and TBI status were self-reported using the Military Service History Questionnaire (MSHQ) and the Brain Injury Screening Questionnaire (BISQ), respectively. MCI was the outcome of interest, and was defined as subjective cognitive impairment and objective cognitive impairment. Results: The sample population comprised of veterans (n = 701) and non-veterans (n = 12,389). TBI was a significant risk factor for MCI in the overall sample (OR = 1.21, 95% CI 1.11–1.31) compared to individuals without TBI. The prevalence of TBI was significantly higher in veterans compared to non-veterans (69.9% vs 59.5%, p < .001). There was no significant difference in the risk of MCI between veterans with TBI and non-veterans with TBI (OR = 1.19, 95% CI 0.98–1.45). Conclusion: TBI remains an important risk factor for MCI, irrespective of veteran status. The clinical implications indicate the need for early intervention for MCI prevention after TBI.Resumen: Antecedentes: El traumatismo encéfalocraneano (TEC) es frecuente en veteranos, el cual puede ocurrir en cualquier etapa de sus vidas (antes, durante o después del servicio militar). Esto es motivo de preocupación, ya que evidencia previa en la población general ha identificado al TEC como un fuerte factor de riesgo de Deterioro Cognitivo Leve (DCL), un precursor conocido de demencia. Objetivo: Este estudio tuvo como objetivo investigar si la exposición a al menos un Traumatismo encéfalocraneano a lo largo de la vida era un factor de riesgo de Deterioro Cognitivo Leve en veteranos del Reino Unido en comparación con no veteranos. Método: Este estudio de corte transversal incluyó datos de PROTECT, un estudio de cohorte que incluye a veteranos y no veteranos del Reino Unido de ≥50 años al inicio del estudio. El estatus de veterano y de Traumatismo encéfalocraneano (TEC) se auto-reportaron utilizando el Cuestionario de Historia de Servicio Militar (MSHQ, por sus siglas en inglés) y el Cuestionario de Detección de Traumatismo encéfalocraneano (BISQ, por sus siglas en inglés), respectivamente. El Deterioro Cognitivo Leve (DCL) fue el resultado de interés, definido como deterioro cognitivo subjetivo y deterioro cognitivo objetivo. Resultados: La muestra poblacional incluyó a veteranos (n = 701) y no veteranos (n = 12.389). El Traumatismo encéfalocraneano (TEC) fue un factor de riesgo significativo de Deterioro Cognitivo Leve (DCL) en la muestra total (OR = 1.21, IC del 95% 1.11–1.31) en comparación con individuos sin TEC. La prevalencia de TEC fue significativamente mayor en veteranos en comparación con no veteranos (69.9% vs 59.5%, p < .001). No hubo diferencia significativa en el riesgo de DCL entre veteranos con TEC y no veteranos con TEC (OR = 1.19, IC del 95% 0.98–1.45). Conclusión: El Traumatismo encéfalocraneano (TEC) continúa siendo un factor de riesgo significativo de Deterioro Cognitivo Leve (DCL), independiente del estatus de veterano. Las implicaciones clínicas sugieren la necesidad de intervenciones tempranas para la prevención de DCL después de un TEC.PhD studentship by the Alzheimer’s Society (award no. 475 [AS-PhD-18b-002]). The PROTECT study was externally funded/supported by the National Institute of Health and Care Research, Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The Family History of Neurological Disease Questionnaire was funded in part by the Alzheimer’s Research UK South West Network

Psychosocial impact of the COVID-19 pandemic on 4378 UK healthcare workers and ancillary staff: initial baseline data from a cohort study collected during the first wave of the pandemic

OBJECTIVES: This study reports preliminary findings on the prevalence of, and factors associated with, mental health and well-being outcomes of healthcare workers during the early months (April-June) of the COVID-19 pandemic in the UK. METHODS: Preliminary cross-sectional data were analysed from a cohort study (n=4378). Clinical and non-clinical staff of three London-based NHS Trusts, including acute and mental health Trusts, took part in an online baseline survey. The primary outcome measure used is the presence of probable common mental disorders (CMDs), measured by the General Health Questionnaire. Secondary outcomes are probable anxiety (seven-item Generalised Anxiety Disorder), depression (nine-item Patient Health Questionnaire), post-traumatic stress disorder (PTSD) (six-item Post-Traumatic Stress Disorder checklist), suicidal ideation (Clinical Interview Schedule) and alcohol use (Alcohol Use Disorder Identification Test). Moral injury is measured using the Moray Injury Event Scale. RESULTS: Analyses showed substantial levels of probable CMDs (58.9%, 95% CI 58.1 to 60.8) and of PTSD (30.2%, 95% CI 28.1 to 32.5) with lower levels of depression (27.3%, 95% CI 25.3 to 29.4), anxiety (23.2%, 95% CI 21.3 to 25.3) and alcohol misuse (10.5%, 95% CI 9.2 to 11.9). Women, younger staff and nurses tended to have poorer outcomes than other staff, except for alcohol misuse. Higher reported exposure to moral injury (distress resulting from violation of one's moral code) was strongly associated with increased levels of probable CMDs, anxiety, depression, PTSD symptoms and alcohol misuse. CONCLUSIONS: Our findings suggest that mental health support for healthcare workers should consider those demographics and occupations at highest risk. Rigorous longitudinal data are needed in order to respond to the potential long-term mental health impacts of the pandemic

Mutation-specific reporter for optimization and enrichment of prime editing

Prime editing is a versatile genome-editing technique that shows great promise for the generation and repair of patient mutations. However, some genomic sites are difficult to edit and optimal design of prime-editing tools remains elusive. Here we present a fluorescent prime editing and enrichment reporter (fluoPEER), which can be tailored to any genomic target site. This system rapidly and faithfully ranks the efficiency of prime edit guide RNAs (pegRNAs) combined with any prime editor variant. We apply fluoPEER to instruct correction of pathogenic variants in patient cells and find that plasmid editing enriches for genomic editing up to 3-fold compared to conventional enrichment strategies. DNA repair and cell cycle-related genes are enriched in the transcriptome of edited cells. Stalling cells in the G1/S boundary increases prime editing efficiency up to 30%. Together, our results show that fluoPEER can be employed for rapid and efficient correction of patient cells, selection of gene-edited cells, and elucidation of cellular mechanisms needed for successful prime editing

Ethnic inequalities among NHS staff in England: workplace experiences during the COVID-19 pandemic

Objectives This study aims to determine how workplace experiences of National Health Service (NHS) staff varied by ethnicity during the COVID-19 pandemic and how these experiences are associated with mental and physical health at the time of the study. Methods An online Inequalities Survey was conducted by the Tackling Inequalities and Discrimination Experiences in Health Services study in collaboration with NHS CHECK. This Inequalities Survey collected measures relating to workplace experiences (such as personal protective equipment (PPE), risk assessments, redeployments and discrimination) as well as mental health (Patient Health Questionnaire (PHQ-9), Generalised Anxiety Disorder 7 (GAD-7)), and physical health (PHQ-15) from NHS staff working in the 18 trusts participating with the NHS CHECK study between February and October 2021 (N=4622). Results Regression analysis of this cross-sectional data revealed that staff from black and mixed/other ethnic groups had greater odds of experiencing workplace harassment (adjusted OR (AOR) 2.43 (95% CI 1.56 to 3.78) and 2.38 (95% CI 1.12 to 5.07), respectively) and discrimination (AOR 4.36 (95% CI 2.73 to 6.96) and 3.94 (95% CI 1.67 to 9.33), respectively) compared with white British staff. Staff from black ethnic groups also had greater odds than white British staff of reporting PPE unavailability (AOR 2.16 (95% CI 1.16 to 4.00)). Such workplace experiences were associated with negative physical and mental health outcomes, though this association varied by ethnicity. Conversely, understanding employment rights around redeployment, being informed about and having the ability to inform redeployment decisions were associated with lower odds of poor physical and mental health. Conclusions Structural changes to the way staff from ethnically minoritised groups are supported, and how their complaints are addressed by leaders within the NHS are urgently required