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

Predictors of internalised HIV-related stigma: a systematic review of studies in sub-Saharan Africa

This systematic review aims to synthesise evidence on predictors of internalised HIV stigma amongst people living with HIV in sub-Saharan Africa. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used. Studies were identified through electronic databases, grey literature, reference harvesting and contacts with key researchers. Quality of findings was assessed through an adapted version of the Cambridge Quality Checklists. A total of 590 potentially relevant titles were identified. Seventeen peer-reviewed articles and one draft book chapter were included. Studies investigated socio-demographic, HIV-related, intra-personal and interpersonal correlates of internalised stigma. Eleven articles used cross-sectional data, six articles used prospective cohort data and one used both prospective cohort and cross-sectional data to assess correlates of internalised stigma. Poor HIV-related health weakly predicted increases in internalised HIV stigma in three longitudinal studies. Lower depression scores and improvements in overall mental health predicted reductions in internalised HIV stigma in two longitudinal studies, with moderate and weak effects, respectively. No other consistent predictors were found. Studies utilising analysis of change and accounting for confounding factors are necessary to guide policy and programming but are scarce. High-risk populations, other stigma markers that might layer upon internalised stigma, and structural drivers of internalised stigma need to be examined

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

Mental health outcomes of male UK military personnel deployed to Afghanistan and the role of combat injury: analysis of baseline data from the ADVANCE cohort study

Background: The long-term psychosocial outcomes of UK armed forces personnel who sustained serious combat injuries during deployment to Afghanistan are largely unknown. We aimed to assess rates of probable post-traumatic stress disorder (PTSD), depression, anxiety, and mental health-associated multimorbidity in a representative sample of serving and ex-serving UK military personnel with combat injuries, compared with rates in a matched sample of uninjured personnel. Methods: This analysis used baseline data from the ADVANCE cohort study, in which injured individuals were recruited from a sample of UK armed forces personnel who were deployed to Afghanistan and had physical combat injuries, according to records provided by the UK Ministry of Defence. Participants from the uninjured group were frequency-matched by age, rank, regiment, deployment, and role on deployment. Participants were recruited through postal, email, and telephone invitations. Participants completed a comprehensive health assessment, including physical health assessment and self-reported mental health measures (PTSD Checklist, Patient Health Questionnaire-9, and Generalised Anxiety Disorder-7). The mental health outcomes were rates of PTSD, depression, anxiety, and mental health-associated multimorbidity in the injured and uninjured groups. The ADVANCE study is ongoing and is registered with the ISRCTN registry, ISRCTN57285353. Findings: 579 combat-injured participants (161 with amputation injuries and 418 with non-amputation injuries) and 565 uninjured participants were included in the analysis. Participants had a median age of 33 years (IQR 30–37 years) at the time of assessment. 90·3% identified as White and 9·7% were from all other ethnic groups. The rates of PTSD (16·9% [n=89] vs 10·5% [n=53]; adjusted odds ratio [AOR] 1·67 [95% CI 1·16–2·41], depression (23·6% [n=129] vs 16·8% [n=87]; AOR 1·46 [1·08–2·03]), anxiety (20·8% [n=111] vs 13·5% [n=71]; AOR 1·56 [1·13–2·24]) and mental health-associated multimorbidity (15·3% [n=81] vs 9·8% [n=49]; AOR 1·62 [1·12–2·49]) were greater in the injured group than the uninjured group. Minimal differences in odds of reporting any poor mental health outcome were noted between the amputation injury subgroup and the uninjured group (AOR range 0·77–0·97), whereas up to double the odds were noted for the non-amputation injury subgroup compared with the uninjured group (AOR range 1·74–2·02). Interpretation: Serious physical combat injuries were associated with poor mental health outcomes. However, the type of injury sustained influenced this relationship. Regardless of injury, this cohort represents a group who present with greater rates of PTSD than the general population, as well as increased psychological burden from multimorbidity. Funding: The ADVANCE Charity

How can we actually change help-seeking behaviour for mental health problems among the general public? Development of the ‘PLACES’ model

Good treatment uptake is essential for clinically effective interventions to be fully utilised. Numerous studies have examined barriers to help-seeking for mental health treatment and to a lesser extent, facilitators. However, much of the current research focuses on changing help-seeking attitudes, which often do not lead to changes in behaviour. There is a clear gap in the literature for interventions that successfully change help-seeking behaviour among the general public. This gap is particularly relevant for early intervention. Here we describe the development of a new model which combines facilitators to treatment and an engaging, acceptable intervention for the general public. It is called the ‘PLACES’ (Publicity, Lay, Acceptable, Convenient, Effective, Self-referral) model of treatment engagement. It is based on theoretical work, as well as empirical research on a low intensity psychoeducational cognitive behavioural therapy (CBT) intervention: one-day workshops for stress and depression. In this paper, we describe the development of the model and the results of its use among four different clinical groups (adults experiencing stress, adults experiencing depression, adolescents (age 16–18) experiencing stress, and mothers with postnatal depression). We recorded high rates of uptake by people who have previously not sought help and by racial and ethnic minority groups across all four of these clinical groups. The clinical and research implications and applications of this model are discussed

The underlying mechanisms by which Post-Traumatic Growth is associated with cardiovascular health in male UK military personnel: The ADVANCE cohort study

Post-Traumatic Growth (PTG) is associated with good cardiovascular health, but the mechanisms of this are poorly understood. This cross-sectional analysis assessed whether factors of PTG (Appreciation of Life (AOL), New Possibilities (NP), Personal Strength (PS), Relating to Others (RTO) and Spiritual Change (SC)) are associated with cardiovascular health in a cohort of 1006 male UK military personnel (median age 34). The findings suggest AOL, PS and RTO are associated with better cardiovascular health through cardiometabolic effects (lower levels of triglycerides, and total cholesterol) and haemodynamic functioning (lower diastolic blood pressure), but not inflammation. However, NP and SC were associated with poorer cardiovascular health through cardiometabolic effects (lower levels of high-density lipoproteins and higher levels of total cholesterol) and AOL had a non-linear association with low-density lipoproteins. These findings suggest that the relationship between PTG and cardiovascular functioning is complex and in need of further scrutiny

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

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

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