Complement-Mediated Virus Infectivity Neutralisation by HLA Antibodies Is Associated with Sterilising Immunity to SIV Challenge in the Macaque Model for HIV/AIDS.

Sterilising immunity is a desired outcome for vaccination against human immunodeficiency virus (HIV) and has been observed in the macaque model using inactivated simian immunodeficiency virus (SIV). This protection was attributed to antibodies specific for cell proteins including human leucocyte antigens (HLA) class I and II incorporated into virions during vaccine and challenge virus preparation. We show here, using HLA bead arrays, that vaccinated macaques protected from virus challenge had higher serum antibody reactivity compared with non-protected animals. Moreover, reactivity was shown to be directed against HLA framework determinants. Previous studies failed to correlate serum antibody mediated virus neutralisation with protection and were confounded by cytotoxic effects. Using a virus entry assay based on TZM-bl cells we now report that, in the presence of complement, serum antibody titres that neutralise virus infectivity were higher in protected animals. We propose that complement-augmented virus neutralisation is a key factor in inducing sterilising immunity and may be difficult to achieve with HIV/SIV Env-based vaccines. Understanding how to overcome the apparent block of inactivated SIV vaccines to elicit anti-envelope protein antibodies that effectively engage the complement system could enable novel anti-HIV antibody vaccines that induce potent, virolytic serological response to be developed

The association between trajectories of change in social functioning and psychological treatment outcome in university students: a growth mixture model analysis

BACKGROUND: The transition to university and resultant social support network disruption can be detrimental to the mental health of university students. As the need for mental health support is becoming increasingly prevalent in students, identification of factors associated with poorer outcomes is a priority. Changes in social functioning have a bi-directional relationship with mental health, however it is not clear how such measures may be related to effectiveness of psychological treatments. METHODS: Growth mixture models were estimated on a sample of 5221 students treated in routine mental health services to identify different trajectories of change in self-rated impairment in social leisure activities and close relationships during the course of treatment. Multinomial regression explored associations between trajectory classes and treatment outcomes. RESULTS: Five trajectory classes were identified for social leisure activity impairment while three classes were identified for close relationship impairment. In both measures most students remained mildly impaired. Other trajectories included severe impairment with limited improvement, severe impairment with delayed improvement, and, in social leisure activities only, rapid improvement, and deterioration. Trajectories of improvement were associated with positive treatment outcomes while trajectories of worsening or stable severe impairment were associated with negative treatment outcomes. CONCLUSIONS: Changes in social functioning impairment are associated with psychological treatment outcomes in students, suggesting that these changes may be associated with treatment effectiveness as well as recovery experiences. Future research should seek to establish whether a causal link exists to understand whether integrating social support within psychological treatment may bring additional benefit for students

Examining the Lancet Commission risk factors for dementia using Mendelian randomisation

BACKGROUND: Dementia incidence is increasing across the globe and currently there are no disease-modifying pharmaceutical treatments. The Lancet Commission on dementia identified 12 modifiable risk factors which explain 40% of dementia incidence. However, whether these associations are causal in nature is unclear. OBJECTIVE: To examine the modifiable risk factors for dementia as identified in the Lancet Commission review using Mendelian randomisation (MR) to establish if, based on genetic evidence, these associations with different dementia subtypes are causal in nature. METHODS: Publicly available genome-wide association study data were used for 10 risk factors and Alzheimer’s disease (AD), frontotemporal dementia and dementia with Lewy bodies. Two-sample MR using the inverse varianceweighted method was conducted to test for causal relationships. Weighted median MR and MR-Egger were used to test for pleiotropic effects. RESULTS: Genetic proxied risk for higher levels of smoking (OR: 0.80 (95% CI: 0.69; 0.92), p=0.002), obesity (OR: 0.87 (95% CI: 0.82; 0.92), p<0.001) and blood pressure (OR: 0.90 (95% CI: 0.82; 0.99), p=0.035) appeared to be protective against the risk of AD. Post hoc analyses indicated these associations had pleiotropic effects with the risk of coronary artery disease. Genetic proxied risk of educational attainment was found to be inconsistently associated with the risk of AD. CONCLUSIONS AND IMPLICATIONS: Post hoc analysis indicated that the apparent protective effects of smoking, obesity and blood pressure were a result of survivor bias. The findings from this study did not support those presented by the Lancet Commission. Evidence from causal inference studies should be considered alongside evidence from epidemiological studies and incorporated into reviews of the literature

Measurement invariance of the PHQ-9 and GAD-7 across males and females seeking treatment for common mental health disorders

BACKGROUND: The nine-item Patient Health Questionnaire (PHQ-9) and the seven-item Generalised Anxiety Disorder scale (GAD-7) scales are routinely used in research and clinical practice. Whilst measurement invariance of these measures across gender has been demonstrated individually in general population studies and clinical samples, less is known about invariance of the distinct but correlated latent factors ('depression' and 'anxiety'). The current study assessed measurement invariance of these constructs across males and females seeking treatment for common mental health disorders. METHODS: Data were provided from eight psychological treatment services in London, England. Data from initial assessments with the services where individual items on the PHQ-9 and GAD-7 were available were included in analyses. Measurement invariance was explored across self-identified genders, with 'male' and 'female' categories available in the dataset. Sensitivity analyses were conducted using propensity score matching on sociodemographic and clinical variables. RESULTS: Data were available for 165,872 patients (110,833 females, 55,039 males). There was evidence of measurement invariance between males and females in both the full sample and a propensity score matched sample (n = 46,249 in each group). CONCLUSIONS: Measurement invariance of the correlated depression and anxiety factors of PHQ-9 and GAD-7 were indicated in this sample of individuals seeking psychological treatment for CMHDs. These results support the use of these measures in routine clinical practice for both males and females. This is of particular importance for assessing the prevalence of clinically significant levels of symptoms as well as comparing treatment outcomes across genders

A service evaluation of phased- and stepped-care psychological support for health and social care workers during the COVID-19 pandemic

BACKGROUND: The COVID-19 pandemic has disproportionally affected the mental health of health and social care workers (HSCWs), with many experiencing symptoms of depression, anxiety and post-traumatic stress disorder. Psychological interventions have been offered via mental health services and in-house psychology teams, but their effectiveness in this context is not well documented. AIMS: To evaluate a stepped-care psychological support pathway for HSCWs from Homerton Healthcare Foundation Trust in London, which offered psychological first aid, evidence-based psychological therapies and group-based well-being workshops. METHOD: The service evaluation used a pre-post approach to assess depression, anxiety, functional impairment and post-traumatic stress disorder symptom change for those who attended sessions of psychological first aid, low- or high-intensity cognitive-behavioural therapy or a combination of these. In addition, the acceptability of the psychological first aid sessions and well-being workshops was explored via feedback data. RESULTS: Across all interventions, statistically significant reductions of depression (d = 1.33), anxiety (d = 1.37) and functional impairment (d = 0.93) were observed, and these reductions were equivalent between the interventions, as well as the demographic and occupational differences between the HSCWs (ethnicity, staff group and redeployment status). HSCWs were highly satisfied with the psychological first aid and well-being workshops. CONCLUSIONS: The evaluation supports the utility of evidence-based interventions delivered as part of a stepped-care pathway for HSCWs with common mental health problems in the context of the COVID-19 pandemic. Given the novel integration of psychological first aid within the stepped-care model as a step one intervention, replication and further testing in larger-scale studies is warranted

Gene conversion in human rearranged immunoglobulin genes

Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V&lt;sub&gt;H&lt;/sub&gt; segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V&lt;sub&gt;H&lt;/sub&gt; replacements with no addition of untemplated nucleotides at the V&lt;sub&gt;H&lt;/sub&gt;–V&lt;sub&gt;H&lt;/sub&gt; joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V&lt;sub&gt;H&lt;/sub&gt; replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion

Psychological therapies for depression and cardiovascular risk: evidence from national healthcare records in England

Aims: People with depression are up to 72% more at risk to develop cardiovascular disease (CVD) in their lifetime. Evidence-based psychotherapies are first-line interventions for the treatment of depression and are delivered nationally in England through the National Health Service via the Improving Access to Psychological Therapy (IAPT) primary care programme. It is currently unknown whether positive therapy outcomes may be associated with cardiovascular risk reduction. This study aimed to examine the association between psychotherapy outcomes for depression and incident CVD. Methods and results: A cohort of 636 955 individuals who have completed a course of psychotherapy was built from linked electronic healthcare record databases of national coverage in England: the national IAPT database, the Hospital Episode Statistics (HES) database, and the HES–ONS (Office of National Statistics) mortality database. Multivariable Cox models adjusting for clinical and demographic covariates were run to estimate the association between reliable improvement from depression and the risk of subsequent incidence of cardiovascular events. After a median follow-up of 3.1 years, reliable improvement from depression symptoms was associated with a lower risk of new onset of any CVD [hazard ratio (HR): 0.88, 95% confidence interval (CI): 0.86, 0.89], coronary heart disease (HR: 0.89, 95% CI: 0.86, 0.92), stroke (HR: 0.88, 95% CI: 0.83, 0.94), and all-cause mortality (HR: 0.81, 95% CI: 0.78, 0.84). This association was stronger in the under 60 compared with the over 60 for all outcomes. Results were confirmed in sensitivity analyses. Conclusion: Management of depression through psychological interventions may be associated with reduced risk of CVD. More research is needed to understand the causality of these associations

Autism in England: assessing underdiagnosis in a population-based cohort study of prospectively collected primary care data

Background: Autism has long been viewed as a paediatric condition, meaning that many autistic adults missed out on a diagnosis as children when autism was little known. We estimated numbers of diagnosed and undiagnosed autistic people in England, and examined how diagnostic rates differed by socio-demographic factors. / Methods: This population-based cohort study of prospectively collected primary care data from IQVIA Medical Research Data (IMRD) compared the prevalence of diagnosed autism to community prevalence to estimate underdiagnosis. 602,433 individuals registered at an English primary care practice in 2018 and 5,586,100 individuals registered between 2000 and 2018 were included. / Findings: Rates of diagnosed autism in children/young people were much higher than in adults/older adults. As of 2018, 2.94% of 10- to 14-year-olds had a diagnosis (1 in 34), vs. 0.02% aged 70+ (1 in 6000). Exploratory projections based on these data suggest that, as of 2018, 463,500 people (0.82% of the English population) may have been diagnosed autistic, and between 435,700 and 1,197,300 may be autistic and undiagnosed (59–72% of autistic people, 0.77%–2.12% of the English population). Age-related inequalities were also evident in new diagnoses (incidence): c.1 in 250 5- to 9-year-olds had a newly-recorded autism diagnosis in 2018, vs. c.1 in 4000 20- to 49-year-olds, and c.1 in 18,000 people aged 50+. / Interpretation: Substantial age-related differences in the proportions of people diagnosed suggest an urgent need to improve access to adult autism diagnostic services

Are students less likely to respond to routinely delivered psychological treatment? A retrospective cohort analysis

BACKGROUND: Depression and anxiety disorders are increasingly prevalent among university students, making the provision of effective treatment in this population a priority. Whilst campus-based services provide some psychological treatments, many students are treated by routine adult psychological treatment services which have no focus or adaptations to treatment for student populations. We aimed to compare psychological treatment outcomes between university students and young adults (aged 18-25) in employment to explore whether routinely delivered psychological interventions are equally effective for these groups, or whether students report poorer outcomes. METHODS: A retrospective cohort was formed of 19,707 patients treated by eight National Health Service (NHS) Improving Access to Psychological Therapies (IAPT) services in England. Associations between student status (compared to same-age employed adults) and psychological treatment outcomes were explored using logistic regression models. Models were adjusted for important treatment, clinical and demographic characteristics, and propensity score matching was used to explore the robustness of effects. RESULTS: Students and the employed comparison group were similar on baseline characteristics at assessment, but students were less likely to reliably recover (OR = 0.90 [95% CI = 0.83;0.96]) and reliably improve (OR = 0.91 [95% CI = 0.84;0.98]) by the end of treatment in fully adjusted models. Students and the employed group did not differ regarding the likelihood of deterioration (OR = 0.89 [95% CI = 0.78;1.02]) or treatment dropout (OR = 1.01 [95% CI = 0.93;1.11]). CONCLUSIONS: Students appear at risk of poorer outcomes compared to employed younger adults when treated in routine psychological treatment services. Students may require additional support and treatment adaptations that account for student-specific stressors as this might improve psychological treatment outcomes

Salivary cortisol in longitudinal associations between affective symptoms and midlife cognitive function: A British birth cohort study

Affective disorders are associated with accelerated cognitive ageing. However, current understanding of biological mechanisms which underlie these observed associations is limited. The aim of this study was to test: 1) Whether cortisol acts as a pathway in the association between depressive or anxiety symptoms across adulthood and midlife cognitive function; 2) Whether cortisol is associated with later depressive or anxiety symptoms, and cognitive function. Data were used from the National Child Development Study, a sample of infants born in mainland UK during one week of 1958. A measure of the accumulation of affective symptoms was derived from data collected from age 23 to 42 using the Malaise Inventory Scale. Salivary cortisol measures were available at age 44–45. Cognitive function (memory, fluency, information processing) and affective symptoms were assessed at the age of 50. Path models were run to test whether salivary cortisol explained the longitudinal association between depressive or anxiety disorder symptoms and cognitive function. Direct effects of affective symptoms are shown across early to middle adulthood on cognitive function in midlife (memory and information processing errors). However, there were no effects of affective symptoms on cognitive function through cortisol measures. Additionally, cortisol measures were not significantly associated with subsequent affective symptoms or cognitive function at the age of 50. These results do not provide clear evidence to suggest that cortisol plays a role in the association between affective symptoms and cognitive function over this period of time. These findings contribute to our understanding of how the association between affective symptoms and cognitive function operates over time