Identifying prognostic indicators for cognitive stimulation therapy for dementia: protocol for a systematic review and individual participant data meta-analysis

BACKGROUND: Cognitive stimulation therapy (CST) is the only non-pharmacological, treatment for dementia recommended by the UK National Institute for Health and Care Excellence, following multiple international trials demonstrating beneficial cognitive outcomes in people with mild-to-moderate dementia. However, there is limited understanding of whether treatment prognosis is influenced by sociodemographic and clinical variables (such as dementia subtype and gender), information which could inform clinical decision-making. AIM: We describe the protocol for a systematic review and individual patient data meta-analysis assessing the prognostic factors related to CST. In publishing this protocol, we hope to increase the transparency of our work, and keep healthcare professionals aware of the latest evidence for effective CST. METHOD: A systematic review will be conducted with searches of the bibliographic databases Medline, EMBASE and PsycINFO, from inception to 7 February 2023. Studies will be included if they are clinical trials of CST, use the Alzheimer's Disease Assessment Scale - Cognitive Subscale (gold-standard measure of cognition in dementia in clinical trials) and include participants with mild-to-moderate dementia. Following harmonisation of the data-set, mixed-effect models will be constructed to explore the relationship between the prognostic indicators and change scores post-treatment. CONCLUSIONS: This is the first individual patient data meta-analyses on CST, and has the potential to significantly optimise patient care. Previous analyses suggest people with advanced dementia could benefit more from CST treatment. Given that CST is currently used post-diagnosis in people with mild-to-moderate dementia, the implications of confirming this finding, among identifying other prognostic indicators, are profound

Understanding differences in mental health service use by men: an intersectional analysis of routine data

Purpose: Rates of help-seeking for common mental health problems are lower for men, but less is known about patterns of engagement once they are in contact with services. Previous research has been limited in its ability to understand the intersection between service user characteristics and engagement. This study compared analytic approaches to investigate intersectional associations between sociodemographic and socioeconomic indicators and use of psychological treatment services by men. Method: Data from 9,904 male service users attending two psychological treatment services in London were analysed. The association between ethnicity, sexual orientation, religious affiliation and employment status of service users and service use outcomes was explored using multinomial logistic regression and latent class analysis (LCA). Results: Being from a minoritised ethnic background, of Muslim faith, being unemployed, and living in the most deprived neighbourhoods were associated with greater risk of not commencing or completing treatment. Seven classes were identified in LCA, with men predominately differentiated by self-reported ethnicity and religion. Compared with the ‘White British, non-religious’ class, the ‘Asian Muslim’ class and the ‘minoritised ethnic, non-religious’ class were at higher risk of disengagement, whilst the ‘Asian, other religion’ class were at higher risk of being referred elsewhere rather than completing initiated treatment. Conclusions: There were significant inequalities in engagement by men associated with ethnicity, religion and socioeconomic status. Compared with the regression models, further nuance was apparent in LCA regarding the intersection of gender, religion and ethnicity. Identifying groups at greater risk of discontinuation of treatment could inform more personalised pathways through care

Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel

Background Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis. Objective To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease. Design, setting, and participants We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at ≤60 yr) and 1160 selected controls. Outcome measurements and statistical analysis Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and aggressive (Gleason score ≥8, n = 201) versus nonaggressive (Gleason score ≤7, n = 1048) cases. Results and limitations We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio [OR] = 1.29, 95% confidence interval [CI] 1.01–1.64, p = 0.036). Gene-level analyses selected NBN (pSKAT-O = 2.4 × 10−4) for overall risk and XPC (pSKAT-O = 1.6 × 10−4) for aggressive disease, both at candidate-level significance (p < 3.1 × 10−4 and p < 3.4 × 10−4, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR = 3.2, 95% CI 2.1–4.8, pADA = 4.1 × 10−3) and four genes that increased risk of aggressive disease (OR = 11.2, 95% CI 4.6–27.7, pADA = 5.6 × 10−3), three of which overlap the predisposition gene set. Conclusions The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential. Patient summary This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice

Symptom-specific effects of counselling for depression compared to cognitive-behavioural therapy

BACKGROUND: Cognitive-behavioural therapy (CBT) and counselling for depression (CfD) are recommended first-line treatments for depression. While they approach change differently, there is little understanding of the impact those approaches have on change during treatment. OBJECTIVES: This study aimed to identify whether CBT and CfD target different symptoms and explore the implications of modelling choices when quantifying change during treatment. METHODS: Symptom-specific effects of treatment were identified using moderated network modelling. This was a retrospective cohort study of 12 756 individuals who received CBT or CfD for depression in primary/community care psychological therapy services in England. Change was modelled several ways within the whole sample and a propensity score matched sample (n=3446). FINDINGS: CBT for depression directly affected excessive worry, trouble relaxing and apprehensive expectation and had a stronger influence on changes between suicidal ideation and concentration. CfD had a stronger direct influence on thoughts of being a failure and on the associated change between being an easily annoyed and apprehensive of expectation. There were inconsistencies when modelling change using the first and second appointments as the baseline. Residual score models produced more conservative findings than models using difference scores. CONCLUSIONS: CfD and CBT for depression have differential effects on symptoms demonstrating specific mechanisms of change. CLINICAL IMPLICATIONS: CBT was uniquely associated with changes in symptoms associated with anxiety and may be better suited to those with anxiety symptoms comorbid to their depression. When assessing change, the baseline should be the first therapy session, not the pretreatment assessment. Residual change scores should be preferred over difference score methods

PCBs Exert an Estrogenic Effect through Repression of the Wnt7a Signaling Pathway in the Female Reproductive Tract

Polychlorinated biphenyls (PCBs) have been proposed to have a weak estrogenic activity and therefore pose a risk as potential environmental endocrine disruptors to the perinatal development of the female reproductive tract. Perinatal exposure to high concentrations of the potent synthetic estrogen diethylstilbestrol (DES) induces abnormal development of the female reproductive tract via a mechanism that acts through the down-regulation of Wnt7a (wingless-type MMTV integration site family, member 7A). To test the hypothesis that PCBs act as weak estrogens, we injected neonatal mice with a commercial PCB mixture (Aroclor 1254) or with low levels of DES and measured effects of exposure on Wnt7a expression and uterine morphology. We report here that neonatal PCB or low-level DES exposure resulted in the down-regulation of Wnt7a expression. In addition, both PCB and low-level DES exposure induced changes in the uterine myometrium and gland formation. These data reveal that weak estrogens such as the PCBs act through a Wnt7a-dependent pathway and suggest that Wnt7a regulation is a sensitive biomarker for testing weak estrogenic candidate compounds. The morphologic changes that were elicited by PCBs and DES were different immediately after exposure, suggesting that Wnt7a-independent pathways are also activated by one or both of these compounds. Although Wnt7a down-regulation is transient after estrogenic exposure, subsequent morphologic changes became more pronounced during postnatal and adult life, suggesting that the female reproductive tract is permanently reprogrammed after exposure even to weak estrogenic compounds. In addition, Wnt7a heterozygous mice were more sensitive to PCB exposure, revealing an important genetic predisposition to risks of environmental endocrine disruptors

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

LocusExplorer: a user-friendly tool for integrated visualization of human genetic association data and biological annotations.

Unlabelled : In this article, we present LocusExplorer, a data visualization and exploration tool for genetic association data. LocusExplorer is written in R using the Shiny library, providing access to powerful R-based functions through a simple user interface. LocusExplorer allows users to simultaneously display genetic, statistical and biological data for humans in a single image and allows dynamic zooming and customization of the plot features. Publication quality plots may then be produced in a variety of file formats.Availability and implementation LocusExplorer is open source and runs through R and a web browser. It is available at www.oncogenetics.icr.ac.uk/LocusExplorer/ or can be installed locally and the source code accessed from https://github.com/oncogenetics/LocusExplorerContact [email protected]