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Abstract SNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.

The story of the past 30 years has been the relentless hollowing-out of industrial Britain, the single biggest change to the British economy in the post-war era. During this period, whole communities have become destabilised by mass long-term unemployment resulting in discarded generations that have been excluded socially and economically from the benefits widely available to those in work (Hutton, 1996; Buchanan, 2000). It has been against this backdrop that the youth of the 80s and 90s turned to heroin in an attempt to block out the harsh social and economic realities of their lives (Buchanan and Wyke, 1987). Drawing on semi-structured interviews with twelve opiate-involved users (OIUs), this paper illuminates the harms experienced by those who began their drug taking during the 80s and 90s. Particularly, I argue that the negative consequences brought about by the broad umbrella of drug treatment policy that adopts a framework of risk-based strategies designed to regulate and control drug users has had a cumulative effect contributing to further experiences of stigma, unemployment, physical and mental ill health.

Post-COVID syndrome, defined as symptoms persisting for more than twelve weeks after the diagnosis of COVID-19, has been recognised as a new clinical entity in the context of SARS-CoV-2 infection. This study was conducted to characterise the burden and predictors for post-COVID-19 syndrome in the local population. It was a community-based web-survey study conducted in Norfolk, East England, UK. We sent the survey to patients with confirmed COVID-19 infection by real-time polymerase chain reaction by December 6th, 2020. Questions related to the pre-COVID and post-COVID level of symptoms and further healthcare use. Baseline characteristics were collected from the primary care records. Logistic regression analysis was conducted to establish predictors for post-COVID-19 syndrome and further healthcare utilisation. Of 6,318 patients, survey responses were obtained from 1,487 participants (23.5%). Post-COVID-19 syndrome symptoms were experienced by 774 (52.1%) respondents. Male sex compared to female sex was a factor protective of post-COVID symptoms; relative risk (RR) 0.748, 95% confidence interval (CI), 0.605-0.924. Body mass index was associated with a greater risk of developing post-COVID-19 symptoms (RR 1.031, 95% CI, 1.016-1.047, for 1 kg/m2). A total of 378 (25.4%) people used further health services after their index COVID-19 infection, of whom 277 (73.2%) had post-COVID symptoms. Male sex was negatively associated with the use of further health services (RR 0.618, 95% CI, 0.464-0.818) whereas BMI was positively associated (RR 1.027, 95% CI, 1.009-1.046). Overall, post-COVID-19 symptoms increased the probability of using health services with RR 3.280, 95% CI, 2.540-4.262. This survey of a large number of people previously diagnosed with COVID-19 across East England shows a high prevalence of self-reported post-COVID-19 syndrome. Female sex and BMI were associated with an increased risk of post-COVID-19 syndrome and further utilisation of healthcare.

Abstract Background Substance misuse, including problematic drug and alcohol use, are significant issues in society that can have multiple detrimental effects. Many people access support for their substance misuse during prison sentences, due to the associations between substance misuse and offending, and the high proportion of the prison population who have drug and alcohol issues. Breaking Free Online Health and Justice is a computer-assisted therapy program that has been developed to support substance-involved offenders to address their substance misuse and associated offending within prison settings. Methods This will be a parallel-group randomized controlled trial of 4-week Breaking Free Online Health and Justice program as an adjunct to standard treatment for substance misuse, in comparison to standard treatment only, in a male Category D open prison. Interventional and control groups will be compared in terms of the changes in their scores on multiple measures from baseline to post-treatment assessment at 4-weeks, and then 3- and 6-months follow-up. Participants will be adult male offenders serving sentences in prison in England who have demonstrable difficulties with drugs and/or alcohol for at least the past 12-months. The primary outcome measure will be self-reported substance misuse, with secondary outcomes being standardized psychometric assessments of substance dependence, mental health, biopsychosocial functioning, quality of life and post-release offending. Other secondary measures will include frequency of completion of specific intervention strategies in the program. Discussion This study will examine whether Breaking Free Online Health and Justice as an adjunct to standard substance misuse interventions in prisons, improves outcomes for substance-involved offenders receiving interventions in custodial settings. Findings from the study will be used to inform further developments of the program and potential improvements to custodial treatment. Trials registration ISRCTN09846981.

Background: Within the United Kingdom’s ‘Transforming Rehabilitation’ agenda, reshaping drug and alcohol interventions in prisons is central to the Government’s approach to addressing substance dependence in the prison population and reduce reoffending. To achieve this, a through-care project to support offenders following release, ‘Gateways’, is taking place providing ‘through the gate’ support to released offenders, including help with organising accommodation, education and employment, and access to a peer supporter. In addition, Gateways is providing access to an evidence-based computer-assisted therapy (CAT) programme for substance misuse, Breaking Free Health & Justice (BFHJ). Developed in partnership with the Ministry of Justice (MoJ) National Offender Management Services (NOMS), and based on a community version of the programme, Breaking Free Online (BFO), BFHJ provides access to clinically-robust techniques based on cognitive behavioural therapy (CBT) and promotes the role of technology-enhanced approaches in recovery from substance misuse. The BFHJ programme is provided via ‘Virtual Campus’ (VC), a secure, web-based learning environment delivered by NOMS and the Department for Business, Innovation and Skills, which has no links to websites not approved by MoJ, and provides prisoners with access to online training courses around work and skills. Providing BFHJ on VC makes the programme the world’s first online healthcare programme to be provided in prisons. Aims: Although here is an emerging evidence-base for the effectiveness of the community version of the BFO programme and its implementation within community treatment settings (Davies, Elison, Ward, & Laudet, 2015; Elison, Davies, & Ward, 2015a, 2015b; Elison, Humphreys, Ward, & Davies, 2013; Elison, Ward, Davies, Lidbetter, et al., 2014; Elison, Ward, Davies, & Moody, 2014), its potential within prison settings requires exploration. This study therefore sought to examine the processes of implementation of this novel digital health programme and the various barriers and facilitators of this, including the practicalities of providing an online treatment programme in an environment in which there are multiple, complex security requirements and considerations. Additionally, the acceptability of the BFHJ programme to prisoners who may have limited experience of using online technologies was also explored. Clinical outcomes in terms of the programmes impact on substance dependence and use were also examined. Methods: In line with the Medical Research Council (MRC) guidelines around development and evaluation of complex interventions (Craig et al., 2008), a mixed-methods approach was used including a qualitative study to explore the implementation of this online treatment programme within the secure prison environment, and offender perceptions of this novel, technology-enhanced approach to substance misuse treatment. In addition, quantitative data derived from a battery of standardised psychometric assessments was used to examine clinical effectiveness of BFHJ. Results: In order to meet MoJ security requirements prior to implementation, the BFHJ programme had to be reviewed and ‘white listed’ by NOMS and their security partner XMA to ensure the programme met all security, quality and information assurance processes and standards. This was a lengthy and costly process that entailed freshly developing the programme in partnership with VC experts at NOMS to ensure the programme is ‘sterile’ i.e., there are no holes in the system or links to external websites – this comprised some aspects of the programme content and resulted in some clinical techniques requiring reworking e.g., removing Google maps from one section of the programme. Themes emerging from qualitative data around offenders experiences of BFHJ illustrate its potential for use in prison settings and also to provide, for the first time, genuine continuity of care during transfer between different prisons and upon release from prison into the community, given prisoners can access their BFHJ programme account regardless of their location. In terms of clinical outcomes, changes in psychometric scores from baseline to follow-up indicated significant reductions in dependence to drugs and alcohol, alongside improvements to quality of life and other aspects of psychosocial functioning relevant to substance misuse and recovery progression. Linear regression were conducted for each psychometric outcome to examine whether time periods in weeks between baseline and follow-up assessment acted as predictors of change in psychometric scores. Time elapsed between assessments did not predict change in scores for severity of dependence to drugs and alcohol or quality of life. However, time between baseline and follow-up assessment did significantly predict change in psychosocial aspects of recovery progression. In addition, degree of improvement on the outcomes measured appeared to be associated with prisoner age, with older prisoners demonstrating greater improvements than younger prisoners. Conclusions: Findings from this study support the use of BFHJ within prisons settings in terms of acceptability of this technology-enhanced approach to treatment, despite the complexities around implementing an online treatment programme in the highly digitally secure setting of the prison estate. Additionally, clinical outcomes appear to replicate the outcomes from studies of the programme in community-based substance misuse treatment settings. Further work is now underway, including a randomised controlled trial (RCT) and longer-term follow-up of substance use and offending outcomes, which is being conducted in collaboration with the MoJ Justice Data Lab.