“You’re 18 now, goodbye”: The experiences of young people with Attention Deficit Hyperactivity Disorder of the transition from child to adult services

This is the author accepted manuscript. The final version is available from Taylor & Francis (Routledge) via the DOI in this record.The term ‘transition’ is used to refer to the process of moving from child to adult services. Among child and adolescent mental health services attenders, young people with Attention Deficit Hyperactivity Disorder (ADHD) are less likely to transition successfully, but there is a gap in understanding their views and why they might disengage from services. The aim of this study was to explore the experiences of transition of young people with ADHD in Southwest England using semi-structured interviews and thematic analysis. Seven young people aged 17-19 years participated. Four key themes were identified: professionals’ roles and relationships with young people; the role of ADHD medication, uncertainties around transition and medication management, and identified needs and increasing independence. Although this study presents the experiences of a small number of people, their stories suggest that best practice around transition is not always being followed. There is consequently a need to better understand the facilitators and barriers to best practice implementation.This research was funded as part of a Doctoral Research Fellowship from the National Institute for Health Research held by Tamsin Newlove-Delgado(Reference: DRF-2012-05- 221). Tamsin Newlove-Delgado is currently funded by an NIHR Academic Clinical Lectureship. Ken Stein is funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula at Royal Devon and Exeter NHS Foundation Trust. This report is independent research and the views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health

Prescribing of medication for attention deficit hyperactivity disorder among young people in the Clinical Practice Research Datalink 2005-2013: analysis of time to cessation

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.The aim of this study was to examine the time to cessation of ADHD medication amongst young people with ADHD aged 16 in the period 2005-2013. Previous studies of prescribing in primary care reported high rates of medication cessation amongst 16 and 17 year olds with ADHD. The examination of trends since the introduction of new NICE guidance in 2008 will support service planning and improvement of outcomes over the vulnerable transition period from child to adult services. We used primary care records from the Clinical Practice Research Datalink and identified cases prescribed ADHD medication at the time of their 16th birthday during the study period. The outcome was time to medication cessation from the age of 16. Cessation of medication was defined as occurring at the beginning of a gap of over 6 months in prescriptions. 1620 cases were included. The median time to cessation was 1.51 years (95% CI 1.42-1.67).The estimated probability of remaining on medication was 0.63 (95% CI 0.61-0.65) at age 17 (i.e., at 1 year) and 0.41 (95% CI 0.39-0.43) at age 18. Young people with ADHD remain at high risk of cessation of medication during the transition from child to adult services. Despite the restriction that only primary care prescribing data were available, the results suggest continuing disparity between expected levels of symptom persistence and continuation of medication.This research was funded as part of a Doctoral Research Fellowship from the National Institute for Health Research held by Tamsin Newlove-Delgado (Reference: DRF-2012-05-221). Tamsin Newlove-Delgado is currently funded by an NIHR Academic Clinical Lectureship. Ken Stein and Obioha C. Ukoumunne were funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula at Royal Devon and Exeter NHS Foundation Trust. This report is independent research and the views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health

Children and young people’s reported contact with professional services for mental health concerns: a secondary data analysis

This is the final version. Available on open access from Springer via the DOI in this recordData availability: MHCYP 2017 survey data is available through data access request to NHS England’s DARS service, [email protected] and young people’s mental health services have been under increasing pressure following COVID-19. Understanding, for which channels help is sought from, will highlight services needing support. This study aims to explore the professional services that parents of children, and young people get help from when they have a concern for the child’s/their mental health. Secondary analysis of data is taken from Mental Health of Children and Young People in England Survey, 2017. 7608 reports of mental health-related contact with professional services from parents of 5–16 year-olds and self-reports from young people aged 17–19 were available. Service contact was reported by Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnosis, age, gender and ethnicity. Less than two-thirds of children and young people with a DSM-V diagnosis (63.5% (95% CI 58.6–68.1) aged 5–10, and 64.0% (95% CI 59.4–68.4) aged 11–16) reported contact with any professional services. The figure was lower for those aged 17–19; 50.1% (95% CI 42.8–58.2), p = 0.005. Children and young people aged 5–16 from Black (11.7%; 95% CI 2.4–41.4), Asian (55.1%; 95% CI 34.7–73.9) and Mixed (46.0%; 95% CI 32.4–60.3) ethnic groups reported less contact with professional services compared to those from the White group (66.9%; 95% CI 63.5–70.2). Patterns of service access during the three main educational stages aid with understanding service need during childhood. These lower levels of reported service access for young people aged 17–19 with a DSM-V diagnosis and those in ethnic minority groups demand further investigation.National Institute for Health and Care Research (NIHR)DHS

Superluminal neutrinos in long baseline experiments and SN1987a

Precise tests of Lorentz invariance in neutrinos can be performed using long baseline experiments such as MINOS and OPERA or neutrinos from astrophysical sources. The MINOS collaboration reported a measurement of the muonic neutrino velocities that hints to super-luminal propagation, very recently confirmed at 6 sigma by OPERA. We consider a general parametrisation which goes beyond the usual linear or quadratic violation considered in quantum-gravitational models. We also propose a toy model showing why Lorentz violation can be specific to the neutrino sector and give rise to a generic energy behaviour E^alpha, where alpha is not necessarily an integer number. Supernova bounds and the preferred MINOS and OPERA regions show a tension, due to the absence of shape distortion in the neutrino bunch in the far detector of MINOS. The energy independence of the effect has also been pointed out by the OPERA results.Comment: 22 pages, 7 figures; comment on Cherenkov emission added, version matching JHEP published pape

Experiences of help-seeking from professional services for a child or young person’s mental health concerns during the pandemic: A qualitative study

This is the final version. Available from Public Library of Science via the DOI in this record. Introduction The immediate response to the Covid-19 pandemic saw school closures and a shift in provision to online health services for children and young people experiencing mental health concerns. This study provides mental health and referral services with an insight into difficulties experienced as well as recommendations on potential improvements. Methods Semi-structured interviews with 11 parents and six young people. Reflexive thematic analysis was used to analyse the data. Results Parents and young people reported mixed experiences on accessing mental health support. Priorities and pressures on health services impacted the likelihood of choosing to seek and being able to obtain help. Parents and young people had varying expectations and experiences in help-seeking during the pandemic which were also impacted by others’ experiences and views. For many, the relationship with the professional they were in contact with impacted their mental health treatment. Provision was sometimes accessed via private services due to long waiting lists or problems that did not “meet threshold”. Conclusion Understanding the experiences of seeking mental healthcare during the pandemic can inform improvements to access to services at a time when people are most vulnerable. Accessible provision other than private services needs to be made for those on waiting lists. For those who do not meet service threshold, intermediary support needs to be secured to prevent unnecessary exacerbation of symptoms and prolonged problems. If schools are to remain the hub for children and young people’s mental health services, they should be considered essential services at all times.UK Research and InnovationNational Institute for Health Researc

Generation and characterization of two immortalized human osteoblastic cell lines useful for epigenetic studies

Different model systems using osteoblastic cell lines have been developed to help understand the process of bone formation. Here, we report the establishment of two human osteoblastic cell lines obtained from primary cultures upon transduction of immortalizing genes. The resulting cell lines had no major differences to their parental lines in their gene expression profiles. Similar to primary osteoblastic cells, osteocalcin transcription increased following 1,25-dihydroxyvitamin D3 treatment and the immortalized cells formed a mineralized matrix, as detected by Alizarin Red staining. Moreover, these human cell lines responded by upregulating ALPL gene expression after treatment with the demethylating agent 5-aza-2 Œ-deoxycytidine (AzadC), as shown before for primary osteoblasts. We further demonstrate that these cell lines can differentiate in vivo, using a hydroxyapatite/tricalcium phosphate composite as a scaffold, to produce bone matrix. More importantly, we show that these cells respond to demethylating treatment, as shown by the increase in SOST mRNA levels, the gene encoding sclerostin, upon treatment of the recipient mice with AzadC. This also confirms, in vivo, the role of DNA methylation in the regulation of SOST expression previously shown in vitro. Altogether our results show that these immortalized cell lines constitute a particularly useful model system to obtain further insight into bone homeostasis, and particularly into the epigenetic mechanisms regulating sclerostin production

Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours

Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only partially corresponded to the existing histological classification. Furthermore, by additional molecular analyses, we were able to identify pathogenic mutations in BRAF and FGFR1, specific to each group, in a high proportion of cases. Finally, by interrogating our expression data, we were able to show that each molecular group possessed expression phenotypes suggesting different cellular differentiation: astrocytic in one group and oligodendroglial in the second. Informed by this, we were able to identify CCND1, CSPG4, and PDGFRA as immunohistochemical targets which could distinguish between molecular groups. Our data suggest that the current histological classification of glioneuronal tumours does not adequately represent their underlying biology. Instead, we show that there are two molecular groups within glioneuronal tumours. The first of these displays astrocytic differentiation and is driven by BRAF mutations, while the second displays oligodendroglial differentiation and is driven by FGFR1 mutations

The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia

CD56 is expressed in 15–20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56+ monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56+ AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML

Positron Emission Tomography Imaging of CD105 Expression with a 64Cu-Labeled Monoclonal Antibody: NOTA Is Superior to DOTA

Optimizing the in vivo stability of positron emission tomography (PET) tracers is of critical importance to cancer diagnosis. In the case of 64Cu-labeled monoclonal antibodies (mAb), in vivo behavior and biodistribution is critically dependent on the performance of the bifunctional chelator used to conjugate the mAb to the radiolabel. This study compared the in vivo characteristics of 64Cu-labeled TRC105 (a chimeric mAb that binds to both human and murine CD105), through two commonly used chelators: 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Flow cytometry analysis confirmed that chelator conjugation of TRC105 did not affect its CD105 binding affinity or specificity. PET imaging and biodistribution studies in 4T1 murine breast tumor-bearing mice revealed that 64Cu-NOTA-TRC105 exhibited better stability than 64Cu-DOTA-TRC105 in vivo, which resulted in significantly lower liver uptake without compromising the tumor targeting efficiency. In conclusion, this study confirmed that NOTA is a superior chelator to DOTA for PET imaging with 64Cu-labeled TRC105

Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE(TM) study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE(TM) study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%), and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs. ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared to patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs. later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations