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Aim(s): This systematic review aims to provide an overview of evidence regarding the link between offending and mental health difficulties, before focusing upon young people's (YP's), parents' and professionals' experiences of mental health provision. Method/Rationale: Within the literature there is a wealth of quantitative research focused upon the needs of young offenders (YOs); however, less weighting is given to individuals' perspectives. Consequently, this paper aims to explore how mental health provision is experienced by those in the system. Four databases were included in the systematic search (PsychINFO (1806 to present), EBSCO, ERIC, and ProQuest) and seven papers were selected, published between 2004 and 2016. Findings: Findings indicate that barriers to help-seeking include: stigma, self-reliance, lack of trust, poor relationships, perceived lack of control and poor emotional literacy. Accessibility of social support was identified as a facilitating factor, alongside non-judgemental, trustworthy professionals with sound knowledge of YP's developmental and mental health needs. Limitations: This paper outlines a small-scale systematic literature review including seven qualitative papers; therefore, findings cannot be generalised to the wider population of YOs. Conclusions: Results support a contextualised understanding of YOs' experience of mental health provision. Findings are expected to support the development of effective mental health strategies for young offenders in the future. Implications for professional practice are considered alongside recommendations for the role of Educational Psychologists (EPs).

BackgroundThe appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy.MethodsUsing an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis.ResultsA total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]).ConclusionsIn this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.).

Childhood-onset psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), mood disorders, obsessive compulsive spectrum disorders (OCSD), and schizophrenia (SZ), affect many school-age children, leading to a lower quality of life, including difficulties in school and personal relationships that persist into adulthood. Currently, the causes of these psychiatric disorders are poorly understood, resulting in difficulty diagnosing affected children, and insufficient treatment options. Family and twin studies implicate a genetic contribution for ADHD, ASD, mood disorders, OCSD, and SZ. Identification of candidate genes and chromosomal regions associated with a particular disorder provide targets for directed research, and understanding how these genes influence the disease state will provide valuable insights for improving the diagnosis and treatment of children with psychiatric disorders. Transgenic mouse models are one important approach in the study of human diseases, allowing for the use of a variety of experimental approaches to dissect the contribution of a specific chromosomal or genetic abnormality in human disorders. While it is impossible to model an entire psychiatric disorder in a single mouse model, these models can be extremely valuable in dissecting out the specific role of a gene, pathway, neuron subtype, or brain region in a particular abnormal behavior. In this review we discuss existing transgenic mouse models for childhood-onset psychiatric disorders. We compare the strength and weakness of various transgenic mouse models proposed for each of the common childhood-onset psychiatric disorders, and discuss future directions for the study of these disorders using cutting-edge genetic tools.

Background/Aims: Actively engaging patient partners in the conduct of trials is crucial to ensure the studies answer genuine, patient-centered, unmet clinical needs, and to facilitate participant recruitment and retention. The aim of this article is to demonstrate the feasibility of patient engagement within a large pragmatic multicenter randomized controlled trial, specifically for the purposes of dissemination of study information/updates and to favorize recruitment and retention. Methods: In the patient-centric, pragmatic ADAPTABLE randomized trial, transparent and timely dissemination of information on the study updates to the trial participants was undertaken to create meaningful engagement and to facilitate retention. A national panel of patient partners, the Adaptors, were directly involved in this information dissemination strategy, and study participants were engaged both nationally and locally to design recruitment methods iteratively during the conduct of the trial. All Adaptors had a lived experience with cardiovascular disease. Results: Adaptors attended bi-weekly meetings facilitated by the director of the study's patient-powered research network. They drafted and/or edited newsletters and ad hoc educational information written in a lay-friendly manner for study participants, which were regularly distributed to the ADAPTABLE community, in addition to online forums where participants could share their experience of their involvement in ADAPTABLE. To spur recruitment, a patient-driven initiative was to draft letters sharing their story, which were distributed by the local study teams. Patient partners thought that using patients' voice to provide their perspectives on why they believed this project was important would be more engaging for prospective participants than traditional approaches. Conclusions: ADAPTABLE's experience has demonstrated the feasibility of engaging patients as partners in the conduct of a large-scale, multi-center, pragmatic randomized controlled trial. Future trials should embrace and iteratively improve this model by engaging patient partners as early as study protocol development and funding applications, and quantify its impact on the effectiveness and value of the trial. [ABSTRACT FROM AUTHOR]

Targeting the MAPK signaling pathway has transformed the treatment of metastatic melanoma. CRISPR‐Cas9 genetic screens provide a genome‐wide approach to uncover novel genetic dependencies that might serve as therapeutic targets. Here, we analyzed recently reported CRISPR‐Cas9 screens comparing data from 28 melanoma cell lines and 313 cell lines of other tumor types in order to identify fitness genes related to melanoma. We found an average of 1,494 fitness genes in each melanoma cell line. We identified 33 genes, inactivation of which specifically reduced the fitness of melanoma. This set of tumor type‐specific genes includes established melanoma fitness genes as well as many genes that have not previously been associated with melanoma growth. Several genes encode proteins that can be targeted using available inhibitors. We verified that genetic inactivation of DUSP4 and PPP2R2A reduces the proliferation of melanoma cells. DUSP4 encodes an inhibitor of ERK, suggesting that further activation of MAPK signaling activity through its loss is selectively deleterious to melanoma cells. Collectively, these data present a resource of genetic dependencies in melanoma that may be explored as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

NMDA receptor-dependent long-term potentiation (LTP) and depression (LTD) are forms of synaptic plasticity underlying learning andmemory that are expressed through increases and decreases, respectively, in dendritic spine size and AMPA receptor(AMPAR)phosphorylation and postsynaptic localization. The A-kinase anchoring protein 79/150 (AKAP79/150) signaling scaffold regulates AMPAR phosphorylation, channel activity, and endosomal trafficking associated with LTP and LTD. AKAP79/150 is targeted to dendritic spine plasma membranes by an N-terminal polybasicdomainthat binds phosphoinositide lipids, F-actin, and cadherin cell adhesion molecules. However, we do not understand how regulation of AKAP targeting controls AMPAR endosomal trafficking. Here, we report that palmitoylation of the AKAP N-terminal polybasic domain targets it to postsynaptic lipid rafts and dendritic recycling endosomes. AKAP palmitoylation was regulated by seizure activity in vivo and LTP/LTD plasticity-inducing stimuli in cultured rat hippocampal neurons. With chemical LTP induction, we observed AKAP79 dendritic spine recruitment that required palmityolation and Rab11-regulated endo some recycling coincident with spine enlargement and AMPAR surface delivery. Importantly, a palmitoylation-deficient AKAP79 mutant impaired regulation of spine size, endosome recycling, AMPAR trafficking, and synaptic potentiation. These finding semphasize the emerging importance of palmitoylation in controlling synaptic function and reveal novel roles for the AKAP79/150 signaling complex in dendritic endosomes. [ABSTRACT FROM AUTHOR]

A-kinase anchoring protein (AKAP) 79/150 is a scaffold protein found in dendritic spines that recruits the cAMP-dependent protein kinase (PKA) and protein phosphatase 2B-calcineurin (CaN) to membrane-associated guanylate kinase (MAGUK)-linked AMPA receptors (AMPARs) to control receptor phosphorylation and synaptic plasticity. However, AKAP79/150 may also coordinate regulation of AMPAR activity with spine structure directly through MAGUK binding and membrane-cytoskeletal interactions of its N-terminal targeting domain. In cultured hippocampal neurons, we observed that rat AKAP150 expression was low early in development but then increased coincident with spine formation and maturation. Over expression of human AKAP79 in immature or mature neurons increased the number of dendritic filopodia and spines and enlarged spine area. However, RNA interference knockdown of AKAP150 decreased dendritic spine area only in mature neurons. Importantly, AKAP79 over expression in immature neurons increased AMPAR post synaptic localization and activity. Neither the AKAP79PKA nor CaN anchoring domain was required for increasing dendritic protrusion numbers, spine area, or AMPAR synaptic localization; however, an internal region identified as the MAGUK binding domain was found to be essential as shown by expression of a MAGUK binding mutant that formed mainly filopodia and decreased AMPAR synaptic localization and activity. Expression of the AKAP79 N-terminal targeting domain alone also increased filopodia numbers but not spine area. Overall, these results demonstrate a novel structural role for AKAP79/150 in which the N-terminal targeting domain induces dendritic filopodia and binding to MAGUKs promotes spine enlargement and AMPAR recruitment. [ABSTRACT FROM AUTHOR]