Mental health interventions for children and young people with long-term health conditions in Children and Young People's Mental Health Services in England.

BACKGROUND: Almost a quarter of children and young people (CYP) in England have a long-term health condition (LTC), which increases the risk of developing mental health difficulties. There is a lack of understanding regarding the routine provision and efficacy of mental health interventions for CYP with LTCs within Children and Young People's Mental Health Services (CYPMHS). METHODS: This study analysed national service-reported data in England from two secondary datasets. Data were submitted by services between 2011 and 2019. We evaluated data on the presence or absence of a serious physical health or neurological issue, and which interventions were offered. RESULTS: A total of 789 CYP had serious physical health issues and 635 had neurological issues. The most common interventions delivered to CYP in either group have some evidence in the literature. Most CYP showed improvements across a range of outcomes. CONCLUSIONS: This study found that prevalence rates and psychological intervention and outcome data were widely under-reported across both datasets, posing questions about their utility for this population. Such data would benefit from triangulation with data from other sources to understand pathways of care for these young people and the extent to which clinical datasets underreport the number of CYP with LTCs.

Almost a quarter of children and young people (CYP) in England have a long-term health condition (LTC), such as asthma, diabetes, or epilepsy. We know that these young people are at increased risk of developing mental health difficulties. It is important these young people are able to access safe and effective treatments for their mental health. Therefore, they are sometimes referred to Children and Young People's Mental Health Services (CYPMHS) for appropriate treatment. However, at the moment, not much is known about the types of mental health support these services offer to children with co-existing physical health needs, or if this support is effective. The aim of this study was to try and find this out. We used data that had already been collected from mental health services across England. We looked at specific parts of this data that gave us information about the type of mental health treatments delivered to children with a long-term health condition. We separated long-term health conditions into two categories: physical health, such as diabetes or asthma; and neurological, such as epilepsy. In the sample we looked at, a range of mental health treatments were delivered to young people in both groups. Encouragingly, many of the young people's mental health improved. However, a lot of information we would hope to find was not available in the datasets. Also, the number of children with a long-term health condition was much lower than we expected. This might have been for a number of reasons, which we recommend other future research tries to find out. Going forward, it is important to think about how to make sure that accurate information about these children is collected from mental health services. This will help ensure that the right decisions are made for the care of young people with long-term health conditions.

Predictors of amounts of child and adolescent mental health service use.

The aim of this study was to build evidence about how to tailor services to meet the individual needs of young people by identifying predictors of amounts of child and adolescent mental health service use. We conducted a secondary analysis of a large administrative dataset from services in England was conducted using the Mental Health Services Data Set (years 2016-17 and 2017-18). The final sample included N = 27,362 episodes of care (periods of service use consisting of at least two attended care contacts and less than 180 days between care contacts) from 39 services. There were 50-10,855 episodes per service. The descriptive statistics for episodes of care were: Mage = 13 years, SDage = 4.71, range = 0-25 years; 13,785 or 50% male. Overall, there were high levels of heterogeneity in number of care contacts within episodes of care: M = 11.12, SD = 28.28, range = 2-1529. Certain characteristics predicted differential patterns of service use. For example, young people with substance use (beta = 6.29, 95% CI = 5.06-7.53) or eating disorders (beta = 4.30, 95% CI = 3.29-5.30) were particularly more likely to have higher levels of service use. To build on this, evidence is needed about predictors of child and adolescent mental health treatment outcome and whether the same characteristics predict levels of improvement as well as levels of service use.

Predictors of child and adolescent mental health treatment outcome.

BACKGROUND: To examine the predictors of treatment outcome or improvement in mental health difficulties for young people accessing child and adolescent mental health services. METHODS: We conducted a secondary analysis of routinely collected data from services in England using the Mental Health Services Data Set. We conducted multilevel regressions on N = 5907 episodes from 14 services (Mage = 13.76 years, SDage = 2.45, range = 8-25 years; 3540 or 59.93% female) with complete information on mental health difficulties at baseline. We conduct similar analyses on N = 1805 episodes from 10 services (Mage = 13.59 years, SDage = 2.33, range = 8-24 years; 1120 or 62.05% female) also with complete information on mental health difficulties at follow up. RESULTS: Girls had higher levels of mental health difficulties at baseline than boys (ß = 0.28, 95% CI = 0.24-0.32). Young people with higher levels of mental health difficulties at baseline also had higher levels of deterioration in mental health difficulties at follow up (ß = 0.72, 95% CI = 0.67-0.76), and girls had higher levels of deterioration in mental health difficulties at follow up than boys (ß = 0.09, 95% CI = 0.03-0.16). Young people with social anxiety, panic disorder, low mood, or self-harm had higher levels of mental health difficulties at baseline and of deterioration in mental health difficulties at follow up compared to young people without these presenting problems. CONCLUSIONS: Services seeing higher proportions of young people with higher levels of mental health difficulties at baseline, social anxiety, panic disorder, low mood, or self-harm may be expected to show lower levels of improvement in mental health difficulties at follow up.

Developing a case mix classification for child and adolescent mental health services: the influence of presenting problems, complexity factors and service providers on number of appointments.

Background: Case-mix classification is a focus of international attention in considering how best to manage and fund services, by providing a basis for fairer comparison of resource utilization. Yet there is little evidence of the best ways to establish case mix for child and adolescent mental health services (CAMHS).Aim: To develop a case mix classification for CAMHS that is clinically meaningful and predictive of number of appointments attended and to investigate the influence of presenting problems, context and complexity factors and provider variation.Method: We analysed 4573 completed episodes of outpatient care from 11 English CAMHS. Cluster analysis, regression trees and a conceptual classification based on clinical best practice guidelines were compared regarding their ability to predict number of appointments, using mixed effects negative binomial regression.Results: The conceptual classification is clinically meaningful and did as well as data-driven classifications in accounting for number of appointments. There was little evidence for effects of complexity or context factors, with the possible exception of school attendance problems. Substantial variation in resource provision between providers was not explained well by case mix.Conclusion: The conceptually-derived classification merits further testing and development in the context of collaborative decision making.

Abelson kinase acts as a robust, multifunctional scaffold in regulating embryonic morphogenesis.

Abelson family kinases (Abls) are key regulators of cell behavior and the cytoskeleton during development and in leukemia. Abl's SH3, SH2, and tyrosine kinase domains are joined via a linker to an F-actin-binding domain (FABD). Research on Abl's roles in cell culture led to several hypotheses for its mechanism of action: 1) Abl phosphorylates other proteins, modulating their activity, 2) Abl directly regulates the cytoskeleton via its cytoskeletal interaction domains, and/or 3) Abl is a scaffold for a signaling complex. The importance of these roles during normal development remains untested. We tested these mechanistic hypotheses during Drosophila morphogenesis using a series of mutants to examine Abl's many cell biological roles. Strikingly, Abl lacking the FABD fully rescued morphogenesis, cell shape change, actin regulation, and viability, whereas kinase-dead Abl, although reduced in function, retained substantial rescuing ability in some but not all Abl functions. We also tested the function of four conserved motifs in the linker region, revealing a key role for a conserved PXXP motif known to bind Crk and Abi. We propose that Abl acts as a robust multidomain scaffold with different protein motifs and activities contributing differentially to diverse cellular behaviors.

Development of a framework for prospective payment for child mental health services.

OBJECTIVES: There is a need to develop a payment system for services for children with mental health problems that allows more targeted commissioning based on fairness and need. This is currently constrained by lack of clinical consensus on the best way forward, wide variation in practice, and lack of data about activity and outcomes. In the context of a national initiative in England our aim was to develop a basis for an improved payment system. METHODS: Three inter-related studies: a qualitative consultation with child and adolescent mental health services (CAMHS) stakeholders on what the key principles for establishing a payment system should be, via online survey (n = 180) and two participatory workshops (n = 91); review of relevant national clinical guidelines (n = 15); and a quantitative study of the relationship between disorders and resource use (n = 1774 children from 23 teams). RESULTS: CAMHS stakeholders stressed the need for a broader definition of need than only diagnosis, including the measurement of indirect service activities and appropriate outcome measurement. National clinical guidance suggested key aspects of best practice for care packages but did not include consideration of contextual factors such as complexity. Modelling data on cases found that problem type and degree of impairment independently predicted resource use, alongside evidence for substantial service variation in the allocation of resources for similar problems. CONCLUSIONS: A framework for an episode-based payment system for CAMHS should include consideration of: complexity and indirect service activities; evidence-based care packages; different needs in terms of impairment and symptoms; and outcome measurement as a core component.

Determinants at the N- and C-termini of Gα12 required for activation of Rho-mediated signaling.

BACKGROUND: Heterotrimeric guanine nucleotide binding proteins of the G12/13 subfamily, which includes the α-subunits Gα12 and Gα13, stimulate the monomeric G protein RhoA through interaction with a distinct subset of Rho-specific guanine nucleotide exchange factors (RhoGEFs). The structural features that mediate interaction between Gα13 and RhoGEFs have been examined in crystallographic studies of the purified complex, whereas a Gα12:RhoGEF complex has not been reported. Several signaling responses and effector interactions appear unique to Gα12 or Gα13, despite their similarity in amino acid sequence. METHODS: To comprehensively examine Gα12 for regions involved in RhoGEF interaction, we screened a panel of Gα12 cassette substitution mutants for binding to leukemia-associated RhoGEF (LARG) and for activation of serum response element mediated transcription. RESULTS: We identified several cassette substitutions that disrupt Gα12 binding to LARG and the related p115RhoGEF. These Gα12 mutants also were impaired in activating serum response element mediated signaling, a Rho-dependent response. Most of these mutants matched corresponding regions of Gα13 reported to contact p115RhoGEF, but unexpectedly, several RhoGEF-uncoupling mutations were found within the N- and C-terminal regions of Gα12. Trypsin protection assays revealed several mutants in these regions as retaining conformational activation. In addition, charge substitutions near the Gα12 N-terminus selectively disrupted binding to LARG but not p115RhoGEF. CONCLUSIONS: Several structural aspects of the Gα12:RhoGEF interface differ from the reported Gα13:RhoGEF complex, particularly determinants within the C-terminal α5 helix and structurally uncharacterized N-terminus of Gα12. Furthermore, key residues at the Gα12 N-terminus may confer selectivity for LARG as a downstream effector.

Identification of polycystin-1 and Gα12 binding regions necessary for regulation of apoptosis.

Most patients with autosomal dominant polycystic kidney disease (ADPKD) harbor mutations in PKD1, the gene for polycystin-1 (PC1), a transmembrane protein with a cytoplasmic C-terminus that interacts with numerous signaling molecules, including Gα12. The functions of PC1 and the mechanisms of cyst development leading to renal failure are complex. Recently, we reported that PC1 expression levels modulate activity of Gα12-stimulated apoptosis (Yu et al., J. Biol. Chem. 2010 285(14):10243-51). Herein, a mutational analysis of Gα12 and PC1 was undertaken to identify regions required for their interaction and ability to modulate apoptosis. A set of Gα12 mutations with systematic replacement of six amino acids with NAAIRS was tested for binding to the PC1 C-terminus in GST pulldowns. Additionally, a series of deletions within the PC1 C-terminus was examined for binding to Gα12. We identified 3 NAAIRS substitutions in Gα12 that completely abrogated binding, and identified a previously described 74 amino acid Gαi/o binding domain in the PC1 C-terminus as necessary for Gα12 interaction. The functional consequences of uncoupling PC1/Gα12 binding were studied in apoptosis assays utilizing HEK293 cells with inducible PC1 overexpression. Gα12 mutants deficient in PC1 binding were refractory to PC1 inhibition of Gα12-stimulated apoptosis. Likewise, deletion of the Gα12-interacting sequence from the PC1 cytoplasmic domain abrogated its inhibition of Gα12-stimulated apoptosis. Based on the crystal structure of Gα12, the PC1 interaction sites are likely to reside on exposed regions within the G protein helical domain. These structural details should facilitate the design of reagents to uncouple PC1/Gα12 signaling in ADPKD.