Prevalence of mental health disorders in children and adolescents in the Republic of Ireland: a systematic review.

Referrals to Child and Adolescent Mental Health Services (CAMHS) have increased in recent years. Services are already under-resourced and the adverse psychological impact of Covid-19 is likely to increase demand. Accordingly, an understanding of prevalence of mental health (MH) disorders among youth is imperative to help inform and plan services. AIM: To establish prevalence of MH disorders among youth (under 18) in Ireland. METHOD: A systematic review using pre-defined search terms in PubMed, PsycInfo, Embase and CINAHL was conducted. Empirical studies conducted in Ireland, in youth and focusing on MH disorders were included. RESULTS: From a total of 830 papers identified, 38 papers met inclusion criteria. Significant variation in rates of MH disorders was evident based on study methodology. Screening questionnaires for general psychopathology reported rates of 4.8-17.8% scoring above clinical cut-offs, with higher rates for ADHD (7.3%). Studies examining depression ranged from 4% to 20.8%, while rates for 'current' MH disorder, determined by semi-structured interview, were 15.5%, while 'lifetime' rates varied from 19.9% to 31.2%. Fewer than half (44%) of those identified as 'in need' of specialist MH services were accessing CAMHS. CONCLUSION: Data on MH disorders among Irish youth is limited, and studies showed significant variance in rates, making service planning difficult. There is an urgent need for serial epidemiological surveys, with clear operational criteria for clinically impairing MH difficulties. Such studies are essential to understand potential demand and service planning. This is most urgent given the expected increased demand post Covid-19.

Systematic review of effectiveness and satisfaction evaluation in child and adolescent mental health services in Ireland.

OBJECTIVES: Increasing numbers of youth experience mental illness, and also require and benefit from specialist child and adolescent mental health services (CAMHS). Worldwide, such services are underfunded and under-resourced, and services in Ireland are no different. It is vital that existing services are regularly reviewed for both efficacy and acceptability. Our objective was to review published studies evaluating service user satisfaction with CAMHS in Ireland and CAMHS therapeutic efficacy. METHODS: MEDLINE, PsycINFO and CINAHL databases were systematically searched. Studies were included if they reported on service user satisfaction or an evaluation of CAMHS in Ireland. RESULTS: From an initial 125 articles identified, 15 studies meet the inclusion criteria: four reporting on overall CAMHS satisfaction, three on satisfaction where a specific diagnosis was present, while eight evaluated various interventions offered. Whilst most service users perceived services to be satisfactory, important issues relating to accessibility were present. Evidence of efficacy was present for a small number of interventions, but studies were limited by methodological issues. CONCLUSIONS: There is a dearth of studies evaluating CAMHS in Ireland. The extant literature suggests a positive experience once accessed, but long waiting times and poor collaboration are seen to limit services users' experience. More robust methodologically sound studies are urgently required. Given the expected increased demand linked to the current COVID-19 pandemic, coupled with the resultant compromised financial position, it is essential that scant resources are appropriately directed.

Method of self-harm and risk of self-harm repetition: findings from a national self-harm registry.

BACKGROUND: Risk of self-harm repetition has consistently been shown to be higher following self-cutting compared to intentional drug overdose (IDO) and other self-harm methods. The utility of previous evidence is limited due to the large heterogeneous method categories studied. This study examined risk of hospital presented self-harm repetition according to specific characteristics of self-harm methods. METHODS: Data on consecutive self-harm presentations to hospital emergency departments (2010-2016) were obtained from the National Self-Harm Registry Ireland. Associations between self-harm method and repetition were analysed using survival analyses. RESULTS: Overall, 65,690 self-harm presentations were made involving 46,661 individuals. Self-harm methods associated with increased repetition risk included minor self-cutting, severe self-cutting, multiple drug IDOs involving psychotropic drugs and self-harm by blunt object. Minor self-cutting was the method associated with highest repetition risk (adjusted hazard ratio (AHR) 1.38, 95% CI 1.31-1.45). Risk of repetition was comparable following IDOs of four or more drugs involving psychotropic drugs (AHR = 1.29, 95% CI 1.20-1.39), severe self-cutting (AHR 1.25, 95% CI 1.16-1.34) and blunt object (AHR = 1.23, 95% CI 1.07-1.42). LIMITATIONS: Information was not available on suicide or other causes of mortality. CONCLUSIONS: Self-harm method and the associated risk of repetition should form a core part of biopsychosocial assessments and should inform follow-up care for self-harm patients. The observed differences in repetition associated with specific characteristics of IDO underline the importance of safety planning and monitoring prescribing for people who have engaged in IDO.

Conscientiousness and adherence to the oral contraceptive pill: A prospective study.

OBJECTIVE: We assess the association between conscientiousness and adherence to the oral contraceptive pill (OCP), and examine if such a relationship is independent of a measure of prospective memory and a range of social cognitive variables. METHOD: Data were collected from 150 OCP users at baseline, and 99 provided follow-up data four weeks later. Conscientiousness, a range of social cognitive predictors and prospective memory were assessed at baseline. OCP adherence was measured at baseline, and again at Time 2. Data were analysed using correlation and multiple linear regression. RESULTS: Higher conscientiousness was associated with higher overall OCP adherence in both cross-sectional (r = -0.28, p < 0.01) and prospective analysis (r = -0.34, p < 0.01). Conscientiousness predicted OCP adherence at Time 2, adjusting for OCP adherence at Time 1 (R(2) change = 0.02, p = 0.04). The association was reduced to non-significance when social cognitive predictors and prospective memory were included in the multivariable model. Prospective memory was an independent predictor of OCP adherence at Time 2. DISCUSSION: This is the first study to identify an association between conscientiousness and OCP adherence. The association is not independent from social cognitive predictors and prospective memory. Facet-level analysis of conscientiousness and formal mediation analyses are recommended in future replications.

How social context impacts on the development, identification and treatment of mental and substance use disorders among young people - a qualitative study of health care workers.

Introduction Social context has a major influence on the detection and treatment of youth mental and substance use disorders in socioeconomically disadvantaged urban areas, particularly where gang culture, community violence, normalisation of drug use and repetitive maladaptive family structures prevail. This paper aims to examine how social context influences the development, identification and treatment of youth mental and substance use disorders in socioeconomically disadvantaged urban areas from the perspectives of health care workers. METHOD: Semi-structured interviews were conducted with health care workers (n=37) from clinical settings including: primary care, secondary care and community agencies and analysed thematically using Bronfenbrenner's Ecological Theory to guide analysis. RESULTS: Health care workers' engagement with young people was influenced by the multilevel ecological systems within the individual's social context which included: the young person's immediate environment/'microsystem' (e.g., family relationships), personal relationships in the 'mesosystem' (e.g., peer and school relationships), external factors in the young person's local area context/'exosystem' (e.g., drug culture and criminality) and wider societal aspects in the 'macrosystem' (e.g., mental health policy, health care inequalities and stigma). CONCLUSIONS: In socioeconomically disadvantaged urban areas, social context, specifically the micro-, meso-, exo-, and macro-system impact both on the young person's experience of mental health or substance use problems and services, which endeavour to address these problems. Interventions that effectively identify and treat these problems should reflect the additional challenges posed by such settings.

Youth mental health in deprived urban areas: a Delphi study on the role of the GP in early intervention.

BACKGROUND: GPs, as healthcare professionals with whom young people commonly interact, have a central role in early intervention for mental health problems. However, successfully fulfilling this role is a challenge, and this is especially in deprived urban areas. AIMS: To inform a complex intervention to support GPs in this important role, we aim to identify the key areas in which general practice can help address youth mental health and strategies to enhance implementation. METHODS: We conducted a modified Delphi study which involved establishing an expert panel involving key stakeholders/service providers at two deprived urban areas. The group reviewed emerging literature on the topic at a series of meetings and consensus was facilitated by iterative surveys. RESULTS: We identified 20 individual roles in which GPs could help address youth mental health, across five domains: (1) prevention, health promotion and access, (2) assessment and identification, (3) treatment strategies, (4) interaction with other agencies/referral, and (5) ongoing support. With regard to strategies to enhance implementation, we identified a further 19 interventions, across five domains: (1) training, (2) consultation improvements, (3) service-level changes, (4) collaboration, and (5) healthcare-system changes. CONCLUSIONS: GPs have a key role in addressing youth mental health and this study highlights the key domains of this role and the key components of a complex intervention to support this role.

Mutations of FLT3/ITD confer resistance to multiple tyrosine kinase inhibitors.

FMS-like tyrosine kinase 3 (FLT3) normally functions in the survival/proliferation of hematopoietic stem/progenitor cells, but its constitutive activation by internal tandem duplication (ITD) mutations correlates with a poor prognosis in AML. The development of FLT3 tyrosine kinase inhibitors (TKI) is a promising strategy, but resistance that arises during the course of treatment caused by secondary mutations within the mutated gene itself poses a significant challenge. In an effort to predict FLT3 resistance mutations that might develop in patients, we used saturation mutagenesis of FLT3/ITD followed by selection of transfected cells in FLT3 TKI. We identified F621L, A627P, F691L and Y842C mutations in FLT3/ITD that confer varying levels of resistance to FLT3 TKI. Western blotting confirmed that some FLT3 TKI were ineffective at inhibiting FLT3 autophosphorylation and signaling through MAP kinase, STAT5 and AKT in some mutants. Balb/c mice transplanted with the FLT3/ITD Y842C mutation confirmed resistance to sorafenib in vivo but not to lestaurtinib. These results indicate a growing number of FLT3 mutations that are likely to be encountered in patients. Such knowledge, combined with known remaining sensitivity to other FLT3 TKI, will be important to establish as secondary drug treatments that can be substituted when these mutants are encountered.

Can general practice help address youth mental health? A retrospective cross-sectional study in Dublin's south inner city.

AIMS: With general practice potentially having an important role in early intervention of mental and substance use disorders among young people, we aim to explore this issue by determining the prevalence of psychological problems and general practice/health service utilization among young people attending general practice. METHODS: A retrospective cross-sectional study of patients attending three general practices in Dublin city. RESULTS: Among a sample of young people (mostly women, 44% general medical services (GMS) eligible), we observed considerable contact with general practice, both lifetime and for the 2 years of the study. The mean consultation rate was 3.9 consultations in 2 years and psychosocial issues (most commonly stress/anxiety and depression) were documented in 35% of cases. Identification of psychosocial issues was associated with GMS eligibility, three or more doctor consultations, and documentation of smoking and drinking status. CONCLUSIONS: Psychosocial issues are common among young people attending general practice and more work on their epidemiology and further identification in general practice are advocated.

Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.

BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity. MATERIALS AND METHODS: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation. RESULTS: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability. CONCLUSIONS: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.

The human stratum corneum as extended, covalently cross-linked biopolymer: mathematics, molecules, and medicine.

A novel mathematical and molecular hypothesis is proposed to account for the peculiar organization of human epidermis. Mathematically, the organization of the interfollicular epidermis is hypothesized to be a tetratomic identity manifesting a gravitational logic in the arrangement of its functional compartments. The squares of the natural numbers; i.e., 1, 4, 9, and 16 are taken, on empirical grounds, to correspond to the number of cell layers in the respective epidermal strata (germinativum, spinosum, granulosum, and corneum). The outer two strata, overlying the Langerhans cells, constitute the 'living' and 'dead' components of the traditional 'epidermal barrier'. Together, these two strata illustrate in their union of 9 + 16 = 25 cells, a way of conceiving the skin surface (the body-environment identity) as both closure and contact. The organization of human epidermis into functional units based on phi, the golden section ratio, builds upon this gravitational logic. Finally, the fact that the extensively cross-linked proteolipid envelope of the cornified epidermal cell is a single multi-gene molecule is deemed scientifically incontrovertible. The molecular hypothesis in need of validation and verification is whether the corneodesmosomal 'rivets' linking one corneocyte to another are covalently bonded structures. If so, the cornified scaffolding of the stratum corneum constitutes a highly organized, extended, multi-gene, polymer molecule strategically located precisely at the shared surface of the body and environment. This hypothesis places the differentiated structure of the epidermis, an ectodermal derivative like the brain, front and center in the translation of molecular biology to clinical bedside care.

Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in human plasma.

Estimation of xenobiotic kinetics in humans frequently relies upon extrapolation from experimental data generated in animals. In an accompanying paper, we have presented a unique, generic, physiologically based pharmacokinetic model and described its application to the prediction of rat plasma pharmacokinetics from in vitro data alone. Here we demonstrate the application of the same model, parameterized for human physiology, to the estimation of plasma pharmacokinetics in humans and report a comparative evaluation against some recently published predictive methods that involve scaling from in vivo animal data. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature, and validated using a separate test set of published in vivo data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was 0.47 log unit. For the training set, more than 80% of the predicted values of a standardized measure of the area under the concentration-time curve were within 3-fold of the observed values; over 70% of the test set predictions were within the same margin. Furthermore, in terms of predicting human clearance for the test set, the model was found to match or exceed the performance of three published interspecies scaling methods, all of which showed a distinct bias toward overprediction. We conclude that the generic physiologically based pharmacokinetic model, as a means of integrating readily determined in vitro and/or in silico data, is potentially a powerful, cost-effective tool for predicting human xenobiotic kinetics in drug discovery and risk assessment.

Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in rat plasma.

The routine assessment of xenobiotic in vivo kinetic behavior is currently dependent upon data obtained through animal experimentation, although in vitro surrogates for determining key absorption, distribution, metabolism, and elimination properties are available. Here we present a unique, generic, physiologically based pharmacokinetic (PBPK) model and demonstrate its application to the estimation of rat plasma pharmacokinetics, following intravenous dosing, from in vitro data alone. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature and validated using a separate test set of in vivo discovery compound data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was approximately 0.5 log unit. Around 70% of all the predicted values of a standardized measure of area under the concentration-time curve (AUC) were within 3-fold of the observed values, as were over 90% of the training set t1/2 predictions and 60% of those for the test set; however, there was a tendency to overpredict t1/2 for the test set compounds. The capability of the model to rank compounds according to a given criterion was also assessed: of the 25% of the test set compounds ranked by the model as having the largest values for AUC, 61% were correctly identified. These validation results lead us to conclude that the generic PBPK model is potentially a powerful and cost-effective tool for predicting the mammalian pharmacokinetics of a wide range of organic compounds, from readily available in vitro inputs only.

Automated QSPR through Competitive Workflow.

This paper describes a novel software architecture, Competitive Workflow, which implements workflow as a distributed and competitive multi-agent system. The implementation of a competitive workflow architecture designed to model important computer-aided molecular design workflows, the Discovery Bus, is described. QSPR modelling results for three example ADME datasets, for solubility, human plasma protein binding and P-glycoprotein substrates using an autonomous QSPR modelling workflow implemented on the Discovery Bus are presented. The autonomous QSPR system allows exhaustive exploration of descriptor and model space, automated model validation and continuous updating as new data and methods are made available. Prediction of properties of novel structures by an ensemble of models is also a feature of the system.

The organization of human epidermis: functional epidermal units and phi proportionality.

The concept that mammalian epidermis is structurally organized into functional epidermal units has been proposed on the basis of stratum corneum (SC) architecture, proliferation kinetics, melanocyte:keratinocyte ratios (1:36), and, more recently, Langerhans cell: epidermal cell ratios (1:53). This article examines the concept of functional epidermal units in human skin in which the maintenance of phi (1.618034) proportionality provides a central organizing principle. The following empirical measurements were used: 75,346 nucleated epidermal cells per mm2, 1394 Langerhans cells per mm2, 1999 melanocytes per mm2, 16 (SC) layers, 900-microm2 corneocyte surface area, 17,778 corneocytes per mm2, 14-d (SC) turnover time, and 93,124 per mm2 total epidermal cells. Given these empirical data: (1) the number of corneocytes is a mean proportional between the sum of the Langerhans cell + melanocyte populations and the number of epidermal cells, 3393/17,778-17,778/93,124; (2) the ratio of nucleated epidermal cells over corneocytes is phi proportional, 75,346/17,778 approximately phi3; (3) assuming similar 14-d turnover times for the (SC) and Malpighian epidermis, the number of corneocytes results from subtraction of a cellular fraction equal to approximately 2/phi2 x the number of living cells, 75,436 - (2/phi2 x 75,346) approximately 17,778; and (4) if total epidermal turnover time equals (SC) turnover time x the ratio of living/dead cells, then compartmental turnover times are unequal (14 d for (SC) to 45.3 d for nucleated epidermis approximately 1/2phi) and cellular replacement rates are 52.9 corneocytes/69.3 keratinocytes per mm2 per h approximately 2/phi2. These empirically derived equivalences provide logicomathematical support for the presence of functional epidermal units in human skin. Validation of a phi proportional unit architecture in human epidermis will be important for tissue engineering of skin and the design of instruments for skin measurement.

Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains.

Members of the Frizzled family of seven-pass transmembrane proteins serve as receptors for Wnt signalling proteins. Wnt proteins have important roles in the differentiation and patterning of diverse tissues during animal development, and inappropriate activation of Wnt signalling pathways is a key feature of many cancers. An extracellular cysteine-rich domain (CRD) at the amino terminus of Frizzled proteins binds Wnt proteins, as do homologous domains in soluble proteins-termed secreted Frizzled-related proteins-that function as antagonists of Wnt signalling. Recently, an LDL-receptor-related protein has been shown to function as a co-receptor for Wnt proteins and to bind to a Frizzled CRD in a Wnt-dependent manner. To investigate the molecular nature of the Wnt signalling complex, we determined the crystal structures of the CRDs from mouse Frizzled 8 and secreted Frizzled-related protein 3. Here we show a previously unknown protein fold, and the design and interpretation of CRD mutations that identify a Wnt-binding site. CRDs exhibit a conserved dimer interface that may be a feature of Wnt signalling. This work provides a framework for studies of homologous CRDs in proteins including muscle-specific kinase and Smoothened, a component of the Hedgehog signalling pathway.

A mammalian expression vector for expression and purification of secreted proteins for structural studies.

A mammalian expression vector with features optimized for simple expression and purification of secreted proteins has been developed. This vector was constructed to facilitate X-ray crystallographic studies of cysteine-rich glycoproteins that are difficult to express by other means. Proteins expressed with this vector possess an N-terminal human growth hormone domain and an octahistidine tag separated from the desired polypeptide sequences by a tobacco etch virus protease recognition site. Advantages of this vector are high levels of expression, simple detection and purification of expressed proteins, and reliable cleavage of the fusion protein. Cotransfection of this vector with a dihydrofolate reductase gene allows amplification of expression levels with methotrexate. Over one dozen cysteine-rich secreted proteins have been expressed in sufficient quantity for structural studies using this vector; the structure of at least one of these proteins has been determined.

Prediction of in vivo tissue distribution from in vitro data 1. Experiments with markers of aqueous spaces.

PURPOSE: The aim of this study was to evaluate the ability of an in vitro method of tissue distribution to accurately predict total water and extracellular aqueous spaces using marker compounds urea and inulin. METHODS: Slices (50-200 mg) of all the major tissues in the rat were incubated with Hanks/HEPES pH7.4 buffer containing 14C-urea and 3H-inulin for 2 h at 37 degrees C. Tissue weight was noted before and after incubation and the tissue-to-buffer ratios determined. RESULTS: 14C-Urea Kp estimates were generally greater than total tissue water due to tissue swelling, which varied widely among the tissues, up to 41% in muscle. In most cases, Kp values were much closer to in vivo values after correcting for the 14C-urea in the imbibed media (Kpcorr). The method was able to distinguish between 14C-urea and 3H-inulin Kp values and indicated that inulin occupied a smaller space than urea, which for the majority of tissues corresponded to the extracellular space. CONCLUSIONS: The Kp(corr) values for 14C-urea and Kp for 3H-inulin were consistent with total tissue water and extracellular space for the majority of tissues studied, indicating their suitability as marker compounds for checking the viability of this in vitro method for estimating tissue distribution.

Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition.

Homer EVH1 (Ena/VASP Homology 1) domains interact with proline-rich motifs in the cytoplasmic regions of group 1 metabotropic glutamate receptors (mGluRs), inositol-1,4,5-trisphosphate receptors (IP3Rs), and Shank proteins. We have determined the crystal structure of the Homer EVH1 domain complexed with a peptide from mGluR (TPPSPF). In contrast to other EVH1 domains, the bound mGluR ligand assumes an unusual conformation in which the side chains of the Ser-Pro tandem are oriented away from the Homer surface, and the Phe forms a unique contact. This unusual binding mode rationalizes conserved features of both Homer and Homer ligands that are not shared by other EVH1 domains. Site-directed mutagenesis confirms the importance of specific Homer residues for ligand binding. These results establish a molecular basis for understanding the biological properties of Homer-ligand complexes.

bcl-2 protein expression is associated with better prognosis in colorectal cancer.

AIMS: To investigate the expression of bcl-2 in colorectal carcinoma and to examine its association with mediators of apoptosis (p53 and mdm-2), clinicopathological features and long-term outcome. METHODS AND RESULTS: We determined by immunohistochemistry the expression of bcl-2 in 102 colorectal carcinomas with 10-year follow-up. In 66 of these cases in which we had previously assessed p53 status, no correlation was seen between bcl-2 and p53. The mdm-2 protein was not detected in any of the 66 cases. Cytoplasmic staining of the bcl-2 gene product was seen in the tumour cells of 22 cases (22%). Using a polymerase chain reaction technique we showed that overexpression of bcl-2 was not due to rearrangement of the bcl-2 gene. Expression of bcl-2 protein was related to tumour grade but was unrelated to patient age, sex, tumour site, tumour size or Dukes' stage. There was a trend towards increased survival in those whose tumours expressed bcl-2 protein (P = 0.055). When entered into a multivariate analysis, this survival difference was independent of tumour stage (P = 0.05). CONCLUSIONS: These results suggest that bcl-2 expression in colorectal carcinoma is associated with a better long-term prognosis.