RESUMEN
Ephrin (Eph) receptors are the largest family of receptor tyrosine kinases. Interactions between Eph receptors and their membrane-bound ephrin protein ligands are associated with many developmental processes as well as various cancers and neurodegenerative diseases. With significant crosstalk between different Eph receptors and ephrin ligands, there is an urgent need for high-affinity ligands that bind specifically to individual Eph receptors to interrogate and modulate their functions. Here, we describe the rational development of potent EphB2 receptor inhibitors derived from the EphB2 receptor-specific SNEW peptide. To improve inhibitory potency, we evaluated 20+ cross-linkers with the goal of spanning and stabilizing a single polyproline II helical turn observed when SNEW binds to the EphB2 receptor. Of the cross-linkers evaluated, an 11-atom cross-linker, composed of a rigid 2,7-dimethylnaphthyl moiety between two cysteine residues, was found to yield the most potent inhibitor. Analysis of the cyclized region of this peptide by NMR and molecular dynamics simulations suggests that cross-linking stabilizes the receptor-bound polyproline II helix structure observed in the receptor-peptide complex. Cross-linked SNEW variants retained binding specificity for EphB2 and showed cross-linker-dependent resistance to trypsin proteolysis. Beyond the discovery of more potent EphB2 receptor inhibitors, these studies illustrate a novel cyclization approach with potential to stabilize polyproline II helical structure in various peptides for specific targeting of the myriad protein-protein interactions (PPIs) mediated by polyproline II helices.
Asunto(s)
Péptidos , Receptor EphB2 , Receptor EphB2/química , Receptor EphB2/metabolismo , Receptor EphB2/antagonistas & inhibidores , Péptidos/química , Péptidos/farmacología , Humanos , Simulación de Dinámica Molecular , Unión ProteicaRESUMEN
OBJECTIVES: To describe and compare the association between suicidality and subsequent readmission for patients hospitalized for eating disorder treatment, within 2 years of discharge, at two large academic medical centers in two different countries. METHODS: Over an 8-year study window from January 2009 to March 2017, we identified all inpatient eating disorder admissions at Weill Cornell Medicine, New York, USA (WCM) and South London and Maudsley Foundation NHS Trust, London, UK (SLaM). To establish each patient's-suicidality profile, we applied two natural language processing (NLP) algorithms, independently developed at the two institutions, and detected suicidality in clinical notes documented in the first week of admission. We calculated the odds ratios (OR) for any subsequent readmission within 2 years postdischarge and determined whether this was to another eating disorder unit, other psychiatric unit, a general medical hospital admission or emergency room attendance. RESULTS: We identified 1126 and 420 eating disorder inpatient admissions at WCM and SLaM, respectively. In the WCM cohort, evidence of above average suicidality during the first week of admission was significantly associated with an increased risk of noneating disorder-related psychiatric readmission (OR 3.48 95% CI = 2.03-5.99, p-value < .001), but a similar pattern was not observed in the SLaM cohort (OR 1.34, 95% CI = 0.75-2.37, p = .32), there was no significant increase in risk of admission. In both cohorts, personality disorder increased the risk of any psychiatric readmission within 2 years. DISCUSSION: Patterns of increased risk of psychiatric readmission from above average suicidality detected via NLP during inpatient eating disorder admissions differed in our two patient cohorts. However, comorbid diagnoses such as personality disorder increased the risk of any psychiatric readmission across both cohorts. PUBLIC SIGNIFICANCE: Suicidality amongst is eating disorders is an extremely common presentation and it is important we further our understanding of identifying those most at risk. This research also provides a novel study design, comparing two NLP algorithms on electronic health record data based in the United States and United Kingdom on eating disorder inpatients. Studies researching both UK and US mental health patients are sparse therefore this study provides novel data.
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Trastornos de Alimentación y de la Ingestión de Alimentos , Suicidio , Humanos , Readmisión del Paciente , Registros Electrónicos de Salud , Procesamiento de Lenguaje Natural , Cuidados Posteriores , Alta del PacienteRESUMEN
INTRODUCTION: Actigraphy is commonly used to record free living physical activity in both typically and atypically developing children. While the accuracy and reliability of actigraphy have been explored extensively, research regarding young people's opinion towards these devices is scarce. This review aims to identify and synthesise evidence relating to the acceptability of actigraphic devices in 5-11 year olds. METHODS AND ANALYSIS: Database searches will be applied to Embase, MEDLINE, PsychInfo and Social Policy and Practice through the OVID interface; and Education Resources Information Center (ERIC), British Education Index and CINAHL through the EBSCO interface from January 2018 until February 2023. Supplementary forward and backward citation and grey literature database searches, including Healthcare Management Information Consortium (HMIC) and PsycEXTRA will be conducted. Qualitative and quantitative studies, excluding review articles and meta-analyses, will be eligible, without date restrictions. Article screening and data extraction will be undertaken by two review authors and disagreements will be deferred to a third reviewer. The primary outcome, actigraphic acceptability, will derive from the narrative synthesis of the main themes identified from included qualitative literature and pooled descriptive statistics relating to acceptability identified from quantitative literature. Subgroup analyses will determine if acceptability changes as a function of the key participant and actigraphic device factors. ETHICS AND DISSEMINATION: Ethical approval is not required for this systematic review as it uses data from previously published literature. The results will be presented in a manuscript and published in a peer review journal and will be considered alongside a separate stream of codesign research to inform the development of a novel child-worn actigraphic device. PROSPERO REGISTRATION NUMBER: CRD42021232466.
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Actigrafía , Literatura de Revisión como Asunto , Humanos , Adolescente , Reproducibilidad de los Resultados , Revisiones Sistemáticas como Asunto , Metaanálisis como Asunto , Bases de Datos FactualesRESUMEN
INTRODUCTION: Self-harm and suicide are major public health concerns among children and adolescents. Many risk and protective factors for suicide and self-harm have been identified and reported in the literature. However, the capacity of these identified risk and protective factors to guide assessment and management is limited due to their great number. This protocol describes an ongoing systematic review and meta-analysis which aims to examine longitudinal studies of risk factors for self-harm and suicide in children and adolescents, to provide a comparison of the strengths of association of the various risk factors for self-harm and suicide and to shed light on those that require further investigation. METHODS AND ANALYSIS: We perform a systematic search of the literature using the databases EMBASE, PsycINFO, Medline, CINAHL and HMIC from inception up to 28 October 2020, and the search will be updated before the systematic review publication. Additionally, we will contact experts in the field, including principal investigators whose peer-reviewed publications are included in our systematic review as well as investigators from our extensive research network, and we will search the reference lists of relevant reviews to retrieve any articles that were not identified in our search. We will extract relevant data and present a narrative synthesis and combine the results in meta-analyses where there are sufficient data. We will assess the risk of bias for each study using the Newcastle-Ottawa Scale and present a summary of the quantity and the quality of the evidence for each risk or protective factor. ETHICS AND DISSEMINATION: Ethical approval will not be sought as this is a systematic review of the literature. Results will be published in mental health journals and presented at conferences focused on suicide prevention. PROSPERO REGISTRATION NUMBER: CRD42021228212.
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Conducta Autodestructiva , Prevención del Suicidio , Niño , Adolescente , Humanos , Factores Protectores , Conducta Autodestructiva/epidemiología , Conducta Autodestructiva/prevención & control , Factores de Riesgo , Salud Pública , Metaanálisis como Asunto , Revisiones Sistemáticas como AsuntoRESUMEN
BACKGROUND: Individuals with autism spectrum disorder (ASD) are at particularly high risk of suicide and suicide attempts. Presentation to a hospital with self-harm is one of the strongest risk factors for later suicide. We describe the use of a novel data linkage between routinely collected education data and child and adolescent mental health data to examine whether adolescents with ASD are at higher risk than the general population of presenting to emergency care with self-harm. METHODS: A retrospective cohort study was conducted on the population aged 11-17 resident in four South London boroughs between January 2009 and March 2013, attending state secondary schools, identified in the National Pupil Database (NPD). Exposure data on ASD status were derived from the NPD. We used Cox regression to model time to first self-harm presentation to the Emergency Department (ED). RESULTS: One thousand twenty adolescents presented to the ED with self-harm, and 763 matched to the NPD. The sample for analysis included 113,286 adolescents (2.2% with ASD). For boys only, there was an increased risk of self-harm associated with ASD (adjusted hazard ratio 2·79, 95% CI 1·40-5·57, P<0·01). Several other factors including school absence, exclusion from school and having been in foster care were also associated with a higher risk of self-harm. CONCLUSIONS: This study provides evidence that ASD in boys, and other educational, social and clinical factors, are risk factors for emergency presentation with self-harm in adolescents. These findings are an important step in developing early recognition and prevention programmes.
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Trastorno del Espectro Autista , Conducta Autodestructiva , Adolescente , Trastorno del Espectro Autista/epidemiología , Niño , Humanos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Conducta Autodestructiva/epidemiología , Conducta Autodestructiva/psicología , Reino Unido/epidemiologíaRESUMEN
OBJECTIVE: The association between depression and educational attainment in young people is unclear. This systematic review and meta-analysis examines the longitudinal association between depression and subsequent attainment, and its potential effect modifiers and mediators. METHOD: We searched Embase, PsycINFO, PubMed, ERIC, and the British Education Index from inception to October 23, 2019, conducted citation searching, and contacted authors for articles. Eligible studies reported on the longitudinal association between depression in children and adolescents 4 to 18 years of age and later educational attainment. Two reviewers independently conducted screening, data extraction, and risk of bias assessment. Correlation coefficients were pooled in meta-analysis, and effect modifiers were explored using meta-regression and stratification. Other evidence on confounders, modifiers, and mediators was narratively synthesized. The PROSPERO record for the study is CRD42019123068. RESULTS: A total of 31 studies were included, of which 22 were pooled in meta-analysis. There was a small but statistically significant association between depression and lower subsequent attainment (pooled Fisher z = -0.19, 95% CI = -0.22 to -0.16, I2 = 62.9%). A total of 15 studies also reported an enduring effect after adjusting for various confounders. No statistically significant effect modifiers were identified. Social and school problems may mediate between depression and low attainment. CONCLUSION: Depression was associated with lower educational attainment, but further research is needed to establish mechanisms. Nonetheless, there is a clear need for mental health and educational support among children and adolescents with depression.
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Éxito Académico , Depresión , Adolescente , Niño , Depresión/epidemiología , Escolaridad , Familia , Humanos , Salud MentalRESUMEN
Self-harm and suicidal ideation in children and adolescents are common and are risk factors for completed suicide. Social exclusion, which can take many forms, increases the risk of self-harm and suicidal ideation. One important marker of social exclusion in young people is school absenteeism. Whether school absenteeism is associated with these adverse outcomes, and if so to what extent, remains unclear. To determine the association between school absenteeism and both self-harm (including completed suicide) and suicidal ideation in children and adolescents, we conducted a systematic review of observational studies. We conducted meta-analysis and report a narrative synthesis where this was not possible. Meta-analysis of cross-sectional studies showed that school absenteeism was associated with an increased risk of self-harm [pooled adjusted odds ratio (aOR) 1.37, 95% confidence interval 1.20-1.57, P = 0.01] and of suicidal ideation (pooled aOR 1.20, 95% CI 1.02-1.42, P = 0.03). A small number of studies showed that school absenteeism had a longitudinal association with both adverse outcomes. Heterogeneity in the exposure and outcome variables, study design and reporting was prominent and limited the extent to which it was appropriate to pool results. School absenteeism was associated with both self-harm and suicidal ideation in young people, but this evidence was derived from a small number of cross-sectional studies. Further research into the mechanisms of this association could help to inform self-harm and suicide prevention strategies at clinical, school and population levels.
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Absentismo , Conducta Autodestructiva/psicología , Ideación Suicida , Adolescente , Adulto , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Factores de Riesgo , Adulto JovenRESUMEN
INTRODUCTION: Depression represents a major public health concern for children and adolescents, and is thought to negatively impact subsequent educational attainment. However, the extent to which depression and educational attainment are directly associated, and whether other factors play a role, is uncertain. Therefore, we aim to systematically review the literature to provide an up-to-date estimate on the strength of this association, and to summarise potential mediators and moderators on the pathway between the two. METHODS AND ANALYSIS: To identify relevant studies, we will systematically search Embase, PsycINFO, PubMed, Education Resources Information Centre and British Education Index, manually search reference lists and contact experts in the field. Studies will be included if they investigate and report on the association between major depression diagnosis or depressive symptoms in children and adolescents aged 4-18 years (exposure) and later educational attainment (outcome). Two independent reviewers will screen titles, abstracts and full texts according to eligibility criteria, perform data extraction and assess study quality according to a modified version of the Newcastle-Ottawa Scale. If sufficiently homogeneous studies are identified, summary effect estimates will be pooled in meta-analysis, with further tests for study heterogeneity, publication bias and the effects of moderators using meta-regression. ETHICS AND DISSEMINATION: Because this review will make use of already published data, ethical approval will not be sought. The review will be submitted for publication in a peer-reviewed journal, presented at practitioner-facing conferences, and a lay summary will be written for non-scientific audiences such as parents, young people and teachers. The work will inform upcoming investigations on the association between child and adolescent mental health and educational attainment. PROSPERO REGISTRATION NUMBER: CRD42019123068.
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Depresión/epidemiología , Escolaridad , Proyectos de Investigación , Revisiones Sistemáticas como Asunto , Adolescente , Niño , HumanosRESUMEN
Suicidal ideation is a risk factor for self-harm, completed suicide and can be indicative of mental health issues. Adolescents are a particularly vulnerable group, but few studies have examined suicidal behaviour prevalence in large cohorts. Electronic Health Records (EHRs) are a rich source of secondary health care data that could be used to estimate prevalence. Most EHR documentation related to suicide risk is written in free text, thus requiring Natural Language Processing (NLP) approaches. We adapted and evaluated a simple lexicon- and rule-based NLP approach to identify suicidal adolescents from a large EHR database. We developed a comprehensive manually annotated EHR reference standard and assessed NLP performance at both document and patient level on data from 200 patients ( 5000 documents). We achieved promising results (>80% f1 score at both document and patient level). Simple NLP approaches can be successfully used to identify patients who exhibit suicidal risk behaviour, and our proposed approach could be useful for other populations and settings.
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Procesamiento de Lenguaje Natural , Suicidio , Adolescente , Registros Electrónicos de Salud , Humanos , Salud Mental , Ideación SuicidaRESUMEN
BACKGROUND AND AIMS: The prevalence of alcohol-related conditions is often reported as higher in hospital in-patients compared with the general population. However, formal prevalence estimates are commonly derived from small studies which report highly varied results. This systematic review and meta-analysis, within the UK hospital system, aimed to estimate the pooled prevalence of the 26 ICD-10 conditions that are wholly attributable to alcohol in in-patient settings. METHODS: We searched Medline, Embase, PsychINFO and CENTRAL from database inception until 1 May 2018. We included studies of any design that reported the prevalence of one of 26 wholly attributable alcohol conditions defined by the ICD-10. Studies were required to be conducted in one or more of the constituent nations of the United Kingdom and in an in-patient setting (general wards, intensive care units, accident and emergency departments or mental health in-patient units). Estimates were pooled using random-effects meta-analysis, and meta-regression tested study and patient factors contributing to variation. Quality was assessed using the Grading of Recommendations Assessment Development and Evaluation (GRADE) framework. RESULTS: A total of 124 studies were included, reporting on a total of 1 657 614 patients. The majority of studies reported on harmful use of alcohol and alcohol dependence, for which the pooled prevalence was 19.76% [95% confidence interval (CI) = 15.61-24.26%] and 10.25% (95% CI = 7.06-13.96%), respectively. Mean patient age and type of in-patient setting were identified as the main sources of variation in prevalence estimates, but not date of data collection. Both estimates were deemed very low quality according to GRADE. CONCLUSIONS: An estimated one in five patients in the UK hospital system use alcohol harmfully, and one in 10 are alcohol-dependent.
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Trastornos Inducidos por Alcohol/epidemiología , Intoxicación Alcohólica/epidemiología , Alcoholismo/epidemiología , Hospitalización , Trastornos Relacionados con Alcohol/epidemiología , Humanos , Prevalencia , Reino Unido/epidemiologíaRESUMEN
PURPOSE OF REVIEW: Suicide is the second leading cause of death in youth aged 10-24 years old globally, but detecting those at risk is challenging. Novel preventive strategies with wide influence across populations are required. Interest in the potential for both detrimental and supportive influences of social media/internet use on suicidal behaviour has been growing; however, the relationship remains unclear. RECENT FINDINGS: A systematic search of articles from database inception up to 25 January 2019 across five databases: Medline, PsycINFO, EMBASE, HMIC and CINAHL revealed nine independent studies investigating social media/internet use and suicide attempts in young people less than 19 years old (nâ=â346â416). An independent direct association was found between heavy social media/internet use and increased suicide attempts in seven studies (adjusted ORs ranged from 1.03 to 5.10), although adjusting for cyberbullying victimization and sleep disturbance reduced the strength of this association. Two studies found that some social media/internet use, versus no use, may be associated with fewer suicide attempts. There were no studies investigating the relationship between social media/internet use and completed suicide. SUMMARY: There is an independent association between problematic use of social media/internet and suicide attempts in young people. However, the direction of causality, if any, remains unclear. Further evaluation through longitudinal studies is needed.
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Internet , Medios de Comunicación Sociales , Intento de Suicidio/estadística & datos numéricos , Adolescente , Adulto , Acoso Escolar/psicología , Niño , Humanos , Estudios Longitudinales , Masculino , Ideación Suicida , Intento de Suicidio/psicología , Adulto JovenRESUMEN
OBJECTIVES: Creation of linked mental health, social and education records for research to support evidence-based practice for regional mental health services. SETTING: The Clinical Record Interactive Search (CRIS) system was used to extract personal identifiers who accessed psychiatric services between September 2007 and August 2013. PARTICIPANTS: A clinical cohort of 35 509 children and young people (aged 4-17 years). DESIGN: Multiple government and ethical committees approved the link of clinical mental health service data to Department for Education (DfE) data on education and social care services. Under robust governance protocols, fuzzy and deterministic approaches were used by the DfE to match personal identifiers (names, date of birth and postcode) from National Pupil Database (NPD) and CRIS data sources. OUTCOME MEASURES: Risk factors for non-matching to NPD were identified, and the potential impact of non-match biases on International Statistical Classification of Diseases, 10th Revision (ICD-10) classifications of mental disorder, and persistent school absence (<80% attendance) were examined. Probability weighting and adjustment methods were explored as methods to mitigate the impact of non-match biases. RESULTS: Governance challenges included developing a research protocol for data linkage, which met the legislative requirements for both National Health Service and DfE. From CRIS, 29 278 (82.5%) were matched to NPD school attendance records. Presenting to services in late adolescence (adjusted OR (aOR) 0.67, 95% CI 0.59 to 0.75) or outside of school census timeframes (aOR 0.15, 95% CI 0.14 to 0.17) reduced likelihood of matching. After adjustments for linkage error, ICD-10 mental disorder remained significantly associated with persistent school absence (aOR 1.13, 95% CI 1.07 to 1.22). CONCLUSIONS: The work described sets a precedent for education data being used for medical benefit in England. Linkage between health and education records offers a powerful tool for evaluating the impact of mental health on school function, but biases due to linkage error may produce misleading results. Collaborative research with data providers is needed to develop linkage methods that minimise potential biases in analyses of linked data.
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Educación , Registros Electrónicos de Salud , Almacenamiento y Recuperación de la Información/métodos , Servicios de Salud Mental , Registros , Servicio Social , Adolescente , Niño , Preescolar , Bases de Datos Factuales , Práctica Clínica Basada en la Evidencia , Femenino , Humanos , Londres , Masculino , Informática Médica , Medicina EstatalRESUMEN
AIMS: To understand the opinions of children with type 1 diabetes about their everyday use of flash glucose monitoring. (FGM). METHODS: Children with type 1 diabetes using the FreeStyle Libre® FGM system and/or their parents were surveyed in several French medical centers between December 2016 and June 2017, regardless of their treatment regimen and metabolic control. RESULTS: Of the 347 patients recruited, 79.5% had been using the sensor for more than three months (average usage time: 285 days). The main reported motivations for initiating this type of monitoring were to avoid finger prick pain (for 85.9% of patients) and to allow parents to check nocturnal glucose levels (60.8%). Two-thirds of respondents experienced difficulties, mainly the sensor falling off (47.6%), measurement discrepancies (25.1%) and cutaneous reactions (22.2%); 89.5% changed their habits: 70.6% took more scans, 37.2% corrected their hyperglycemia more promptly, and 37.5% used trends to adjust their insulin dosage. About one-third of the study group (35.1%) experienced lower HbA1c levels, and two thirds (67.1%) were satisfied with the device. CONCLUSIONS: Our results show that FGM is a widely accepted option for self-monitoring diabetes, but that specific training is required to improve its use for insulin dosage adjustment and metabolic results.
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Automonitorización de la Glucosa Sanguínea/instrumentación , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/diagnóstico , Satisfacción del Paciente , Adolescente , Conducta del Adolescente , Factores de Edad , Biomarcadores/sangre , Niño , Conducta Infantil , Preescolar , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/psicología , Diseño de Equipo , Femenino , Francia , Hemoglobina Glucada , Hábitos , Encuestas de Atención de la Salud , Conocimientos, Actitudes y Práctica en Salud , Humanos , Hipoglucemiantes/administración & dosificación , Lactante , Recién Nacido , Insulina/administración & dosificación , Masculino , Motivación , Padres/psicología , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de TiempoRESUMEN
INTRODUCTION: Schools have an important role in recognising and preventing self-harm and suicidal behaviour in their students, however little is known about which educational factors are associated with heightened risk. We will systematically review the existing evidence on two key educational performance indicators that are routinely collected by school administrative systems: school attendance and exclusion. We will investigate their association with self-harm and suicidal behaviour in school-age children and adolescents. Knowledge of this association could help inform suicide prevention strategies at clinical, school and population levels. METHODS AND ANALYSIS: We will conduct a systematic search of Medline, EMBASE, PsycINFO, British Education Index and Education Resources Information Centre (ERIC) from 1 January 1990, and conduct a manual search for additional references. We aim to identify studies that explore the association between poor school attendance or exclusion and self-harm or suicidal behaviours in school-age children and adolescents. Two independent reviewers will screen titles, abstracts and full-text documents and independently extract relevant data for analysis. Study quality will be assessed using a modified Newcastle-Ottawa Scale. A descriptive analysis will be performed, and where appropriate, results will be combined in meta-analyses. ETHICS AND DISSEMINATION: This is a systematic review of published literature, and therefore ethical approval will not be sought. We will publish reports in health and education journals, present our work at conferences focused on school mental health and communicate our findings to practitioners and managers in public health, education and child mental health. PROSPERO REGISTRATION NUMBER: CRD42018088608.