Prevalence and Correlates of the Concurrence of Autism Spectrum Disorder and Obsessive Compulsive Disorder in Children and Adolescents: A Systematic Review and Meta-Analysis.

BACKGROUND: Autism spectrum disorder (ASD) and obsessive compulsive disorder (OCD) are two common and impairing neurodevelopmental conditions with partial symptomatic overlap. The aim of this study is to systematically and meta-analytically examine the following: (i) the prevalence of an OCD diagnosis among young people with ASD, (ii) the prevalence of an ASD diagnosis among young people with OCD, and (iii) the clinical and therapeutic implications of such comorbidity. METHOD: A multistep literature search was performed from database inception until 17 November 2023. This PRISMA/MOOSE-compliant systematic review, registered in PROSPERO (CRD42023480543), identified studies reporting on the prevalence, sociodemographic, psychopathologic, prognostic, and therapeutic correlates of OCD and ASD concurrence in children and adolescents. A quantitative meta-analysis with random effects was conducted to analyse the pooled prevalence of OCD among samples with a mean age of < 18 years old with ASD and the prevalence of ASD among individuals under 18 with OCD. Sensitivity analyses were performed to investigate the effect of diagnostic criteria and different continents. Meta-regression analyses were conducted to examine the effect of gender, age, IQ, and OCD severity scores. A narrative review of the clinical and therapeutical implications of the comorbidity was provided. RESULTS: 42 studies were selected for the systematic review (SR), and 31 of them were also included in one of the meta-analyses. The pooled prevalence of OCD among ASD youth samples (n = 8916, mean age = 10.6 ± 1.6; 16.4% female) was 11.6% (95% confidence intervals [CI] = 6.9%; 18.8%), and the pooled prevalence of ASD among OCD children and adolescent samples (n = 6209, mean age = 14.1 ± 1.4; 45.7% female) was 9.5% (95% CI = 6.0%; 14.7%). Meta-regressions found a statistically higher prevalence of ASD among samples with a lower prevalence of females (ß = -4.7; 95%CI = -8.6; -0.8). Children with both OCD and ASD present higher rates of functional impairment, psychopathology, and other comorbidities, compared to youth with either of the disorders alone. CONCLUSIONS: OCD and ASD are highly concurrent conditions in youth, with symptomatic, prognostic, severity, and therapeutic implications. Future research should focus on conducting longitudinal cohort studies prospectively to determine development trajectories, along with randomized controlled trials to assess the efficacy of specific therapeutic interventions.

Health service and psychotropic medication use for mental health conditions among healthcare workers active during the Spain Covid-19 Pandemic - A prospective cohort study using web-based surveys.

Little is known about healthcare workers' (HCW) use of healthcare services for mental disorders. This study presents data from a 16-month prospective cohort study of Spanish HCW (n = 4,809), recruited shortly after the COVID-19 pandemic onset, and assessed at four timepoints using web-based surveys. Use of health services among HCW with mental health conditions (i.e., those having a positive screen for mental disorders and/or suicidal thoughts and behaviours [STB]) was initially low (i.e., 18.2 %) but increased to 29.6 % at 16-month follow-up. Service use was positively associated with pre-pandemic mental health treatment (OR=1.99), a positive screen for major depressive disorder (OR=1.50), panic attacks (OR=1.74), suicidal thoughts and behaviours (OR=1.22), and experiencing severe role impairment (OR=1.33), and negatively associated with being female (OR = 0.69) and a higher daily number of work hours (OR=0.95). Around 30 % of HCW with mental health conditions used anxiolytics (benzodiazepines), especially medical doctors. Four out of ten HCW (39.0 %) with mental health conditions indicated a need for (additional) help, with most important barriers for service use being too ashamed, long waiting lists, and professional treatment not being available. Our findings delineate a clear mental health treatment gap among Spanish HCW.

Gene expression imputation provides clinical and biological insights into treatment-resistant schizophrenia polygenic risk.

Genome-wide association studies (GWAS) have revealed the polygenic nature of treatment-resistant schizophrenia TRS. Gene expression imputation allowed the translation of GWAS results into regulatory mechanisms and the construction of gene expression (GReX) risk scores (GReX-RS).  In the present study we computed GReX-RS from the largest GWAS of TRS to assess its association with clinical features. We perform transcriptome imputation in the largest GWAS of TRS to find GReX associated with TRS using brain tissues. Then, for each tissue, we constructed a GReX-RS of the identified genes in a sample of 254 genotyped first episode of psychosis (FEP) patients to test its association with clinical phenotypes, including clinical symptomatology, global functioning and cognitive performance. Our analysis provides evidence that the polygenic basis of TRS includes genetic variants that modulate the expression of certain genes in certain brain areas (substantia nigra, hippocampus, amygdala and frontal cortex), which at the same time are related to clinical features in FEP patients, mainly persistence of negative symptoms and cognitive alterations in sustained attention, which have also been suggested as clinical predictors of TRS. Our results provide a clinical explanation of the polygenic architecture of TRS and give more insight into the biological mechanisms underlying TRS.

Negative symptoms and sex differences in first episode schizophrenia: What's their role in the functional outcome? A longitudinal study.

INTRODUCTION: Negative symptoms (NS) include asociality, avolition, anhedonia, alogia, and blunted affect and are linked to poor prognosis. It has been suggested that they reflect two different factors: diminished expression (EXP) (blunted affect and alogia) and amotivation/pleasure (MAP) (anhedonia, avolition, asociality). The aim of this article was to examine potential sex differences among first-episode schizophrenia (FES) patients and analyze sex-related predictors of two NS symptoms factors (EXP and MAP) and functional outcome. MATERIAL AND METHODS: Two hundred and twenty-three FES (71 females and 152 males) were included and evaluated at baseline, six-months and one-year. Repeated measures ANOVA was used to examine the effects of time and sex on NS and a multiple linear regression backward elimination was performed to predict NS factors (MAP-EXP) and functioning. RESULTS: Females showed fewer NS (p=0.031; Cohen's d=-0.312), especially those related to EXP (p=0.024; Cohen's d=-0.326) rather than MAP (p=0.086), than males. In both male and female group, worse premorbid adjustment and higher depressive symptoms made a significant contribution to the presence of higher deficits in EXP at one-year follow-up, while positive and depressive symptoms predicted alterations in MAP. Finally, in females, lower deficits in MAP and better premorbid adjustment predicted better functioning at one-year follow-up (R2=0.494; p<0.001), while only higher deficits in MAP predicted worse functioning in males (R2=0.088; p=0.012). CONCLUSIONS: Slightly sex differences have been found in this study. Our results lead us to consider that early interventions of NS, especially those focusing on motivation and pleasure symptoms, could improve functional outcomes.

The prevention of relapses in first episodes of schizophrenia: The 2EPs Project, background, rationale and study design

Up to 80% of first-episode psychosis patients suffer a relapse within five years of the remission. Relapse should be an important focus of prevention given the potential harm to the patient and family. It threatens to disrupt their psychosocial recovery, increases the risk of resistance to treatment and has been associated with greater direct and indirect costs for society.Based on a previous project entitled “Genotype–phenotype and environment. Application to a predictive model in first psychotic episodes” (PEPs Project), the project “Clinical and neurobiological determinants of second episodes of schizophrenia. Longitudinal study of first episode of psychosis” was designed, also known as the 2EPs Project. It aimed to identify and characterize those factors that predict a relapse within the years immediately following a first episode. This project has focused on following the clinical course, with neuropsychological assessments, biological and neuroanatomical measures, genetic adherence and physical health monitoring in order to compare a subgroup of patients with a second episode to another group of patients which remains in remission. The main objective of the present article is to describe the rationale of the 2EPs Project, explaining the measurement approach adopted and providing an overview of the selected clinical and functional measures.2EPs Project is a multicenter, coordinated, naturalistic, longitudinal follow-up study over three years in a Spanish sample of patients in remission after a first-psychotic episode of schizophrenia. (AU)

Hasta el 80% de los pacientes con un primer episodio de psicosis experimentan una recaída dentro del plazo de 5 años desde la remisión. Dicha recidiva debería constituir un importante enfoque de prevención, dado el daño potencial al paciente y sus familiares, ya que amenaza con perturbar su recuperación psicosocial, incrementa el riesgo de resistencia al tratamiento y se ha asociado a mayores costes directos e indirectos para la sociedad.Basado en un proyecto anterior denominado «Genotipo-fenotipo y entorno. Aplicación a un modelo predictivo en primeros episodios psicóticos –Proyecto PEPs–» (Genotype-phenotype and environment. Application to a predictive model in first psychotic episodes –PEPs Project–), se diseñó el proyecto «Determinantes clínicos y neurobiológicos de segundos episodios de esquizofrenia. Estudio longitudinal del primer episodio de psicosis» (Clinical and neurobiological determinants of second episodes of schizophrenia. Longitudinal study of first episode of psychosis), también conocido como proyecto 2EPs. Su objetivo fue identificar y caracterizar aquellos factores predictivos de recaída dentro del periodo inmediatamente posterior al primer episodio. Este proyecto se centró también en el seguimiento de la evolución clínica, con evaluaciones neuropsicológicas, medidas biológicas y neuroanatómicas, adherencia genética y supervisión de la salud física, a fin de comparar un subgrupo de pacientes que había tenido un segundo episodio con otro grupo de pacientes que sigue en remisión. El principal objetivo del presente artículo es describir el fundamento del Proyecto 2EPs, explicando el enfoque de medición adoptado y aportando una perspectiva general de las medidas clínicas y funcionales seleccionadas. (AU)

El destino del diagnóstico de síndrome de Asperger. ¿Qué le depara el futuro al síndrome de Asperger? / What does the future hold for Asperger syndrome?

No disponible

The Positive and Negative Syndrome Scale for Schizophrenia Autism Severity Scale (PAUSS) in young people with autism and schizophrenia / Escala PAUSS (escala de gravedad del autismo derivada de la PANSS - escala de síndrome positivo y negativo para la esquizofrenia) en una muestra de jóvenes con autismo y esquizofrenia

INTRODUCTION: Schizophrenia spectrum disorders (SSD) share symptoms with autism spectrum disorders (ASD). Autistic phenotypic profiles in SSD may be associated with a poor prognosis. We aimed to assess the evidences for reliability and convergent validity of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Autism Severity Scale (PAUSS) in a sample of young people with ASD and SSD, and to use the PAUSS to explore correlates of "autistic profiles" in the SSD sample. MATERIALS AND METHODS: ASD (n=33, age=13-27 years) and SSD subjects (n=26, age=16-35 years) underwent PANSS, Autism Diagnostic Observation Schedule-Generic (ADOS-G), Autism Diagnostic Interview-Revised (ADI-R), and Social Responsiveness Scale (SRS) assessments. We derived PAUSS total/domain scores from the PANSS and applied these back-to-back with ADOS calibrated severity scores (CSS), ADI-R current behavior algorithm (CBA) scores, and SRS scores. RESULTS: Our results show evidence for an acceptable PAUSS score reliability and convergent validity both in the ASD and SSD samples. PAUSS total and socio-communication scores significantly correlated with ADOS Overall/Social Affect CSS, both in ASD and in SSD. SSD with higher PAUSS scores ("autistic-SSD") showed Overall/Social Affect CSS scores positioned in between ASD and "non-autistic SSD". The PAUSS total score was significantly associated with global functioning in SSD (adjusted R2=0.311). CONCLUSIONS: There seems to be evidence for the reliability and validity of PAUSS scores for quantifying autism symptom severity transdiagnostically and to identify "autistic phenotypes" in adolescents/young adults with SSD

INTRODUCCIÓN: Los trastornos del espectro de la esquizofrenia (TEE) comparten síntomas con los trastornos del espectro del autismo (TEA). En individuos con TEE, perfiles fenotípicos "autistas" parecen estar asociados con un peor pronóstico. Nuestro objetivo fue evaluar la evidencia de fiabilidad y validez convergente de la PAUSS (escala de gravedad del autismo derivada de la escala de síndrome positivo y negativo para la esquizofrenia [PANSS]) en una muestra de jóvenes con TEA y TEE, y utilizar la PAUSS para explorar correlatos de "perfiles autistas" en la muestra de TEE. MATERIALES Y MÉTODOS: En sujetos con TEA (n = 33, edad = 13-27 años) y TEE (n = 26, edad = 16-35 años) se llevaron a cabo las siguientes evaluaciones: la PANSS, la Escala de Observación para el Diagnóstico del Autismo - Genérica (ADOS-G), la Entrevista para el Diagnóstico del Autismo-Revisada (ADI-R), y la Escala de Sensibilidad Social (SRS). Se derivaron de la PANSS las puntuaciones totales/dominio de la PAUSS y se correlacionaron con las puntaciones CSS (gravedad total calibrada) del ADOS, con las puntuaciones del algoritmo de comportamiento actual (CBA) del ADI-R y con las puntuaciones de la SRS. RESULTADOS: Nuestros resultados muestran una evidencia de fiabilidad y validez convergente de la PAUSS aceptables tanto en la muestra TEA como en la TEE. Las puntuaciones totales y del dominio social-comunicación de la PAUSS correlacionaban positiva y significativamente con las puntuaciones CSS total y afectividad social, respectivamente, tanto en la muestra TEA como en la TEE. Los individuos TEE con puntuaciones PAUSS más elevadas ("TEE autistas") mostraban puntuaciones CSS total y afectividad social situadas entre las de los individuos TEA y los "TEE-no autistas". En individuos TEE, la puntuación total PAUSS mostraba una asociación significativa con el funcionamiento global (R2 ajustado = 0.311). CONCLUSIONES: Parece haber evidencia de fiabilidad y validez de las puntuaciones de la PAUSS para cuantificar la gravedad de sintomatología autista a nivel transdiagnóstico, así como para identificar "fenotipos autistas" en adolescentes / adultos jóvenes con TEE

Una década del proyecto de primeros episodios psicóticos (PEPs): avanzando hacia una psiquiatría de precisión / One decade of the first episodes project (PEPs): Advancing towards a precision psychiatry

No disponible

Documento de posicionamiento de la Sociedad Española de Psiquiatría Biológica / Positioning document of the Spanish Biological Psychiatry Society

No disponible

Ir al médico sin miedo: www. doctortea. org para la habituación al entorno médico de pacientes con autismo (AU) / Seeing the doctor without fear: www. doctortea. org for the desensitization for medical visits in Autism Spectrum Disorders

Introducción. Doctor Tea es una página web diseñada para facilitar las visitas médicas de las personas con trastornos del espectro del autismo y/o con otras discapacidades. Las personas con autismo en muchas ocasiones no solo tienen mayores necesidades médicas que la población general, sino que presentan, además, unas características particulares que hacen que acceder a los servicios médicos se convierta en una experiencia muy complicada e incluso a veces traumática. Estas personas tienen grandes dificultades para comprender situaciones y contextos con implicación social como una prueba o consulta médica; dificultad para tolerar situaciones nuevas; y umbrales sensoriales atípicos. Doctor Tea tiene como objetivo reducir la ansiedad ante consultas, procedimientos y profesionales médicos desde un ambiente seguro y conocido (colegio, casa, etc.). Material y método. La página www.doctortea.org proporciona información y materiales (videos, dibujos animados, animaciones 3D, secuencias de pictogramas, etc.) sobre las prácticas médicas más frecuentes a las que los pacientes con trastornos del espectro del autismo se tienen que enfrentar. También ofrece información a los médicos sobre las características de estos pacientes y a las familias sobre los problemas médicos más frecuentemente asociados. Resultados. Durante el año 2015, 17.199 usuarios diferentes visitaron la web. Desde su lanzamiento en noviembre de 2014 el número de visitantes fue de 23.348 personas procedentes de más de 70 países diferentes. Conclusiones. La familiarización con el entorno y los procedimientos médicos parece disminuir la ansiedad frente a los mismos y permite optimizar la eficacia de las visitas médicas y las pruebas complementarias que las personas con discapacidad necesitan (AU)

Introduction. Doctor Tea is an online website designed to facilitate medical visits for those with autism spectrum disorder and other disabilities. People diagnosed with autism not only have greater medical needs than the general population, but also have particular characteristics that are often not accommodated by medical services. This lack of medical accommodation often creates a very complicated, and sometimes traumatic experience, when visiting medical facilities. Individuals with autism have great difficulty understanding social situations and contexts, such as medical tests or consultations, as well as difficulty in tolerating new situations and atypical sensory thresholds. Doctor Tea aims to reduce anxiety before medical consultations and procedures from a safe and well-known environment (school, home, etc.). Material and Method. The website, www.doctortea.org, provides information and materials (videos, cartoon, 3D animations, pictogram sequences, etc.) about the most frequent medical procedures and practices for patients with autism. The website also offers information to the doctors and families of patients with autism about the most common medical problems associated with autism. Results. A total of 17,199 different users visited the website during 2015, with a total of 23,348 online visitors from more than 70 different countries since the website's release in November 2014. Conclusions. The familiarisation with the medical procedures and its environment appears to decrease the anxiety in patients with disabilities during medical visits, as well as optimising the effectiveness of their medical visits and tests (AU)

La función ejecutiva está alterada en los trastornos del espectro autista, pero esta no correlaciona con la inteligencia / Executive function is affected in autism spectrum disorder, but does not correlate with intelligence

Introducción: Los estudios reflejan datos contradictorios sobre un posible deterioro en el funcionamiento ejecutivo en niños y adolescentes con trastorno del espectro autista sin discapacidad intelectual (TEA-SDI). El objetivo del estudio es evaluar el perfil cognitivo de funcionamiento ejecutivo en niños y adolescentes con TEA-SDI y compararlo con el de controles sanos pareados en sexo, edad, estatus socioeconómico, nivel educacional y cociente intelectual (CI). Métodos: Veinticuatro pacientes con TEA-SDI (edad media 12,8 ± 2,5 años; 23 varones; media de CI 99,20 ± 18,81) y 32 controles (edad media 12,9 ± 2,7 años; 30 varones; media de CI 106,81 ± 11,02) fueron seleccionados. Resultados: Se encontraron diferencias estadísticamente significativas en todos los dominios cognitivos evaluados a favor de un mejor rendimiento por parte del grupo control: atención (U = 185,0; p = 0,0005; D = 0,90), memoria de trabajo (T51,48 = 2,597; p = 0,006; D = 0,72), flexibilidad cognitiva (U = 236,0; p = 0,007; D = 0,67), control inhibitorio (U = 210,0; p = 0,002; D = 0,71) y solución de problemas (U = 261,0; p = 0,021; D = 0,62). Estas diferencias se mantuvieron cuando se realizaron los análisis controlando por CI. Conclusión: Los niños y adolescentes con TEA-SDI tienen dificultades para transformar y manipular mentalmente información verbal, presentan latencias de respuesta mayores, problemas atencionales (dificultades en el cambio del set), problemas en la inhibición de respuestas automáticas, así como en la solución de problemas, a pesar de tener un CI normal. Teniendo en cuenta las dificultades en funcionamiento ejecutivo de estos pacientes, se recomienda una intervención integral, que incluya el trabajo en este tipo de dificultades (AU)

Introduction: Studies of executive function in autism spectrum disorder without intellectual disability (ASD-WID) patients are contradictory. We assessed a wide range of executive functioning cognitive domains in a sample of children and adolescents with ASD-WID and compared them with age-, sex-, and intelligence quotient (IQ)-matched healthy controls. Methods: Twenty-four ASD-WID patients (mean age 12.8 ± 2.5 years; 23 males; mean IQ 99.20 ± 18.81) and 32 healthy controls (mean age 12.9 ± 2.7 years; 30 males; mean IQ 106.81 ± 11.02) were recruited. Results: Statistically significant differences were found in all cognitive domains assessed, with better performance by the healthy control group: attention (U = 185.0; P = .0005; D = 0.90), working memory (T51.48 = 2.597; P = .006; D = 0.72), mental flexibility (U = 236.0; P = .007; D = 0.67), inhibitory control (U = 210.0; P = .002; D = 0.71), and problem solving (U = 261.0; P = 0.021; D = 0.62). These statistically significant differences were also found after controlling for IQ. Conclusion: Children and adolescents with ASD-WID have difficulties transforming and mentally manipulating verbal information, longer response latency, attention problems (difficulty set shifting), trouble with automatic response inhibition and problem solving, despite having normal IQ. Considering the low executive functioning profile found in those patients, we recommend a comprehensive intervention including work on non-social problems related to executive cognitive difficulties (AU)

Borderline Intellectual Functioning: Consensus and good practice guidelines

Introducción: El funcionamiento intelectual límite (FIL) se conceptualiza actualmente como la barrera que separa el funcionamiento intelectual «normal» de la discapacidad intelectual (CI 71-85). A pesar de su magnitud, su prevalencia no puede ser cuantificada y no se ha operativizado su diagnóstico. Objetivos: Elaborar un marco conceptual para el FIL y establecer directrices de consenso que permitan la aplicación de una atención integral centrada en la persona. Metodología: Se utilizó una metodología mixta cualitativa que combinaba un análisis del marco conceptual con el desarrollo de grupos nominales. Se realizó una revisión bibliográfica extensiva en bases de datos de evidencia médica, publicaciones científicas y literatura gris. Se estudió la información encontrada y se redactó un documento de marco conceptual sobre el FIL. Resultados: Las publicaciones centradas en el colectivo de personas con FIL son escasas. El término que mayor número de publicaciones arrojó fue «Borderline Intelligence». Se detectaron una serie de temas sobre los que era necesario alcanzar un consenso y se redactó un documento con las conclusiones del grupo de trabajo. Conclusiones: Es necesario establecer un consenso a nivel internacional sobre el constructo del FIL y sus criterios operativos, y desarrollar instrumentos específicos de detección y diagnóstico. También es necesario elaborar criterios que permitan calcular su incidencia y prevalencia. Saber qué intervenciones son las más adecuadas y cuáles son las necesidades de atención que presenta este colectivo es de vital importancia para implementar un modelo de atención integral centrado en la persona(AU)

Introduction: The Borderline Intellectual Functioning (BIF) is conceptualised as the frontier that delimits ‘‘normal’’ intellectual functioning from intellectual disability (IQ 71-85). In spite of its magnitude, its prevalence cannot be quantified and its diagnosis has not yet been defined. Objectives: To elaborate a conceptual framework and to establish consensus guidelines. Method: A mixed qualitative methodology, including frame analysis and nominal groups techniques, was used. The literature was extensively reviewed in evidence based medical databases, scientific publications, and the grey literature. This information was studied and a framing document was prepared. Results: Scientific publications covering BIF are scarce. The term that yields a bigger number of results is ‘‘Borderline Intelligence’’. The Working Group detected a number of areas in which consensus was needed and wrote a consensus document covering the conclusions of the experts and the framing document. Conclusions: It is a priority to reach an international consensus about the BIF construct and its operative criteria, as well as to develop specific tools for screening and diagnosis. It is also necessary to define criteria that enable its incidence and prevalence. To know what interventions are the most efficient, and what are the needs of this population, is vital to implement an integral model of care centred on the individual(AU)

Criterios de valoración clínicos y de funcionamiento en un estudio de interacción gen-ambiente en primeros episodios psicóticos (PEPs) / Assessing clinical and functional outcomes in a gene-environment interaction study in first episode of psychosis (PEPs)

PEPs es un estudio multicéntrico, naturalístico, prospectivo y longitudinal diseñado para evaluar las variables clínicas, neuropsicológicas, de neuroimagen, bioquímicas, ambientales y genéticas en una muestra de casi 350 pacientes con un primer episodio psicótico y 250 controles sanos. El proyecto PEPs ha sido realizado en España desde enero de 2009 hasta diciembre de 2011. En este artículo se describe la justificación de los métodos de evaluación adoptados, proporcionando una breve descripción de las medidas clínicas y funcionales seleccionadas. Los objetivos principales son: a) el examen clínico y la caracterización neuropsicológica de una muestra de primeros episodios de psicosis, y b) el estudio de las interacciones entre las variables genéticas y ambientales seleccionadas para predecir los resultados clínicos y de estructura cerebral y determinar la relación de polimorfismos genéticos implicados en la farmacocinética y la farmacodinámica, y la respuesta en los efectos adversos del tratamiento(AU)

The PEPs study is multicenter, naturalistic, prospective, longitudinal study designed to evaluate clinical, neuropsychological, neuroimaging, biochemical, environmental and pharmacogenetic variables in a sample of nearly 350 first episode of psychosis patients and 250 healthy controls. The PEPs project was conducted in Spain from January 2009 to December 2011. This article describes the rationale for the measurement approach adopted, providing an overview of the selected clinical and functional measures. The main objectives are: (a) the thorough clinical and neurocognitive characterization of a sample of first episodes of psychosis and (b) the study of the interactions between the genetic and environmental variables selected to predict clinical and brain structural outcomes, and to determine the relationship of genetic polymorphisms involved in the pharmacokinetics and pharmacodynamics, and the responses and adverse effects of treatment(AU)