Showing papers by "David Cohen published in 2014"

Biological insights from 108 schizophrenia-associated genetic loci

Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

Why synchrony matters during mother-child interactions: a systematic review.

Abstract: Background: Assessment of mother-child interactions is a core issue of early child development and psychopathology. This paper focuses on the concept of “synchrony” and examines (1) how synchrony in mother-child interaction is defined and operationalized; (2) the contribution that the concept of synchrony has brought to understanding the nature of mother-child interactions. Method: Between 1977 and 2013, we searched several databases using the following key-words: « synchrony » « interaction » and « mother-child ». We focused on studies examining parent-child interactions among children aged 2 months to 5 years. From the 63 relevant studies, we extracted study description variables (authors, year, design, number of subjects, age); assessment conditions and modalities; and main findings. Results: The most common terms referring to synchrony were mutuality, reciprocity, rhythmicity, harmonious interaction, turn-taking and shared affect; all terms were used to characterize the mother-child dyad. As a consequence, we propose defining synchrony as a dynamic and reciprocal adaptation of the temporal structure of behaviors and shared affect between interactive partners. Three main types of assessment methods for studying synchrony emerged: (1) global interaction scales with dyadic items; (2) specific synchrony scales; and (3) micro-coded time-series analyses. It appears that synchrony should be regarded as a social signal per se as it has been shown to be valid in both normal and pathological populations. Better mother-child synchrony is associated with familiarity (vs. unknown partner), a healthy mother (vs. pathological mother), typical development (vs. psychopathological development), and a more positive child outcomes. Discussion: Synchrony is a key feature of mother-infant interactions. Adopting an objective approach in studying synchrony is not a simple task given available assessment tools and due to its temporality and multimodal expression. We propose an integrative approach combining clinical observation and engineering techniques to improve the quality of synchrony analysis.

Interactive Technologies for Autistic Children: A Review

Abstract: Recently, there have been considerable advances in the research on innovative information communication technology (ICT) for the education of people with autism. This review focuses on two aims: (1) to provide an overview of the recent ICT applications used in the treatment of autism and (2) to focus on the early development of imitation and joint attention in the context of children with autism as well as robotics. There have been a variety of recent ICT applications in autism, which include the use of interactive environments implemented in computers and special input devices, virtual environments, avatars and serious games as well as telerehabilitation. Despite exciting preliminary results, the use of ICT remains limited. Many of the existing ICTs have limited capabilities and performance in actual interactive conditions. Clinically, most ICT proposals have not been validated beyond proof of concept studies. Robotics systems, developed as interactive devices for children with autism, have been used to assess the child’s response to robot behaviors; to elicit behaviors that are promoted in the child; to model, teach and practice a skill; and to provide feedback on performance in specific environments (e.g., therapeutic sessions). Based on their importance for both early development and for building autonomous robots that have humanlike abilities, imitation, joint attention and interactive engagement are key issues in the development of assistive robotics for autism and must be the focus of further research.

Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms.

Abstract: Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene X environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention and early therapeutic intervention of ASD.

Costs of Periprocedural Complications in Patients Treated With Transcatheter Aortic Valve Replacement Results From the Placement of Aortic Transcatheter Valve Trial

Abstract: Background—In patients with severe aortic stenosis, transcatheter aortic valve replacement (TAVR) improves survival when compared with nonsurgical therapy but with higher in-hospital and lifetime costs. Complications associated with TAVR may decrease with greater experience and improved devices, thereby reducing the overall cost of the procedure. Therefore, we sought to estimate the effect of periprocedural complications on in-hospital costs and length of stay of TAVR. Methods and Results—Using detailed cost data from 406 TAVR patients enrolled in the Placement of Aortic Transcatheter Valve (PARTNER) I trial, we developed multivariable models to estimate the incremental cost and length of stay associated with specific periprocedural complications. Attributable costs and length of stay for each complication were calculated by multiplying the independent cost of each event by its frequency in the treatment group. Mean cost for the initial hospitalization was $79 619±40 570 ($50 891 excluding the valve); 49%...

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

Abstract: Copy number variants (CNVs) have repeatedly been found to cause or predispose to autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194 individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we also analyzed candidate genes located in inherited deletions to unmask autosomal recessive variants. Three CNVs, a de novo triplication of chromosome 15q11–q12 of paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were identified as the cause of the disorder in one individual each. An autosomal recessive cause was considered possible in two patients: a homozygous 1p31.1 deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated with a rare hemizygous missense variant. We also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents. Although highly penetrant CNVs or variants inherited in an autosomal recessive manner were detected in rare cases, our results mainly support the hypothesis that most CNVs contribute to ASDs in association with other CNVs or point variants located elsewhere in the genome. Identification of these genetic interactions in individuals with ASDs constitutes a formidable challenge.

Correlates and outcomes of late and very late drug-eluting stent thrombosis: results from DESERT (International Drug-Eluting Stent Event Registry of Thrombosis).

Abstract: Objectives The aim of this study was to identify clinical, procedural, and angiographic correlates of late/very late drug-eluting stent (DES) thrombosis as well as to determine the clinical outcomes of these events. Background Late/very late DES thromboses are a poorly studied phenomenon, partly due to the relative infrequency of these events, even in large cohort studies. Methods In the DESERT (International Drug-Eluting Stent Event Registry of Thrombosis), a retrospective, case-control registry, 492 cases of late/very late definite DES thrombosis from 21 international sites were matched in a 1:1 fashion with controls without stent thrombosis (ST). Controls were matched according to 2 criteria: same enrolling institution and date of initial DES implantation. Baseline and procedural variables were collected, and clinical follow-up was obtained for patients with ST as long as 1 year after the event. Offline quantitative coronary angiography was performed for a subset of 378 case-control pairs. Results The majority of ST events occurred after 1 year (75%) and continued to occur for as long as 7.3 years. The clinical presentation of late/very late ST events was mainly myocardial infarction (66.7% ST-segment elevation myocardial infarction and 22.0% non–ST-segment elevation myocardial infarction); in-hospital mortality was 3.8%. A minority of patients (30%) with ST were receiving dual-antiplatelet therapy at the time of the event. Independent clinical correlates of late/very late ST were younger age, African-American race, current smoking, multivessel disease, longer stented length, overlapping stents, and percutaneous coronary intervention of vein graft lesions. Independent angiographic correlates for late/very late ST were lesions within the left anterior descending artery or a bypass graft, thrombus, and a larger residual diameter stenosis after the initial DES implantation. Despite the large sample of ST cases, all identified correlates of late/very late ST had weak associations with subsequent ST (all odds ratios Conclusions Despite a large sample of ST cases and use of limited matching to maximize the identification of predictive factors associated with late/very late ST, the variables associated with the development of late/very late ST were only weakly predictive of subsequent events. Additionally, a relatively low observed mortality rate of ST in this series may reflect a different pathophysiology of these late/very late events compared with acute/subacute ST. (Drug Eluting Stent Registry of Thrombosis [DESERT]; NCT00812552 ).

Systematic review of management for treatment-resistant depression in adolescents

Abstract: Current guidelines for treatment-resistant depression in adolescents remain inadequate. This study aimed to systematically review the management of treatment-resistant depression in adolescent patients. We conducted an electronic database search of PUBMED, EMBASE, Cochrane, Web of Science and PsycINFO for studies with adolescent treatment-resistant depression published up to January 2014. Treatment-resistant depression was defined as failure to respond to at least one course of psychological or pharmacological treatment for depression with an adequate dosage, duration, and appropriate compliance during the current illness episode. The Cochrane risk-of-bias method was used to assess the quality of randomized controlled trials. A meta-analysis of all active treatments was conducted. Eight studies with 411 depressed adolescents that fit predetermined criteria investigated pharmacological treatments and psychotherapies. Six were open-label studies, and two were randomized controlled trials. The overall response rate for all active treatments investigated was 46% (95% CI 33 to 59; N = 411) with a moderately high degree of heterogeneity (I2 = 76.1%, 95% CI = 47%-86%). When only the two randomized trials were included, the overall response rate of active treatment was 53% (95% CI = 38-67; N = 347). In these randomized trials, SSRI therapy plus CBT was significantly more effective than SSRI therapy alone, while amitriptyline was not more effective than placebo. Approximately half of the adolescents who presented with treatment-refractory depression responded to active treatment, which suggests that practitioners should remain persistent in managing these challenging cases. The combination of antidepressant medication and psychotherapy should be recommended for adolescents who present with treatment-resistant depression.

Infant's engagement and emotion as predictors of autism or intellectual disability in West syndrome.

Abstract: West syndrome (WS) is a rare epileptic encephalopathy with early onset and a high risk of autistic outcome. The PreAut grid assesses this risk following WS onset by taking into account synchrony and emotion in interactions and by evaluating the baby’s active desire to engage in pleasant interactions (especially the infant’s early active behaviors that encourage being gazed at or kissed by the mother or to share joy with her). We followed a sample of 25 WS patients prospectively from disease onset and assessed whether the PreAut grid before 9 months, and the checklist for autism in toddlers (CHAT) at 18 and 24 months predicted autism or intellectual disability (ID) outcomes at 4 years. We found that the PreAut grid at 9 months (sensitivity = 0.83; specificity = 1) had similar prediction parameters as the CHAT at 18 months (sensitivity = 0.90; specificity = 0.83) and 24 months (sensitivity = 0.92; specificity = 1). WS patients with a positive PreAut screening at 9 months had a risk of having autism or ID at 4 years, which is 38 times that of children with a negative PreAut grid [OR = 38.6 (95 % CI 2.2–2961); p = 0.006]. We conclude that the PreAut grid could be a useful tool for the early detection of autism or ID risk in the context of WS. Further research is needed to assess the PreAut grid in other contexts (e.g. infants at high-risk for non-syndromic autism).

Approches psychothérapiques de l’autisme. Résultats préliminaires à partir de 50 études intensives de cas

Abstract: Resume Contexte Depuis les annees 2000, la recherche en psychotherapie evaluative s’est recentree sur les questions « Pourquoi, comment et dans quelles conditions une psychotherapie agit-elle ? ». L’atteinte de ces objectifs, dont les perspectives sont a la fois cliniques et fondamentales, necessite de donner de l’importance aux etudes intensives de cas naturalistes et aux reseaux de recherche fondes sur les pratiques. Cet article presente les premiers resultats d’une etude longitudinale processus-resultat, multicentrique, explorant des psychotherapies individuelles menees dans des conditions naturelles, pendant un an, avec des enfants autistes dans le cadre du Reseau Inserm de recherches fondees sur les pratiques psychotherapiques. Methodes La methodologie generale est celle d’etudes intensives de cas individuels repondant aux criteres de preuve de l’American Psychological Association. Les indicateurs concernent, d’une part, les symptomes, le processus de developpement et le fonctionnement psychique et, d’autre part, l’action therapeutique a partir des principales caracteristiques du patient, du therapeute et de leurs interactions au cours de la therapie. L’analyse associe et met en relation l’etude de chaque cas, celle des cas reunis et la comparaison de cas analogues. Cet article porte sur les resultats issus des 50 premiers cas regroupes (25 psychotherapies d’enfants de 3–6 ans et 25 de 7–15 ans). Resultats L’analyse montre des changements significatifs dans la reduction des troubles du comportement (taille d’effet = 2,1 ; p Conclusions Nos resultats appuient l’idee que la psychotherapie, menee dans des conditions naturelles par des praticiens experimentes et formes a la specificite de l’autisme, est associee a des changements significatifs. Nos resultats suggerent que les mecanismes qui sous-tendent les changements chez l’enfant pourraient etre le respect de ses initiatives, l’expression, et la comprehension mutuelle comme promoteurs de la communication et du langage, et de la structuration du Soi. Les limites de ces resultats preliminaires sont discutees et des objectifs pour les reduire sont presentes.

Social signal processing for studying parent-infant interaction.

Abstract: Studying early interactions is a core issue of infant development and psychopathology. Automatic social signal processing theoretically offers the possibility to extract and analyse communication by taking an integrative perspective, considering the multimodal nature and dynamics of behaviours (including synchrony). This paper proposes an explorative method to acquire and extract relevant social signals from a naturalistic early parent-infant interaction. An experimental setup is proposed based on both clinical and technical requirements. We extracted various cues from body postures and speech productions of partners using the IMI2S (Interaction, Multimodal Integration, and Social Signal) Framework. Preliminary clinical and computational results are reported for two dyads (one pathological in a situation of severe emotional neglect and one normal control) as an illustration of our cross-disciplinary protocol. The results from both clinical and computational analyses highlight similar differences: the pathological dyad shows dyssynchronic interaction led by the infant whereas the control dyad shows synchronic interaction and a smooth interactive dialog. The results suggest that the current method might be promising for future studies.

French Version of the Brief Infant-Toddler Social and Emotional Assessment Questionnaire–BITSEA

Abstract: OBJECTIVE: The aim of the present study was to examine the psychometric properties of the French version of the Brief Infant-Toddler Social and Emotional Assessment (BITSEA). METHODS: The sample consisted of 589 low-risk infants aged 12-36 months and their parents. Parents completed the BITSEA, the Child Behavior Checklist 1½-5 (CBCL - 18 months to 5 years version), and the Parenting Stress Index - Short Form (PSI-SF). RESULTS: Multitrait-multimethod and confirmatory factor analyses revealed adequate psychometric properties for the French version of the BITSEA. Scores on the BITSEA Problem scale were positively correlated to all CBCL and PSI-SF subscales, whereas negative correlations were found between BITSEA Competence scale and CBCL and PSI-SF subscales. The BITSEA Problem score significantly increased with level of parental worry, examined through a single-item question that is part of the BITSEA. CONCLUSION: Findings support the validity of the French version of the BITSEA. However, additional work on the clinical validity of the BITSEA, including with at-risk children, is warranted. Language: en

Validation de la version française du Coding Interactive Behavior sur une population d’enfants à la naissance et à 2 mois

Abstract: Resume Objectif L’evaluation des interactions mere–enfant est un enjeu majeur de la psychopathologie perinatale du fait de son impact important sur le developpement de l’enfant aussi bien sur le plan affectif que cognitif. Cet article presente les proprietes psychometriques de la validation francaise du Coding Interactive Behavior (CIB) developpe par Ruth Feldman, echelle permettant l’evaluation de la dyade mere–enfant. Methode La version francaise a d’abord ete traduite et adaptee a la terminologie francaise, puis validee par les auteurs d’origine. Elle a ensuite ete appliquee a 74 interactions dyadiques, cliniques et non cliniques recrutees en maternite, a la naissance et a 2 mois post-partum. Les cotations ont ete realisees par des professionnels formes a l’outil et aveugle du statut de la dyade. Resultats La validite interjuge (coefficient de correlation intraclasse) a la naissance et a 2 mois varie de 0,85 a 1 pour chacun des items. Les analyses soutiennent une bonne structure factorielle de l’echelle, comparable a celles rapportees pour la version d’origine israelienne avec une consistance interne allant de α = 0,67 a α = 0,96 pour les videos realisees a la naissance et α = 0,63 a 0,95 pour celles realisees a 2 mois. Conclusion Nos resultats indiquent que la version francaise du CIB dispose de la meme structure factorielle que l’outil originel et constitue une echelle utile pour l’evaluation des interactions mere–enfant.

Abus, maltraitance et négligence : (1) épidémiologie et retentissements psychiques, somatiques et sociaux

Abstract: Resume En 2006, l’OMS a reconnu la maltraitance infantile comme un probleme de sante publique majeur pour l’enfant au meme titre que d’autres pathologies chroniques. Les situations de maltraitance concerneraient entre 1 a 5 % des enfants dans les pays a hauts revenus, avec une association frequente des differents types de maltraitances. Les etudes recoupant les informations d’enquetes retrospectives realisees a l’âge adulte et les donnees de recueil officiel mettent en evidence une sous-evaluation des comportements de maltraitances. En France sur les dernieres annees on assiste a une stabilisation du nombre d’enfants concernes avec une diminution du taux d’abus sexuels et une augmentation des situations de negligences graves et d’abus emotionnel signalees. Les travaux d’epidemiologie observationnelle ont permis de mieux definir les differents facteurs de risque associes au contexte de maltraitance (individuels, environnementaux et familiaux), et d’evaluer les retentissements psychiques mais aussi somatiques et sociaux a long terme de la maltraitance juvenile. Sur le plan psychiatrique, l’association avec les troubles anxieux, depressifs et les troubles du comportement de l’adolescent est forte, et surtout presente chez les filles en cas d’addiction. Le suicide reste la premiere cause de mortalite dans cette population. Au-dela de leurs plus fortes prevalences, ces troubles sont aussi plus souvent severes, resistants et recurrents. L’association avec des troubles somatiques comme l’obesite ou le diabete a ete mise en evidence, mais semble moins claire en cas de plaintes douloureuses comme les plaintes digestives ou les cephalees. Les etudes de devenir socioprofessionnel et medico-economique montrent que l’impact se prolonge au-dela de l’enfance. Les travaux sur le developpement precoce cerebral ont permis de mieux comprendre les mecanismes impliques dans le retentissement de ces traumatismes sur le developpement affectif et cognitif. La vulnerabilite pour des troubles psychopathologiques ulterieurs serait en partie modulee par le polymorphisme genetique des sujets qui constitueraient des facteurs de risque ou protecteurs. L’impact sur le developpement cerebral de ces contextes environnementaux impliquerait les remaniements epigenetiques concernant le systeme hormonal de la regulation du stress (le systeme hypothalamo-hypophysaire) et des structures anatomiques impliquees dans la regulation emotionnelle (comme l’amygdale) ou les fonctions inhibitrices (comme le cortex frontal).

Are There Cultural Differences in Parental Interest in Early Diagnosis and Genetic Risk Assessment for Autism Spectrum Disorder

Abstract: Background: There are many societal and cultural differences between healthcare systems and the use of genetic testing in the U.S. and France. These differences may affect the diagnostic process for Autism Spectrum Disorder (ASD) in each country and influence parental opinions regarding the use of genetic screening tools for ASD. Methods: Using an internet-based tool, a survey of parents with at least one child with ASD was conducted. A total of 162 participants from the U.S. completed an English version of the survey and 469 participants from France completed a French version of the survey. Respondents were mainly females (90%) and biological parents (94.3% in the U.S.; 97.2% in France).Results: The mean age of ASD diagnosis reported was not significantly different between France (57.5±38.4 months) and the U.S. (56.5±52.7 months) (p=0.82) despite significant difference in the average age at which a difference in development was first suspected (29.7 months (± 28.4) vs. 21.4 months (± 18.1), respectively, p=7.10-4). Only 27.8% of U.S. participants indicated that their child diagnosed with ASD had undergone diagnostic genetic testing, whereas 61.7% of the French participants indicated this was the case (p=2.7.10-12). In both countries, the majority of respondents (69.3% and 80% from France and the U.S., respectively) indicated high interest in the use of a genetic screening test for autism. Conclusions: Parents from France and the U.S. report a persistent delay between the initial suspicion of a difference in development and the diagnosis of ASD. Significantly fewer U.S. participants underwent genetic testing although this result should be regarded as exploratory given the limitations. The significance of these between country differences will be discussed.

Mothers With Borderline Personality Disorder: Transition to Parenthood, Parent–Infant Interaction, and Preventive/Therapeutic Approach

Abstract: Borderline personality disorder (BPD) is among the most severe and perplexing mental disorders. Adults with BPD appear particularly exposed to severe difficulties in the transition to parenthood, infant caregiving, and the establishment of healthy early interactions. Studies on the offspring of parents with BPD show a high prevalence of social and emotional symptoms, including BPD features. This article reviews the possible consequences of this mental disorder for women during the transition to parenthood, for the quality of early mother–infant relationships, and for infant development. A presentation of a clinical case illustrates these issues, and some features of the preventive/therapeutic approach of these dyads are discussed.

Diagnosis of erectile dysfunction.

Abstract: Purpose of review Erectile dysfunction is a very prevalent condition and impairs quality of life of men and their partners. The diagnosis strategy of erectile dysfunction has changed, and it is important for every health professional to learn how to deal with erectile dysfunction. Recent findings Although very prevalent, the sexual dysfunctions, including erectile dysfunction, continue to be underdiagnosed. Patients often expect physicians to initiate the conversation and ask about their troubles having sex. The routine to identify erectile dysfunction causes has undergone significant changes over the last decade. Identification of erectile dysfunction can be made through questionnaires or a complete medical and sexual history. Anamnesis and laboratory tests are sufficient in most cases to identify erectile dysfunction and to manage the treatment. Supplementary tests are used in special cases or when there is a need for an etiological diagnosis. Summary Sexual function must be a part of every medical consultation, as any other body function. Erectile dysfunction diagnosis is not a complex task and can be accomplished by any physician. Even when the professional does not feel secure to treat erectile dysfunction, he or she can just identify the dysfunction and refer the patient to an expert.

Analysis of early out-of hospital mortality after transcatheter aortic valve implantation among patients with aortic stenosis successfully discharged from the hospital and alive at 30 days (from the Placement of Aortic Transcatheter Valves Trial)

Abstract: In high-risk or inoperable patients with severe symptomatic aortic stenosis, transcatheter aortic valve implantation (TAVI) is a proven alternative to standard (i.e., medical) therapy or surgical aortic valve replacement. Concerns have been raised, however, about patients who survive the procedure but have short subsequent survival. The aim of this study was therefore to identify correlates of early out-of-hospital mortality (EOHM) in patients who underwent successful TAVI, rendering TAVI potentially "futile." Patients who were discharged from the hospital and survived >30 days but <12 months after TAVI were identified (the EOHM group). Independent predictors of EOHM were explored, including patient-level factors and procedural nonfatal major complications (NFMCs). A sensitivity analysis was also performed, excluding patients with NFMCs. Among 485 patients who were discharged from the hospital and survived 30 days after TAVI, 101 (21%) were dead within 1 year. Independent predictors of EOHM included serum creatinine, liver disease, coagulopathy, mental status, body mass index, male gender, and Society of Thoracic Surgeons score. Although NFMCs were strongly associated with EOHM, patient-level risk factors for EOHM were similar between patients who did and those who did not experience NFMCs. Compared with standard therapy, TAVI patients with EOHM had similar 6-month 6-minute walk distances and functional classes, with higher rates of repeat hospitalization. In conclusion, in high-risk or inoperable patients who underwent TAVI and were discharged and alive at 30 days, EOHM was not infrequent and was determined largely by presenting characteristics and the occurrence of periprocedural NFMCs. Careful screening and minimization of NFMCs may maximize the benefit of TAVI.

A scoring strategy combining statistics and functional genomics supports a possible role for common polygenic variation in autism

Abstract: Autism spectrum disorders (ASD) are highly heritable complex neurodevelopmental disorders with a 4:1 male: female ratio. Common genetic variation could explain 40-60% of the variance in liability to autism. Because of their small effect, genome-wide association studies (GWASs) have only identified a small number of individual single-nucleotide polymorphisms (SNPs). To increase the power of GWASs in complex disorders, methods like convergent functional genomics (CFG) have emerged to extract true association signals from noise and to identify and prioritize genes from SNPs using a scoring strategy combining statistics and functional genomics. We adapted and applied this approach to analyze data from a GWAS performed on families with multiple children affected with autism from Autism Speaks Autism Genetic Resource Exchange (AGRE). We identified a set of 133 candidate markers that were localized in or close to genes with functional relevance in ASD from a discovery population (545 multiplex families); a gender specific genetic score based on these common variants explained 1% (P = 0.01 in males) and 5% (P = 8.7x10-7 in females) of genetic variance in an independent sample of multiplex families. Overall, our work demonstrates that prioritization of GWAS data based on functional genomics identified common variants associated with autism and provided additional support for a common polygenic background in autism.

Management of Adverse Effects of Second-generation Antipsychotics in Youth

Abstract: Second-generation antipsychotics (SGAs) have been proven effective in treating several psychiatric conditions in children and adolescents. These atypical antipsychotic medications are being used with increasing frequency in Europe, the U.S., and Canada. We aim to expose short-term and long-term adverse effects (AEs) of SGAs in youth populations and to provide management recommendations for major adverse effects. These proposals are based on (1) an in-depth literature review of both short- and long-term studies on the use of SGAs in youth; (2) our own clinical experience in managing such treatment in this population; and (3) the work of the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA). AEs are frequent in youth treated with SGAs, and include primarily weight gain, metabolic and hormonal changes, somnolence, extrapyramidal syndrome, and QT modifications. However, frequency and type of AE vary according to compound, and each compound’s AE profile is specific. Acknowledgment of these distinct profiles should aid clinicians in making treatment decisions. After an SGA is prescribed, routine monitoring of AEs is recommended, and should an AE occur, clinical management recommendations should be followed. To date, there are no clinically validated monitoring recommendations.

Statin therapy in patients with chronic kidney disease undergoing percutaneous coronary intervention (from the Evaluation of Drug Eluting Stents and Ischemic Events Registry).

Abstract: Secondary prevention trials have demonstrated the efficacy of statins in reducing cardiovascular morbidity and mortality in patients with coronary artery disease and events after percutaneous coronary intervention (PCI). However, there are few data describing the clinical value of statins in patients with coronary artery disease and chronic kidney disease (CKD) undergoing PCI. Of 10,148 patients who entered into Evaluation of Drug Eluting Stents and Ischemic Events, a multicenter registry of unselected patients undergoing PCI from July 2004 to December 2007, we studied 2,306 patients with CKD (estimated glomerular filtration rate ≤60 ml/min based on the Modified Diet in Renal Disease calculation). Patients were stratified into those receiving statins at discharge (n = 1,833, 79%) or not (n = 473, 21%). Patients in the statin group had a greater prevalence of hypertension, recent myocardial infarction (MI), and use of β blockers and angiotensin-converting enzyme inhibitors. Outcomes were assessed from discharge through 1-year follow-up. One-year all-cause mortality was 5.7% in statin group versus 8.7% in the no statin group (adjusted hazard ratio 0.55, 95% confidence interval 0.34 to 0.88). The composite of death, MI, and repeat revascularization was lower in statin group (adjusted hazard ratio 0.71, 95% confidence interval 0.51 to 0.99). In conclusion, among patients with CKD undergoing PCI, the prescription of statins at hospital discharge was associated with a significant improvement in subsequent outcomes including mortality and composite end point of death, MI, and repeat revascularization.

Prise en charge du trouble bipolaire de type 1 chez l’enfant et l’adolescent

Abstract: Resume La prevalence du trouble bipolaire (TB) type I est estimee a 0,1 % chez l’enfant et l’adolescent. Bien qu’il soit rare, un interet grandissant est porte a ce trouble compte tenu du pronostic severe de la maladie, du retentissement fonctionnel et du risque suicidaire eleve. Ce diagnostic est complexe, en partie a cause des comorbidites plus frequentes a cet âge, des specificites developpementales de l’expression clinique et du recoupement symptomatique avec d’autres troubles (comme le trouble deficitaire attention-hyperactivite, TDAH). Alors que chez les adolescents, la presentation est proche de celle de l’adulte, chez les enfants prepuberes, les symptomes sont plus souvent chroniques sans retour clair a une phase d’euthymie ; l’irritabilite et la labilite emotionnelle sont souvent au premier plan. Cette presentation ne repond que rarement aux criteres de trouble bipolaire type I (TB-1) ; le diagnostic de trouble bipolaire non specifie (TB-NOS) est alors souvent pose chez ces enfants aux Etats-Unis, ce qui a contribue a une inflation du diagnostic ces dernieres annees. Les etudes sur de telles dysregulations emotionnelles de l’enfant ne retrouvent pas de continuite avec le TB a l’âge adulte, mais une evolution plus frequente vers un trouble depressif. Pour mieux identifier ces patients et eviter l’amalgame avec le TB, le diagnostic de Disruptive Mood Dysregulation Disorder (DMDD) a ete propose dans le DSM-5. Au plan de la prise en charge, l’objectif des traitements pharmacologique et psychosocial est de traiter l’episode aigu, de prevenir la rechute, d’ameliorer le fonctionnement global intercritique et de prevenir le risque suicidaire. Plusieurs traitements medicamenteux ont ete evalues dans le TB-1 de l’adolescent dans des essais randomises en double insu. Aux Etat-Unis, outre les sels de lithium, quatre antipsychotiques ont l’AMM pour l’episode maniaque aigu de l’adolescent a partir de 10 a 13 ans (risperidone, olanzapine, aripiprazole et quetiapine). En France, les sels de lithium ont l’AMM a partir de 16 ans ; l’aripiprazole a partir de 13 ans. Les essais therapeutiques sur les autres formes de TB sont peu concluants. Plusieurs strategies psychotherapeutiques individuelles et familiales ont aussi ete proposees.

Abus, maltraitance et négligence : (2) prévention et principes de prise en charge

Abstract: Resume La premiere partie de cet article rappelait la prevalence des differents types de maltraitance infantile ainsi que leurs consequences medicales psychologiques et sociales a long terme. Cette seconde partie a pour objectif de presenter une revue de la litterature des etudes evaluant l’efficacite de differentes strategies de prises en charge medico-sociales. Plusieurs revues soulignent les lacunes du systeme de signalement actuel. Une meilleure reconnaissance des cas reste un des enjeux majeurs pour intervenir precocement. Des travaux interessants ont pointe les facteurs associes a un retard ou a l’absence de signalement. Plusieurs propositions ont ete faites pour y remedier, comme la promotion de la formation continue des professionnelles de l’enfance sur les signes d’alerte a reperer. Si l’accompagnement psychologique de ces enfants peut prendre differentes formes en fonction du contexte clinique, l’encouragement d’un travail de verbalisation des emotions et d’identification des personnes soutenantes dans l’entourage est unanimement reconnu ; tout comme l’importance de poursuivre le suivi au long cours chez les enfants les plus fragilises. Au cours des vingt dernieres annees, plusieurs travaux ont ete consacres a l’evaluation des interventions sociales aupres des enfants victimes de maltraitance averee, lors de placement extrafamilial ou d’intervention au domicile. Ces etudes ont permis de mettre en evidence une reversibilite des troubles presentes dans la majorite des cas ainsi que des effets positifs sur le developpement et l’etat de sante general a l’âge adulte. Par ailleurs, les recherches sur les facteurs de risques de maltraitance ont encourage le developpement d’interventions ciblees aupres des familles cumulant des facteurs de risques psychosociaux pour promouvoir la qualite des liens parents–enfants et les competences parentales. Des programmes, prenant par exemple la forme de visites regulieres au domicile en collaboration avec les services de perinatalite, ont montre des resultats satisfaisants, bien que les effets directs sur la maltraitance restent encore a preciser. De telles interventions sont actuellement en cours d’evaluation en France.

Dépistage échographique anténatal des anomalies mineures de bon pronostic : impact émotionnel, représentations parentales et relation mère-enfant

Abstract: L’echographie fœtale est un outil a present banalise du depistage antenatal. Des anomalies mineures considerees comme de bon pronostic sont reperees chez 5 a 10 % des femmes enceintes, et leur annonce a un impact psychologique substantiel. L’approche psychanalytique met en lumiere la maturation progressive des representations maternelles de l’enfant au cours de la grossesse, ses relations avec les interactions postnatales, et la suspension des investissements lors d’un traumatisme psychique comme l’annonce d’une anomalie fœtale. Les etudes par autoquestionnaires montrent que la revelation de signes mineurs augmente l’anxiete des couples. Le niveau d’angoisse est d’autant plus important que l’information fournie aux futurs parents est floue et qu’il existe une incertitude sur le pronostic de l’anomalie. Les etudes cliniques a partir d’entretiens semistructures et d’observations des interactions montrent une suspension de l’investissement du futur enfant au cours de la grossesse, une modification des representations maternelles et des modifications des interactions precoces mere-enfant. L’anxiete, associee a des symptomes depressifs, et les troubles des interactions peuvent persister jusqu’a deux mois post-partum. Des mesures de prevention sont discutees : formation des professionnels a l’annonce au cours de l’echographie, information des patientes sur les enjeux de l’echographie avant meme la realisation de l’examen, elaboration de consensus sur la valeur diagnostique des signes mineurs pour clarifier l’information, reperage des familles necessitant un accompagnement et des propositions de prise en charge precoce en fin de grossesse et en post-partum precoce.

Dysrégulation émotionnelle et comportementale sévère : une nouvelle entité pour des enfants irritables ?

Abstract: Resume Le trouble de dysregulation emotionnelle et comportementale severe est un nouveau diagnostic relativement peu connu. Il est integre dans la classification du DSM 5 sous le terme de disruptive mood dysregulation disorder pour DMDD. Cette entite a ete isolee a partir des travaux anglo-saxons sur les troubles bipolaires de l’enfant pre-pubere. Ces enfants souffrent de symptomes thymiques d’allure hypomaniaque ou dysphorique accompagnes de reactions de coleres explosives ayant un retentissement important sur leur environnement familial et scolaire. Ce trouble apparait precocement et evolue de facon chronique et non episodique. On retrouve un mauvais controle emotionnel, ainsi qu’une incapacite a acceder a l’euthymie et a un attachement secure chez ces enfants. L’objet de cet article est de rappeler les controverses qui ont conduit a l’elaboration de cette entite en particulier les travaux sur les troubles bipolaires pediatriques. Nous avons examine les arguments scientifiques qui plaident en faveur de son individualisation. Nous avons aussi etudie les liens avec d’autres troubles psychiatriques comorbides, dont le trouble deficitaire de l’attention avec hyperactivite. Notre discussion est illustree par deux vignettes cliniques.

Traitement par lithium dans le trouble bipolaire du sujet jeune

Abstract: Resume La pharmacologie dans les troubles bipolaires chez l’enfant et l’adolescent beneficie d’un interet croissant mais peu d’etudes concernent le lithium. L’efficacite du lithium en monotherapie est moderee, avec des taux de reponse de l’ordre de 35 a 63 %. Le benefice des combinaisons therapeutiques (association au divalproate de sodium, a la carbamazepine ou a la risperidone) est net avec des taux de reponse atteignant 70 a 90 %. Le taux de rechute sous lithium en monotherapie est eleve (37 a 56 %) mais peu etudie. Si le profil de tolerance du lithium est rassurant, les effets secondaires rapportes semblent plus frequents que chez l’adulte, et l’on ne dispose d’aucune donnee a long terme. Enfin, la lisibilite de tous ces resultats souffre d’une limite majeure liee a l’heterogeneite clinique avec l’usage extensif du diagnostic de bipolarite chez l’enfant prepubere. Les etudes futures beneficieront du cadre diagnostique distinguant les diagnostics de « Dysregulation Emotionnelle Severe » (ou « Temper Dysregulation Disorder with Dysphoria » dans le DSM-5) chez l’enfant et de trouble bipolaire de type I chez l’adolescent.