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Abstract Background Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Abstract This study of a cohort of 1-year treatment-compliant survivors of a suicide attempt examined for the first time whether a high CYP2D6-CYP2C19 metabolic capacity (pharmacogenes related to psychopathology, suicide, and attempt severity) and/or polypharmacy treatments predicted repeat suicide attempts, adjusting for sociodemographic and clinical factors as confounders. Of the 461 (63% women) consecutively hospitalized patients who attempted suicide and were evaluated and treated after an index attempt, 191 (67.5% women) attended their 6- and 12-month follow-up sessions. Clinicians were blinded to the activity scores (AS) of their genotypes, which were calculated as the sum of the values assigned to each allele (CYP2C19 *2, *17; CYP2D6 *3, *4, *4xN, *5, *6, *10, wtxN). No differences were found in polypharmacy prescription patterns and the variability of CYP2D6 and CYP2C19 genotypes between adherents and dropouts, but the formers were older, with a higher frequency of anxiety and bipolar disorders and fewer alcohol and substance use disorders. The risk of reattempts was higher for CYP2D6 ultrarapid (AS > 2) metabolizers (β = 0.561, p = 0.005) and violent suicide survivors (β = −0.219, p = 0.042) if the attempt occurred during the first 6-month period, individuals with an increased number of MINI DSM-IV Axis I mental disorders (β = 0.092, p = 0.032) during the second 6-month period and individuals with a combined high CYP2D6-CYP2C19 metabolic capacity (AS > 4) (β = 0.345, p = 0.024) and an increased use of drugs other than antidepressants, anxiolytics-depressants and antipsychotics-lithium (β = 0.088, p = 0.005) in multiple repeaters during both periods. CYP2D6 and CYP2C19 rapid metabolism and polypharmacy treatment for somatic comorbidities must be considered to prevent the severe side effects of short-term multiple suicide reattempts after a previous attempt.

Transnational history has grown significantly over the last three decades. This approach offers new research perspectives for historical inquiries by focusing on processes of interconnection that often transcend national boundaries. In line with this historiographical trend, this special issue aims to analyze, from a historical perspective, the national and international circulation of actors, knowledge and models in education drawing on case studies from the 19th- and 20th-centuries. This special issue additionally offers a survey of the historiography of transnational circulations in education in the late modern and contemporary periods.

Since the last quarter of the 20th century, many researchers and historians have endeavored to trace the emer-gence, development, and establishment of a site of circulation – involving actors, objects, knowledge, networks, etc. – between different regions of the world. This historical scholarship has been central to the emergence of what is now commonly known as the transnational turn in the humanities and social sciences. In the field of the history of education, this transnational perspective has grown quite significantly in France in recent years. Without claiming to be exhaustive, this article aims at highlighting the interest and stakes of this scholarly approach that has signifi-cantly contributed to our understanding of educational realities in the 19th- and 20th-centuries, especially in tran-satlantic areas.

Abstract Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.

Abstract Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p

ObjectiveThe potential role of sub-optimal pharmacological treatment in the poorer outcomes observed in bipolar disorder (BD) with vs. without comorbid substance use disorders (SUDs) is not known. Thus, we investigated whether patients with BD and comorbid SUD had different medication regimens than those with BD alone, in samples from France and Norway, focusing on compliance to international guidelines.MethodsSeven hundred and seventy patients from France and Norway with reliably ascertained BD I or II (68% BD-I) were included. Medication information was obtained from patients and hospital records, and preventive treatment was categorized according to compliance to guidelines. We used Bayesian and regression analyses to investigate associations between SUD comorbidity and medication. In the Norwegian subsample, we also investigated association with lack of medication.ResultsComorbid SUDs were as follows: current tobacco smoking, 26%, alcohol use disorder (AUD), 16%; cannabis use disorder (CUD), 10%; other SUDs, 5%. Compliance to guidelines for preventive medication was lacking in 8%, partial in 44%, and complete in 48% of the sample. Compliance to guidelines was not different in BD with and without SUD comorbidity, as was supported by Bayesian analyses (highest Bayes Factor = 0.16). Cross national differences in treatment regimens led us to conduct country-specific adjusted regression analyses, showing that (1) CUD was associated with increased antipsychotics use in France (OR = 2.4, 95% CI = 1.4–3.9, p = 0.001), (2) current tobacco smoking was associated with increased anti-epileptics use in Norway (OR = 4.4, 95% CI = 1.9–11, p < 0.001), and (3) AUD was associated with decreased likelihood of being medicated in Norway (OR = 1.2, 95% CI = 1.04–1.3, p = 0.038).ConclusionSUD comorbidity in BD was overall not associated with different pharmacological treatment in our sample, and not related to the level of compliance to guidelines. We found country-specific associations between comorbid SUDs and specific medications that warrant further studies.

Abstract in German Hintergrund Reproduktive und psychische Gesundheit sind Schlüsselbereiche des jugendlichen Wohlbefindens, aber mögliche Zusammenhänge sind kaum verstanden. Diese Querschnittsstudie untersuchte den Zusammenhang zwischen Psychopathologie und reproduktivem Gesundheitsrisiko bei europäischen Jugendlichen. Methoden: Im Rahmen des von der EU-Kommission geförderten Projektes "Saving and Empowering Young Lives in Europe" (SEYLE) wurden 12.395 Schüler von 179 zufällig ausgewählten Schulen in 11 europäischen Ländern mit einem strukturierten Fragebogen befragt. Der Fragebogen umfasste Fragen zur sexuellen Initiation und Risikofaktoren der reproduktiven Gesundheit, wie z. B. die Anzahl der Sexualpartner, Häufigkeit der Kondomnutzung und Schwangerschaften. Die psychopathologischen Auffälligkeiten wurden mit validierten Instrumenten und / oder Ad-hoc-Fragen evaluiert. Ergebnisse Von 11.406 Befragten (Median 15; Interquartilbereich [IQR] 14-15; 57% Mädchen) gaben 18,8% an sexuell aktiv geworden zu sein. Sechzig Prozent von ihnen berichteten auch mindestens einen reproduktiven Risikofaktor. Sexuelle Initiation war signifikant häufiger bei Schülern, die älter als 15 Jahre waren (38% versus 13,2% jüngeren Schülern) und bei Jungen (21,3% versus 16,9% Mädchen). Eine sexuelle Initiation lag auch häufiger bei Schülern mit Depressionen (Alter / Geschlechts-adjustiertes Odds Ratio [aOR] 1.871), Angstsymptomen (aOR 2.190), schweren Suizidgedanken (aOR 2.259), selbstverletzendem Verhalten (aOR 2.892) und Selbstmordversuchen (aOR 3.091) vor. Diese Assoziationen waren besonders ausgeprägt bei Schülern ≤15 Jahren und bei deutlich auffälliger Psychopathologie bei Schülern mit geringem nicht-sexuellem Risikoverhalten und beim weiblichen Geschlecht. Depressive Symptome (aOR 1.937), Angstsymptome (aOR 2.282), schwere Suizidgedanken (aOR 2.354), selbstverletzendes Verhalten (aOR 3.022) und Suizidversuche (aOR 3.284) waren mit einem erhöhten Risiko für die reproduktive Gesundheit verbunden - definiert durch eine steigende Anzahl von koexistierenden reproduktiven Risikofaktoren. Schlussfolgerungen Diese Ergebnisse deuten auf eine Beziehung zwischen Risiken für die psychische und reproduktive Gesundheit hin und unterstützen den Wert der domänenübergreifenden Zusammenarbeit bei der Gesundheit von Jugendlichen. Der Zusammenhang zwischen Psychopathologie und reproduktivem Gesundheitsrisiko sowie seine alters- und geschlechtsspezifischen Unterschiede und damit verbundenem Risikoverhalten sollten bei der Gestaltung gesundheitsfördernder oder krankheitsvorbeugender Maßnahmen für Jugendliche berücksichtigt werden.

Abstract Background Chronic low-grade inflammation is believed to contribute, at least in a subset of patients, to the development of bipolar disorder (BD). In this context, the most investigated biological marker is the acute phase response molecule, C-reactive protein (CRP). While the genetic diversity of CRP was amply studied in various pathological settings, little is known in BD. Methods 568 BD patients along with 163 healthy controls (HC) were genotyped for the following single-nucleotide polymorphisms (SNPs) on the CRP gene: intron rs1417938 (+ 29) T/A, 3′-UTR rs1130864 (+ 1444) G/A, and downstream rs1205 (+ 1846) (C/T). The statistical analysis was performed using Chi-square testing and consisted of comparisons of allele/genotype frequencies between patients and controls and within patient sub-groups according to BD clinical phenotypes and the presence of thyroid disorders. Results We found that the frequencies of the studied SNPs were similar in BD and HC groups. However, the CRP rs1130864 A allele carrier state was significantly more frequent: (i) in BD patients with thyroid disorders than in those without (pc = 0.046), especially among females (pc = 0.01) and independently of lithium treatment, (ii) in BD patients with rapid cycling than in those without (pc = 0.004). Conclusions Overall, our findings suggest the possibility that CRP genetic diversity may contribute to the development of auto-immune comorbid disorders and rapid cycling, both proxy of BD severity. Such findings, if replicated, may allow to predict complex clinical presentations of the disease, a possible step towards precision medicine in psychiatry.

Objective: Chest CT is the reference test for assessing pulmonary injury in suspected or diagnosed COVID‐19 with signs of clinical severity. This study aimed to evaluate the association of a lung ultrasonography score and unfavorable clinical evolution at 28 days. Methods: The eChoVid is a multicentric study based on routinely collected data that was conducted in 8 emergency units in France; patients were included between March 19, 2020 and April 28, 2020 and underwent lung ultrasonography, a short clinical assessment by 2 emergency physicians blinded to each other's assessment, and chest CT. Lung ultrasonography consisted of scoring lesions from 0 to 3 in 8 chest zones, thus defining a global score (GS) of severity from 0 to 24. The primary outcome was the association of lung damage severity as assessed by the GS at day 0 and patient status at 28 days. Secondary outcomes were comparing the performance between GS and CT scan and the performance between a new trainee physician and an ultrasonography expert in scores. Results: For the 328 patients analyzed, the GS showed good performance in predicting clinical worsening at 28 days (area under the receiver operating characteristic curve [AUC] 0.83, sensitivity 84.2%, specificity 76.4%). The GS showed good performance in predicting the CT severity assessment (AUC 0.84, sensitivity 77.2%, specificity 83.7%). Conclusion: A lung ultrasonography GS is a simple tool that can be used in the emergency department to predict unfavorable assessment at 28 days in patients with COVID‐19. [ABSTRACT FROM AUTHOR]

Background Migration has been reported to be associated with higher prevalence of mental disorders and suicidal behaviour. Aims To examine the prevalence of emotional and behavioural difficulties, suicidal ideation and suicide attempts among migrant adolescents and their non-migrant peers. Method A school-based survey was completed by 11 057 European adolescents as part of the Saving and Empowering Young Lives in Europe (SEYLE) study. Results A previous suicide attempt was reported by 386 (3.6%) adolescents. Compared with non-migrants, first-generation migrants had an elevated prevalence of suicide attempts (odds ratio (OR) 2.08; 95% CI 1.32–3.26; P=0.001 for European migrants and OR 1.86; 95% CI 1.06–3.27; P=0.031 for non-European migrants) and significantly higher levels of peer difficulties. Highest levels of conduct and hyperactivity problems were found among migrants of non-European origin. Conclusions Appropriate mental health services and school-based supports are required to meet the complex needs of migrant adolescents.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Sexuality is a physiological component of adolescent development, though early initiation is associated with reproductive health risk. This study aimed at identifying correlates and predictors of sexual initiation in a large multinational cohort of European adolescents.A questionnaire addressing socio-demographics, behaviours, mental health and sexual activity, was delivered to 11,110 adolescents recruited from 168 randomly selected schools in 10 European countries between 2009 and 2011. A follow-up questionnaire was delivered after 12 months. The longitudinal association of baseline risk behaviors, psychological attributes and contextual vulnerabilities, with sexual initiation during follow-up was evaluated through simple and multivariable age/sex stratified logistic regression. Multinomial logistic regression measured the association between predictors and sexual initiation with or without coexisting reproductive risk factors, such as multiple partners or infrequent condom use.Baseline sexual experience was reported by 19.2% of 10,757 respondents (median age 15; IQR 14-15; females 59.6%). This was significantly more frequent among pupils older than 15 (41%) and males (20.8%). Of 7,111 pupils without previous experience who were available at follow-up (response rate 81.8%), 17% reported sexual initiation, without differences between females and males. Baseline smoking (age/sex adjusted odds ratio [aOR] 3.63), alcohol use (aOR 2.95), illegal drugs use (aOR 2.72), and poor sleep (aOR 1.71) predicted sexual initiation. Stratified analyses showed a particularly strong association in case of younger and female pupils, and, among girls, when initiation was reported together with multiple partners and/or infrequent condom use. Externalizing (i.e. conduct and hyperactivity) symptoms independently predicted sexual initiation. Internalizing difficulties (i.e. emotional and peer problems) were negatively associated with early and risky sexual initiation among boys. Significant predictors included also being bullied, fighting, truancy, and low parental involvement.Adolescent sexual behaviours are related to non-sexual risk behaviours, psychological difficulties and contextual vulnerabilities. While gateway effects explain some associations, a comprehensive model is needed to understand adolescent sexual behaviours, their physical, mental, and social health outcomes, and their potential positive effects on wellbeing. Tailored interventions may need to consider younger girls as a particularly vulnerable group in view of a strong association between non-sexual and sexual behaviors.

Poor adherence to medication is frequent in bipolar disorder (BD) and has been associated with several factors. To date, the relationship between low adherence and neuropsychological functioning in BD is still unclear. As age and neuropsychological functioning might have opposing influences on adherence, our aim was to investigate this link with a particular focus on the effect of age.In a cross-sectional study, we included 353 patients divided into two age-groups (16-46; 47-71) from a French cohort diagnosed with BD (type I, II, NOS) and strictly euthymic. All patients had a standardized clinical and neuropsychological assessment and were categorized as high (n = 186) or low (n = 167) adherent based on their score from the Medication Adherence Rating Scale. Clinical information was collected based on a standardized interview and clinical validated scales. Neuropsychological performances were evaluated with an established standardized neuropsychological battery for bipolar disorder patients. After univariate analysis, neuropsychological and clinical predictors of low adherence were included in two age-specific stepwise multiple logistic regressions.A smaller number of hospitalizations (OR = 0.846, p = 0.012), a shorter illness duration (OR = 0.937, p = 0.003) and higher adverse effects (OR = 1.082, p

Além das grandes reformas realizadas na organização institucional da escola primária, gratuidade, obrigação, laicidade, os republicanos franceses do final do século 19 quiseram operar uma profunda transformação dos conteúdos de ensino e das normas pedagógicas. As ciências experimentais foram imensamente beneficiadas com isso e se tornaram, em 1882, uma disciplina regular da escola primária com os seus programas e a sua carga horária. A lição de coisas, procedimento pedagógico pelo qual os reformadores se entusiasmaram desde 1860, ficará estreita e naturalmente associada a esse ensino. Ela é, inicialmente, de fato, uma lição de observação: onde os alunos encontrarão melhores oportunidades para observar do que nas aulas de história natural ou de física elementar? Assim, ligados entre si, o ensino das ciências e a lição de coisas têm dois aspectos, um prosaico, outro encantador. Contexto prosaico: o ensino das ciências, destinado a alunos que, na sua maioria, não conhecerão outra escola a não ser a primária, deve permanecer prático e usual. A lição de coisas convém especialmente a esse ensino porque ela trata primordialmente das realidades concretas e familiares. Contexto encantador: o ensino das ciências é um instrumento poderoso de educação intelectual, até mesmo de educação moral e política. Ele representa a esperança de uma educação liberal primária tão completa, digna e válida em seu gênero, quanto às humanidades clássicas do secundário. A lição de coisas, ao fazer corresponder a abordagem pedagógica ao próprio método da ciência, o método indutivo, se torna então, por excelência, o que permite esta educação intelectual. Esta tensão não é própria ao ensino das ciências. Essa análise enseja, antes de mais nada, evidenciar o duplo discurso que os republicanos tiveram sobre uma escola que eles transformaram, simultaneamente, em realidade e sonho.Palavras-chave: atividade (do aluno), escola primária, educação intelectual, educação prática, ensino concreto, ensino das ciências, lição de coisas, método indutivo, método intuitivo, observação, pedagogia. OBJECT LESSONS AND SCIENCE EDUCATION IN FRANCE IN THE LATE NINETEENTH CENTURY: CONTRIBUTION TO A HISTORY OF THE SCHOOL CULTUREAbstractApart from the major reforms carried out in the institutional organization of primary school (gratuity, obligation, secularism), the French Republicans in the late nineteenth century were willing to make a profound transformation of educational content and teaching standards. Experimental sciences have benefited greatly in 1882 and become a regular discipline of primary school, its programs and its time distribution. The lesson, teaching method which reformers were raving since the 1860s, will be closely and naturally associated with this teaching. It is indeed a first observation lesson or where students find they best opportunities to observe that in natural history lessons or basic physics? And related to each other, and science education and object lesson has two sides, one prosaic, another enchanted. Versant prosaic science education, for students who, for the most part, do not know of another school that the primary must be practical and conventional . If the lesson is particularly suitable for this teaching is that it focuses on concrete and familiar realities. Versant enchanted science education is a powerful instrument intellectual education (even moral and political education). It embodies the hope of a primary liberal education as complete, valid and worthy of its kind that classical humanities school. The lesson, matching the pedagogical approach to the same method of science (inductive method) becomes by allowing this intellectual education. This tension is not unique to science education. Analysis allows rather highlighting the double discourse that Republicans held on a school they simultaneously turned into reality and dream.Keywords: activity (student), elementary school, intellectual education, education practice, concrete education, science education, object lesson, inductive method, intuitive method, observation, pedagogy. LECCIONES PRÁCTICAS Y ENSEÑANZA DE LAS CIENCIAS EN FRANCIA A FINALES DEL SIGLO 19: CONTRIBUCIÓN A UNA HISTORIA DE LA CULTURA ESCOLARResumenAdemás de las importantes reformas llevadas a cabo en la organización institucional de la escuela primaria (gratuito, obligación, secularismo), a finales del siglo 19, los franceses republicanos estaban dispuestos a hacer una profunda transformación de los contenidos y de las normas pedagógicas. Ciencias experimentales han beneficiado en gran medida en 1882 y convertido en una disciplina regular de la escuela primaria, sus programas y su distribución en el tiempo. La Lección de las cosas, método de enseñanza que los reformistas estaban entusiasmados, desde la década de 1860, será destrecha y de forma natural asociado a esta enseñanza. De hecho, es una primera lección de observación o donde los estudiantes se mejores oportunidades de observar que en las clases de historia natural o física básica? Y en relación con la otra, y la lección educación científica tiene dos caras, una prosaica, otro "encantado". La educación científica prosaico, para los estudiantes que, en su mayor parte, no saben de otra escuela que el principal debe ser práctico y convencional. Si la lección es particularmente adecuada para esta enseñanza es que se centra en las realidades concretas y conocidas. En contexto encantador, la enseñanza és un poderoso instrumento de educación intelectual (incluso la educación moral y política). Encarna la esperanza de una "educación liberal" primaria completa, válida y digna de su tipo que las humanidades clásicas escuela. La lección de las cosas, que coincide con el enfoque pedagógico con el mismo método de la ciencia (método inductivo) se convierte en la excelencia, al permitir este tipo de educación intelectual. Esta tensión no es aplicable sólo a la educación científica. La análisis de este estudio permite, ante todo, poner de relieve el doble discurso que los republicanos celebraron en una escuela a la que al mismo tiempo se convirtieron en realidad y el sueño.Palabras-clave: actividad (estudiantes), escuela primaria, educación intelectual, educación práctica, enseñanza concreta, enseñanza de las ciencias, lección de las cosas, método inductivo, método intuitivo, observación, pedagogía. LEÇONS DE CHOSES ET ENSEIGNEMENT DES SCIENCES EN FRANCE A LA FIN DU 19E SIECLE: CONTRIBUTION A UNE HISTOIRE DE LA CULTURE SCOLAIRERésuméOutre les grandes réformes accomplies dans l’organisation institutionnelle de l’école primaire (gratuité, obligation, laïcité), les républicains français de la fin du 19e siècle ont eu la volonté d’opérer une profonde transformation des contenus d’enseignement et des normes pédagogiques. Les sciences expérimentales en ont fortement bénéficié et deviennent en 1882 une discipline régulière de l’école primaire, avec ses programmes et sa répartition horaire. La leçon de choses, procédé pédagogique pour lequel les réformateurs s’enthousiasment depuis les années 1860, va être étroitement et naturellement associée à cet enseignement. Elle est en effet d’abord une leçon d’observation; or, où les élèves trouveront-ils meilleures occasions d’observer qu’au cours de leçons d’histoire naturelle ou de physique élémentaire? Ainsi liés l’un à l’autre, enseignement des sciences et leçon de choses ont deux versants, l’un prosaïque, l’autre enchanté. Versant prosaïque: l’enseignement des sciences, destiné à des élèves qui, pour la plupart, ne connaîtront pas d’autre école que le primaire, doit rester pratique et usuel. Si la leçon de choses convient particulièrement à cet enseignement, c’est qu’elle porte avant tout sur des réalités concrètes et familières. Versant enchanté: l’enseignement des sciences est un instrument puissant d’éducation intellectuelle (voire d’éducation morale et politique). Il incarne l’espoir d’une éducation libérale primaire aussi complète, digne et valable en son genre que les humanités classiques du secondaire. La leçon de choses, en faisant correspondre la démarche pédagogique à la méthode même de la science (la méthode inductive) devient alors par excellence ce qui permet cette éducation intellectuelle. Cette tension n’est pas propre à l’enseignement des sciences. L’analyse de celui-ci permet bien plutôt de mettre en évidence le double discours que les républicains ont tenu sur une école qu’ils ont simultanément transformé en réalité et en rêve.Mots-clé: activité (de l’élève), ecole primaire, education intellectuelle, education pratique, enseignement concret, enseignement des sciences, leçon de choses, méthode inductive, méthode intuitive, observation, pédagogie.

Gene-environment interactions may play an important role in modulating the impact of early-life stressful events on the clinical course of bipolar disorder (BD), particularly associated to early age at onset. Immune dysfunction is thought to be an important mechanism linking childhood trauma with early-onset BD, thus the genetic diversity of immune-related loci may account for an important part of the interindividual susceptibility to this severe subform. Here we investigated the potential interaction between genetic variants of Toll-like receptors 2 (TLR2) and 4 (TLR4), major innate immune response molecules to pathogens, and the childhood trauma questionnaire (CTQ) in age at onset of BD. We recruited 531 BD patients (type I and II or not otherwise specified), genotyped for the TLR2 rs4696480 and rs3804099 and TLR4 rs1927914 and rs11536891 single-nucleotide polymorphisms and recorded for history of childhood trauma using the CTQ. TLR2 and TLR4 risk genotype carrier state and history of childhood emotional, physical and sexual abuses were evaluated in relation to age at onset as defined by the age at first manic or depressive episode. We observed a combined effect of TLR2 rs3804099 TT genotype and reported sexual abuse on determining an earlier age at onset of BD by means of a Kaplan-Meier survival curve (p = 0.002; corrected p = 0.02). Regression analysis, however, was non-significant for the TLR2-CTQ sexual abuse interaction term. The negative effects of childhood sexual abuse on age at onset of BD may be amplified in TLR2 rs3804099 risk genotype carriers through immune-mediated pathways. Clinical characteristics of illness severity, immune phenotypes and history of early life infectious insults should be included in future studies involving large patient cohorts.

Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.