Short Report: 10-year follow-up of a boy with ARID1B-related disorder. Early intervention, longitudinal dimensional phenotype, brain imaging and outcome.

ARID1B-related disorders constitute a clinical continuum, from classic Coffin-Siris syndrome to intellectual disability (ID) with or without nonspecific dysmorphic features. Here, we describe an 11-year-old boy with an ARID1B mutation whose phenotype changed from severe developmental delay and ID to a complex neurodevelopmental disorder with multidimensional impairments, including normal intelligence despite heterogeneous IQ scores, severe motor coordination disorder, oral language disorder and attention-deficit/hyperactivity disorder. Phenotypic changes occurred after early intensive remediation and paralleled the normalization of myelination impairments, as evidenced by early brain imaging. WHAT THIS PAPER ADDS?: This report describes a 10-year multidisciplinary follow-up of a child with an ARID1B mutation who received early intensive remediation and whose phenotype changed during development. Clinical improvement paralleled the normalization of myelination impairments. This case supports a dimensional approach for complex neurodevelopmental disorders.

Transidentities and autism spectrum disorder: A systematic review.

Transidentity and autism frequently co-occur. Previous reviews have focused mainly on frequencies. Here, we conducted a systematic review to condense all the studies and themes on this co-occurrence and to offer a global view. We followed the PRISMA method and selected 77 articles (including 59 clinical studies) in April 2022. We found 5 main themes (sex ratio, theories, sexual orientation, clinical and social consequences, and care implications) in addition to frequencies. Many theories have been proposed to explain the co-occurrence. One posits that social difficulties related to autism would lead to less identification with gender norms and less pressure to conform to these norms, allowing for greater gender diversity in people with autism. Given their difficulties with social interactions and communication, the announcement of one's transidentity to one's social group is often discredited, increasing the risk of suffering and delayed care. Many reports reaffirm the importance of providing specialised care for transgender people with autism. Autism is not a contraindication for gender-affirming treatment. However, some cognitive specificities can affect the planning of care, and transgender people with autism are at high risk of discrimination and harassment. We conclude that there is a need to raise awareness about gender and autism.

[Specificities and non-specificities of the accompaniment of transgender and/or questioning people]. / Spécificités et non-spécificités de l'accompagnement des personnes transgenres et/ou en questionnement.

Gender transitions have been taking place in France for more than fifty years. Recently, case law has come to fruition and has further strengthened the rights of transgender people. However, the issues related to being transgender, including in the medical field, remain too often unknown. This article reports on the specificities and non-specificities of the transidentitarian experience.

Examining the hikikomori syndrome in a French sample of hospitalized adolescents with severe social withdrawal and school refusal behavior.

While the term hikikomori (HKM) has spread internationally to describe a chronic and severe form of social withdrawal, its place in current nosography and its transposition into non-Asian cultures are still debated. A retrospective chart review was conducted to determine the rate and the clinical profiles of HKM among a French sample of adolescent inpatients. Data were obtained from 191 adolescents aged 12-18 years (M = 15.0, 44% boys) consecutively admitted in two inpatient units from January 2017 to December 2019. Using a retrospective diagnosis of HKM based on Teo and Gaw's criteria, we compared socio-demographic characteristics, clinical features, and treatment outcomes between HKM patients and those with other forms of social withdrawal and/or school refusal (SW/SR). At admission, 7% of participants met HKM criteria (n = 14, M = 14.3, 64% boys), one out of six adolescents with SW/SR. Among those with SW/SR, HKM + vs. HKM- participants had higher rates of anxiety disorder (Odd Ratio, OR = 35.2) and lower disruptive behavioral disorder (OR = 0.03). A minority of the participants with anxiety and depressive disorders met the HKM criteria (respectively, 15% and 9%), but those with HKM had a longer duration of symptoms, longer hospitalization, and required more daily care facilities at discharge compared to HKM-. While HKM syndrome could not be delimitated from anxiety disorder, it was associated with specific clinical features and treatment outcomes. The clinical characteristics observed were consistent with the features reported in Asian HKM adults, supporting face validity of this clinical concept in adolescent inpatients with different cultural contexts.

"It Is Not the Robot Who Learns, It Is Me." Treating Severe Dysgraphia Using Child-Robot Interaction.

Writing disorders are frequent and impairing. However, social robots may help to improve children's motivation and to propose enjoyable and tailored activities. Here, we have used the Co-writer scenario in which a child is asked to teach a robot how to write via demonstration on a tablet, combined with a series of games we developed to train specifically pressure, tilt, speed, and letter liaison controls. This setup was proposed to a 10-year-old boy with a complex neurodevelopmental disorder combining phonological disorder, attention deficit/hyperactivity disorder, dyslexia, and developmental coordination disorder with severe dysgraphia. Writing impairments were severe and limited his participation in classroom activities despite 2 years of specific support in school and professional speech and motor remediation. We implemented the setup during his occupational therapy for 20 consecutive weekly sessions. We found that his motivation was restored; avoidance behaviors disappeared both during sessions and at school; handwriting quality and posture improved dramatically. In conclusion, treating dysgraphia using child-robot interaction is feasible and improves writing. Larger clinical studies are required to confirm that children with dysgraphia could benefit from this setup.

Transgender fathering: Children's psychological and family outcomes.

Medical advances in assisted reproductive technology have created new ways for transgender persons to become parents outside the context of adoption. The limited empirical data does not support the idea that trans-parenthood negatively impacts children's development. However, the question has led to lively societal debates making the need for evidence-based studies urgent. We aimed to compare cognitive development, mental health, gender identity, quality of life and family dynamics using standardized instruments and experimental protocols in 32 children who were conceived by donor sperm insemination (DSI) in French couples with a cisgender woman and a transgender man, the transition occurring before conception. We constituted two control groups matched for age, gender and family status. We found no significant difference between groups regarding cognitive development, mental health, and gender identity, meaning that neither the transgender fatherhood nor the use of DSI had any impact on these characteristics. The results of the descriptive analysis showed positive psycho-emotional development. Additionally, when we asked raters to differentiate the family drawings of the group of children of trans-fathers from those who were naturally conceived, no rater was able to differentiate the groups above chance levels, meaning that what children expressed through family drawing did not indicate cues related to trans-fatherhood. However, when we assessed mothers and fathers with the Five-Minute Speech Sample, we found that the emotions expressed by transgender fathers were higher than those of cisgender fathers who conceived by sex or by DSI. We conclude that the first empirical data regarding child development in the context of trans-parenthood are reassuring. We believe that this research will also improve transgender couple care and that of their children in a society where access to care remains difficult in this population. However, further research is needed with adolescents and young adults.

The Developmental Implications of the Use of Reproductive Technologies for Transgender People: A Comparative Cross-Section Protocol.

BACKGROUND: Today, individuals and couples with fertility issues can use advances in biomedical technologies to conceive. Transgender persons also benefit from these advances and can not only actualize their self-identified gender identities but also experience parenthood. These strategies for persons to self-actualize and to access parenthood have improved the condition of transgender persons. However, some may question the welfare of the offspring because such transfamily forms are often confusing to many. The sparse research on the psychological well-being of children of transgender people is reassuring. However, the limited empirical research justifies more studies to be conducted with an evidence-based methodology to assess whether these new methods of parenting have any adverse impact on children. AIMS: The current report details the protocol we built to compare cognitive development, mental health, gender identity, quality of life, and family dynamics in children of transgender fathers and donor sperm insemination (DSI) and two control groups matched for age and gende typically developing (TD) children and children from cisgender parents and DSI. HYPOTHESIS: To calculate sample sizes, we hypothesize no significant difference between groups. SUBJECTS AND METHODS: Since 2008, married couples that include a transgender father have been able to access DSI and have started conceiving children in France. They are always invited to participate in research to assess their children's well-being. To date, the cohort includes 53 children in 37 families. We propose to carry out a cross-sectional comparative study exploring cognitive development with the Brunet-Lézine Psychomotor Development Scale or Wechsler's Intelligence Scales according to age; mental health with the Child Behaviour Checklist; gender identity with the Gender Identity Interview for Children; quality of life with the KIDSCREEN and the Adolescent Coping Questionnaire; and family dynamics with the Parental Bonding Instrument, the Inventory of Parent and Peer Attachment, the Five-Minute Speech Sample, and Corman's Family Drawing Test. To assess possible subtle differences between children's family drawings, we will use a generalization of the "lady-tasting-tea" procedure to link qualitative and quantitative approaches in psychiatric research. Twenty raters [four child and family psychoanalysts (CHILDPSY), four adult psychiatrists (ADUPSY), four biologists working in assistive reproduction technology (BIOL), four endocrinologists working with transgender individuals (ENDOC), and four students (STUD)] will be randomly shown the drawings and asked to blindly classify them using a Likert scale according to whether the child has a transgender father. STATISTICAL ANALYSIS: After testing normality, comparisons between the three groups will be performed with appropriate statistical tests (Kruskal-Wallis, ANOVA, Chi2 or Fisher's exact test). For the "lady-tasting-tea" procedure, we will use a permutation test. ETHICS: The study protocol has been approved by the CERES (Comité d'Ethique de Recherche en Santé) of Paris 5 University. Registration number is 2015/31.

LdtMav2, a nonclassical transpeptidase and susceptibility of Mycobacterium avium to carbapenems.

AIM: Mycobacterium avium infections, especially in immune-compromised individuals, present a significant challenge as therapeutic options are limited. In this study, we investigated if M. avium genome encodes nonclassical transpeptidases and if newer carbapenems are effective against this mycobacteria. MATERIALS & METHODS: Biochemical and microbiological approaches were used to identify and characterize a nonclassical transpeptidase, namely L,D-transpeptidase, in M. avium. RESULTS & CONCLUSION: We describe the biochemical and physiological attributes of a L,D-transpeptidase in M. avium, LdtMav2. Suggestive of a constitutive requirement, levels of LdtMav2, a L,D-transpeptidase in M. avium, remain constant during exponential and stationary phases of growth. Among ß-lactam antibacterials, only a subset of carbapenems inhibit LdtMav2 and tebipenem, a new oral carbapenem, inhibits growth of M. avium.

Ecological Momentary Assessment and Smartphone Application Intervention in Adolescents with Substance Use and Comorbid Severe Psychiatric Disorders: Study Protocol.

CONTEXT: Substance use disorders (SUDs) are highly prevalent among inpatient adolescents with psychiatric disorders. In this population, substance use and other psychiatric outcomes can reinforce one another. Despite the need for integrated interventions in youths with dual diagnoses, few specific instruments are available. App-based technologies have shown promising results to help reduce substance use in adolescents, but their applicability in youths with associated severe psychiatric disorders is poorly documented. We aim to evaluate the feasibility of an ecological momentary assessment (EMA) intervention for all substance users, and of a smartphone application for cannabis users (Stop-Cannabis), for outpatient treatment after hospital discharge. METHODS AND ANALYSIS: All inpatient adolescents with psychiatric disorders hospitalized between 2016 and 2018 in a university hospital will be systematically screened for SUD and, if positive, will be assessed by an independent specialist addiction team. Participants with confirmed SUDs will be invited and helped to download an EMA app and, if required, the Stop-Cannabis app, the week preceding hospital discharge. Information about the acceptability and use of both apps and the validity of EMA data in comparison to clinical assessments will be assessed after 6 months and 1 year. DISCUSSION: This research has been designed to raise specific issues for consideration regarding the sequence between substance use, contextual factors, and other psychiatric symptoms among adolescents with comorbid severe psychiatric disorders. A better understanding of the mechanisms involved will inform the development of integrated treatment for dual disorders at that age. ETHICS AND DISSEMINATION: The study has already been approved and granted. Dissemination will include presentations at international congresses as well as publications in peer-reviewed journals. TRIAL REGISTRATION: European Clinical Trials Database: Number 2016-001999-30.

Ribosomes slide on lysine-encoding homopolymeric A stretches.

Protein output from synonymous codons is thought to be equivalent if appropriate tRNAs are sufficiently abundant. Here we show that mRNAs encoding iterated lysine codons, AAA or AAG, differentially impact protein synthesis: insertion of iterated AAA codons into an ORF diminishes protein expression more than insertion of synonymous AAG codons. Kinetic studies in E. coli reveal that differential protein production results from pausing on consecutive AAA-lysines followed by ribosome sliding on homopolymeric A sequence. Translation in a cell-free expression system demonstrates that diminished output from AAA-codon-containing reporters results from premature translation termination on out of frame stop codons following ribosome sliding. In eukaryotes, these premature termination events target the mRNAs for Nonsense-Mediated-Decay (NMD). The finding that ribosomes slide on homopolymeric A sequences explains bioinformatic analyses indicating that consecutive AAA codons are under-represented in gene-coding sequences. Ribosome 'sliding' represents an unexpected type of ribosome movement possible during translation.

Diagnostic transition towards schizophrenia in adolescents with severe bipolar disorder type I: an 8-year follow-up study.

BACKGROUND: The diagnosis of bipolar disorder-I (BD-I) is currently well-established. However, more studies exploring diagnostic stability and psychosocial adaptation during follow-up in adulthood are needed. OBJECTIVES: We assessed factors at follow-up (FU): (1) the diagnostic stability of manic/mixed episodes from adolescence to adulthood, (2) psychosocial adaptation, and (3) factors associated with psychosocial adaptation. METHODS: A sample of 80 adolescents hospitalized in a university hospital between 1993 and 2004 for a manic or mixed episode were contacted for an FU assessment on average 8 years after the index episode. Assessments included socio-demographic data, mortality, lifetime psychiatric diagnosis, the Social Adaptation Scale, negative life events and insight. RESULTS: Of the 64 patients with available information, one patient died from a heart attack. Of the 55 patients available for an FU assessment, 35 (63.6%) still presented a diagnosis of BD-I at FU, whereas 20 (36.4%) had changed diagnosis towards a schizophrenia spectrum disorder. Psychosocial adaptation was moderate to poor for most patients, and 91% of the patients had at least one relapse. A low socio-economic status, intellectual disability, negative life events, a history of sexual abuse, and treatment with classical antipsychotics at FU were significantly associated with poorer psychosocial adaptation. In contrast, better insight, a family history of depression and a diagnosis of BD-I at FU were associated with better psychosocial adaptation. CONCLUSION: BD-I in adolescent inpatients can lead to important morbidity and mortality during outcome. Diagnostic stability is high, but a high proportion of patients also show a transition towards a schizophrenia spectrum disorder.

Communities of microbial eukaryotes in the mammalian gut within the context of environmental eukaryotic diversity.

Eukaryotic microbes (protists) residing in the vertebrate gut influence host health and disease, but their diversity and distribution in healthy hosts is poorly understood. Protists found in the gut are typically considered parasites, but many are commensal and some are beneficial. Further, the hygiene hypothesis predicts that association with our co-evolved microbial symbionts may be important to overall health. It is therefore imperative that we understand the normal diversity of our eukaryotic gut microbiota to test for such effects and avoid eliminating commensal organisms. We assembled a dataset of healthy individuals from two populations, one with traditional, agrarian lifestyles and a second with modern, westernized lifestyles, and characterized the human eukaryotic microbiota via high-throughput sequencing. To place the human gut microbiota within a broader context our dataset also includes gut samples from diverse mammals and samples from other aquatic and terrestrial environments. We curated the SILVA ribosomal database to reflect current knowledge of eukaryotic taxonomy and employ it as a phylogenetic framework to compare eukaryotic diversity across environment. We show that adults from the non-western population harbor a diverse community of protists, and diversity in the human gut is comparable to that in other mammals. However, the eukaryotic microbiota of the western population appears depauperate. The distribution of symbionts found in mammals reflects both host phylogeny and diet. Eukaryotic microbiota in the gut are less diverse and more patchily distributed than bacteria. More broadly, we show that eukaryotic communities in the gut are less diverse than in aquatic and terrestrial habitats, and few taxa are shared across habitat types, and diversity patterns of eukaryotes are correlated with those observed for bacteria. These results outline the distribution and diversity of microbial eukaryotic communities in the mammalian gut and across environments.

[Bipolar disorder in adolescence]. / Trouble bipolaire de l'adolescent.

Juvenile mania is a concept widely developed but also highly debated since the 1990s. In the heart of this debate, Severe Mood Dysregulation (SMD) and "Temper Dysregulation disorder with Dysphoria" (recently integrated in DSM-5) showed their interest. Actually, the objective is to distinguish two clinical phenotypes in order to avoid confusion between (1) what would raise more of mood dysregulation with chronic manic like symptoms, and (2) bipolar disorder type I with episodic and acute manic episodes. Therapeutic stakes are major. In adolescents, even if DSM adult diagnostic criteria can be used and bipolar disorder type I clearly established, differential diagnostic at onset between acute manic episode and schizophrenia onset remain sometimes difficult to assess. Furthermore, it is crucial to better assess outcome of these adolescents, in terms of morbidity and potential prognosis factors, knowing that a younger age at onset is associated with a poorer outcome according to several adult studies. Therapeutic implications could then be drawn.

One-dimensional SDS-polyacrylamide gel electrophoresis (1D SDS-PAGE).

This protocol describes a denaturing polyacrylamide gel system utilizing sodium dodecyl sulfate (SDS) to separate protein molecules based on size as first described by Laemmli (1970). SDS-PAGE can be used to monitor protein purifications, check the purity of samples, and to estimate molecular weights for unknown proteins.

Coomassie blue staining.

This protocol describes Coomassie brilliant blue staining, one of the most common methods of detecting proteins in polyacrylamide gels (PAGE).

RF3:GTP promotes rapid dissociation of the class 1 termination factor.

Translation termination is promoted by class 1 and class 2 release factors in all domains of life. While the role of the bacterial class 1 factors, RF1 and RF2, in translation termination is well understood, the precise contribution of the bacterial class 2 release factor, RF3, to this process remains less clear. Here, we use a combination of binding assays and pre-steady state kinetics to provide a kinetic and thermodynamic framework for understanding the role of the translational GTPase RF3 in bacterial translation termination. First, we find that GDP and GTP have similar affinities for RF3 and that, on average, the t1/2 for nucleotide dissociation from the protein is 1-2 min. We further show that RF3:GDPNP, but not RF3:GDP, tightly associates with the ribosome pre- and post-termination complexes. Finally, we use stopped-flow fluorescence to demonstrate that RF3:GTP enhances RF1 dissociation rates by over 500-fold, providing the first direct observation of this step. Importantly, catalytically inactive variants of RF1 are not rapidly dissociated from the ribosome by RF3:GTP, arguing that a rotated state of the ribosome must be sampled for this step to efficiently occur. Together, these data define a more precise role for RF3 in translation termination and provide insights into the function of this family of translational GTPases.

In vitro transcription from plasmid or PCR-amplified DNA.

This protocol describes the synthesis and purification of RNAs using plasmid DNA or PCR-amplified DNA as a template. This procedure should give NTP-free, full-length RNA for all sizes of RNA. This protocol is derived from Milligan and Uhlenbeck, the classic paper on T7 transcription reactions, with modifications.

Psychodynamic-oriented psychological assessment predicts evolution to schizophrenia at 8-year follow-up in adolescents hospitalized for a manic/mixed episode: interest of an overall subjective rating.

Little is known concerning the prognostic significance of manic/mixed episodes in adolescents. In particular, whether the use of psychodynamic-oriented projective psychological testing predicts evolution to schizophrenia at follow-up has not been established. Eighty subjects, aged 12-20years old, consecutively hospitalized for a manic or mixed episode between 1994 and 2003 were recruited. All patients were contacted in 2005-2006 for a follow-up assessment. For the subgroup of adolescents (N=40) who had psychodynamic-oriented psychological testing (Rorschach and TAT), two scores regarding psychosocial risk and schizophrenia risk were computed using the clinical global impression (CGI) assessment based on an overall subjective rating given by a panel of expert psychologists who reviewed all protocols. At follow-up (average 8years), 25 (62.5%) patients, 16 females and nine males, were assessed: 14 still had a diagnosis of bipolar disorder; eight changed to schizo-affective disorder and three to schizophrenia. Inter-rater reliability of both CGI-risk scores (psychosocial risk and schizophrenia risk) showed good clinical consensus with intraclass correlation and Kappa scores ranging from 0.53 to 0.75. Univariate analysis showed that CGI-psychosocial risk score (p=0.017), type of index episode (p=0.049) and CGI-schizophrenia risk score (p=0.09) were associated with transition to schizophrenia spectrum disorder at follow-up. Age, sex, socioeconomic status, duration of stay and the presence of psychotic features at index episode were not associated with the transition. We conclude that the CGI assessment appears to be valid to score risk of poor outcome using psychodynamic-oriented psychological testing and that these scores may predict, in part, the transition to schizophrenia in adolescents with a history of manic/mixed episode.

Allosteric regulation of Argonaute proteins by miRNAs.

Small interfering RNAs (siRNAs) and microRNAs (miRNAs) bind to Argonaute (AGO) family proteins to form a related set of effector complexes that have diverse roles in post-transcriptional gene regulation throughout the eukaryotic lineage. Here sequence and structural analysis of the MID domain of the AGO proteins identified similarities with a family of allosterically regulated bacterial ligand-binding domains. We used in vitro and in vivo approaches to show that certain AGO proteins (those involved in translational repression) have conserved this functional allostery between two distinct sites, one involved in binding miRNA-target duplex and the other in binding the 5' cap feature (m(7)GpppG) of eukaryotic mRNAs. This allostery provides an explanation for how miRNA-bound effector complexes may avoid indiscriminate repressive action (mediated through binding interactions with the cap) before full target recognition.

Medication use in adolescents treated in a French psychiatric setting for acute manic or mixed episode.

OBJECTIVE: In the absence of recommendations from drug regulatory agencies for most medications to treat severe manic or mixed episode in adolescence, this study aims to (i) describe the pharmacological treatment prescribed in an inpatient setting for acute manic or mixed episodes in adolescents; (ii) determine whether type of episode, duration of stay, improvement, and psychotic features were associated with the nature of the given treatment; (iii) compare the results with evidence-based data. METHOD: From 1993 to 2003, we received 80 subjects, aged 12 to 20 years, consecutively hospitalized for a manic or mixed episode. Socio-demographic, clinical and treatment data were extracted by reviewing patients' charts. Treatment data were available for 75 subjects. RESULTS: Most patients received a combination treatment including mood stabilizer (82.6%), classical antipsychotic (AP) (86.6%) and atypical AP (24%). Despite prolonged hospitalisation (minimum stay = 17 days), 69 (86.2%) patients were scored very much or much improved at discharge. Secondary therapeutic options occurred in 15 subjects because of poor therapeutic response (N=13), severe adverse effects (N=5) or both. Two patients had electroconvulsive therapy as third therapeutic option. Adolescents with psychotic symptoms were significantly more frequently treated by lithium (Fisher exact test: p=0,0052). No other variable was associated with treatment. CONCLUSIONS: This study reported on patterns of medication use that mainly followed treatment recommendations and evidence-based data existing in adults. However, the presence of psychotic features appeared to favour the use of lithium in this French sample.