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Objective: To review the use of aripiprazole in children and adolescents. Methods: Medline and Embase databases were systematically searched using the keywords aripiprazole and child or adolescent over the period from 2000 to 2019. The initial screen yielded 163 publications, from which 99 studies were reviewed. Results: Aripiprazole is one of the most widely prescribed atypical antipsychotics. Like others, its use in children and adolescents is becoming commonplace and occurs in off-label indications. Aripiprazole has proven efficacy for several indications in children and adolescents, including schizophrenia, bipolar disorder, Tourette's syndrome, and behavioral impairments associated with autism and intellectual disability. Adverse effects are more important in children and adolescents than adults, particularly weight gain, drowsiness, extrapyramidal effects, and metabolic effects, even though the latter may appear less important than with other atypical antipsychotics. Severe adverse effects often occur in multiple-prescription settings. At present, postprescription monitoring is very poor. Conclusion: Aripiprazole has proven efficacy for several indications in children and adolescents. However, its use requires clinical and paraclinical monitoring to assess the occurrence of adverse events that may challenge the benefit/risk ratio. In addition, off-label prescriptions should be limited, as they appear to account for a significant proportion of aripiprazole use worldwide.

Early-Onset Schizophrenia (EOS) is rare but severe mental health disorder in children and adolescents. Diagnosis of schizophrenia before the age of 18 years remains complex and challenging, especially in young children. In France, there are no recent reliable epidemiological data about the prevalence of EOS. The present study evaluates the EOS rate in a target clinical population of children and adolescents in psychiatric and medico-social care centres in the South-East of France. Psychiatric and medico-social centres for children and adolescent in the geographical area have been contacted, and after receiving their agreement to participate in the study, eligible patients corresponding to inclusion criteria were selected based on patients' medical records. Main inclusion criteria were age 7 to 17 years and intelligence quotient > 35. EOS categorical diagnosis was assessed by Kiddie-SADS Present and Lifetime psychosis section. 37 centres participated and 302 subjects have been included in the study. The main result was the categorical diagnosis of EOS in 27 subjects, corresponding to a rate of 8.9% in the study population. Half of the patients presented mild to moderate intellectual deficiency. Interestingly, only 2.3% had a diagnosis of schizophrenia spectrum disorder noted in their medical records before standardized assessment. The results of the study highlight the importance of using a standardized diagnostic tool for the diagnosis of schizophrenia in the paediatric population. In fact, EOS might be underdiagnosed in children and adolescents with neurodevelopmental disorders and subnormal cognitive functioning.

Significance To trigger cell death (apoptosis), two members of the B-cell lymphoma-2 protein family, Bak and Bax, change shape and convert from inert monomers into the oligomers that disrupt the outer mitochondrial membrane, but how they perturb the membrane is poorly understood. A longstanding model is that they rearrange and insert two central helices, α5 and α6, as a hairpin through the membrane. We show, however, that the hairpin insertion model does not hold. Instead, these helices in the oligomers insert only shallowly in the membrane, in its plane. The results favor a model in which these and probably other helices of Bak and Bax crowd the outer leaflet of the membrane, producing membrane curvature that leads to its disruption. The pivotal step on the mitochondrial pathway to apoptosis is permeabilization of the mitochondrial outer membrane (MOM) by oligomers of the B-cell lymphoma-2 (Bcl-2) family members Bak or Bax. However, how they disrupt MOM integrity is unknown. A longstanding model is that activated Bak and Bax insert two α-helices, α5 and α6, as a hairpin across the MOM, but recent insights on the oligomer structures question this model. We have clarified how these helices contribute to MOM perforation by determining that, in the oligomers, Bak α5 (like Bax α5) remains part of the protein core and that a membrane-impermeable cysteine reagent can label cysteines placed at many positions in α5 and α6 of both Bak and Bax. The results are inconsistent with the hairpin insertion model but support an in-plane model in which α5 and α6 collapse onto the membrane and insert shallowly to drive formation of proteolipidic pores.

Background Over the last decades, antipsychotic prescriptions in children have increased worldwide. However, adverse events are frequently observed, with some such as psychiatric adverse events remaining poorly documented. Method The French ETAPE study is a 12-month naturalistic prospective multisite study that included 190 antipsychotic-naïve pediatric patients (mean age = 12 ± 3 years), treated by antipsychotic for psychotic or non-psychotic symptoms. From the ETAPE database, we performed additional analyses focusing on psychiatric adverse events. Results Children received mainly second-generation antipsychotic for conditions out of regulatory approval, with risperidone and aripiprazole being the most frequent (respectively 52.5% and 30.83%). Clinicians reported 2447 adverse events, mainly non-psychiatric (n = 2073, 84.72%), including neuromuscular, metabolic, gastroenterological, and (n = 374, 15.28%) psychiatric. 55.88% of psychiatric adverse events were attributable to antipsychotic by the clinician, compared to 89% of non-psychiatric adverse events ( p < 0.001 ). 63.2% (n = 120) of the 190 children and adolescents presented at least one psychiatric adverse event. The most frequent were externalized behaviors such as aggressiveness or agitation (22.7%), mood changes (18.4%) and suicidal ideas or behaviors (11.8%). Half of psychiatric adverse events occurred during the first quarter, 49.46%, compared to 23.79% during the second, 15.77% during the third, and 10.96% during the fourth. Conclusion This additional analysis from the French ETAPE study emphasizes that psychiatric adverse events might be more frequent than expected in the pediatric population. Also, the potential risk of psychiatric adverse events should be part of the benefit-risk evaluation and sub-sequent follow-up.

The current management of patients with Dementia, primarily with Alzheimer's Disease (AD) is rapidly evolving. However, limited information is available about the current gaps and decision-making in primary care. To evaluate factors associated with gaps, risk preferences regarding diagnostic and therapeutic choices in the management of patients with AD by primary care physicians (PCP) from across Canada. We propose a non-interventional, cross-sectional pilot study involving 120 primary care physicians referred from the College of Family Physicians of Canada to assess diagnostic and therapeutic decisions in the management of ten simulated AD-related case-scenarios commonly encountered in clinical practice. We initially describe the current landscape and gaps regarding diagnostic and therapeutic challenges in the management of patients with AD in primary care. Then, we provide concepts from behavioral economics and neuroeconomics applied to medical decision-making. Specifically, we include standardized tests to measure risk aversion, physicians' reactions to uncertainty, and questions related to risk preferences in different domains. Finally, we summarize the protocol to be implemented to address our goals. The primary study outcome is the proportion of participants that elect to defer initial investigations to the specialist and the associated factors. Secondary outcomes include the proportion of PCP willing to order cerebral spinal fluid studies, PET scans, or initiate treatment according to the simulated case-scenarios. The study will be conducted in English and French. The study findings will contribute a better understanding of relevant factors associated with diagnostic and therapeutic decisions of PCP in the management of AD, identifying participant's preferences and evaluating the role of behavioral aspects such tolerance to uncertainty, aversion to ambiguity, and therapeutic inertia.

IntroductionSecond-generation antipsychotics (SGAs) are widely used in the paediatric population. It is currently established that SGAs may induce metabolic adverse events (AEs) such as weight gain, perturbation of blood lipids or glucose with risk of potential cardiovascular morbidity and mortality. The Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in children (CAMESA) has published recommendations for monitoring the metabolic AEs of SGAs. Factors that may be associated with the onset of SGA’s metabolic AEs and long-term consequences are less studied in the literature. The objectives of our research are to evaluate some factors that can influence the development of the SGA’s metabolic AEs and to study clinical adherence to CAMESA guidelines.Methods and analysisThe Monitoring des Effets Métaboliques des Antipsychotiques de Seconde Génération study is a multicenter, prospective, longitudinal observational study with repeated measures of metabolic monitoring over 24 months. Two recruiting centres have been selected for patients under 18 years of age, previously naive of antipsychotics, starting an SGA or who have started an SGA for less than 4 weeks regardless of the diagnosis that motivated the prescription. Assessments are performed for anthropometric measures, blood pressure, blood tests at baseline and 1, 2, 3, 6, 9, 12 and 24 months of follow-up.Ethics and disseminationThe study protocol was approved by the CHU Sainte-Justine’s Research Ethics Board (MP-21-2016-1201) in 2016 and obtained institutional suitability for the ‘Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l’Île-de-Montréal’ Research Center in May 2018. For all participants, written consent will be obtained from parents/caregivers as well as the participant’s assent in order to enable their participation in this research project. The results of this research will be published.Trial registration numberClinicalTrials.gov (number NCT04395326).

On 2 October 2020, a violent storm (Alex) reached the French Riviera and caused significant damage in three inhabited valleys in the hinterland of the city of Nice. Entire populations were exposed to prolonged stress (no means of communication, electricity nor water) and were particularly at risk of suffering from psychological consequences. We first hypothesized that a majority of children would experience an acute stress reaction. However, we also hypothesized that their clinical expression would differ depending on their developmental age. Thus, we aimed to evaluate, according to the child's level of development, the presence of acute stress symptoms. Consecutive interviews with the child/adolescent and his/her parents were conducted by child and adolescent psychologists and psychiatrists to assess symptomatology following storm Alex (from day 1 to day 3). Each interview assessed nine classes of symptoms that have been compared according to age-groups. 116 children have been evaluated (0.2-17.6 years, mean 9.1). The 0-5-years-old showed more agitation as well as developmental regression than children aged 6-11 (p = .011, p = .045) and 12-18 years (p < .001, p < .001). Anxiety was reported more frequently among the 6-11 years old than the 0-5 years children (p = .018). Overall, the interviewed children presented at least one manifestation of acute stress after the storm (94% for the 0-5 years; 83% for the 6-11 years and 74% for the 12-18 years). The results highlight the high rate of acute stress symptoms in a natural disaster context, their specificity depending on children's age. Therefore; it emphasizes the need to develop, improve and validate specific assessment tools. Scheduled follow-up evaluations will help to understand, after a natural disaster, the long-term stress response in children, paving the way for targeting early, intensive, specific and multidisciplinary symptomatic treatment approaches. Trial registration: ClinicalTrials.gov identifier: NCT04850924. Acute stress symptoms in children and adolescents are very frequent in the context of exposure to a natural disaster with specifications depending on the developmental age.

The automation of pollen identification has seen vast improvements in the past years, with Convolutional Neural Networks coming out as the preferred tool to train models. Still, only a small portion of works published on the matter address the identification of fossil pollen. Fossil pollen is commonly extracted from organic sediment cores and are used by paleoecologists to reconstruct past environments, flora, vegetation, and their evolution through time. The automation of fossil pollen identification would allow paleoecologists to save both time and money while reducing bias and uncertainty. However, Convolutional Neural Networks require a large amount of data for training and databases of fossilized pollen are rare and often incomplete. Since machine learning models are usually trained using labelled fresh pollen associated with many different species, there exists a gap between the training data and target data. We propose a method for a large-scale fossil pollen identification workflow. Our proposed method employs an accelerated fossil pollen extraction protocol and Convolutional Neural Networks trained on the labelled fresh pollen of the species most commonly found in Northeastern American organic sediments. We first test our model on fresh pollen and then on a full fossil pollen sequence totalling 196,526 images. Our model achieved an average per class accuracy of 91.2% when tested against fresh pollen. However, we find that our model does not perform as well when tested on fossil data. While our model is overconfident in its predictions, the general abundance patterns remain consistent with the traditional palynologist IDs. Although not yet capable of accurately classifying a whole fossil pollen sequence, our model serves as a proof of concept towards creating a full large-scale identification workflow.

Objectives: Osteoporosis is a major risk factor for fracture and treatment is mainly preventive. Patients with severe psychiatric condition and treated with antipsychotics are at risk for vitamin D deficiency and iatrogenic hyperprolactinemia, two serious risk factors of osteoporosis. We aim to determine whether all antipsychotics are similar regarding the risk of osteoporosis in young patients. Methods: From January 2009 to March 2015, we determined the vitamin D blood level (VDBL) among 484 inpatients and from January 2012 to March 2015, we determined the prolactin blood level (PBL) among 205 inpatients. We systematically recorded well-documented risk factors (e.g., age, gender, ethnic origin, body mass index, or season) and suspected risk factors (e.g., disease type or antipsychotic treatment). Results: Up to 89% of the inpatients had a VDBL under the recommended threshold. Up to 60% of the inpatients had hyperprolactinemia. The multivariate model found a significant effect on VDBL for seasonality (higher VDBL in summer), ethnicity (lower VDBL in Black individuals), and treatment exposure. The multivariate model found a significant effect on PBL for gender and treatment exposure. In both models, aripiprazole had a safer profile compared with other antipsychotics. Conclusion: Because adolescence is a period of bone construction and a critical window of opportunity for maximizing bone mass, we recommend vitamin D supplementation in young patients with severe mental condition. It could be interesting to reconsider to regularly monitor PBL among youth patients treated with antipsychotic, with the exception of aripiprazole.

IntroductionEarly-onset schizophrenia (EOS) is a rare and severe condition. A higher rate of neurodevelopmental abnormalities, such as intellectual or communication impairments as well as attention deficit hyperactivity disorder, is observed in EOS compared with adult-onset schizophrenia. Early signs of autism spectrum disorders (ASD) are present in about 30% of patients. Genetic abnormalities, including copy number variations, are frequent in neurodevelopmental disorders and have been associated to ASD physiopathology. Implicated genes encode proteins involved in brain development, synapses morphology and plasticity and neurogenesis. In addition, an increasing number of genetic abnormalities are shared by EOS and ASD, underlying the neurodevelopmental hypothesis of EOS.The main objective of our study is to identify disease-causing genetic mutations in a cohort of patients affected by both EOS and ASD. Special attention will be paid to genes involved in neurodevelopmental pathways.Methods and analysisWe describe a multicentric study in a paediatric population. The study started in April 2014. Inclusion criteria are: age 7–22 years, diagnosis of EOS with comorbid ASD and IQ >50; Parents and siblings are also enrolled. We perform psychiatric assessments (Mini International Neuropsychiatric Interview, Kiddie Schedule for Affective Disorders and Schizophrenia -Present and Lifetime Version, Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms) together with neurocognitive evaluations (IQ, Trail Making Test A/B and verbal fluency). Then, we study variants of the coding part of DNA (exome), using next-generation sequencing process on trio (mother, father and child). Bioinformatics tools (RVIS and PolyPhen-2) are used to prioritise disease-causing mutations in candidate genes. The inclusion period will end in November 2019.Ethics and disseminationThe study protocol was approved by the Local Ethic Committee and by the French National Agency for Medicines and Health Products Safety. All patients signed informed consent on enrolment in the study. Results of the present study should help to unravel the molecular pathology of EOS, paving the way for an early therapeutic intervention.Trial registration number NCT0256552; Pre-results.