Cleft palate and minor metabolic disturbances in a mouse global Arl15 gene knockout.

ARL15, a small GTPase protein, was linked to metabolic traits in association studies. We aimed to test the Arl15 gene as a functional candidate for metabolic traits in the mouse. CRISPR/Cas9 germline knockout (KO) of Arl15 showed that homozygotes were postnatal lethal and exhibited a complete cleft palate (CP). Also, decreased cell migration was observed from Arl15 KO mouse embryonic fibroblasts (MEFs). Metabolic phenotyping of heterozygotes showed that females had reduced fat mass on a chow diet from 14 weeks of age. Mild body composition phenotypes were also observed in heterozygous mice on a high-fat diet (HFD)/low-fat diet (LFD). Females on a HFD showed reduced body weight, gonadal fat depot weight and brown adipose tissue (BAT) weight. In contrast, in the LFD group, females showed increased bone mineral density (BMD), while males showed a trend toward reduced BMD. Clinical biochemistry analysis of plasma on HFD showed transient lower adiponectin at 20 weeks of age in females. Urinary and plasma Mg2+ concentrations were not significantly different. Our phenotyping data showed that Arl15 is essential for craniofacial development. Adult metabolic phenotyping revealed potential roles in brown adipose tissue and bone development.

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder.

OBJECTIVE: For adolescents, DSM-5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI-centile-for-age. We hypothesized that the diagnostic weight cut-off yields (i) lower weight loss in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN. METHOD: Based on admission BMI-centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t-tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders. RESULTS: Weight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI-standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN. DISCUSSION: Whereas the weight cut-off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight-specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity. PUBLIC SIGNIFICANCE: Because body weights of patients with AN must drop below the 5th BMI-centile per DSM-5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight.

Age-related brain deviations and aggression.

BACKGROUND: Disruptive behavior disorders (DBD) are heterogeneous at the clinical and the biological level. Therefore, the aims were to dissect the heterogeneous neurodevelopmental deviations of the affective brain circuitry and provide an integration of these differences across modalities. METHODS: We combined two novel approaches. First, normative modeling to map deviations from the typical age-related pattern at the level of the individual of (i) activity during emotion matching and (ii) of anatomical images derived from DBD cases (n = 77) and controls (n = 52) aged 8-18 years from the EU-funded Aggressotype and MATRICS consortia. Second, linked independent component analysis to integrate subject-specific deviations from both modalities. RESULTS: While cases exhibited on average a higher activity than would be expected for their age during face processing in regions such as the amygdala when compared to controls these positive deviations were widespread at the individual level. A multimodal integration of all functional and anatomical deviations explained 23% of the variance in the clinical DBD phenotype. Most notably, the top marker, encompassing the default mode network (DMN) and subcortical regions such as the amygdala and the striatum, was related to aggression across the whole sample. CONCLUSIONS: Overall increased age-related deviations in the amygdala in DBD suggest a maturational delay, which has to be further validated in future studies. Further, the integration of individual deviation patterns from multiple imaging modalities allowed to dissect some of the heterogeneity of DBD and identified the DMN, the striatum and the amygdala as neural signatures that were associated with aggression.

Phage liquid crystalline droplets form occlusive sheaths that encapsulate and protect infectious rod-shaped bacteria.

The opportunistic pathogen Pseudomonas aeruginosa is a major cause of antibiotic-tolerant infections in humans. P. aeruginosa evades antibiotics in bacterial biofilms by up-regulating expression of a symbiotic filamentous inoviral prophage, Pf4. We investigated the mechanism of phage-mediated antibiotic tolerance using biochemical reconstitution combined with structural biology and high-resolution cellular imaging. We resolved electron cryomicroscopy atomic structures of Pf4 with and without its linear single-stranded DNA genome, and studied Pf4 assembly into liquid crystalline droplets using optical microscopy and electron cryotomography. By biochemically replicating conditions necessary for antibiotic protection, we found that phage liquid crystalline droplets form phase-separated occlusive compartments around rod-shaped bacteria leading to increased bacterial survival. Encapsulation by these compartments was observed even when inanimate colloidal rods were used to mimic rod-shaped bacteria, suggesting that shape and size complementarity profoundly influences the process. Filamentous inoviruses are pervasive across prokaryotes, and in particular, several Gram-negative bacterial pathogens including Neisseria meningitidis, Vibrio cholerae, and Salmonella enterica harbor these prophages. We propose that biophysical occlusion mediated by secreted filamentous molecules such as Pf4 may be a general strategy of bacterial survival in harsh environments.

Emotion recognition profiles in clusters of youth based on levels of callous-unemotional traits and reactive and proactive aggression.

Youth with disruptive behavior showing high callous-unemotional (CU) traits and proactive aggression are often assumed to exhibit distinct impairments in emotion recognition from those showing mainly reactive aggression. Yet, reactive and proactive aggression and CU traits may co-occur to varying degrees across individuals. We aimed to investigate emotion recognition in more homogeneous clusters based on these three dimensions. In a sample of 243 youth (149 with disruptive behavior problems and 94 controls) aged 8-18 years, we used model-based clustering on self-report measures of CU traits and reactive and proactive aggression and compared the resulting clusters on emotion recognition (accuracy and response bias) and working memory. In addition to a Low and Low-Moderate symptom cluster, we identified two high CU clusters. The CU-Reactive cluster showed high reactive and low-to-medium proactive aggression; the CU-Mixed cluster showed high reactive and proactive aggression. Both CU clusters showed impaired fear recognition and working memory, whereas the CU-Reactive cluster also showed impaired recognition of disgust and sadness, partly explained by poor working memory, as well as a response bias for anger and happiness. Our results confirm the importance of CU traits as a core dimension along which youth with disruptive behavior may be characterized, yet challenge the view that high CU traits are closely linked to high proactive aggression per se. Notably, distinct neurocognitive processes may play a role in youth with high CU traits and reactive aggression with lower versus higher proactive aggression.

The effects of callous-unemotional traits and aggression subtypes on amygdala activity in response to negative faces.

BACKGROUND: Brain imaging studies have shown altered amygdala activity during emotion processing in children and adolescents with oppositional defiant disorder (ODD) and conduct disorder (CD) compared to typically developing children and adolescents (TD). Here we aimed to assess whether aggression-related subtypes (reactive and proactive aggression) and callous-unemotional (CU) traits predicted variation in amygdala activity and skin conductance (SC) response during emotion processing. METHODS: We included 177 participants (n = 108 cases with disruptive behaviour and/or ODD/CD and n = 69 TD), aged 8-18 years, across nine sites in Europe, as part of the EU Aggressotype and MATRICS projects. All participants performed an emotional face-matching functional magnetic resonance imaging task. RESULTS: Differences between cases and TD in affective processing, as well as specificity of activation patterns for aggression subtypes and CU traits, were assessed. Simultaneous SC recordings were acquired in a subsample (n = 63). Cases compared to TDs showed higher amygdala activity in response to negative faces (fearful and angry) v. shapes. Subtyping cases according to aggression-related subtypes did not significantly influence on amygdala activity; while stratification based on CU traits was more sensitive and revealed decreased amygdala activity in the high CU group. SC responses were significantly lower in cases and negatively correlated with CU traits, reactive and proactive aggression. CONCLUSIONS: Our results showed differences in amygdala activity and SC responses to emotional faces between cases with ODD/CD and TD, while CU traits moderate both central (amygdala) and peripheral (SC) responses. Our insights regarding subtypes and trait-specific aggression could be used for improved diagnostics and personalized treatment.

Subgrouping children and adolescents with disruptive behaviors: symptom profiles and the role of callous-unemotional traits.

Disruptive behavior during childhood and adolescence is heterogeneous and associated with several psychiatric disorders. The identification of more homogeneous subgroups might help identify different underlying pathways and tailor treatment strategies. Children and adolescents (aged 8-18) with disruptive behaviors (N = 121) and healthy controls (N = 100) were included in a European multi-center cognition and brain imaging study. They were assessed via a battery of standardized semi-structured interviews and questionnaires. K-means cluster-model analysis was carried out to identify subgroups within the group with disruptive behaviors, based on clinical symptom profiles, callous-unemotional (CU) traits, and proactive and reactive aggression. The resulting subgroups were then compared to healthy controls with regard to these clinical variables. Three distinct subgroups were found within the group with disruptive behaviors. The High CU Traits subgroup presented elevated scores for CU traits, proactive aggression and conduct disorder (CD) symptoms, as well as a higher proportion of comorbidities (CD + oppositional defiant disorder + attention deficit hyperactivity disorder (ADHD). The ADHD and Affective Dysregulation subgroup showed elevated scores for internalizing and ADHD symptoms, as well as a higher proportion of females. The Low Severity subgroup had relatively low levels of psychopathology and aggressive behavior compared to the other two subgroups. The High CU Traits subgroup displayed more antisocial behaviors than the Low Severity subgroup, but did not differ when compared to the ADHD and Affective Dysregulation subgroup. All three subgroups differed significantly from the healthy controls in all the variables analyzed. The present study extends previous findings on subgrouping children and adolescents with disruptive behaviors using a multidimensional approach and describes levels of anxiety, affective problems, ADHD, proactive aggression and CU traits as key factors that differentiate conclusively between subgroups.

Age dependency of body mass index distribution in childhood and adolescent inpatients with anorexia nervosa with a focus on DSM-5 and ICD-11 weight criteria and severity specifiers.

Both DSM-5 and ICD-11 have provided weight cut-offs and severity specifiers for the diagnosis of anorexia nervosa (AN) in childhood, adolescence and adulthood. The aims of the current study focusing on inpatients aged < 19 years were to assess (1) the relationship between age and body mass index (BMI; kg/m2), BMI-centiles, BMI-standard deviation scores (BMI-SDS) and body height-SDS at referral, (2) the percentages of patients fulfilling the DSM-5 and ICD-11 weight criteria and severity categories for AN, and (3) the validity of the AN severity specifiers via analysis of both weight related data at discharge and inpatient treatment duration. The German Registry for Anorexia Nervosa encompassed complete data sets for 469 female patients (mean age = 15.2 years; range 8.9-18.9 years) with a diagnosis of AN (n = 404) or atypical AN (n = 65), who were ascertained at 16 German child and adolescent psychiatric hospitals. BMI at referral increased up to age 15 to subsequently plateau. Approximately one tenth of all patients with AN had a BMI above the fifth centile. The ICD-11 specifier based on a BMI-centile of 0.3 for childhood and adolescent AN entailed two equally sized groups of patients. Discharge data revealed limited validity of the specifiers. Height-SDS was not correlated with age thus stunting had no impact on our data. We corroborate the evidence to use the tenth instead of the fifth BMI-centile as the weight criterion in children and adolescents. Weight criteria should not entail major diagnostic shifts during the transition from adolescence to adulthood. The severity specifiers based on BMI or BMI-centiles do not seem to have substantial clinical validity.

Aggression subtypes relate to distinct resting state functional connectivity in children and adolescents with disruptive behavior.

There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes [mean age (standard deviation) = 13.30 (2.60); range = 8.02-18.35] as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala-precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggression-subtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control.

Neural substrates of anorexia nervosa patient's deficits to decode emotional information.

PURPOSE: The aim of the study was to define specific substrates of pathological behaviour patterns by analysing cortical activity using functional magnetic resonance imaging (fMRI) during an emotional processing task. METHODS: In a sample of N = 11 adolescent patients with AN (16.36 years, SD ± 1.36) and N = 11 age-matched controls, we performed a functional MRI study to detect BOLD signal changes in a 3 T MRI scanner while presenting emotional facial stimuli. RESULTS: Young people with AN presented with a generally reduced cortical activation pattern in key areas of emotion recognition for happy and fearful faces. Areas essential for control of social behaviour were associated with symptoms of depression. CONCLUSION: Obviously, there are already indications of cortical patterns in young affected persons, which indicate a changed emotional reaction to potentially aversive stimuli in the sense of a changed top-down process of emotion avoidance. Thus, the current study provides further evidence that the disorder of anorexia nervosa is closely related to deficits in emotion processing in the early course of ontogenesis. Depressive symptoms might additionally trigger pathological behavior. Due to the small sample size, the data should be considered preliminary and require further validation. LEVEL OF EVIDENCE: Level of evidence III: case-control study.

Incontinence and constipation in adolescent patients with anorexia nervosa-Results of a multicenter study from a German web-based registry for children and adolescents with anorexia nervosa.

OBJECTIVE: Nocturnal enuresis (NE), daytime urinary incontinence (DUI), and fecal incontinence (FI) are common disorders in childhood and are frequently accompanied by comorbid psychiatric disorders. Despite a high association between urinary and fecal incontinence with psychiatric and neurodevelopmental disorders, research on comorbidity between incontinence and anorexia nervosa (AN) remains scarce. Yet, it is well known that somatic consequences of AN include metabolic and gastrointestinal disorders. The study sought to assess the prevalence of incontinence and constipation in children and adolescents with AN and to examine associations of these two symptoms with body weight at admission and with BMI changes during inpatient treatment. METHODS: Data collected between 2015 and 2017 by a multicenter German web-based registry for AN were analyzed. Three hundred and forty-eight patients with AN (96.3% female, mean age = 15.1 ± 1.8 years) were assessed regarding AN subtype, psychiatric comorbidity, body weight, incontinence, and constipation. RESULTS: Overall, 27.6% of patients had constipation, 1.8% had NE and 1.8% DUI. Prevalence of constipation did not significantly differ between AN subtypes. Constipation did not lead to any significant differences in weight/BMI changes during inpatient treatment. DISCUSSION: This is the largest study of incontinence and constipation in patients with AN, so far. Our results indicate that constipation is highly prevalent in adolescent patients with AN and reflects a clinically relevant condition. Despite, patients with AN do not have an increased prevalence of incontinence compared with the general population. Future studies should include medical examinations like ultrasound and physical examination of the lower abdomen to evaluate the severity of constipation.

Transition as a topic in psychiatry training throughout Europe: trainees' perspectives.

The majority of adolescents with mental health problems do not experience continuity of care when they reach the transition boundary of their child and adolescent mental health service. One of the obstacles for a smooth transition to adult mental health services concerns the lack of training for health-care professionals involved in the transition process. This study aims to seek psychiatric trainees' opinions regarding training on transition and the knowledge and skills required for managing transition. A survey was distributed to trainees residing in European countries. Trainees from 36 countries completed the questionnaire, of which 63% reported that they came into contact with youth and young adults (16-26 years) during their clinical practice. Twenty-seven percent of trainees stated they have good to very good knowledge about the transition process. Theoretical training about transition was reported in only 17% of the countries, and practical training in 28% of the countries. Ninety-four percent of trainees indicated that further training about transition is necessary. The content of subsequent transition-related training can be guided by the findings of the MILESTONE project.

A cross-cultural qualitative study of the ethical aspects in the transition from child mental health services to adult mental health services.

BACKGROUND: Transitioning from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS) raises novel ethical aspects for healthcare professionals, as well as for young people, their parents and carers. METHOD: Focus groups were conducted in Croatia, Ireland and the United Kingdom with youth mental health groups and youth representatives with no mental health (MH) remit. One hundred and eleven participants, aged from 16 to 60 years, contributed to discussions. RESULTS: Perpetuation of stigma, autonomy and decision-making were central themes as both enablers and deterrents of successful transition. The tension between professional (and at times parental) paternalism and young persons' growing autonomy was well captured in the themes; (a) desired practice, (b) who should decide, (c) the process of decision-making and (d) potential harm(s). CONCLUSIONS: This study provides insight into the ethical values, particularly autonomy and collaboratively working, which people expect to underpin the transition between CAMHS and AMHS. KEY PRACTITIONER MESSAGE: Engaging young people early in making decisions about their future care can enhance trust between practitioner and the young person. In addition to diagnosis, a number of factors (such as moving home; waiting lists and stigma) may need to be taken into account when considering the direction of future health care. When possible, alternatives to AMHS should be considered if considered by the young person to be a less-stigmatising treatment option.

Training of adult psychiatrists and child and adolescent psychiatrists in europe: a systematic review of training characteristics and transition from child/adolescent to adult mental health services.

BACKGROUND: Profound clinical, conceptual and ideological differences between child and adult mental health service models contribute to transition-related discontinuity of care. Many of these may be related to psychiatry training. METHODS: A systematic review on General Adult Psychiatry (GAP) and Child and Adult Psychiatry (CAP) training in Europe, with a particular focus on transition as a theme in GAP and CAP training. RESULTS: Thirty-four full-papers, six abstracts and seven additional full text documents were identified. Important variations between countries were found across several domains including assessment of trainees, clinical and educational supervision, psychotherapy training and continuing medical education. Three models of training were identified: i) a generalist common training programme; ii) totally separate training programmes; iii) mixed types. Only two national training programs (UK and Ireland) were identified to have addressed transition as a topic, both involving CAP exclusively. CONCLUSION: Three models of training in GAP and CAP across Europe are identified, suggesting that the harmonization is not yet realised and a possible barrier to improving transitional care. Training in transition has only recently been considered. It is timely, topical and important to develop evidence-based training approaches on transitional care across Europe into both CAP and GAP training.

[Management of Transition - Problems and Suggestions for Improvement from Psychiatric Outpatient Clinics]. / Übergangsmanagement ­ Probleme und Optimierungsvorschläge aus den Psychiatrischen Institutsambulanzen (PIA).

The structure of psychiatric outpatient clinics with multi-professional treatment teams provides a suitable frame for a successful transition from child to adult treatment settings. At present, however, the management of transition, especially for severely mentally ill adolescents, is unsatisfactory. In order to optimize conditions of transition, the following measures are proposed:▪ use of structured transfer sheets▪ round table conferences▪ shared trainings of child and adult psychiatrists▪ development of specific consultation hours for adolescents in transition; financial funding has to be established by health insurances.

Correction to: The interface between child/adolescent and adult mental health services: results from a European 28­country survey.

The original version of this article contained an error in Table 1. The correct table is presented below.

The interface between child/adolescent and adult mental health services: results from a European 28-country survey.

Transition-related discontinuity of care is a major socioeconomic and societal challenge for the EU. The current service configuration, with distinct Child and Adolescent Mental Health (CAMHS) and Adult Mental Health Services (AMHS), is considered a weak link where the care pathway needs to be most robust. Our aim was to delineate transitional policies and care across Europe and to highlight current gaps in care provision at the service interface. An online mapping survey was conducted across all 28 European Countries using a bespoke instrument: The Standardized Assessment Tool for Mental Health Transition (SATMEHT). The survey was directed at expert(s) in each of the 28 EU countries. The response rate was 100%. Country experts commonly (12/28) reported that between 25 and 49% of CAMHS service users will need transitioning to AMHS. Estimates of the percentage of AMHS users aged under 30 years who had has previous contact with CAMHS were most commonly in the region 20-30% (33% on average).Written policies for managing the interface were available in only four countries and half (14/28) indicated that no transition support services were available. This is the first survey of CAMHS transitional policies and care carried out at a European level. Policymaking on transitional care clearly needs special attention and further elaboration. The Milestone Study on transition should provide much needed data on transition processes and outcomes that could form the basis for improving policy and practice in transitional care.

Implementation and sex-specific analysis of students' attitudes toward a longitudinal, gender-specific medical curriculum - a pilot study.

BACKGROUND: Gender medicine has gained importance over the past 20 years. Nevertheless, the scientific findings concerning gender- and sex-specific patient care have not been sufficiently integrated into the education of physicians. It was therefore our aim, against initial resistance in our school, to integrate clinically relevant aspects of gender medicine into the existing medical curriculum. This paper describes the implementation process of a lecture-based interdisciplinary, longitudinal, basic gender curriculum and evaluates students' attitudes in relation to sex and semester level. METHODS: The curriculum encompasses 15 lecture sessions scheduled in years 1 through 5 of the medical curriculum at Ulm University, Germany. Prospectively gathered evaluation data of two cross-sectional analyses of this basic curriculum in the first and fifth semesters are analyzed by sex. RESULTS: More than 80% of the students have registered for this new curriculum. Evaluation data show a predominantly positive (75.5%) student response; however, only about half of those surveyed indicated that they had learned new material or judged the content on gender to be relevant to their practice of medicine. Students at a more advanced semester level (88.2% vs. 55.2%) and male participants more than female participants (36.7% vs. 62.4%) showed lower acceptance. DISCUSSION: It was possible to integrate gender issues into the existing medical student curriculum. Despite the overall positive rating, our evaluation data identified the aspects of rejection and resistance in some students, particularly male and more advanced students. Further studies on the development of student attitudes toward gender issues are needed.

First Sociodemographic, Pretreatment and Clinical Data from a German Web-Based Registry for Child and Adolescent Anorexia Nervosa.

OBJECTIVE: The first web-based registry for childhood and adolescent anorexia nervosa (AN) in Germany was established to systematically collect demographic and clinical data. These data as well as information on how young individuals with AN can find access to healthcare services are presented. METHOD: Patients´ data from child and adolescent psychiatry departments of 12 university hospitals and two major nonuniversity hospitals in Germany were collected between January 2015 and December 2016. All patients met the ICD-10 diagnostic criteria for (atypical) AN. Sociodemographic data, type and amount of healthcare utilization before admission, and clinical data at admission and discharge were compiled. RESULTS: 258 patients with a mean age of 14.7 years and a mean BMI at admission of 15.3 kg/m2 were included. The parents and patients had a higher educational level than the general German population. More than 80 % of the patients reported having utilized healthcare before hospitalization. The mean duration of outpatient treatment before hospitalization was 7 months. CONCLUSIONS: There seem to be major barriers to specialist treatment for young patients with AN in Germany, which should be analyzed in future studies.