Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

Autonomous thyroid adenomas (ATAs) are a frequent cause of hyperthyroidism. Mutations in the genes encoding the TSH receptor (TSHR) or the Gs protein alpha subunit (GNAS) are found in approximately 70% of ATAs. The involvement of other genes and the pathogenesis of the remaining cases are presently unknown. Here, we performed whole-exome sequencing in 19 ATAs that were paired with normal DNA samples and identified a recurrent hot-spot mutation (c.1712A>G; p.Gln571Arg) in the enhancer of zeste homolog 1 (EZH1) gene, which codes for a catalytic subunit of the polycomb complex. Targeted screening in an independent cohort confirmed that this mutation occurs with high frequency (27%) in ATAs. EZH1 mutations were strongly associated with known (TSHR, GNAS) or presumed (adenylate cyclase 9 [ADCY9]) alterations in cAMP pathway genes. Furthermore, functional studies revealed that the p.Gln571Arg EZH1 mutation caused increased histone H3 trimethylation and increased proliferation of thyroid cells. In summary, this study revealed that a hot-spot mutation in EZH1 is the second most frequent genetic alteration in ATAs. The association between EZH1 and TSHR mutations suggests a 2-hit model for the pathogenesis of these tumors, whereby constitutive activation of the cAMP pathway and EZH1 mutations cooperate to induce the hyperproliferation of thyroid cells.IZKF Wurzburg [B-281]; ERA-NET E-Rare [01GM1407B]; Deutsche KrebshilfeDeutsche Krebshilfe [109994]; Wilhelm Sander Stiftung [2013.010.1]We wish to thank Eileen Bosenberg, Bianca Klupfel, and Ines Elsner for technical support and Ulrike Zabel for DNA cloning. This study was partially supported by grants from the IZKF Wurzburg (B-281, to DC and MF); the ERA-NET E-Rare (01GM1407B, to MF and DC); the Deutsche Krebshilfe (109994, to ME); and the Wilhelm Sander Stiftung (project 2013.010.1, to RP)

An app-based training for adolescents with problematic digital-media use and their parents (Res@t digital): protocol for a cluster-randomized clinical trial

BackgroundDigital media-use disorders (DMUD) in adolescents are a rising phenomenon associated with psychological distress, comorbid mental disorders, and high burden on affected families. Since the ICD-11 introduced criteria for gaming disorder, these can now be transferred to describe additional DMUD associated with social media platforms and streaming services. Most evidence for effective treatments comes from cognitive-behavioral therapy (CBT). However, interventions based on theoretical models for adolescents and their parents are widely missing, leading to a significant clinical gap.MethodsRes@t digital (Resource-Strengthening Training for Adolescents with Problematic Digital-Media Use and their Parents) is the app-based translation of the first model-based digital intervention for adolescents with DMUD and their parents based on CBT. It comprises separate but content-related modules for adolescents (Res@t–A) and parents (Res@t–P), applying multimodal techniques. The effectiveness of Res@t will be evaluated within a multicenter cluster-randomized controlled evaluator-blinded pre–post follow-up trial with the waitlist control group (CG). In addition to the Res@t program in the intervention group, both groups will receive treatment as usual within primary child and adolescent psychiatric/psychotherapeutic healthcare. The primary outcome addresses DMUD symptom reduction after 10 weeks. Secondary outcomes are related to a reduction in psychological and family-related problems and an increase in parental self-efficacy. All outcomes will be assessed using standardized self-report measures. A total of 1,334 participating adolescent–parent dyads from a large clinical network throughout Germany are planned to be included in the primary analyses based on an intention-to-treat approach, applying linear mixed models.DiscussionAssuming superiority of Res@t over the control condition, the intervention has the potential to provide evidence-based treatment for a significant number of help-seeking families, supporting local healthcare structures and resources. It is a promising program for practicable implementation and flexible use in different settings.Clinical trial registrationhttps://drks.de, DRKS00031043

Cognitive processes of mental rotation: a multimodal approach

Die Aufgabe der Mentalen Rotation nach Shepard RN und Metzler J (1971) ist ein etabliertes Forschungsparadigma zur Untersuchung kognitiver Prozesse im Bereich der räumlichen Vorstellung. In der vorliegenden Arbeit wurde im Rahmen von Mentalen-Rotations-Aufgaben der Einfluss der Winkeldifferenz zwischen den Figuren von Shepard-Metzler-Stimuluspaaren und deren Konfiguration (gleich/gespiegelt zueinander) auf Leistungs-, Blickbewegungs- und neuronale Aktivierungsparameter in einem self-paced event-related-fMRT-Design mit pupil tracking erfasst. Die Blickbewegungsparameter konnten drei Faktoren zugeordnet werden, die die Dauer und den Wechsel von Fixationen sowie Sakkadeneigenschaften bei der Aufgabenlösung repräsentieren. Reaktionszeit, Dauer und Anzahl der Fixationen sowie neuronale Aktivitäten in frontoparietalen Arealen des Mentalen-Rotations-Netzwerkes zeigen erwartungsgemäß eine Zunahme mit steigender Winkeldifferenz zwischen den Einzelfiguren eines Stimuluspaares im Sinne eines analogen Mentalen-Rotations-Vorganges (Zacks 2008). Dabei bleiben Sakkadenmuster konstant. Dies spiegelt gleichbleibende Strategien in der Aufgabenlösung wider. Zusätzliche winkelabhängige Aktivierungen in somatosensorischen Arealen werden im Rahmen von räumlichen Repräsentations- und mentalen Manipulationsprozessen erklärt. Gespiegelte Stimuli führen zu einem gegenüber gleichen Stimuli abweichenden Reaktionszeitverlauf über die Winkeldifferenzen. Dies spricht für einen früheren Wechsel der mentalen Rotationsrichtung durch die Nutzung dreidimensionaler Informationen. Außerdem führt die Präsentation gespiegelter Stimuli zu höheren Aktivierungen in frühen visuellen und weniger Aktivierungen im rechten frontalen Augenfeld als die Präsentation gleicher Stimuli. Dieser Befund wird auf Unterschiede in erstellten Salienzkarten zurückgeführt. Die Bearbeitung gleicher und gespiegelter Stimuli scheint sich somit bereits auf der frühen Prozessstufe der visuellen Enkodierung zu unterscheiden. Auch die vorliegenden Blickbewegungsergebnisse unterstützen diese Interpretation: gespiegelte Stimuli gehen mit einer kleineren Sakkadenamplitude als gleiche Stimuli einher. Die Sakkadenamplitude kennzeichnet die Größe des funktionellen Sichtfeldes und ist somit ebenfalls enkodierungsassoziiert. Um den Einfluss der Prozessdauer zu berücksichtigen, wurde sie in die fMRT-Gruppenanalyse integriert. Lediglich der Effekt gespiegelter gegenüber gleichen Stimuli auf frühe visuelle Areale bleibt hierunter stabil. Dies spricht dafür, dass der Prozessschritt der visuellen Enkodierung unabhängig von anderen Schritten des Mentalen-Rotations-Prozesses ist. Ein Vorschlag zur Erweiterung des bestehenden Prozessmodells wird ausgeführt

Res@t: Resource-Strengthening Training for Adolescents with Problematic Digital-Media Use and their Parents

<jats:p> Abstract: Aims: Given rising prevalence of digital-media related disorders (DMRD, i. e. the problematic use of digital games, social media, and streaming platforms) in children and adolescents, the new therapy program Res@t (Resource strengthening program for adolescents with DMRD and their parents) aims to close a significant evidence-based treatment gap. It addresses affected adolescents and their parents in different settings. Methods: Res@t is a fully manualized CBT program based on current research results and clinical experiences. It was initially developed for adolescents with problematic gaming (Res@t-A) and their parents (Res@t-P) in a face-to-face group setting. A digital translation into a fully automated application (Res@t digital [Res@pp]) should allow support independently of available local therapy options or the use within blended therapy. Besides DMRD symptom reduction in adolescents through Res@t-A, Res@t-P shall increase parental self-efficacy. Pilot-study data of Res@t-P within a pre-post-follow-up design showed promising effects on a decrease of parental stress perception and an increase of family functioning, as well as on DMRD symptom reduction in affected adolescents. However, a missing control group and rather small sample size reduces interpretability. Res@t-A is currently being evaluated within a comparable design. Multi-center randomized controlled studies are planned to evaluate the effectiveness of all offline and digital program versions. Conclusion: Res@t is the first manualized treatment program focusing on adolescents with DMRD and their parents for different settings (group therapy, digital application). Effective treatments addressing both target groups are highly warranted. </jats:p&gt

Assessing ICD-11 Gaming Disorder in Adolescent Gamers: Development and Validation of the Gaming Disorder Scale for Adolescents (GADIS-A)

Background: Adolescents affected by Gaming Disorder (GD) show substantial impairments in daily functioning. GD was included in the 11th revision of the International Classification of Diseases (ICD-11) as a new diagnosis coming into effect in January 2022. An instrument to screen for GD in adolescents has not yet been published and is urgently needed for scientific research and clinical practice. Methods: In the present study, the ICD-11-based Gaming Disorder Scale for Adolescents (GADIS-A) was developed by clinical experts and scientists. It was validated with 819 frequent gamers of 10 to 17 years and a respective caregiver in an online survey. Criterion validity was examined by assessing gaming behavior, emotional dysregulation, and academic performance. Item structure was investigated by factorial analyses. ROC- and Latent Profile Analyses were computed for differentiation between GD and Non-GD. Results: In line with the ICD-11 approach and accounting for cognitive-behavioral symptoms and negative consequences equally, GADIS-A items were best described by two factors. The new instrument showed excellent internal consistency, good criterion validity, and excellent discriminatory power. Conclusions: GADIS-A is the first successfully validated questionnaire to assess ICD-11 GD in adolescents. Thus, it can significantly contribute to reliably identify affected adolescents in clinical and research settings

Parents Rate Problematic Video Streaming in Adolescents: Conceptualization and External Assessment of a New Clinical Phenomenon Based on the ICD-11 Criteria of Gaming Disorder

In recent years, video streaming (VS) increased substantially. Adolescents are at significant risk of presenting problematic VS patterns associated with a spectrum of mental-health difficulties. Because VS platforms rely on similar mechanisms as digital games, the ICD-11 criteria for Gaming Disorder (GD) have been successfully implemented to measure Streaming Disorder (StrD) in adolescents. For proper diagnoses, external rating scales are urgently required in addition to self-reports. The Streaming Disorder Scale for Parents (STREDIS-P) was created and validated in a representative sample of n = 891 adolescent-parent dyads. Mental health problems were assessed with standardized instruments. Confirmatory factor analysis was conducted to examine the underlying factor structure. Cutoff scores were determined using ROC analysis. Accordance between parental and adolescents’ self-ratings was calculated. Consistent with the results of previous validation studies for screening instruments assessing similar phenomena based on ICD-11-GD criteria, two factors, cognitive-behavioral symptoms and negative consequences, were confirmed. STREDIS-P demonstrated good to excellent internal consistency, criterion validity, and discriminatory power. Accordance with adolescents’ self-ratings was moderate. STREDIS-P is the first screening tool for assessing StrD in adolescents by parental ratings. It is highly relevant for conceptualizing a new phenomenon in clinical routine and academic research

Phosphatidylethanol Reliably and Objectively Quantifies Alcohol Consumption in Adolescents and Young Adults.

BACKGROUND Alcohol contributes to numerous annual deaths and various societal problems not just in adult, but also in adolescent, populations. Therefore, it is vital to find methods for reliably detecting alcohol use for early preventative measures. Research has shown phosphatidylethanol (PEth) to be superior to self-report instruments and indirect biomarkers for alcohol consumption in adult populations. However, the transferability onto an adolescent population has not yet been investigated. METHODS N = 106 adolescents and young adults aged between 13 and 21 years were included. PEth analysis using high-pressure liquid chromatography-tandem mass spectrometry was performed on dried blood spot samples. Self-report questionnaires for alcohol consumption (Alcohol Use Disorders Identification Test-Consumption, AUDIT-C, and Timeline Followback, TLFB) and drug and alcohol consumption (Detection of Alcohol and Drug Problems in Adolescents, DEP-ADO) were completed by each participant. RESULTS AUDIT-C scores showed large correlations with PEth 16:0/18:1 (rs  = 0.732) and PEth 16:0/18:2 (rs  = 0.661) concentrations. AUDIT-C with a cutoff value ≥3 was largely correlated with PEth 16:0/18:1 (η = 0.411) and showed a medium-sized correlation with PEth 16:0/18:2 (η = 0.397) concentrations. Using an AUDIT-C cutoff value ≥5 showed large correlations with both PEth 16:0/18:1 (η = 0.510) and PEth 16:0/18:2 (η = 0.497) concentrations, respectively. ROC curves indicated higher PEth concentrations are a good model for detecting positive AUDIT-C cutoff values (AUROC range: 0.800 to 0.849). PEth concentrations showed medium to large correlations with DEP-ADO and TLFB subscales (range rs  = 0.469 to 0.746). CONCLUSION The results suggest that PEth is a reliable and objective marker for quantifying alcohol consumption in adolescents and young adults. This could be of importance for early preventative measures against hazardous alcohol consumption, which is increasingly common at younger ages

Pregnancy complications, substance abuse, and prenatal care predict birthweight in adolescent mothers

Abstract Background Reduced birthweight is associated with adverse physical and mental health outcomes later in life. Children of adolescent mothers are at higher risk for reduced birthweight. The current study aimed to identify the key risk factors affecting birthweight in a well-characterized sample of adolescent mothers to inform preventive public health efforts. Methods Sixty-four adolescent mothers (≤ 21 years of age) provided detailed data on pregnancy, birth and psychosocial risk. Separate regression analyses with (1) birthweight and (2) low birthweight (LBW) as outcomes, and pregnancy complications, prenatal care, maternal age, substance abuse during pregnancy, socioeconomic risk, stressful life events and the child’s sex as independent variables were conducted. Exploratively, a receiver operating characteristic (ROC) analysis was performed to investigate the quality of the discriminatory power of the risk factors. Results The following variables explained variance in birthweight significantly: prenatal care attendance (p = .006), pregnancy complications (p = .006), and maternal substance abuse during pregnancy (p = .044). Prenatal care attendance (p = .023) and complications during pregnancy (p = .027) were identified as significant contributors to LBW. Substance abuse (p = .013), pregnancy complications (p = .022), and prenatal care attendance (p = .044) showed reasonable accuracy in predicting low birthweight in the ROC analysis. Conclusions Among high-risk adolescent mothers, both biological factors, such as pregnancy complications, and behavioural factors amenable to intervention, such as substance abuse and insufficient prenatal care, seem to contribute to reduced birthweight in their children, a predisposing factor for poorer health outcomes later in life. More tailored intervention programmes targeting the specific needs of this high-risk group are needed

Sex hormones and mental rotation: An intensive longitudinal investigation

The present study used an intensive longitudinal design to examine whether mental rotation performance varies according to a monthly cycle in both males and females and whether these variations are related to variations in progesterone, estradiol, and testosterone levels. We collected reaction time and accuracy data for 10 males and seven females each workday over eight weeks using 136 pairs of mental rotation stimuli/ day, and measured sexual hormones concentrations in the saliva twice a week. A mixed linear model statistical analysis revealed that all females and seven males showed significant cycle effects in mental rotation performance. The female cycle showed an amplitude that was twice as large compared with the amplitude found in males. For males and females, estradiol and testosterone were significantly linearly and quadratically related to interindividual variation in performance at the beginning of the study (progesterone was linearly related to performance for females). The association between testosterone and performance differed across sexes: for males, it had an inverse U-shape, for females it was U-shaped. Towards the end of the study, none of the hormones were significantly related to performance anymore. Thus, the relationship between hormones and mental rotation performance disappeared with repeated testing. Only estradiol levels were significantly elevated at the lowest point of the cycle in mental rotation performance in females. In conclusion, in this intensive longitudinal study spanning two months, a monthly cycle in mental rotation performance was found among both males and females, with a larger cycle's amplitude for females