Comprehensive analysis of two hotspot codons in the TUBB4B gene and associated phenotypes.

Our purpose was to elucidate the genotype and ophthalmological and audiological phenotype in TUBB4B-associated inherited retinal dystrophy (IRD) and sensorineural hearing loss (SNHL), and to model the effects of all possible amino acid substitutions at the hotspot codons Arg390 and Arg391. Six patients from five families with heterozygous missense variants in TUBB4B were included in this observational study. Ophthalmological testing included best-corrected visual acuity, fundus examination, optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ERG). Audiological examination included pure-tone and speech audiometry in adult patients and auditory brainstem response testing in a child. Genetic testing was performed by disease gene panel analysis based on genome sequencing. The molecular consequences of the substitutions of residues 390 and 391 on TUBB4B and its interaction with α-tubulin were predicted in silico on its three-dimensional structure obtained by homology modelling. Two independent patients had amino acid exchanges at position 391 (p.(Arg391His) or p.(Arg391Cys)) of the TUBB4B protein. Both had a distinct IRD phenotype with peripheral round yellowish lesions with pigmented spots and mild or moderate SNHL, respectively. Yet the phenotype was milder with a sectorial pattern of bone spicules in one patient, likely due to a genetically confirmed mosaicism for p.(Arg391His). Three patients were heterozygous for an amino acid exchange at position 390 (p.(Arg390Gln) or p.(Arg390Trp)) and presented with another distinct retinal phenotype with well demarcated pericentral retinitis pigmentosa. All showed SNHL ranging from mild to severe. One additional patient showed a variant distinct from codon 390 or 391 (p.(Tyr310His)), and presented with congenital profound hearing loss and reduced responses in ERG. Variants at codon positions 390 and 391 were predicted to decrease the structural stability of TUBB4B and its complex with α-tubulin, as well as the complex affinity. In conclusion, the twofold larger reduction in heterodimer affinity exhibited by Arg391 substitutions suggested an association with the more severe retinal phenotype, compared to the substitution at Arg390.

Acceptability and feasibility of SUCCEAT, an intervention for parents of adolescents with anorexia nervosa.

OBJECTIVE: "Supporting Carers of Children and Adolescents with Eating Disorders in Austria" (SUCCEAT), a skills training for parents, delivered via workshops (WS) or online modules (ONL), has been proven to be effective in terms of parental distress, caregiver skills, and adolescents' outcome. This study examined the adherence to and the acceptability and feasibility of SUCCEAT. METHOD: One-hundred parents (86% mothers) of adolescents with anorexia nervosa participated in the 8-week training. Parents were assigned to the WS (n = 50) or ONL (n = 50) format using a quasi-randomised design. Adherence, acceptability, and feasibility were assessed using self-report questionnaires. RESULTS: Adherence to the sessions was high (66%-98%) for both groups. The usage of the material was comparable between the groups. However, in the WS group, participants actively approached the coaches (71.8% vs. 48.9% often/very often) or other parents (63% vs. 4.4% often/very often) more often. Perceived helpfulness was high in both groups, overall satisfaction and practicability were higher in the WS group. CONCLUSIONS: Good adherence, acceptability, and feasibility were confirmed for both formats of SUCCEAT, with minimal advantages of the WS regarding satisfaction and contact with other parents and coaches. Thus, both formats can be recommended for implementation in clinical routine.

Fathers in the spotlight: parental burden and the effectiveness of a parental skills training for anorexia nervosa in mother-father dyads.

PURPOSE: Research on the engagement of fathers in the treatment of childhood psychiatric disorders is scarce. This study aims to investigate differences between mothers and fathers of adolescents with anorexia nervosa regarding parental burden and effectiveness of a parental skills training. METHODS: Ninety-one mother-father dyads caring for a child with anorexia nervosa participated in an 8-week parental skills training and completed a set of questionnaires assessing parental psychopathology, eating disorder related burden, caregiver skills and expressed emotion at baseline and post-intervention. RESULTS: Fathers showed lower levels of general psychological distress, depression, anxiety and eating disorder related burden as well as lower emotional overinvolvement compared to mothers. The skills training was effective in reducing parental psychopathology, eating disorder-related burden and emotional overinvolvement as well as in increasing caregiver skills with no differences between mothers and fathers. However, session adherence and the willingness to practice skills between the sessions were slightly lower in fathers. CONCLUSIONS: These findings show that fathers are a great resource for the child's eating disorder treatment as they may counterbalance maternal emotional overinvolvement and over-protection. Furthermore, this is the first study demonstrating that fathers can profit from a parental skills training for anorexia nervosa in a similar way as mothers. LEVEL III: Evidence obtained from well-designed cohort or case-control analytic studies.

Therapeutic drug monitoring in adolescents with anorexia nervosa for safe treatment with adjunct olanzapine.

OBJECTIVE: Medication is commonly used in anorexia nervosa (AN) despite largely missing high grade evidence. Olanzapine (OLZ) is the best-evidenced substance used off-label in this group, with conflicting outcome regarding BMI, clinical and safety parameters. Therefore, it is important to strictly assure quality of treatment with OLZ in AN by using 'Therapeutic Drug Monitoring' according to AGNP-guidelines, including serum levels and adverse drug reactions (ADRs) to support safety for adolescents with AN and attempt to generate an initial age- and disorder-specific therapeutic reference range. METHOD: Sixty-five adolescents with AN (aged 10-18) treated with OLZ (98% female; 97.5% AN-restricting-type) were prospectively observed, ADRs reported, and correlations between dosage and serum levels measured at trough level were calculated, a preliminary therapeutic range defined. RESULTS: Mean dosage of OLZ was 8.15 (SD: 2.91) mg and 0.19 (SD: 0.07) mg/kg respectively, average concentration was 26.57 (SD: 13.46) ng/mL. Correlation between daily dosage/dosage per kg and serum level was 0.72 (**p < 0.001)/0.65 (**p < 0.001), respectively. ADRs with impairment were rare (6.3%). 75% improved clinically (CGI). BMI increased significantly by 1.5 kg/m2 (t = 10.6, p < 0.001). A preliminary therapeutic reference range is 11.9 and 39.9 ng/mL. CONCLUSIONS: OLZ in the hands of specialists is a well-tolerated and safe treatment adjunct for adolescents with AN.

The Maudsley model of anorexia nervosa treatment for adolescents and emerging adults: A multi-centre cohort study.

OBJECTIVE: The aim of this study was examining the efficacy of the Maudsley Model of Anorexia Nervosa Treatment for Adolescents and Young Adults (MANTRa) compared to individual psychotherapy that can be considered as standard in Austria (TAU-O). METHOD: In this cohort study, 92 patients between 13 and 21 years suffering from full-syndrome, atypical or weight-restored anorexia nervosa (AN) received either 24-34 individual MANTRa sessions (n = 45) or TAU-O (n = 47). Outcome variables were age- and sex-related BMI, eating disorder and comorbid psychopathology at 6-, 12- and 18-month post baseline as well as acceptability of treatment and therapeutic alliance. RESULTS: Both treatments resulted in significant improvements in age- and sex related BMI and reductions in eating disorder and comorbid psychopathology over time with significant differences between groups in favour of MANTRa. The percentage of participants with fully remitted AN was significantly higher in the MANTRa group compared to TAU-O at 18-month follow-up (MANTRa: 46% vs. TAU-O: 16%, p = 0.006). Satisfaction with both treatments was high. CONCLUSIONS: MANTRa is an effective treatment programme for adolescents and young adults with AN. Randomised controlled trials comparing MANTRa with existing treatments are necessary. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov (Identifier: NCT03535714).

Isoform-specific translational control is evolutionarily conserved in primates.

Alternative splicing (AS) alters messenger RNA (mRNA) coding capacity, localization, stability, and translation. Here we use comparative transcriptomics to identify cis-acting elements coupling AS to translational control (AS-TC). We sequenced total cytosolic and polyribosome-associated mRNA from human, chimpanzee, and orangutan induced pluripotent stem cells (iPSCs), revealing thousands of transcripts with splicing differences between subcellular fractions. We found both conserved and species-specific polyribosome association patterns for orthologous splicing events. Intriguingly, alternative exons with similar polyribosome profiles between species have stronger sequence conservation than exons with lineage-specific ribosome association. These data suggest that sequence variation underlies differences in the polyribosome association. Accordingly, single nucleotide substitutions in luciferase reporters designed to model exons with divergent polyribosome profiles are sufficient to regulate translational efficiency. We used position specific weight matrices to interpret exons with species-specific polyribosome association profiles, finding that polymorphic sites frequently alter recognition motifs for trans-acting RNA binding proteins. Together, our results show that AS can regulate translation by remodeling the cis-regulatory landscape of mRNA isoforms.

Mental Health and Health-Related Quality of Life in Austrian Adolescents with Chronic Physical Health Conditions: Results from the MHAT Study.

Chronic physical health conditions (CPHC) are on the rise in younger age groups and might have a negative impact on children and adolescents. In a representative sample of Austrian adolescents aged 10-18 years, internalizing, externalizing, and behavioral problems were assessed cross-sectionally using the Youth Self-Report and health-related quality of life (HrQoL) using the KIDSCREEN questionnaire. Sociodemographic variables, life events, and chronic illness specific parameters were considered as associated variables with mental health problems in individuals with CPHC. Of 3469 adolescents, 9.4% of girls and 7.1% of boys suffered from a chronic pediatric illness. Of these individuals, 31.7% and 11.9% had clinically relevant levels of internalizing and externalizing mental health problems, respectively, compared to 16.3% and 7.1% adolescents without a CPHC. Anxiety, depression, and social problems were twice as high in this population. Medication intake due to CPHC and any traumatic life-event were related to mental health problems. All HrQoL domains were deteriorated in adolescents with a double burden of mental and CPHC, whereas adolescents with a CPHC without mental health problems did not differ significantly from adolescents without a chronic illness. Targeted prevention programs for adolescents with a CPHC are urgently needed to prevent mental health problems in the long term.

Psychological distress and caregiving experience during the first two years of the COVID-19 pandemic among parents of an offspring with anorexia nervosa.

OBJECTIVE: To compare different aspects of caregiving distress and experience in parents of patients with anorexia nervosa (AN) before and during the COVID-19 pandemic. METHODS: Three cohorts of parents of AN patients (cohort 1-pre-pandemic: N = 78, cohort 2-first pandemic year: N = 51, cohort 3-second pandemic year: N = 119) were recruited from child and adolescent psychiatry wards and cross-sectionally assessed as part of the clinical routine. Quantitative measures of psychological distress, psychopathology, eating disorder (ED)-related burden, expressed emotion and caregiver skills were obtained at the beginning of the child's inpatient or outpatient treatment. RESULTS: Cohort 2 showed lower levels of anxiety and a tendency of lower emotional overinvolvement and higher caregiving skills compared to the pre-pandemic cohort. In contrast, the levels of general psychological distress, depression, ED-related burden and criticism observed in cohort 3 significantly exceeded pre-pandemic levels. The prevalence of clinically relevant depression was higher in cohort 3 (41.5%) compared to cohorts 1 (24.4%) and 2 (21.6%). DISCUSSION: The pandemic effects on parents seem to be time-specific. Lower distress in the early phase of the pandemic may be associated with improvements in parent-child-relationships reported in previous studies. However, the pandemic may has negative consequences in the long-term emphasising the need of ongoing parental support.

An investigation of the factor structure of a German version of the Eating Disorder Symptom Impact Scale (EDSIS) among parents of adolescents and young adults with anorexia nervosa.

The aim of this study was to explore the factor structure, scale characteristics and convergent validity of a German version of the Eating Disorder Symptom Impact Scale (EDSIS). A total of 335 parents of adolescents and young adults with anorexia nervosa in inpatient or outpatient treatment completed the 24-item German translation of the EDSIS and other measures of caregiving burden and psychological distress. We tested a 4 vs. 6-factor model of the EDSIS using confirmatory factor analyses. The 6-factor model treating items as ordinal variables showed the best fit to the data (CFI = 0.949, RMSEA = 0.064). Strong invariance of this model was shown between the sample of mothers and fathers. Internal consistencies of the EDSIS scales were in the acceptable-to-good range. Bottom effects were observed for the 'Binge-Purge-Impacts' subscale only. Mothers had significantly higher EDSIS scores compared to fathers. The EDSIS total score and most of the subscores showed substantial positive correlations with caregivers' psychological distress, level of depression, anxiety and expressed emotion as well as negative associations with the level of perceived caregiving skills. The German version of the EDSIS is a useful tool to assess caregiving burden in mothers and fathers of patients with anorexia nervosa.

The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis.

Despite recent advances in therapeutic approaches, patients with MLL-rearranged leukemia still have poor outcomes. Here, we find that the RNA-binding protein IGF2BP3, which is overexpressed in MLL-translocated leukemia, strongly amplifies MLL-Af4-mediated leukemogenesis. Deletion of Igf2bp3 significantly increases the survival of mice with MLL-Af4-driven leukemia and greatly attenuates disease, with a minimal impact on baseline hematopoiesis. At the cellular level, MLL-Af4 leukemia-initiating cells require Igf2bp3 for their function in leukemogenesis. At the molecular level, IGF2BP3 regulates a complex posttranscriptional operon governing leukemia cell survival and proliferation. IGF2BP3-targeted mRNA transcripts include important MLL-Af4-induced genes, such as those in the Hoxa locus, and the Ras signaling pathway. Targeting of transcripts by IGF2BP3 regulates both steady-state mRNA levels and, unexpectedly, pre-mRNA splicing. Together, our findings show that IGF2BP3 represents an attractive therapeutic target in this disease, providing important insights into mechanisms of posttranscriptional regulation in leukemia.

Effects of an intensive slow cortical potentials neurofeedback training in female and male adolescents with autism spectrum disorder : Are there sex differences?

BACKGROUND: This study aims to compare the effects of neurofeedback training on male and female adolescents with autism spectrum disorder (ASD). Furthermore, it examines sex differences regarding improvements in co-occurring psychopathological symptoms, cognitive flexibility and emotion recognition abilities. The study might provide first hints whether there is an influence of sex on treatment outcomes. METHODS: Six female and six male adolescents with ASD were matched according to age, IQ and symptom severity. All participants received 24 sessions of electroencephalography-based neurofeedback training. Before and after the intervention, psychological data for measuring co-occurring psychopathological symptoms as well as behavioral data for measuring cognitive flexibility and emotion recognition abilities were recorded. RESULTS: Caregivers rated statistically significant higher psychopathological problems in female than in male adolescents with ASD at baseline. Apart from that, no statistically significant sex-related differences were revealed in this sample; however, male adolescents tended to report greater improvements of externalizing, internalizing and total symptoms, whereas females experienced smaller improvements of externalizing and total problems, but no improvements of internalizing problems. Regarding caregivers' assessments, more improvement of total problems was reported for females. For males, only improvements of internalizing and total problems were described. CONCLUSION: This study reveals preliminary results that sex-related differences might play a role when evaluating treatment outcomes after neurofeedback training regarding comorbid psychopathological symptoms. Adolescents' self-report and parental assessments, especially concerning psychopathological symptoms, should be combined and considered in future studies to help prevent sex bias in adolescents with ASD.

White matter integrity is disrupted in adolescents with acute anorexia nervosa: A diffusion tensor imaging study.

Anorexia nervosa (AN) is a highly debilitating mental illness with multifactorial etiology. It oftentimes begins in adolescence, therefore understanding the pathophysiology in this period is important. Few studies investigated the possible impact of the acute state of illness on white matter (WM) tissue properties in the developing adolescent brain. The present study expands our understanding of the implications of AN and starvation on WM integrity. 67 acutely ill adolescent patients suffering from AN restricting type were compared with 32 healthy controls using diffusion tensor imaging assessing fractional anisotropy (FA) and mean diffusivity (MD). We found widespread alterations in the vast majority of the WM regions with significantly decreased FA and increased MD in the AN group. In this highly selective sample in the acute stage of AN, the alterations are likely to be the consequence of starvation. Still, we cannot rule out that some of the affected regions might play a key role in AN-specific psychopathology.

Psychopathological Symptoms and Well-Being in Overweight and Underweight Adolescents: A Network Analysis.

Overweight and underweight adolescents have an increased risk of psychological problems and reduced quality of life. We used a network analysis approach on a variety of psychopathology and well-being variables to identify central factors in these populations. The network analysis was conducted on data of 344 overweight adolescents (>90th BMI-percentile) and 423 underweight adolescents (<10th BMI-percentile) drawn from a large community sample (10-19 years) including behavioral and emotional problems (Youth Self-Report), eating disorder risk (SCOFF) and well-being variables (KIDSCREEN). Additionally, psychopathology and well-being scores of overweight and underweight individuals were compared with 1.560 normal weight adolescents. Compared to their normal weight peers, overweight adolescents showed elevated psychopathology and eating disorder risk as well as reduced well-being. Underweight adolescents reported increased levels of internalizing problems but no increased eating disorder risk or reduced well-being. The network analysis revealed that anxious/depressed mood and attention problems were the most central and interconnected nodes for both overweight and underweight subsamples. Among underweight individuals, social problems and socially withdrawn behavior additionally functioned as a bridge between other nodes in the network. The results support psychological interventions focusing on improving mood, coping with negative emotions and tackling inner tension.

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy.

High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7-independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype.

Short-Term Outcome of Inpatient Treatment for Adolescents with Anorexia Nervosa Using DSM-5 Remission Criteria.

This study evaluated the short-term outcome of a multimodal inpatient treatment concept for adolescents with anorexia nervosa (AN). In this prospective observational study, a cohort of 126 female adolescents with AN (age range: 11-17, mean age: 14.83) was longitudinally followed from admission to discharge (average duration of stay: 77 days). We used gold-standard clinical interviews and self-report data, as well as DSM-5 remission criteria, to evaluate the treatment outcome. From admission to discharge, body-mass-index (BMI) significantly improved by 2.6 kg/m2. Data from clinical interviews and self-reports yielded similar improvements in restraint eating and eating concerns (large effects). Lower effects were observed for variables assessing weight/shape concerns and drive for thinness. At discharge, 23.2% of patients showed full remission of AN, 31.3% partial remission, and 45.5% no remission according to DSM-5 criteria. Differences in remission groups were found regarding AN severity, age at admission, and use of antidepressant medication. Living with both parents, longer duration of inpatient treatment and the use of antipsychotic medication were significantly associated with higher BMI change. The findings provide evidence for the short-term effectiveness of our inpatient treatment concept. We recommend using DSM-5 based remission criteria to evaluate the treatment outcome to improve the comparability of studies.

Does a Skills Intervention for Parents Have a Positive Impact on Adolescents' Anorexia Nervosa Outcome? Answers from a Quasi-Randomised Feasibility Trial of SUCCEAT.

Skills trainings for caregivers of patients with anorexia nervosa (AN) have been proven to be effective in improving caregiver skills and reducing caregivers' psychopathology. The effects on patients, especially adolescents, are largely unknown. The aim of this study was to evaluate the effectiveness of a caregivers' skills training program (Supporting Carers of Children and Adolescents with Eating Disorders in Austria, SUCCEAT, workshop or online version) on adolescents with AN delivered as workshops (WS) or online (ONL). Outcomes are Body-Mass-Index (BMI) percentile, eating psychopathology (Eating Disorder Examination, EDE), attitudinal and behavioural dimensions of eating disorders (Eating Disorder Inventory-2), motivation to change (AN Stages of Change Questionnaire), emotional and behavioural problems (Youth Self-Report) and quality of life (KINDL). All outcome variables significantly improved across both SUCCEAT groups (WS and ONL) and were sustained at 12-month follow-up. The online and workshop delivery of SUCCEAT were equally effective. Most effect sizes were in the medium-to-high range. Full or partial remission was observed in 72% (WS) and 87% (ONL) of patients. Caregiver skills trainings, either delivered as workshops or online modules, are highly recommended to complement treatment as usual.

The Maudsley model of anorexia nervosa treatment for adolescents and young adults (MANTRa): a study protocol for a multi-center cohort study.

BACKGROUND: The treatment of anorexia nervosa (AN) is often challenging due to medical complications as well as high relapse and mortality rates. Studies about effective treatment options for people with AN are particularly scarce in the adolescent population. This paper is a study protocol for a multi-center cohort study assessing the feasibility, acceptability and efficacy of a new, manualized treatment program, the "Maudsley Model of Anorexia Nervosa Treatment for Adolescents and Young Adults" (MANTRa) compared to psychotherapeutic treatment as usual (TAU). METHODS/DESIGN: One hundred patients between 13 and 21 years who meet the inclusion criteria will receive 24 to 34 individual weekly MANTRa therapy sessions or weekly TAU sessions. Primary outcome variables will be BMI and eating disorder psychopathology 12 months after baseline. Further changes in central coherence, cognitive flexibility, emotion recognition, comorbid psychopathology (e.g. depression, obsessive-compulsive and anxiety disorders, non-suicidal self-injury), personality factors and therapeutic alliance will be assessed. DISCUSSION: This multi-center study will examine the utility of the treatment program MANTRa for adolescents with AN and, therefore enhances the current knowledge about potential treatments for this patient group. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03535714 . Registered: 24/05/2018 (retrospectively registered, still recruiting).

[Cost minimization analysis of flexible ENT-endoscopes]. / Kostenvergleichsanalyse von flexiblen HNO-Endoskopen.

BACKGROUND: Reprocessing of complex instruments like flexible ENT-endoscopes with and without working channel are challanging for clinics and private practices. Aim of the study was to analyse the costs of an examination with a reusable endoscope-system and to compare it with two single-use endoscope-systems. MATERIAL AND METHODS: A cost minimization analysis was performed at the Department of Otorhinolaryngology, Head and Neck Surgery of the University Medical Center in Mainz, Germany. The local reusable endoscopy-system was compared with two single-use endoscopy-systems of Ambu and Karl Storz. RESULTS: Overall costs per examination with a reusable-scope were 23.03 € (11.60 € investment costs + 5.09 € repair costs + 6.34 € reprocessing costs). The single-use Endoscopy-system of Ambu resulted in 120.43 € per examination (120.00 € acquisition costs + 0.43 € storage costs). Overall costs for the single-use endoscopy-system of Karl Storz were 223.44 € per examination (investment costs for monitors 3.01 € + 220.00 € acquisition costs + 0.43 € storage costs). DISCUSSION: Flexible single-use ENT-endoscopy-systems generate higher costs in comparison to conventional reusable ones. But there are also advantages from the medical and economical side. CONCLUSION: A smart mix of reusable and single-use endoscopy systems seems therefore usefull.

A German version of the Caregiver Skills scale for caregivers of patients with anorexia nervosa.

OBJECTIVE: To investigate acceptance, reliability, convergent validity, factor structure and sensitivity to change of a German translation of the Caregiver Skills (CASK) scale measuring skills related to caring for patients with eating disorders. METHODS: Two hundred and thirty-three parents (76% female) of adolescent patients (mean age 15.1) with anorexia nervosa (AN) completed the 27 items of the CASK. We calculated item/scale characteristics, internal consistencies and bivariate correlations with other measures of caregiving burden. We evaluated goodness-of-fit of the 6-factor model using confirmatory factors analysis and explored the sensitivity to change following two skills-based trainings. RESULTS: The fit of the 6-factor model was acceptable (Root Mean Square Error of Approximation: 0.077, Standard Root Mean Square Residual: 0.080). Cronbach's alpha was excellent for the total (.94) and acceptable for all subscales (0.73-0.85). The total CASK score was 68.04 (max. 100) showing relatively high self-rated caregiver skills. Non-completion rates of most items were low (<3%) indicating high acceptance. Convergent validity was found with measures of psychological distress, depression, anxiety and expressed emotion. The total score significantly increased following an 8-week workshop/online skills training (d = 0.70) and a 2-day multi-family intervention (d = 0.47). DISCUSSION: The German CASK version is a useful instrument to assess caregiver skills in parents of patients with AN and to evaluate outcomes of skills-based trainings.

Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target.

Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic. CRISPR knockout of LIN28B-an oncofetal RNA-binding protein exerting diverse effects via negative regulation of let-7 miRNAs and other RNA targets-in cell and animal models confers a less aggressive/metastatic phenotype. This correlates with de-repression of let-7 miRNAs and is mimicked by silencing of downstream let-7 target HMGA2 or chemical inhibition of LIN28B/let-7 binding. Molecular characterization of CTCs provides a unique opportunity to correlated gene set metastatic profiles, identify drivers of dissemination, and develop therapies targeting the "seeds" of metastasis.