Development of MDS in Pediatric Patients with GATA2 Deficiency: Increased Histone Trimethylation and Deregulated Apoptosis as Potential Drivers of Transformation.

GATA2 deficiency is a heterogeneous, multisystem disorder associated with a high risk of developing myelodysplastic syndrome (MDS) and the progression to acute myeloid leukemia. The mechanisms underlying malignant transformation in GATA2 deficiency remain poorly understood, necessitating predictive markers to assess an individual's risk of progression and guide therapeutic decisions. In this study, we performed a systematic analysis of bone marrow biopsies from 57 pediatric MDS patients. Focusing on hematopoiesis and the hematopoietic niche, including its microenvironment, we used multiplex immunofluorescence combined with multispectral imaging, gene expression profiling, and multiplex RNA in situ hybridization. Patients with a GATA2 deficiency exhibited a dysregulated GATA2 transcriptional network. Disease progression (GATA2-EB, n = 6) was associated with increased GATA2 mRNA levels, restored expression of the GATA2 target EZH2, and increased H3K27me3. GATA2-EB was further characterized by the high expression of the anti-apoptotic protein BCL2, a feature absent in children with a GATA2 deficiency and refractory cytopenia of childhood (GATA2-RCC, n = 24) or other pediatric MDS subgroups (RCC, n = 17; MDS-EB, n = 10). The multispectral imaging analysis of additional BCL2 family members revealed significantly elevated Mediators of Apoptosis Combinatorial (MAC) scores in GATA2-EB patients. Taken together, our findings highlight the potential drivers of disease progression in GATA2 deficiency, particularly increased histone trimethylation and dysregulated apoptosis. Furthermore, upregulated BCL2 and EZH2 and increased MAC scores provide a strong rationale for the use of venetoclax and azacitidine in therapeutic regimens for GATA2-EB.

Adrenal tropism of SARS-CoV-2 and adrenal findings in a post-mortem case series of patients with severe fatal COVID-19.

Progressive respiratory failure and hyperinflammatory response is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. Despite mounting evidence of disruption of the hypothalamus-pituitary-adrenal axis in COVID-19, relatively little is known about the tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to adrenal glands and associated changes. Here we demonstrate adrenal viral tropism and replication in COVID-19 patients. Adrenal glands showed inflammation accompanied by inflammatory cell death. Histopathologic analysis revealed widespread microthrombosis and severe adrenal injury. In addition, activation of the glycerophospholipid metabolism and reduction of cortisone intensities were characteristic for COVID-19 specimens. In conclusion, our autopsy series suggests that SARS-CoV-2 facilitates the induction of adrenalitis. Given the central role of adrenal glands in immunoregulation and taking into account the significant adrenal injury observed, monitoring of developing adrenal insufficiency might be essential in acute SARS-CoV-2 infection and during recovery.

[Cognition in children with social anxiety disorder experiencing stress]. / Kognitionen von Kindern mit sozialer Angststörung unter Stress.

Cognition in children with social anxiety disorder experiencing stress Abstract. Empirical data on cognitions of children with social anxiety disorder (SAD) are inconclusive. Objective: The present study examines the significance of cognition in children with SAD. Method: Thirty children suffering from SAD and 30 control children free of diagnosis (HC) aged between 9 and 15 years took part in an experiment. Their cognition was assessed before, during, and after a stress-inducing social situation. The assessment method was a self-report measurement. Coping perception was also assessed. Results: Children with SAD did not report a higher level of negative or coping cognition than those in the HC group. An interaction was apparent on the positive cognition scale: Older children (11-12 or 13-15 years) with SAD reported less positive cognition than those in the HC group, and younger children with SAD (9-10 years) reported more than those in the HC group. No group differences were found for perceived coping. Conclusions: The findings are important to the cognitive model and for the psychological treatment of SAD in children.

Effect of Developmentally Adapted Cognitive Processing Therapy for Youth With Symptoms of Posttraumatic Stress Disorder After Childhood Sexual and Physical Abuse: A Randomized Clinical Trial.

Importance: Despite the high prevalence, evidence-based treatments for abuse-related posttraumatic stress disorder (PTSD) in adolescents have rarely been studied. Objective: To examine whether developmentally adapted cognitive processing therapy (D-CPT) is more effective than a wait-list condition with treatment advice (WL/TA) among adolescents with PTSD related to childhood abuse. Design, Setting, and Participants: This rater-blinded, multicenter, randomized clinical trial (stratified by center) enrolled treatment-seeking adolescents and young adults (aged 14-21 years) with childhood abuse-related PTSD at 3 university outpatient clinics in Germany from July 2013 to June 2015, with the last follow-up interview conducted by May 2016. Of 194 patients, 88 were eligible for randomization. Interventions: Participants received D-CPT or WL/TA. Cognitive processing therapy was enhanced by a motivational and alliance-building phase, by including emotion regulation and consideration of typical developmental tasks, and by higher session frequency in the trauma-focused core CPT phase. In WL/TA, participants received treatment advice with respective recommendations of clinicians and were offered D-CPT after 7 months. Main Outcomes and Measures: All outcomes were assessed before treatment (baseline), approximately 8 weeks after the start of treatment, after the end of treatment (posttreatment), and at the 3-month follow-up. The primary outcome, PTSD symptom severity, was assessed in clinical interview (Clinician-Administered PTSD Scale for Children and Adolescents for DSM-IV [CAPS-CA]). Secondary outcomes were self-reported PTSD severity, depression, borderline symptoms, behavior problems, and dissociation. Results: The 88 participants (75 [85%] female) had a mean age of 18.1 years (95% CI, 17.6-18.6 years). In the intention-to-treat analysis, the 44 participants receiving D-CPT (39 [89%] female) demonstrated greater improvement than the 44 WL/TA participants (36 [82%] female) in terms of PTSD severity (mean CAPS-CA scores, 24.7 [95% CI, 16.6-32.7] vs 47.5 [95% CI, 37.9-57.1]; Hedges g = 0.90). This difference was maintained through the follow-up (mean CAPS-CA scores, 25.9 [95% CI, 16.2-35.6] vs 47.3 [95% CI, 37.8-56.8]; Hedges g = 0.80). Treatment success was greatest during the trauma-focused core phase. The D-CPT participants also showed greater and stable improvement in all secondary outcomes, with between-groups effect sizes ranging from 0.65 to 1.08 at the posttreatment assessment (eg, for borderline symptoms, 14.1 [95% CI, 8.0-20.2] vs 32.0 [95% CI, 23.8-40.2]; Hedges g = 0.91). Conclusions and Relevance: Adolescents and young adults with abuse-related PTSD benefited more from D-CPT than from WL/TA. Treatment success was stable at the follow-up and generalized to borderline symptoms and other comorbidities. Trial Registration: German Clinical Trials Register identifier: DRKS00004787.

Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss.

Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.

Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins.

Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly-GA, poly-GP, and poly-PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly-GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly-GA and cerebellar extracts of C9orf72 patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80 Treatment with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity of C9orf72 brain extracts. Poly-GA-directed immunotherapy may thus reduce DPR aggregation and disease progression in C9orf72 ALS/FTD.

TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons.

Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased ß2-transferrin levels in patient CSF Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase reporter assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed the broad reduction in surface expression of key receptors upon TDP-43 knockdown, including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays the surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43-induced neurodegeneration by blocking trophic signaling.

Psychological Treatments for Symptoms of Posttraumatic Stress Disorder in Children, Adolescents, and Young Adults: A Meta-Analysis.

Meta-analyses of the treatment of posttraumatic stress disorder (PTSD) in childhood and adolescence are restricted to specific trauma, selected interventions, and methodologically rigorous studies. This large meta-analysis quantifies the effects of psychological treatments for PTSD symptoms in children and adolescents. An extensive literature search yielded a total of 13,040 articles; 135 studies with 150 treatment conditions (N = 9562 participants) met the inclusion criteria (psychological interventions with children and/or adolescents with PTSD symptoms that report quantitative measures of symptom change). The mean effect sizes (ESs) for PTSD symptoms ranged from large to small, depending on the control condition. Cognitive behavioral therapy (CBT) yielded the highest ESs. Age and caretaker involvement were identified as moderators. CBT, especially when conducted in individual treatment with the inclusion of parents, is a highly effective treatment for trauma symptoms. Psychological treatments need to be modified to address younger patients' specific needs.

Changes in negative implicit evaluations in patients of hypochondriasis after treatment with cognitive therapy or exposure therapy.

BACKGROUND AND OBJECTIVES: Previous studies using modified versions of the Affect Misattribution Procedure (AMP; Payne, Cheng, Govorun, & Stewart, 2005) have revealed that there is an implicit negative evaluation bias of illness-related information in patients with hypochondriasis (HYP), which might be a maintaining feature of HYP. However, there is no evidence on whether this bias might be targeted successfully by effective treatments, such as exposure therapy (ET) or cognitive therapy (CT). This is the first study to examine the change in negative implicit evaluations in a randomized controlled trial, including individual CT and ET, compared to a wait-list control group for HYP. METHODS: An AMP with illness, symptom and neutral primes was used in 70 patients with HYP before and after treatment (wait-list respectively). RESULTS: There was no significant change in negative implicit affective evaluations in both CT and ET, compared to wait-list. However, comparisons between the two active treatments revealed an interaction effect, that only for CT were the affective reactions on illness-as well as symptom-related prime trials (but not neutral primes) significantly more positive at post-compared to pre-treatment. In CT but not in ET, the reduction of implicit negative evaluation bias regarding symptom-related primes was significantly related to the reduction of self-reported health anxiety. LIMITATIONS: The small subsample sizes for CT and ET, in comparison to wait-list, prohibit the detection of smaller effects. CONCLUSIONS: Formal cognitive restructuring is necessary for reducing implicit negative evaluation bias in HYP, but the latter is not a prerequisite for reducing health anxiety. Thus, the importance of the negative implicit evaluation bias for the maintenance of HYP remains questionable.

Reliability, factor structure, and validity of the German version of the Trauma Symptom Checklist for Children in a sample of adolescents.

BACKGROUND: The Trauma Symptom Checklist for Children (TSC-C) is the most widely used self-report scale to assess trauma-related symptoms in children and adolescents on six clinical scales. The purpose of the present study was to develop a German version of the TSC-C and to investigate its psychometric properties, such as factor structure, reliability, and validity, in a sample of German adolescents. METHOD: A normative sample of N=583 and a clinical sample of N=41 adolescents with a history of physical or sexual abuse aged between 13 and 21 years participated in the study. RESULTS: The Confirmatory Factor Analysis on the six-factor model (anger, anxiety, depression, dissociation, posttraumatic stress, and sexual concerns with the subdimensions preoccupation and distress) revealed acceptable to good fit statistics in the normative sample. One item had to be excluded from the German version of the TSC-C because the factor loading was too low. All clinical scales presented acceptable to good reliability, with Cronbach's α's ranging from .80 to .86 in the normative sample and from .72 to .87 in the clinical sample. Concurrent validity was also demonstrated by the high correlations between the TSC-C scales and instruments measuring similar psychopathology. TSC-C scores reliably differentiated between adolescents with trauma history and those without trauma history, indicating discriminative validity. CONCLUSIONS: In conclusion, the German version of the TSC-C is a reliable and valid instrument for assessing trauma-related symptoms on six different scales in adolescents aged between 13 and 21 years.

Therapeutic adherence and competence scales for Developmentally Adapted Cognitive Processing Therapy for adolescents with PTSD.

Background : The assessment of therapeutic adherence and competence is often neglected in psychotherapy research, particularly in children and adolescents; however, both variables are crucial for the interpretation of treatment effects. Objective : Our aim was to develop, adapt, and pilot two scales to assess therapeutic adherence and competence in a recent innovative program, Developmentally Adapted Cognitive Processing Therapy (D-CPT), for adolescents suffering from posttraumatic stress disorder (PTSD) after childhood abuse. Method : Two independent raters assessed 30 randomly selected sessions involving 12 D-CPT patients (age 13-20 years, M age=16.75, 91.67% female) treated by 11 therapists within the pilot phase of a multicenter study. Results : Three experts confirmed the relevance and appropriateness of each item. All items and total scores for adherence (intraclass correlation coefficients [ICC]=0.76-1.00) and competence (ICC=0.78-0.98) yielded good to excellent inter-rater reliability. Cronbach's alpha was 0.59 for the adherence scale and 0.96 for the competence scale. Conclusions : The scales reliably assess adherence and competence in D-CPT for adolescent PTSD patients. The ratings can be helpful in the interpretation of treatment effects, the assessment of mediator variables, and the identification and training of therapeutic skills that are central to achieving good treatment outcomes. Both adherence and competence will be assessed as possible predictor variables for treatment success in future D-CPT trials.

Cognitive therapy for social anxiety disorder: the impact of the "self-focused attention and safety behaviours experiment" on the course of treatment.

BACKGROUND AND AIMS: Several studies have shown that cognitive therapy is an effective treatment for social anxiety disorder (SAD). However, it remains unclear which of the complex interventions are associated with an anxiety reduction during the course of treatment. The aim of this study was to examine the impact of the intervention referred to as the "self-focused attention and safety behaviours experiment" on treatment outcome. METHOD: This study was part of a randomized controlled trial including 16 sessions of either individual cognitive therapy (CT) or interpersonal therapy (IPT) for SAD. Of particular importance, a concomitant time-series analysis was used to investigate the impact of the self-focused attention and safety behaviours experiment on subsequent social anxiety (1, 2, 3, and 4 weeks after the intervention) in 32 patients with SAD, who are receiving cognitive treatment. RESULTS: The results revealed a significant reduction of social anxiety after the self-focused attention and safety behaviours experiment during the subsequent month of treatment. CONCLUSION: The findings of the current study confirm current cognitive theories of SAD and demonstrate the importance of interventions that target self-focused attention and safety behaviour in cognitive therapy for SAD.

Implicit affective evaluation bias in hypochondriasis: findings from the Affect Misattribution Procedure.

Cognitive theories of hypochondriasis (HYP) suggest that catastrophic misinterpretations of benign body sensations are a core feature for the maintenance of the disorder. There is tentative support from an analog sample that the interpretation of illness-related information also involves an implicit affective component. This is the first study to examine this negative affective evaluation bias implicitly in patients with HYP. An adapted version of the Affect Misattribution Procedure (AMP) with illness, symptom and neutral primes was used in 80 patients with HYP, and compared to 83 patients with an anxiety disorder (AD), as well as 90 healthy controls (CG). The HYP group showed significantly more negative affective reactions in illness prime trials, compared to both control groups, as well as more negative implicit evaluations on symptom prime trials, compared to the CG. Significant inverse relationships were observed only between the implicit evaluations of illness words and health anxiety questionnaires. Thus, an implicit negative affective evaluation bias of serious illnesses rather than symptoms is a unique feature of HYP.

Antibiotic-induced autoactivation of IS256 in Staphylococcus aureus.

The 3' end of rsbU, encoding the positive regulator of the stress factor sigma B, was identified as a hot spot for spontaneous IS256 insertion in Staphylococcus aureus SA137/93G. Interestingly, subinhibitory concentrations of chloramphenicol in combination with heat stress, as well as linezolid and spectinomycin at physiological temperatures, selected for such rsbU::IS256 insertion mutants. In consequence of the inactivation of rsbU, the IS256 transposition frequency was increased 4-fold in S. aureus HG001.

Sudden gains in cognitive therapy and interpersonal therapy for social anxiety disorder.

OBJECTIVE: The present study examined the effects of sudden gains on treatment outcome in a randomized controlled trial including individual cognitive therapy (CT) and interpersonal therapy (IPT) for social anxiety disorder (SAD). METHOD: Participants were 67 individuals with SAD who received 16 treatment sessions. Symptom severity at each session was assessed using the Social Phobia Weekly Summary Scale (Clark et al., 2003). RESULTS: Results indicate that 22.4% of participants experienced a sudden gain during treatment. Individuals with sudden gains had significantly lower social anxiety symptoms at post-treatment and follow-up compared to individuals without sudden gains. Sudden gains in CT and IPT had similar magnitudes, frequencies, and timings. However, sudden gains resulted in lower levels of post-treatment symptoms in CT compared to IPT. Cognitive changes did not precede sudden gains, but sudden gains resulted in cognitive changes. CONCLUSIONS: Sudden gains in CT and IPT for SAD are predictive of long-term outcome. In addition, the effect of sudden gains may be greater in CT compared to IPT.

Haunting self-images? The role of negative self-images in adolescent social anxiety disorder.

BACKGROUND AND OBJECTIVES: Negative distorted self-images (NSI) allegedly maintain social anxiety in adults suffering from social anxiety disorder (SAD). These NSI are activated in feared social situations and are often linked to past socially traumatic events. However, because empirical evidence on the presence and characteristics of such NSI in adolescents suffering from SAD is limited, the aim of the present study is to examine the nature of NSI in adolescent SAD patients. METHODS: Using a semi-structured interview, 31 adolescents with a primary diagnosis of SAD and 31 healthy adolescents (HA) who were matched for age and gender, completed a questionnaire set assessing the characteristics of NSI, social anxiety and depression. RESULTS: Relative to the HA-group, those suffering from SAD reported experiencing NSI significantly more frequently, more vividly, and with greater distress. No significant differences between the groups emerged regarding a link between the NSI and an autobiographical event. However, NSI were reported as more often having an observer-perspective in the SAD as compared to the HA-group. Hierarchical regression analysis revealed that certain characteristics of the NSI predict social anxiety beyond the influence of depression in adolescents with SAD. DISCUSSION: NSI seem to be an important feature of adolescent SAD and phenomenological comparable to NSI in adults suffering from SAD. CONCLUSIONS: Specific interventions aiming to correct NSI, which have proven to be highly effective in adults, should be developmentally-adapted and evaluated in future studies.

Discrepancies between implicit and explicit self-esteem among adolescents with social anxiety disorder.

BACKGROUND AND OBJECTIVES: Previous studies have found high implicit self-esteem (ISE) to prevail concurrently with low explicit self-esteem (ESE) in socially anxious adults. This suggests that self-esteem discrepancies are associated with social anxiety disorder (SAD). Given that the onset of SAD often occurs in adolescence, we investigated self-esteem discrepancies between ISE and ESE in adolescents suffering from SAD. METHODS: Two implicit measures (Affect Misattribution Procedure, Implicit Association Test) were used both before and after a social threat activation in 20 adolescents with SAD (14-20 years), and compared to 20 healthy adolescents who were matched for age and gender. The Rosenberg Self-Esteem Scale, the Social Cognitions Questionnaire and Beck Depression Inventory were administered as explicit measures. We expected discrepant self-esteem (high ISE, low ESE) in adolescents with SAD, in comparison to congruent self-esteem (positive ISE, positive ESE) in healthy controls, after social threat activation. RESULTS: Both the patient and control groups exhibited high positive ISE on both implicit measures, before as well as after social threat induction. Explicitly, patients suffering from SAD revealed lower levels of ESE, compared to the healthy adolescents. CONCLUSIONS: This study is the first to examine ISE and ESE in a clinical sample of adolescent patients with SAD. Our results suggest that SAD is associated with a discrepancy between high ISE and low ESE, after a social-threat manipulation. The findings are discussed in relation to other studies using implicit measures in SAD and may provide a more comprehensive understanding of the role of self-esteem in adolescent SAD.

Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials: a systematic review and meta-analysis.

BACKGROUND: Biases in adverse effect reporting in randomized controlled trials (RCTs) [e.g. due to investigator expectations or assessment quality] can be quantified by studying the rates of adverse events reported in the placebo arms of such trials. OBJECTIVE: We compared the rates of adverse effects reported in the placebo arms of tricyclic antidepressant (TCA) trials and placebo arms of selective serotonin reuptake inhibitor (SSRI) trials. METHODS: We conducted a literature search for RCTs across PUBMED, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL). Only studies allowing adverse effect analysis were included. Publication year ranged from 1981 to 2007. RESULTS: Our systematic review and meta-analysis included 143 placebocontrolled RCTs and data from 12,742 patients. Only 21% of studies used structured and systematic adverse effect ascertainment strategies. The way in which trials recorded adverse events influenced the rate of adverse effects substantially. Systematic assessment led to higher rates than less systematic assessment. Far more adverse effects were reported in TCA-placebo groups compared with SSRI-placebo groups, e.g. dry mouth (odds ratio [OR] = 3.5; 95% CI 2.9, 4.2); drowsiness (OR = 2.7; 95%CI 2.2, 3.4); constipation (OR= 2.7; 95%CI 2.1, 3.6); sexual problems (OR =2.3; 95%CI 1.5, 3.5). Regression analyses controlling for various influencing factors confirmed the results. CONCLUSION: Adverse effect profiles reported in clinical trials are strongly influenced by expectations from investigators and patients. This difference cannot be attributed to ascertainment methods. Adverse effect patterns of the drug group are closely related to adverse effects of the placebo group. These results question the validity of the assumption that adverse effects in placebo groups reflect the 'drug-unspecific effects'.