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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. Progressive respiratory failure is the primary cause of death in patients with COVID-19, but pathologies in other tissues may also occur. Here the authors report that adrenal tropism of SARS-CoV-2 is associated with adrenalitis, reduced adrenal cortisol levels and severe adrenal damage in a post-mortem case series of patients with severe fatal COVID-19.

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.

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.

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. Synopsis The pathogenic G4C2 repeat expansion upstream of C9orf72 is bidirectionally transcribed and translated into five aggregating dipeptide repeat proteins (DPRs). Analysis of cell‐to‐cell transmission of DPRs suggests that DPR‐directed antibodies may have therapeutic potential. The hydrophobic DPR species poly‐GA, poly‐GP and poly‐PA are transmitted between cells. Specific antibodies reduce poly‐GA aggregation in cell lines and primary neurons. Poly‐GA antibodies block the seeding activity of C9orf72 brain extracts. Graphical Abstract The pathogenic G4C2 repeat expansion upstream of C9orf72 is bidirectionally transcribed and translated into five aggregating dipeptide repeat proteins (DPRs). Analysis of cell‐to‐cell transmission of DPRs suggests that DPR‐directed antibodies may have therapeutic potential.

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. 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. 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. 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. 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.

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. 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. 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. 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.

The need for a systemic transformation of the building sector is increasingly recognized, but much of the current discussion and actions focus on the creation of technical innovation, while the question of how to improve the social quality of buildings and building processes is largely ignored. Socially engaged architecture more broadly and design-build projects in particular represent an exception in this regard. Design-build studios have emerged as a new teaching method at numerous universities in North America, Europe and elsewhere to equip students with the skills needed to address pressing sustainability issues. Most design-build projects include an explicit claim to social relevance and change and opt for a co-productive process. However, the extent to which such practices have the potential to enhance the social (and, ultimately, the ecological) sustainability of buildings and construction processes has been insufficiently assessed. Based on a comparative analysis of five design-build projects carried out at the University of Stuttgart, this paper discusses critical factors that influence both the (social) quality of the design-build process as well as its (built) outcome and impact. The findings offer important insights for future design-build projects and their underlying need for revised training and teaching curricula to equip future architects and planners with the necessary knowledge and skills to act as process designers and facilitators and to shape a more people-centered built environment.

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 placebo-controlled 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’.

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.

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.