A Serpin shapes the extracellular environment to prevent influenza A virus maturation

Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPINE1, conferred increased susceptibility to IAV in vitro. Together, our findings reveal that manipulating the extracellular environment to inhibit the last step in a virus life cycle is an important mechanism of the antiviral response

Gut Microbiome Dysbiosis in Antibiotic-Treated COVID-19 Patients is Associated with Microbial Translocation and Bacteremia

Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19

Side-by-side comparison of BH3-mimetics identifies MCL-1 as a key therapeutic target in AML

Despite advances in the treatment of acute myeloid leukemia (AML), prognosis of AML patients is still dismal and better treatment options are required. B-cell Lymphoma 2 (BCL-2) homology domain 3 (BH3)-mimetics are emerging as a novel class of apoptosis-inducing agents that are currently being tested for the treatment of different hematological malignancies including AML. Particularly, the selective BCL-2 inhibitor ABT-199/Venetoclax is demonstrating clinical responses and has recently been approved in combination for the treatment of AML. Compounds targeting the related protein MCL-1 have recently entered clinical trials, highlighting the urgency to compare the different BH3-mimetics and identify the most promising antiapoptotic target in AML. We performed a side-by-side comparison of different highly selective and potent BH3-mimetics targeting BCL-2 (ABT-199), MCL-1 (S63845) or BCL-xL (A1331852) in a panel of AML cell lines and primary patient cells. Gene knockdown using siRNAs was utilized to investigate the functional relevance of BCL-2 proteins. Western blotting and immunoprecipitations were used to explore the influence of BH3-mimetics on interactions between pro- and antiapoptotic BCL-2 proteins. A1331852 induced apoptosis only in selected cases, indicating that BCL-xL is not a very promising therapeutic target in AML. However, S63845 displayed higher potency than ABT-199, with more cell lines and primary cells responding to S63845 than to ABT-199. MCL-1 dependency in AML cells was confirmed by siRNA-mediated knockdown of MCL-1, which was sufficient to induce apoptosis. S63845-induced cell death was accompanied by a displacement of the BH3-only protein BIM as well as BAK, resulting in BAK-dependent apoptosis. In contrast, ABT-199-induced cell death was mediated by BAX rather than BAK, indicating distinct non-redundant molecular functions of BCL-2 and MCL-1 in AML. Our study reveals that MCL-1 may be a more prevalent therapeutic target than BCL-2 in AML and identifies BIM and BAK as important mediators of S63845-induced apoptosis in AML

Adherence Rating Scale for Cognitive Processing Therapy – Cognitive Only: Analysis of Psychometric Properties

Background: The assessment of therapeutic adherence is essential for accurately interpreting treatment outcomes in psychotherapy research. However, such assessments are often neglected. Aims: To fill this gap, we aimed to develop and test a scale that assessed therapeutic adherence to Cognitive Processing Therapy – Cognitive Only (CPT), which was adapted for a treatment study targeting patients with post-traumatic stress disorder and co-occurring borderline personality symptoms. Method: Two independent, trained raters assessed 30 randomly selected treatment sessions involving seven therapists and eight patients who were treated in a multicentre randomized controlled trial. Results: The inter-rater reliability for all items and the total score yielded good to excellent results (intraclass correlation coefficient [ICC] = 0.70 to 1.00). Cronbach's α was .56 for the adherence scale. Regarding content validity, three experts confirmed the relevance and appropriateness of each item. Conclusion: The adherence rating scale for the adapted version of CPT is a reliable instrument that can be helpful for interpreting treatment effects, analysing possible relationships between therapeutic adherence and treatment outcomes and teaching therapeutic skills.Peer Reviewe

Dialectical behaviour therapy for posttraumatic stress disorder related to childhood sexual abuse: a pilot study in an outpatient treatment setting

Background: Dialectical behaviour therapy for posttraumatic stress disorder (DBT-PTSD), which is tailored to treat adults with PTSD and co-occurring emotion regulation difficulties, has already demonstrated its efficacy, acceptance and safety in an inpatient treatment setting. It combines elements of DBT with trauma-focused cognitive behavioural interventions. Objective: To investigate the feasibility, acceptance and safety of DBT-PTSD in an outpatient treatment setting by therapists who were novice to the treatment, we treated 21 female patients suffering from PTSD following childhood sexual abuse (CSA) plus difficulties in emotion regulation in an uncontrolled clinical trial. Method: The Clinician Administered PTSD Symptom Scale (CAPS), the Davidson Trauma Scale (DTS), the Borderline Section of the International Personality Disorder Examination (IPDE) and the Borderline Symptom List (BSL-23) were used as primary outcomes. For secondary outcomes, depression and dissociation were assessed. Assessments were administered at pretreatment, post-treatment and six-week follow-up. Results: Improvement was significant for PTSD as well as for borderline personality symptomatology, with large pretreatment to follow-up effect sizes for completers based on the CAPS (Cohens d = 1.30), DTS (d = 1.50), IPDE (d = 1.60) and BSL-23 (d = 1.20). Conclusion: The outcome suggests that outpatient DBT-PTSD can safely be used to reduce PTSD symptoms and comorbid psychopathology in adults who have experienced CSA

Does treatment specific-, disorder specific- or general therapeutic competence predict symptom reduction in posttraumatic stress disorder?

ABSTRACTBackground: Literature on the association between therapist competence and treatment success in posttraumatic stress disorder (PTSD) treatments is scarce and results are mixed.Aims/Objective: The relationship between different types of therapeutic competence, therapeutic alliance, and PTSD symptom reduction in patients treated with Dialectical Behaviour Therapy for PTSD (DBT-PTSD) or Cognitive Processing Therapy (CPT) was assessed. Competence types were PTSD-specific competence, treatment specific competence, and general competence in cognitive behaviour therapy (CBT).Method: Videotaped therapy sessions from N = 160 women with PTSD and emotion regulation difficulties after child abuse participating in a large randomised controlled trial (Bohus et al., 2020) were rated. Three therapeutic competence-types were assessed using specifically developed rating scales. Alliance was assessed via patient ratings with the Helping Alliance Questionnaire (HAQ). PTSD symptoms were assessed at pre- and post-treatment via clinician rating with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and via self-rating with the PTSD-Checklist for DSM-5 (PCL-5).Results: No significant association between competence and clinician or self-rated PTSD symptoms was found. PTSD specific competence predicted clinician rated PTSD symptom severity on a trend level. Alliance predicted both clinician and self-rated PTSD symptom reduction.Conclusion: Our results provide a starting point for future research on different competence types and their association with PTSD treatment gains. Therapists were highly trained and received weekly supervision, hence a restricted competence range is a possible explanation for non-existing associations between competence and PTSD symptom reduction in our sample. More research in naturalistic settings, such as dissemination studies, is needed

Psychometric Properties and Factor Structure of the German Version of the Clinician-Administered PTSD Scale for DSM-5

The Clinician-Administered PTSD Scale (CAPS) is a widely used diagnostic interview for posttraumatic stress disorder (PTSD). Following fundamental modifications in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM-5), the CAPS had to be revised. This study examined the psychometric properties (internal consistency, interrater reliability, convergent and discriminant validity, and structural validity) of the German version of the CAPS-5 in a trauma-exposed sample ( n = 223 with PTSD; n =51 without PTSD). The results demonstrated high internal consistency (αs = .65-.93) and high interrater reliability (ICCs = .81-.89). With regard to convergent and discriminant validity, we found high correlations between the CAPS severity score and both the Posttraumatic Diagnostic Scale sum score ( r = .87) and the Beck Depression Inventory total score ( r = .72). Regarding the underlying factor structure, the hybrid model demonstrated the best fit, followed by the anhedonia model. However, we encountered some nonpositive estimates for the correlations of the latent variables (factors) for both models. The model with the best fit without methodological problems was the externalizing behaviors model, but the results also supported the DSM-5 model. Overall, the results demonstrate that the German version of the CAPS-5 is a psychometrically sound measure

Does treatment specific-, disorder specific- or general therapeutic competence predict symptom reduction in posttraumatic stress disorder?

Background: Literature on the association between therapist competence and treatment success in posttraumatic stress disorder (PTSD) treatments is scarce and results are mixed. Aims/Objective: The relationship between different types of therapeutic competence, therapeutic alliance, and PTSD symptom reduction in patients treated with Dialectical Behaviour Therapy for PTSD (DBT-PTSD) or Cognitive Processing Therapy (CPT) was assessed. Competence types were PTSD-specific competence, treatment specific competence, and general competence in cognitive behaviour therapy (CBT). Method: Videotaped therapy sessions from N = 160 women with PTSD and emotion regulation difficulties after child abuse participating in a large randomised controlled trial (Bohus et al., 2020) were rated. Three therapeutic competence-types were assessed using specifically developed rating scales. Alliance was assessed via patient ratings with the Helping Alliance Questionnaire (HAQ). PTSD symptoms were assessed at pre- and post-treatment via clinician rating with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and via self-rating with the PTSD-Checklist for DSM-5 (PCL-5). Results: No significant association between competence and clinician or self-rated PTSD symptoms was found. PTSD specific competence predicted clinician rated PTSD symptom severity on a trend level. Alliance predicted both clinician and self-rated PTSD symptom reduction. Conclusion: Our results provide a starting point for future research on different competence types and their association with PTSD treatment gains. Therapists were highly trained and received weekly supervision, hence a restricted competence range is a possible explanation for non-existing associations between competence and PTSD symptom reduction in our sample. More research in naturalistic settings, such as dissemination studies, is needed. Three different types of therapeutic competence and their association to treatment gains in women with posttraumatic stress disorder after child abuse were assessed.Therapist competence was high in all three domains of competence.No association was found between any of the competence types and reduction in posttraumatic stress disorder symptoms. Three different types of therapeutic competence and their association to treatment gains in women with posttraumatic stress disorder after child abuse were assessed. Therapist competence was high in all three domains of competence. No association was found between any of the competence types and reduction in posttraumatic stress disorder symptoms.</p

supplement_EFA_3.4 – Supplemental material for Psychometric Properties and Factor Structure of the German Version of the Clinician-Administered PTSD Scale for <i>DSM-5</i>

<p>Supplemental material, supplement_EFA_3.4 for Psychometric Properties and Factor Structure of the German Version of the Clinician-Administered PTSD Scale for <i>DSM-5</i> by Meike Müller-Engelmann, Ulrich Schnyder, Clara Dittmann, Kathlen Priebe, Martin Bohus, Janine Thome, Thomas Fydrich, Monique C. Pfaltz and Regina Steil in Assessment</p