Research into evidence-based psychological interventions needs a stronger focus on replicability

Background:It is a precondition for evidence-based practice that research is replicable in a wide variety of clinical settings. Current standards for identifying evidence-based psychological interventions and making recommendations for clinical practice in clinical guidelines include criteria that are relevant for replicability, but a better understanding as well refined definitions of replicability are needed enabling empirical research on this topic. Recent advances on this issue were made in the wider field of psychology and in other disciplines, which offers the opportunity to define and potentially increase replicability also in research on psychological interventions. Method: This article proposes a research strategy for assessing, understanding, and improving replicability in research on psychological interventions. Results/Conclusion: First, we establish a replication taxonomy ranging from direct to conceptual replication adapted to the field of research on clinical interventions, propose study characteristics that increase the trustworthiness of results, and define statistical criteria for successful replication with respect to the quantitative outcomes of the original and replication studies. Second, we propose how to establish such standards for future research, i.e., in order to design future replication studies for psychological interventions as well as to apply them when investigating which factors are causing the (non-)replicability of findings in the current literature

The N-terminal region of the ubiquitin regulatory x (UBX) domain-containing Protein 1 (UBXD1) modulates interdomain communication within the valosin-containing Protein p97

Valosin-containing protein/p97 is an ATP-driven protein segregase that cooperates with distinct protein cofactors to control various aspects of cellular homeostasis. Mutations at the interface between the regulatory N-domain and the first of two ATPase domains (D1 and D2) deregulate the ATPase activity and cause a multisystem degenerative disorder, inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia/amyotrophic lateral sclerosis. Intriguingly, the mutations affect only a subset of p97-mediated pathways correlating with unbalanced cofactor interactions and most prominently compromised binding of the ubiquitin regulatory X domain-containing protein 1 (UBXD1) cofactor during endolysosomal sorting of caveolin-1. However, how the mutations impinge on the p97-cofactor interplay is unclear so far. In cell-based endosomal localization studies, we identified a critical role of the N-terminal region of UBXD1 (UBXD1-N). Biophysical studies using NMR and CD spectroscopy revealed that UBXD1-N can be classified as intrinsically disordered. NMR titration experiments confirmed a valosin-containing protein/p97 interaction motif and identified a second binding site at helices 1 and 2 of UBXD1-N as binding interfaces for p97. In reverse titration experiments, we identified two distant epitopes on the p97 N-domain that include disease-associated residues and an additional interaction between UBXD1-N and the D1D2 barrel of p97 that was confirmed by fluorescence anisotropy. Functionally, binding of UBXD1-N to p97 led to a reduction of ATPase activity and partial protection from proteolysis. These findings indicate that UBXD1-N intercalates into the p97-ND1 interface, thereby modulating interdomain communication of p97 domains and its activity with relevance for disease pathogenesis. We propose that the polyvalent binding mode characterized for UBXD1-N is a more general principle that defines a subset of p97 cofactors

A Latent Class Analysis on Symptoms of Prolonged Grief, Post-Traumatic Stress, and Depression Following the Loss of a Loved One

Background: The loss of a significant other can lead to variety of responses, including prolonged grief disorder (PGD), posttraumatic stress disorder (PTSD), and depression. The aim of this study was to replicate and extend previous research that indicated that three subgroups of bereaved individuals can be distinguished based one similar post-loss symptom profiles using latent class analysis (LCA). The second aim was to examine whether sociodemographic and loss-related characteristics as well as the extent of meaning making were related to classes with more pervasive psychopathology. Methods: Telephone-based interviews with 433 Dutch and German speaking persons who had lost a significant other at last 6 months earlier were conducted. Self-rated PGD, PTSD, and depression symptoms were assessed. LCA was conducted and correlates of class-membership were examined using the 3step approach. Results: The LCA resulted in three distinct classes: a no symptoms class (47%), a moderate PGD, low depression/PTSD class (32%), and a high PGD, moderate depression/PTSD class (21%). A multivariate analysis indicated that female gender, a shorter time since loss, an unexpected loss and less meaning made to a loss were significantly associated with membership to the moderate PGD, low depression/PTSD and high PGD, moderate depression/PTSD class compared to membership to the no symptom class. Losing a child or spouse, a shorter time since loss, and having made less meaning to the loss further distinguished between the high PGD, moderate depression/PTSD symptom class and the moderate PGD, low depression/PTSD class. Discussion: We found that the majority of individuals coped well in response to their loss since the no symptom class was the largest class. Post-loss symptoms could be categorized into classes marked by different intensity of symptoms, rather than qualitatively different symptom patterns. The findings indicate that perceiving the loss as more unexpected, finding less meaning in the loss, and loss-related factors, such as the recentness of a loss and the loss of a partner or child, were related to class membership more consistently than sociodemographic factors

The working alliance in a randomized controlled trial comparing online with face-to-face cognitive-behavioral therapy for depression

Background: Although numerous efficacy studies in recent years have found internet-based interventions for depression to be effective, there has been scant consideration of therapeutic process factors in the online setting. In face-to face therapy, the quality of the working alliance explains variance in treatment outcome. However, little is yet known about the impact of the working alliance in internet-based interventions, particularly as compared with face-to-face therapy. Methods: This study explored the working alliance between client and therapist in the middle and at the end of a cognitive-behavioral intervention for depression. The participants were randomized to an internet-based treatment group (n = 25) or face-to-face group (n = 28). Both groups received the same cognitive behavioral therapy over an 8-week timeframe. Participants completed the Beck Depression Inventory (BDI) post-treatment and the Working Alliance Inventory at mid- and post- treatment. Therapists completed the therapist version of the Working Alliance Inventory at post-treatment. Results: With the exception of therapists' ratings of the tasks subscale, which were significantly higher in the online group, the two groups' ratings of the working alliance did not differ significantly. Further, significant correlations were found between clients' ratings of the working alliance and therapy outcome at post-treatment in the online group and at both mid- and post-treatment in the face-to-face group. Correlation analysis revealed that the working alliance ratings did not significantly predict the BDI residual gain score in either group. Conclusions: Contrary to what might have been expected, the working alliance in the online group was comparable to that in the face-to-face group. However, the results showed no significant relations between the BDI residual gain score and the working alliance ratings in either group

Fiber Type Conversion by PGC-1α Activates Lysosomal and Autophagosomal Biogenesis in Both Unaffected and Pompe Skeletal Muscle

PGC-1α is a transcriptional co-activator that plays a central role in the regulation of energy metabolism. Our interest in this protein was driven by its ability to promote muscle remodeling. Conversion from fast glycolytic to slow oxidative fibers seemed a promising therapeutic approach in Pompe disease, a severe myopathy caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) which is responsible for the degradation of glycogen. The recently approved enzyme replacement therapy (ERT) has only a partial effect in skeletal muscle. In our Pompe mouse model (KO), the poor muscle response is seen in fast but not in slow muscle and is associated with massive accumulation of autophagic debris and ineffective autophagy. In an attempt to turn the therapy-resistant fibers into fibers amenable to therapy, we made transgenic KO mice expressing PGC-1α in muscle (tgKO). The successful switch from fast to slow fibers prevented the formation of autophagic buildup in the converted fibers, but PGC-1α failed to improve the clearance of glycogen by ERT. This outcome is likely explained by an unexpected dramatic increase in muscle glycogen load to levels much closer to those observed in patients, in particular infants, with the disease. We have also found a remarkable rise in the number of lysosomes and autophagosomes in the tgKO compared to the KO. These data point to the role of PGC-1α in muscle glucose metabolism and its possible role as a master regulator for organelle biogenesis - not only for mitochondria but also for lysosomes and autophagosomes. These findings may have implications for therapy of lysosomal diseases and other disorders with altered autophagy

Pneumoproteins and biomarkers of inflammation and coagulation do not predict rapid lung function decline in people living with HIV

Chronic obstructive pulmonary disease (COPD) is among the leading causes of death worldwide and HIV is an independent risk factor for the development of COPD. However, the etiology of this increased risk and means to identify persons with HIV (PWH) at highest risk for COPD have remained elusive. Biomarkers may reveal etiologic pathways and allow better COPD risk stratification. We performed a matched case:control study of PWH in the Strategic Timing of Antiretoviral Treatment (START) pulmonary substudy. Cases had rapid lung function decline (> 40 mL/year FEV1 decline) and controls had stable lung function (+ 20 to − 20 mL/year). The analysis was performed in two distinct groups: (1) those who were virally suppressed for at least 6 months and (2) those with untreated HIV (from the START deferred treatment arm). We used linear mixed effects models to test the relationship between case:control status and blood concentrations of pneumoproteins (surfactant protein-D and club cell secretory protein), and biomarkers of inflammation (IL-6 and hsCRP) and coagulation (d-dimer and fibrinogen); concentrations were measured within ± 6 months of first included spirometry. We included an interaction with treatment group (untreated HIV vs viral suppression) to test if associations varied by treatment group. This analysis included 77 matched case:control pairs in the virally suppressed batch, and 42 matched case:control pairs in the untreated HIV batch (n = 238 total) who were followed for a median of 3 years. Median (IQR) CD4 + count was lowest in the controls with untreated HIV at 674 (580, 838). We found no significant associations between case:control status and pneumoprotein or biomarker concentrations in either virally suppressed or untreated PWH. In this cohort of relatively young, recently diagnosed PWH, concentrations of pneumoproteins and biomarkers of inflammation and coagulation were not associated with subsequent rapid lung function decline. Trial registration: NCT00867048 and NCT01797367