Digitally delivered interventions for depression vary in many aspects, including their therapeutic orientation, depth of content, interactivity, individual tailoring, inclusion of multimedia, cost, ...and effectiveness. However, their effectiveness is rarely examined in intervention-specific meta-analyses. An earlier meta-analysis of eight randomized controlled trials (RCT) demonstrated the effectiveness of a tailored, integrative digital intervention (deprexis), which is delivered via the Internet. This updated meta-analysis of twelve deprexis-specific RCT with a total of N = 2901 participants confirmed the effectiveness of deprexis for depression reduction at post-intervention (g = 0.51, 95% CI: 0.40-0.62, I2 = 26%). Results were analogous when study quality, screening and randomization procedure were taken into account. Clinician guidance, developer-involvement, setting (community vs. clinical), and initial symptom severity did not have statistically significant effects on the effect size, and there was no evidence of publication bias. Thus, these findings demonstrate that deprexis can facilitate clinically relevant reduction of depressive symptoms over 8-12 weeks across a broad range of initial symptom severity, and that the intervention can be combined with other forms of depression treatment. There is now a need to study the intervention's implementation in routine care settings as well as its long-term effectiveness and cost-effectiveness in diverse cultural and linguistic settings.
SARS-CoV-2 variants of interest and concern will continue to emerge for the duration of the COVID-19 pandemic. To map mutations in the receptor-binding domain (RBD) of the spike protein that affect ...binding to angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, we applied in vitro evolution to affinity-mature the RBD. Multiple rounds of random mutagenic libraries of the RBD were sorted against decreasing concentrations of ACE2, resulting in the selection of higher affinity RBD binders. We found that mutations present in more transmissible viruses (S477N, E484K and N501Y) were preferentially selected in our high-throughput screen. Evolved RBD mutants include prominently the amino acid substitutions found in the RBDs of B.1.620, B.1.1.7 (Alpha), B1.351 (Beta) and P.1 (Gamma) variants. Moreover, the incidence of RBD mutations in the population as presented in the GISAID database (April 2021) is positively correlated with increased binding affinity to ACE2. Further in vitro evolution increased binding by 1,000-fold and identified mutations that may be more infectious if they evolve in the circulating viral population, for example, Q498R is epistatic to N501Y. We show that our high-affinity variant RBD-62 can be used as a drug to inhibit infection with SARS-CoV-2 and variants Alpha, Beta and Gamma in vitro. In a model of SARS-CoV-2 challenge in hamster, RBD-62 significantly reduced clinical disease when administered before or after infection. A 2.9 Å cryo-electron microscopy structure of the high-affinity complex of RBD-62 and ACE2, including all rapidly spreading mutations, provides a structural basis for future drug and vaccine development and for in silico evaluation of known antibodies.
Measurements of target activation in cells or tissues are key indicators of efficacy during drug development. In contrast to established methods that require reagents and multiple preprocessing ...steps, reagent-free in situ analysis of engaged drug targets or target-proximal pharmacodynamic signatures in solid tumors remains challenging. Here, we demonstrate that label-free quantification of histone acetylation-specific mass shifts by matrix-assisted laser desorption ionization (MALDI) mass spectrometry biotyping can be used for measurement of cellular potency of histone deacetylase inhibitors in intact cells. Furthermore, we employ MALDI mass spectrometry imaging of these mass shifts to visualize the spatiotemporal distribution of acetylated histones and thus the tumor-selective pharmacodynamic responses in a mouse model of gasterointestinal cancer. Taken together, our study suggests that the monitoring of drug-induced mass shifts in protein ion intensity fingerprints or images may be a powerful analytical tool in pharmacology and drug discovery.
After the acute treatment phase, breast cancer patients often experience low quality of life and impaired mental health, which could potentially be improved by offering cognitive behavioural therapy ...(CBT) and addressing exercise and dietary habits. However, CBT and other behavioural interventions are rarely available beyond the acute treatment phase. Internet-based interventions could bridge such treatment gaps, given their flexibility and scalability. In this randomized controlled trial (RCT), we investigated the effects of such an intervention ("Optimune") over three months.
This RCT included 363 female breast cancer survivors (age range = 30-70), recruited from the community, who had completed the active treatment phase. Inclusion criteria were: breast cancer diagnosis less than 5 years ago and acute treatment completion at least 1 month ago. Participants were randomly assigned to (1) an intervention group (n = 181), in which they received care as usual (CAU) plus 12-month access to Optimune immediately after randomization, or (2) a control group (n = 182), in which they received CAU and Optimune after a delay of 3 months. Primary endpoints were quality of life (QoL), physical activity, and dietary habits at three months. We hypothesized that intervention group participants would report better QoL, more physical activity, and improved dietary habits after 3 months.
Intention-to-treat (ITT) analyses revealed significant effects on QoL (d = 0.27, 95% CI: 0.07-0.48) and dietary habits (d = 0.36, 95% CI: 0.15-0.56), but the effect on physical exercise was not significant (d = 0.30; 95% CI: 0.10-0.51).
These findings suggest the effectiveness of Optimune, a new CBT-based Internet intervention for breast cancer survivors, in facilitating improvements in quality of life and dietary habits. Efforts to disseminate this intervention more broadly may be warranted.
ClinicalTrials.gov, NCT03643640. Registered August 23rd 2018, https://clinicaltrials.gov/ct2/show/NCT03643640.
Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease often causing decreased quality of life, social withdrawal and unemployment. Studies examining the effect of pharmacological ...interventions demonstrated only minor effects, whereas non-pharmacological interventions as e.g. patient education programs have shown promising results.
We aim to systematically review the literature to determine the effect of patient education programs on fatigue in MS.
We conducted a comprehensive search in PubMed for randomized controlled trials (RCTs) that evaluated patient education programs for MS-related fatigue. Interventions evaluating physical exercise and/or pharmacological treatments were not included. Meta-analyses were performed using the generic inverse variance method.
The search identified 856 citations. After full-text screening we identified ten trials that met the inclusion criteria. Data of 1021 participants were analyzed. Meta-analyses showed significant positive effects on fatigue severity (weighted mean difference -0.43; 95% CI -0.74 to -0.11) and fatigue impact (-0.48; -0.82 to -0.15), but not for depression (-0.35 (95% CI -0.75 to 0.05; p = 0.08). Essentially, we categorized patient education programs into two types: firstly, interventions with a focus on cognitive-behavioral therapy (CBT) and secondly, interventions that teach patients ways of managing daily fatigue. CBT-based approaches seem to generate better results in reducing patient-reported fatigue severity. Analysing CBT studies only, the pooled weighted mean difference for fatigue severity was -0.60 (95% CI; -1.08 to -0.11) compared to non-CBT approaches (-0.20; 95% CI; -0.60 to -0.19). Furthermore, interventions employing an individual approach seem to reduce fatigue more effectively than group-based approaches (pooled weighted mean difference for fatigue severity in face-to-face studies was -0.80 (95% CI; -1.13 to -0.47) compared to group-based studies with -0,17 (95% CI; -0,39 to 0,05). Longest follow-up data were available for 12 months post-intervention.
Overall, included studies demonstrated that educational programs and especially CBT-based approaches have a positive effect on reducing fatigue. Since fatigue is thought to be a multidimensional symptom, it should be treated with a multidimensional approach targeting patients' behavior as well as their emotional and mental attitude towards fatigue. However, the clinical relevance of the treatment effects i.e. the relevance for patients' daily functioning remains unclear and long-term effects, i.e. sustainability of effects beyond 6 months, warrants further work. This review has been registered in the PROSPERO international prospective register of systematic reviews data base (Registration number: CRD42014014224).
Objective: To examine the effectiveness of an Internet intervention for depression with a randomized, controlled trial in a large sample of adults recruited from the United States. Method: The ...current study examines the effectiveness of Deprexis, an Internet treatment for depression that was provided with relatively minimal support. There were 376 treatment-seeking adults (mean age = 32 years; 74% female; 77% Caucasian, 7% Asian, 7% multiple races, 4% African American, and 11% Hispanic/Latino) with elevated depression (Quick Inventory of Depressive Symptoms-Self-Report QIDS-SR > = 10) who were randomized to receive an 8-week course of treatment immediately (n = 285) or after an 8-week delay (n = 91; i.e., waitlist control). Results: Intention-to-treat analyses indicated that treatment was associated with greater reduction in self-reported symptoms of depression (effect size d = .80) and 12 times greater likelihood of experiencing at least 50% symptom improvement compared with waitlist control. Similar effects were observed for several secondary outcomes, such as interviewer-rated depression symptoms, well-being, and depression-related disability. Treatment effects for symptoms of social anxiety, panic, and traumatic intrusions were relatively small. Conclusion: Results suggest that Deprexis can produce symptomatic improvement among depressed adults recruited from the United States. Additional research is needed that examines whether improvements are maintained over time and who is particularly likely to respond to this form of treatment.
What is the public health significance of this article?
This study suggests that a minimally supported and easily accessible internet intervention, known as Deprexis, can be an effective form of treatment compared with care as usual for adults with depression.
Depression is associated with immense suffering and costs, and many patients receive inadequate care, often because of the limited availability of treatment. Web-based treatments may play an ...increasingly important role in closing this gap between demand and supply. We developed the integrative, Web-based program Deprexis, which covers therapeutic approaches such as behavioral activation, cognitive restructuring, mindfulness/acceptance exercises, and social skills training.
To evaluate the effectiveness of the Web-based intervention in a randomized controlled trial.
There were 396 adults recruited via Internet depression forums in Germany, and they were randomly assigned in an 80:20 weighted randomization sequence to either 9 weeks of immediate-program-access as an add-on to treatment-as-usual (N = 320), or to a 9-week delayed-access plus treatment-as-usual condition (N = 76). At pre- and post-treatment and 6-month follow-up, we measured depression (Beck Depression Inventory) as the primary outcome measure and social functioning (Work and Social Adjustment Scale) as the secondary outcome measure. Complete analyses and intention-to-treat analyses were performed.
Of 396 participants, 216 (55%) completed the post-measurement 9 weeks later. Available case analyses revealed a significant reduction in depression severity (BDI), Cohen's d = .64 (CI 95% = 0.33 - 0.94), and significant improvement in social functioning (WSA), Cohen's d = .64, 95% (CI 95% = 0.33 - 0.95). These improvements were maintained at 6-month follow-up. Intention-to-treat analyses confirmed significant effects on depression and social functioning improvements (BDI: Cohen's d = .30, CI 95% = 0.05 - 0.55; WSA: Cohen's d = .36, CI 95% = 0.10 - 0.61). Moreover, a much higher percentage of patients in the intervention group experienced a significant reduction of depression symptoms (BDI: odds ratio OR = 6.8, CI 95% = 2.90 - 18.19) and recovered more often (OR = 17.3, 95% CI 2.3 - 130). More than 80% of the users felt subjectively that the program had been helpful.
This integrative, Web-based intervention was effective in reducing symptoms of depression and in improving social functioning. Findings suggest that the program could serve as an adjunctive or stand-alone treatment tool for patients suffering from symptoms of depression.
The internet-based intervention Deprexis® has proven to be effective in improving overall depression severity. The current pragmatic randomized controlled trial included 1013 participants with mild ...to moderate symptomatology and aimed to identify the symptom-specific effects of the internet-based intervention Deprexis (intervention group) in comparison to care as usual (control group). All participants -in both conditions- were permitted to use any type of treatment. Of the nine considered symptoms (assessed with the Patient Health Questionnaire), seven showed larger improvements in the intervention condition relative to care as usual (effect sizes ranging from 0.15 to 0.31). No significant differences were found for the two other symptoms. In a next step, a network was estimated including treatment condition as well as changes in all nine symptoms. The resulting network suggests that four of the seven identified symptom-specific effects were direct, whereas the three other symptom-specific effects were indirect and could be explained by effects on other symptoms. Lastly, exploratory analyses showed that the intervention was more effective in improving overall depression severity for participants with higher scores on those four symptoms that were directly affected by the intervention; consequently, the network estimation techniques showed potential in precision psychiatry.
•Internet interventions are effective in improving overall depression severity.•The symptom-specific effectiveness is, however, never considered.•This study showed that the symptom-specific effects of the intervention differ.•Network estimation techniques were used to distinguish direct vs. indirect effects.•The techniques helped in identifying participants who were likely to benefit most.
Glycosphingolipids (GSL) have been associated with a variety of diseases, including cancer and autosomal dominant polycystic kidney disease (ADPKD). In contrast to glucosylceramide and gangliosides, ...alterations in complex neutral GSLs such as globotetraosylceramide (Gb4Cer) have not been investigated in ADPKD yet, and mass spectrometry analysis of Gb4Cer from tissue extracts remains challenging. To this end, we introduce PrimaDrop as an improved and widely applicable sample preparation method for automated matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) analysis of lipid extracts, which promotes homogeneous cocrystallization and enables relative quantification by indirect thin layer chromatography (TLC)–MALDI-time-of-flight (TOF)-MS against an internal bradykinin standard. Application of the method for detailed investigation of Gb4Cer isoforms in kidneys of an ADPKD rat model revealed increased levels of sphingoid base-containing isoforms in cystic kidneys, whereas changes were subtle for Gb4Cer-containing phytosphingoid bases. We furthermore established an absolute LC–ESI-MS/MS quantification method and demonstrate that absolute quantities of Gb4Cer correlate well with relative quantities obtained by indirect TLC–MALDI-TOF-MS. Taken together, our study proposes an effective sample preparation method for automated analysis of lipid extracts and TLC eluates and suggests that indirect high-performace (HP)TLC–MALDI-TOF-MS with automated data acquisition is a viable option for analysis of neutral glycosphingolipids and that Gb4Cer may play a role in the pathogenesis of ADPKD.
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