Prognostic Risk Factors in Randomized Clinical Trials of Face-to-Face and Internet-Based Psychotherapy for Depression: A Systematic Review and Meta-Regression Analysis.

Importance: Variables such as severe symptoms, comorbidity, and sociodemographic characteristics (eg, low educational attainment or unemployment) are associated with a poorer prognosis in adults treated for depressive symptoms. The exclusion of patients with a poor prognosis from RCTs is negatively associated with the generalizability of research findings. Objective: To compare the prognostic risk factors (PRFs) in patient samples of RCTs of face-to-face therapy (FTF) and internet-based therapy (IBT) for depression. Data Sources: PsycINFO, Cochrane CENTRAL, and reference lists of published meta-analyses were searched from January 1, 2000, to December 31, 2021. Study Selection: RCTs that compared FTF (individual or group therapy) and IBT (guided or self-guided interventions) against a control (waitlist or treatment as usual) in adults with symptoms of depression were included. Data Extraction and Synthesis: Data were extracted by 2 independent observers. The Cochrane revised risk-of-bias tool was used to assess the risk of bias. The study was preregistered with OSF Registries and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: The primary outcome was the standardized mean difference (Hedges g effect size) in depressive symptoms at treatment termination (assessed with standard patient self-report questionnaires), with a positive standardized mean difference indicating larger improvements in the intervention compared with those in the control group. Meta-regression analyses were adjusted for the type of control group. Three preregistered and 2 exploratory sensitivity analyses were conducted. A prognostic risk index (PROG) was created that calculated the sum of 12 predefined individual indicators, with scores ranging from 0 to 12 and higher scores indicating that a sample comprised patients with poorer prognoses. Results: This systematic review and meta-regression analysis identified 105 eligible RCTs that comprised 18 363 patients. In total, 48 studies (46%) examined FTF, and 57 studies (54%) examined IBT. The PROG was significantly higher in the RCTs of FTF than in the RCTs of IBT (FTF: mean [SD], 3.55 [1.75]; median [IQR], 3.5 [2.0-4.5]; IBT: mean [SD], 2.27 [1.66]; median [IQR], 2.0 [1.0-3.5]; z = -3.68, P < .001; Hedges g = 0.75; 95% CI, 0.36-1.15). A random-effects meta-regression analysis found no association of the PROG with the effect size. Sensitivity analyses with outliers excluded and accounting for risk of bias or small-study effects yielded mixed results on the association between the PROG and effect size. Conclusions and Relevance: The findings of this systematic review and meta-regression analysis suggest that samples of RCTs of FTF vs IBT differ with regard to PRFs. These findings have implications for the generalizability of the current evidence on IBT for depression. More RCTs of internet-based interventions with clinically representative samples are needed, and the reporting of PRFs must be improved.

Mental health challenges and digital platform opportunities in patients and families affected by pediatric neuromuscular diseases - experiences from Switzerland.

Receiving the diagnosis of a severe disease may present a traumatic event for patients and their families. To cope with the related challenges, digital interventions can be combined with traditional psychological support to help meet respective needs. We aimed to 1) discuss the most common consequences and challenges for resilience in Neuro Muscular Disease patients and family members and 2) elicit practical needs, concerns, and opportunities for digital platform use. We draw from findings of a transdisciplinary workshop and conference with participants ranging from the fields of clinical practice to patient representatives. Reported consequences of the severe diseases were related to psychosocial challenges, living in the nexus between physical development and disease progression, social exclusion, care-related challenges, structural and financial challenges, and non-inclusive urban design. Practical needs and concerns regarding digital platform use included social and professional support through these platforms, credibility and trust in online information, and concerns about privacy and informed consent. Furthermore, the need for safe, reliable, and expert-guided information on digital platforms and psychosocial and relationship-based digital interventions was expressed. There is a need to focus on a family-centered approach in digital health and social care and a further need in researching the suitability of digital platforms to promote resilience in the affected population. Our results can also inform city councils regarding investments in inclusive urban design allowing for disability affected groups to enjoy a better quality of life.

Challenges and best practices for digital unstructured data enrichment in health research: A systematic narrative review.

Digital data play an increasingly important role in advancing health research and care. However, most digital data in healthcare are in an unstructured and often not readily accessible format for research. Unstructured data are often found in a format that lacks standardization and needs significant preprocessing and feature extraction efforts. This poses challenges when combining such data with other data sources to enhance the existing knowledge base, which we refer to as digital unstructured data enrichment. Overcoming these methodological challenges requires significant resources and may limit the ability to fully leverage their potential for advancing health research and, ultimately, prevention, and patient care delivery. While prevalent challenges associated with unstructured data use in health research are widely reported across literature, a comprehensive interdisciplinary summary of such challenges and possible solutions to facilitate their use in combination with structured data sources is missing. In this study, we report findings from a systematic narrative review on the seven most prevalent challenge areas connected with the digital unstructured data enrichment in the fields of cardiology, neurology and mental health, along with possible solutions to address these challenges. Based on these findings, we developed a checklist that follows the standard data flow in health research studies. This checklist aims to provide initial systematic guidance to inform early planning and feasibility assessments for health research studies aiming combining unstructured data with existing data sources. Overall, the generality of reported unstructured data enrichment methods in the studies included in this review call for more systematic reporting of such methods to achieve greater reproducibility in future studies.

Human contact in internet-based interventions for depression: A pre-registered replication and meta-analysis of randomized trials.

Introduction: Internet-based self-help interventions have shown to be effective in the treatment of depression. Several meta-analyses indicated that human contact has a crucial impact on adherence and outcome. While most research focused on the role of guidance during interventions, a review by Andersson and Johansson (2012) suggested that contact before the intervention too may play an important role. Objective: We investigated the impact of the degree of contact in internet-based interventions (IBIs) for depression on outcome in adults suffering from elevated symptoms of depression. Methods: We conducted a preregistered meta-analysis (www.osf.io/4mzyd) and included trials comparing IBIs for depression against control conditions (treatment as usual [TAU] or waiting list [WL]) in patients with symptoms of unipolar depression searching the databases PsycINFO and Cochrane's Central Register of Controlled Trials (CENTRAL) limited to entries from EMBASE and PubMed. Following Andersson and Johansson (2012), contact before an intervention was defined as having had a diagnostic interview before the IBI, and contact during intervention was defined as having received guidance during the IBI. IBIs were grouped as providing (0) no contact, (1) contact before the IBI, (2) contact during the IBI, or (3) contact both before and during the IBI. The primary outcome was standardized mean difference (SMD) of the IBI and control in depressive symptoms at treatment termination. Secondary outcomes were study dropout and adherence to the IBI. Results: We included 56 eligible trials that randomized 13,335 patients to 75 internet-based intervention conditions and control groups (TAU in 23 trials, WL in 33 trials). In total, 44 trials (78.57 %) were judged to show some concerns or a high risk of bias. Overall heterogeneity was high regarding the primary outcome (I2s < 66 %) and even higher for secondary outcomes (I2s < 91 %). Degree of contact was a robust predictor of outcome and adherence in all pre-registered and exploratory analyses. We found the effect of the IBI to increase with higher degree of contact. However, in pair-wise contrasts, only IBIs offering both contact before and during the intervention (SMD = 0.573, 95 % CI: 0.437, 0.709) significantly outperformed interventions offering no contact (SMD = 0.224, 95 % CI: 0.090, 0.340). Conclusions: The results suggest that contact before and during an intervention increases the effects of IBIs. The combination of contact before and during the intervention seems to a pivotal role regarding adherence as well as treatment outcome for patients suffering from depression.

Genomic prediction with haplotype blocks in wheat.

Haplotype blocks might carry additional information compared to single SNPs and have therefore been suggested for use as independent variables in genomic prediction. Studies in different species resulted in more accurate predictions than with single SNPs in some traits but not in others. In addition, it remains unclear how the blocks should be built to obtain the greatest prediction accuracies. Our objective was to compare the results of genomic prediction with different types of haplotype blocks to prediction with single SNPs in 11 traits in winter wheat. We built haplotype blocks from marker data from 361 winter wheat lines based on linkage disequilibrium, fixed SNP numbers, fixed lengths in cM and with the R package HaploBlocker. We used these blocks together with data from single-year field trials in a cross-validation study for predictions with RR-BLUP, an alternative method (RMLA) that allows for heterogeneous marker variances, and GBLUP performed with the software GVCHAP. The greatest prediction accuracies for resistance scores for B. graminis, P. triticina, and F. graminearum were obtained with LD-based haplotype blocks while blocks with fixed marker numbers and fixed lengths in cM resulted in the greatest prediction accuracies for plant height. Prediction accuracies of haplotype blocks built with HaploBlocker were greater than those of the other methods for protein concentration and resistances scores for S. tritici, B. graminis, and P. striiformis. We hypothesize that the trait-dependence is caused by properties of the haplotype blocks that have overlapping and contrasting effects on the prediction accuracy. While they might be able to capture local epistatic effects and to detect ancestral relationships better than single SNPs, prediction accuracy might be reduced by unfavorable characteristics of the design matrices in the models that are due to their multi-allelic nature.

Psycholinguistic changes in the communication of adolescent users in a suicidal ideation online community during the COVID-19 pandemic.

Since the outbreak of the COVID-19 pandemic, increases in suicidal ideation and suicide attempts in adolescents have been registered. Many adolescents experiencing suicidal ideation turn to online communities for social support. In this retrospective observational study, we investigated the communication-language style, contents and user activity-in 7975 unique posts and 51,119 comments by N = 2862 active adolescent users in a large suicidal ideation support community (SISC) on the social media website reddit.com in the onset period of the COVID-19 pandemic. We found significant relative changes in language style markers for hopelessness such as negative emotion words (+ 10.00%) and positive emotion words (- 3.45%) as well as for social disengagement such as social references (- 8.63%) and 2nd person pronouns (- 33.97%) since the outbreak of the pandemic. Using topic modeling with Latent Dirichlet Allocation (LDA), we identified significant changes in content for the topics Hopelessness (+ 23.98%), Suicide Methods (+ 17.11%), Social Support (- 14.91%), and Reaching Out to users (- 28.97%). Changes in user activity point to an increased expression of mental health issues and decreased engagement with other users. The results indicate a potential shift in communication patterns with more adolescent users expressing their suicidal ideation rather than relating with or supporting other users during the COVID-19 pandemic.

Digital Platform Uses for Help and Support Seeking of Parents With Children Affected by Disabilities: Scoping Review.

BACKGROUND: Receiving a diagnosis that leads to severe disability in childhood can cause a traumatic experience with long-lasting emotional stress for patients and family members. In recent decades, emerging digital technologies have transformed how patients or caregivers of persons with disabilities manage their health conditions. As a result, information (eg, on treatment and resources) has become widely available to patients and their families. Parents and other caregivers can use digital platforms such as websites or social media to derive social support, usually from other patients and caregivers who share their lived experiences, challenges, and successes on these platforms. However, gaps remain in our understanding of platforms that are most frequently used or preferred among parents and caregivers of children with disabilities. In particular, it is not clear what factors primarily drive or discourage engagement with these digital tools and what the main ethical considerations are in relation to these tools. OBJECTIVE: We aimed to (1) identify prominent digital platforms used by parents or caregivers of children with disabilities; (2) explore the theoretical contexts and reasons for digital platform use, as well as the experiences made with using these platforms reported in the included studies; and (3) identify any privacy and ethical concerns emerging in the available literature in relation to the use of these platforms. METHODS: We conducted a scoping review of 5 academic databases of English-language articles published within the last 10 years for diseases with childhood onset disability and self-help or parent/caregiver-led digital platforms. RESULTS: We identified 17 papers in which digital platforms used by parents of affected children predominantly included social media elements but also search engines, health-related apps, and medical websites. Information retrieval and social support were the main reasons for their utilization. Nearly all studies were exploratory and applied either quantitative, qualitative, or mixed methods. The main ethical concerns for digital platform users included hampered access due to language barriers, privacy issues, and perceived suboptimal advice (eg, due to missing empathy of medical professionals). Older and non-college-educated individuals and ethnic minorities appeared less likely to access information online. CONCLUSIONS: This review showed that limited scientifically sound knowledge exists on digital platform use and needs in the context of disabling conditions in children, as the evidence consists mostly of exploratory studies. We could highlight that affected families seek information and support from digital platforms, as health care systems seem to be insufficient for satisfying knowledge and support needs through traditional channels.

Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease.

SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host's innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections.

The RIPI-f (Reporting Integrity of Psychological Interventions delivered face-to-face) checklist was developed to guide reporting of treatment integrity in face-to-face psychological interventions.

OBJECTIVES: Intervention integrity is the degree to which the study intervention is delivered as intended. This article presents the RIPI-f checklist (Reporting Integrity of Psychological Interventions delivered face-to-face) and summarizes its development methods. RIPI-f proposes guidance for reporting intervention integrity in evaluative studies of face-to-face psychological interventions. STUDY DESIGN AND SETTING: We followed established procedures for developing reporting guidelines. We examined 56 documents (reporting guidelines, bias tools, and methodological guidance) for relevant aspects of face-to-face psychological intervention integrity. Eighty four items were identified and grouped as per the template for intervention description and replication (TIDieR) domains. Twenty nine experts from psychology and medicine and other scholars rated the relevance of each item in a single-round Delphi survey. A multidisciplinary panel of 11 experts discussed the survey results in three online consensus meetings and drafted the final version of the checklist. RESULTS: We propose RIPI-f, a checklist with 50 items. Our checklist enhances TIDieR with important extensions, such as therapeutic alliance, provider's allegiance, and the adherence of providers and participants. CONCLUSION: RIPI-f can improve the reporting of face-to-face psychological interventions. The tool can help authors, researchers, systematic reviewers, and guideline developers. We suggest using RIPI-f alongside other reporting guidelines.

Cytopathic SARS-CoV-2 screening on VERO-E6 cells in a large-scale repurposing effort.

Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.

Intensity of Treatment as Usual and Its Impact on the Effects of Face-to-Face and Internet-Based Psychotherapy for Depression: A Preregistered Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Treatment as usual (TAU) is the most frequently used control group in randomized trials of psychotherapy for depression. Concerns have been raised that the heterogeneity of treatments in TAU leads to biased estimates of psychotherapy efficacy and to an unclear difference between TAU and control groups like waiting list (WL). OBJECTIVE: We investigated the impact of control group intensity (i.e., amount and degree to which elements of common depression treatments are provided) on the effects of face-to-face and internet-based psychotherapy for depression. METHODS: We conducted a preregistered meta-analysis (www.osf.io/4mzyd). We included trials comparing psychotherapy with TAU or WL in patients with symptoms of unipolar depression. Six indicators were used to assess control group intensity. PRIMARY OUTCOME: Standardized mean difference (SMD) of psychotherapy and control in depressive symptoms at treatment termination. RESULTS: We included 89 trials randomizing 14,474 patients to 113 psychotherapy conditions and 89 control groups (TAU in 42 trials, WL in 47 trials). Control group intensity predicted trial results in preregistered (one-sided ps < 0.042) and exploratory analyses. Psychotherapy effects were significantly smaller (one-sided p = 0.002) in trials with higher intensity TAU (SMD = 0.324, CI 0.209 to 0.439) than in trials with lower intensity TAU (SMD = 0.628, CI 0.455 to 0.801). Psychotherapy effects against lower intensity TAU did not differ from effects against WL (two-sided p = 0.663). CONCLUSIONS: Our results suggest that variation in TAU intensity impacts the outcome of trials. More scrutiny in the design of control groups for clinical trials is recommended.

Changes in Language Style and Topics in an Online Eating Disorder Community at the Beginning of the COVID-19 Pandemic: Observational Study.

BACKGROUND: COVID-19 has affected individuals with lived experience of eating disorders (EDs), with many reporting higher psychological distress, higher prevalence of ED symptoms, and compensatory behaviors. The COVID-19 pandemic and the health and safety measures taken to contain its spread also disrupted routines and reduced access to familiar coping mechanisms, social support networks, and health care services. Social media and the ED communities on social media platforms have been an important source of support for individuals with EDs in the past. So far, it is unknown how discussions in online ED communities changed as offline support networks were disrupted and people spent more time at home in the first months of the COVID-19 pandemic. OBJECTIVE: The aim of this study is to identify changes in language content and style in an online ED community during the initial onset of the COVID-19 pandemic. METHODS: We extracted posts and their comments from the ED community on the social media website Reddit and concatenated them to comment threads. To analyze these threads, we applied top-down and bottom-up language analysis methods based on topic modeling with latent Dirichlet allocation and 13 indicators from the Linguistic Inquiry and Word Count program, respectively. Threads were split into prepandemic (before March 11, 2020) and midpandemic (after March 11, 2020) groups. Standardized mean differences were calculated to estimate change between pre- and midpandemic threads. RESULTS: A total of 17,715 threads (n=8772, 49.5% prepandemic threads; n=8943, 50.5% midpandemic threads) were extracted from the ED community and analyzed. The final topic model contained 21 topics. CIs excluding zero were found for standardized mean differences of 15 topics and 9 Linguistic Inquiry and Word Count categories covering themes such as ED symptoms, mental health, treatment for EDs, cognitive processing, social life, and emotions. CONCLUSIONS: Although we observed a reduction in discussions about ED symptoms, an increase in mental health and treatment-related topics was observed at the same time. This points to a change in the focus of the ED community from promoting potentially harmful weight loss methods to bringing attention to mental health and treatments for EDs. These results together with heightened cognitive processing, increased social references, and reduced inhibition of negative emotions detected in discussions indicate a shift in the ED community toward a pro-recovery orientation.

Mental Health Applications for Primary and Secondary Prevention of Common Mental Disorders: Attitudes of German Employees.

Background: Web-based and mobile mental health applications for the prevention and treatment of common mental disorders (CMDs) are on the rise. Under certain circumstances they have proved to be effective for a range of conditions (e.g., depression). Objective: There is not sufficient evidence regarding the benefits and barriers especially for mobile phone apps and for programs in the field of primary prevention. Studies on the acceptance of potential users of mental health apps yielded mixed outcomes. In a large survey we investigated the attitudes of employees toward mental health apps and various traditional mental health services. Our main research question in this contribution focuses on the acceptance of apps compared to other measures and the moderating influence of individual characteristics. Methods: The standardized survey was completed by members of an online access panel with different job types. A set of 33 self-developed items, including three questions on e-health, captured the perceived relevance of prevention at the (A) occupational, (B) individual, and (C) societal level. On the basis of an exploratory factor analysis, mean scores for mapping seven (sub-)dimensions were constructed and compared using the Wilcoxon test. The influence of potential predictors was analyzed in linear regression models. Results: The data of 610 respondents were analyzed (response rate 75%). Support from mental health applications was rated significantly less important compared to all other dimensions at the levels (A) to (C). Respondents were more likely to use mental health apps if they felt literate with electronic devices, perceived a high relevance of work-related demands as causal factors for CMDs, stated they would be ashamed of having a CMD, and would be willing to begin psychotherapy if recommended. Discussion and Conclusions: The results confirm the critical attitudes of potential mental health app users found in other studies. Since users with a negative attitude toward e-health might have a higher risk for dropout and non-adherence as well as lower intervention effects, well-designed educational strategies should be carried out beforehand.

High-Throughput Screening for CEBPD-Modulating Compounds in THP-1-Derived Reporter Macrophages Identifies Anti-Inflammatory HDAC and BET Inhibitors.

This study aimed to identify alternative anti-inflammatory compounds that modulate the activity of a relevant transcription factor, CCAAT/enhancer binding protein delta (C/EBPδ). C/EBPδ is a master regulator of inflammatory responses in macrophages (Mϕ) and is mainly regulated at the level of CEBPD gene transcription initiation. To screen for CEBPD-modulating compounds, we generated a THP-1-derived reporter cell line stably expressing secreted alkaline phosphatase (SEAP) under control of the defined CEBPD promoter (CEBPD::SEAP). A high-throughput screening of LOPAC®1280 and ENZO®774 libraries on LPS- and IFN-γ-activated THP-1 reporter Mϕ identified four epigenetically active hits: two bromodomain and extraterminal domain (BET) inhibitors, I-BET151 and Ro 11-1464, as well as two histone deacetylase (HDAC) inhibitors, SAHA and TSA. All four hits markedly and reproducibly upregulated SEAP secretion and CEBPD::SEAP mRNA expression, confirming screening assay reliability. Whereas BET inhibitors also upregulated the mRNA expression of the endogenous CEBPD, HDAC inhibitors completely abolished it. All hits displayed anti-inflammatory activity through the suppression of IL-6 and CCL2 gene expression. However, I-BET151 and HDAC inhibitors simultaneously upregulated the mRNA expression of pro-inflammatory IL-1ß. The modulation of CEBPD gene expression shown in this study contributes to our understanding of inflammatory responses in Mϕ and may offer an approach to therapy for inflammation-driven disorders.

A SARS-CoV-2 cytopathicity dataset generated by high-content screening of a large drug repurposing collection.

SARS-CoV-2 is a novel coronavirus responsible for the COVID-19 pandemic, in which acute respiratory infections are associated with high socio-economic burden. We applied high-content screening to a well-defined collection of 5632 compounds including 3488 that have undergone previous clinical investigations across 600 indications. The compounds were screened by microscopy for their ability to inhibit SARS-CoV-2 cytopathicity in the human epithelial colorectal adenocarcinoma cell line, Caco-2. The primary screen identified 258 hits that inhibited cytopathicity by more than 75%, most of which were not previously known to be active against SARS-CoV-2 in vitro. These compounds were tested in an eight-point dose response screen using the same image-based cytopathicity readout. For the 67 most active molecules, cytotoxicity data were generated to confirm activity against SARS-CoV-2. We verified the ability of known inhibitors camostat, nafamostat, lopinavir, mefloquine, papaverine and cetylpyridinium to reduce the cytopathic effects of SARS-CoV-2, providing confidence in the validity of the assay. The high-content screening data are suitable for reanalysis across numerous drug classes and indications and may yield additional insights into SARS-CoV-2 mechanisms and potential therapeutic strategies.

Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen.

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro and have identified 62 additional compounds with IC50 values below 1 µM and profiled their selectivity toward chymotrypsin and 3CL-Pro from the Middle East respiratory syndrome virus. A subset of eight inhibitors showed anticytopathic effect in a Vero-E6 cell line, and the compounds thioguanosine and MG-132 were analyzed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

Stereotyping in the digital age: Male language is "ingenious", female language is "beautiful" - and popular.

The huge power for social influence of digital media may come with the risk of intensifying common societal biases, such as gender and age stereotypes. Speaker's gender and age also behaviorally manifest in language use, and language may be a powerful tool to shape impact. The present study took the example of TED, a highly successful knowledge dissemination platform, to study online influence. Our goal was to investigate how gender- and age-linked language styles-beyond chronological age and identified gender-link to talk impact and whether this reflects gender and age stereotypes. In a pre-registered study, we collected transcripts of TED Talks along with their impact measures, i.e., views and ratios of positive and negative talk ratings, from the TED website. We scored TED Speakers' (N = 1,095) language with gender- and age-morphed language metrics to obtain measures of female versus male, and younger versus more senior language styles. Contrary to our expectations and to the literature on gender stereotypes, more female language was linked to higher impact in terms of quantity, i.e., more talk views, and this was particularly the case among talks with a lot of views. Regarding quality of impact, language signatures of gender and age predicted different types of positive and negative ratings above and beyond main effects of speaker's gender and age. The differences in ratings seem to reflect common stereotype contents of warmth (e.g., "beautiful" for female, "courageous" for female and senior language) versus competence (e.g., "ingenious", "informative" for male language). The results shed light on how verbal behavior may contribute to stereotypical evaluations. They also illuminate how, within new digital social contexts, female language might be uniquely rewarded and, thereby, an underappreciated but highly effective tool for social influence. WC = 286 (max. 300 words).

Discovery of a benzothiophene-flavonol halting miltefosine and antimonial drug resistance in Leishmania parasites through the application of medicinal chemistry, screening and genomics.

Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9 µM for Leishmania infantum, 3.4 µM for L. donovani, 6.7 µM for L. major), Trypanosoma cruzi (EC50 7.5 µM) and T. brucei (EC50 0.8 µM). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2 h; per os (PO): 46.9 h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.

Antidepressant prescription practice and related factors in Switzerland: a cross-sectional analysis of health claims data.

BACKGROUND: The aim of the study was to examine the prevalence of and factors associated with antidepressant (AD) prescriptions in order to draw a comprehensive picture of prescribing practices in Switzerland. METHOD: We conducted a population-based, cross-sectional descriptive study using a large Swiss healthcare claims database, covering approximately 13% of the Swiss population. AD prescription was determined by identifying patients (N = 105,663) with health claims data of at least 1 AD prescription in the year 2016. AD medication was identified using ATC-codes classified by the World Health Organisation. Univariate, bivariate and multivariate analyses using logistic regression were performed. RESULTS: The extrapolated 1-year prevalence of AD prescription was 8.7% (95% CI, 8.7-8.8) with two thirds of AD recipients being female and the average age being 59 years (SD = 19.1). The regional distribution of prescription rates varied between cantons and ranged from 6.5 to 11.7%. Logistic regression revealed higher prescription rates among females compared to males (OR: 1.52) and an increased probability of AD prescription by age up until 54 years (OR: 2.25) and ≥ 85 years (OR: 2.32). Comorbidity is associated with higher odds (OR: 3.26 with 1-2 comorbidities) and enrollment in a managed care plan (compared to standard care) with lower odds for an AD prescription (OR: 0.85). CONCLUSION: This study is the first in Switzerland to describe the prevalence of and factors associated with AD prescription based on a large health claims database reflecting routine care. The results provide important information about regional variation, prescription source, and potential over-prescription in the treatment of depressive disorders.