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Amphibians represent a diverse group of tetrapods, marked by deep divergence times between their three systematic orders and families. Studying amphibian biology through the genomics lens increases our understanding of the features of this animal class and that of other terrestrial vertebrates. The need for amphibian genomic resources is more urgent than ever due to the increasing threats to this group. Amphibians are one of the most imperiled taxonomic groups, with approximately 41% of species threatened with extinction due to habitat loss, changes in land use patterns, disease, climate change, and their synergistic effects. Amphibian genomic resources have provided a better understanding of ontogenetic diversity, tissue regeneration, diverse life history and reproductive modes, anti-predator strategies, and resilience and adaptive responses. They also serve as essential models for studying broad genomic traits, such as evolutionary genome expansions and contractions, as they exhibit the widest range of genome sizes among all animal taxa and possess multiple mechanisms of genetic sex determination. Despite these features, genome sequencing of amphibians has significantly lagged behind that of other vertebrates, primarily due to the challenges of assembling their large, repeat-rich genomes and the relative lack of societal support. The emergence of long-read sequencing technologies, combined with advanced molecular and computational techniques that improve scaffolding and reduce computational workloads, is now making it possible to address some of these challenges. To promote and accelerate the production and use of amphibian genomics research through international coordination and collaboration, we launched the Amphibian Genomics Consortium (AGC, https://mvs.unimelb.edu.au/amphibian-genomics-consortium ) in early 2023. This burgeoning community already has more than 282 members from 41 countries. The AGC aims to leverage the diverse capabilities of its members to advance genomic resources for amphibians and bridge the implementation gap between biologists, bioinformaticians, and conservation practitioners. Here we evaluate the state of the field of amphibian genomics, highlight previous studies, present challenges to overcome, and call on the research and conservation communities to unite as part of the AGC to enable amphibian genomics research to leap to the next level.

Abstract Amphibians represent a diverse group of tetrapods, marked by deep divergence times between their three systematic orders and families. Studying amphibian biology through the genomics lens increases our understanding of the features of this animal class and that of other terrestrial vertebrates. The need for amphibian genomic resources is more urgent than ever due to the increasing threats to this group. Amphibians are one of the most imperiled taxonomic groups, with approximately 41% of species threatened with extinction due to habitat loss, changes in land use patterns, disease, climate change, and their synergistic effects. Amphibian genomic resources have provided a better understanding of ontogenetic diversity, tissue regeneration, diverse life history and reproductive modes, anti-predator strategies, and resilience and adaptive responses. They also serve as essential models for studying broad genomic traits, such as evolutionary genome expansions and contractions, as they exhibit the widest range of genome sizes among all animal taxa and possess multiple mechanisms of genetic sex determination. Despite these features, genome sequencing of amphibians has significantly lagged behind that of other vertebrates, primarily due to the challenges of assembling their large, repeat-rich genomes and the relative lack of societal support. The emergence of long-read sequencing technologies, combined with advanced molecular and computational techniques that improve scaffolding and reduce computational workloads, is now making it possible to address some of these challenges. To promote and accelerate the production and use of amphibian genomics research through international coordination and collaboration, we launched the Amphibian Genomics Consortium (AGC, https://mvs.unimelb.edu.au/amphibian-genomics-consortium ) in early 2023. This burgeoning community already has more than 282 members from 41 countries. The AGC aims to leverage the diverse capabilities of its members to advance genomic resources for amphibians and bridge the implementation gap between biologists, bioinformaticians, and conservation practitioners. Here we evaluate the state of the field of amphibian genomics, highlight previous studies, present challenges to overcome, and call on the research and conservation communities to unite as part of the AGC to enable amphibian genomics research to “leap” to the next level.

Abstract Background The German multicenter research consortium BipoLife aims to investigate the mechanisms underlying bipolar disorders. It focuses in particular on people at high risk of developing the disorder and young patients in the early stages of the disease. Functional and structural magnetic resonance imaging (MRI) data was collected in all participating centers. The collection of neuroimaging data in a longitudinal, multicenter study requires the implementation of a comprehensive quality assurance (QA) protocol. Here, we outline this protocol and illustrate its application within the BipoLife consortium. Methods The QA protocol consisted of (1) a training of participating research staff, (2) regular phantom measurements to evaluate the MR scanner performance and its temporal stability across the course of the study, and (3) the assessment of the quality of human MRI data by evaluating a variety of image metrics (e.g., signal-to-noise ratio, ghosting level). In this article, we will provide an overview on these QA procedures and show exemplarily the influence of its application on the results of standard neuroimaging analysis pipelines. Discussion The QA protocol helped to characterize the various MR scanners, to record their performance over the course of the study and to detect possible malfunctions at an early stage. It also assessed the quality of the human MRI data systematically to characterize its influence on various analyses. Furthermore, by setting up and publishing this protocol, we define standards that must be considered when analyzing data from the BipoLife consortium. It further promotes a systematic evaluation of data quality and a definition of subject inclusion criteria. In the long term, it will help to increase the chance of achieving clinically relevant results.

Burr and film formation occurring when punching polycarbonate/ acrylonitrile butadiene styrene (PC/ABS) cable ducts is a common problem during manufacturing of cable ducts. However, little knowledge on base materials, their thermal and mechanical behavior as well as their initial processing and finally behavior during cable duct manufacturing is available. Therefore, to improve process reliability and gain knowledge on mechanical and failure behavior necessary initial investigations focus on cable duct usage, different geometric types, polymer materials and the punching process itself. Optical analysis on punched PC/ABS cable duct with burr and film formation and corresponding punch led to definition of the test tool’s geometry for subsequent tests. Since the punching process directly influences burr and film formation, it was necessary to design a demo-tool to observe the burr and film origin. Tensile tests at different test speeds focus on in-situ mechanical behavior using coupons taken from industrial cable ducts made of mineral reinforced polycarbonate (PC) and PC/ABS including further additives that are generally used in industry. First results indicate that higher test speeds appear to reduce the influence of the different admixtures on the elongation behavior of PC based materials.

Abstract Background Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

BackgroundMindfulness-based interventions are promising psychological treatment approaches that may have more substantial long-lasting intervention effects than cognitive behavioral therapy when treating individuals with early psychosis. A pilot study analyzed mindfulness-based inpatient group therapy’s feasibility and potential efficacy (Feel-Good).ObjectiveThis paper explores the subjective experiences of participants in the Feel-Good inpatient therapy group to gain insight into the possible changes brought about by the mindfulness-based intervention.MethodsA semi-structured change interview was used to examine the experience of ten participants who participated in the Feel-Good intervention and the additional qualitative assessment. The interviews were conducted 16 weeks after the Feel-Good group ended (16-week Follow-Up). Interviews were transcribed verbatim and analyzed using thematic analysis.ResultsThe analysis generated five themes—one about personal changes brought about by the Feel-Good group, three about the group therapy experience, and one about wishes/modification suggestions to change and improve the Feel-Good group. The findings suggested that the Feel-Good group was perceived as very helpful, leading to numerous changes in one’s overall well-being and relation to emotions. However, patients recommended a more directive therapeutic style and reduced time required for study assessments.ConclusionGathering qualitative insight from participants on the Feel-Good intervention revealed meaningful insight into patients’ experience of change processes. In addition, participant suggestions help to improve the intervention and study design to increase therapy attendance rates and treatment satisfaction, potentially increasing treatment effectiveness in the future.Clinical trial registrationClinicalTrials.gov, identifier NCT04592042.

Summary: A growing number of studies have applied evolutionary and ecological principles to understanding cancer. However, few such studies have examined whether phenotypic plasticity––the ability of a single individual or genome to respond differently to different environmental circumstances––can impact the origin and spread of cancer. Here, we propose the adaptive horizontal transmission hypothesis to explain how flexible decision-making by selfish genetic elements can cause them to spread from the genome of their original host into the genomes of other hosts through the evolution of transmissible cancers. Specifically, we hypothesize that such cancers appear when the likelihood of successful vertical transmission is sufficiently low relative to the likelihood of successful horizontal transmission. We develop an evolutionary optimization model of this hypothesis, highlight empirical findings that support it, and offer suggestions for future research. Generally, phenotypically plastic selfish genetic elements might play an important role in the evolution of transmissible cancers.

BackgroundThe Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score".MethodsThe COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed.ResultsFrom >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex.ConclusionsCOH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health.

This study focuses on developing an experimental setup to investigate the Selective Melt Dispersion (SMD), a Directed Energy Deposition (DED) process. SMD as a means of in-process joining (IPJ) aims to integrate components and assemblies during additive manufacturing, combining the advantages of various processes for eco-friendly and economical resource utilization. The research initially analyzed DED systems and defined requirements for subsystems and the overall system. Critical subsystems, including the energy source, material feed, and others, were sequentially developed, and a proof of concept involved building 20 stacked welded tracks, validated through micrograph analysis. The study concludes by evaluating and discussing the fulfillment of the defined requirements. The system comprises a centrally arranged vibration-assisted powder feed; a laterally arranged laser incidence at a 45° angle; a kinematic structure where all axes are arranged on the workpiece, so the powder supply does not require movement; and a shield gas supply.

We hypothesized that pre-consult patient education videos can improve patient understanding about their diagnosis, lead to high satisfaction and low distress. In this pilot study, we developed a patient education video curriculum for patients with newly-diagnosed anal cancer. Comprehension of key content was evaluated by comparing pre- and post-test scores. Patient satisfaction scores were collected. Patient distress scores (0–10) were collected at the beginning of their consult visit prior to seeing the physician. We found that patient education videos prior to consult improved patient understanding, resulted in high patient satisfaction, and low patient distress at the time of consult.

Audience: This is a lecture paired with facilitated small group sessions and is targeted towards emergency medicine residents and physicians.Background:The enneagram is a well-established and popular personality theory that asserts that there are nine basic personality types, and that each enneagram type, 1-9, operates from a basic fear and a basic desire that produces predictable behavioral patterns and preferences.1-2 The enneagram has long been used as a tool to enhance self-awareness and to better understand internal defenses and reactions,3-5and as such, it has been increasingly utilized to enhance self-growth and development in the fields of education, parenting, and business.6-7 While some studies have used the enneagram as a tool to predict natural empathy or stress levels of those in the medical field, particularly in nursing and medical school students,8-9 little has been published on the use of the enneagram as a tool to enhance self-awareness, leadership, and teamwork in the medical field.  Emergency medicine is a specialty in which residents and physicians must not only be self-aware but must also be attuned to the dynamics of their healthcare team in order to succeed. We believe that the enneagram is the ideal tool to enhance these crucial skills.Educational Objectives:The primary aim of this session was to enhance participants’ self-awareness by identifying their enneagram type and therefore their predictable behavioral patterns.  The secondary aim was to discuss strategies to improve teamwork and physician team leadership by directly addressing the type’s strengths and weaknesses in these interactions.By the end of this session, the learner will be able to: 1) Self-identify with a primary enneagram personality type.  2) List the fears, desires, and motivations of the enneagram type.  3) Describe struggles in interacting with other disparate enneagram types. 4) Discuss strategies for success in facing conflict and interacting with other team members.Educational Methods:This lecture was designed to educate emergency department physicians and residents on the enneagram tool.  The introductory lecture takes about 20 minutes, and following this foundational presentation, learners split into small groups.  Small group sessions take an additional 20 minutes during which facilitators guide learners through a discussion on their enneagram type and the potential strengths and challenges that each type might face in professional situations.  This session was hosted during an Emergency Medicine Resident Education Conference.  Due to COVID-19 restrictions, the session was presented virtually on a synchronous video platform with small group breakout rooms.Research Methods:Following the session, the educational content was evaluated by our residents and faculty by a Likert reaction survey.  The survey assessed both the form and effectiveness of the delivery method and the impact of the content in the session.Results:A total of 17 responses with a mix of faculty and PGY years were collected after the session. In the post-session survey, 23% (6) of participants reported that the session was “moderately important in better understanding myself,” and 38.5% (4) of participants reported that the session was “quite important in better understanding myself.”  62% (11) of participants agreed or strongly agreed that the session helped them to understand their peers’ personalities and communication preferences.Discussion:Overall, this educational content and delivery in this format was well received and effective in enhancing residents’ understanding of themselves and their team’s personalities. Our residents and faculty engaged in insightful conversations around their own enneagram type and shared their successes and struggles in interacting with other enneagram types. At the end of the session, our participants left with not only greater self-awareness but also with an appreciation for the preferences and personalities of others on the medical team.Topics: Enneagram, leadership, teamwork, self-awareness, emotional intelligence.

Abstract THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for key signaling pathways known to regulate the transition from proliferative to neurogenic divisions during human corticogenesis. Together, these findings implicate altered RNA processing in the developmental biology of TIDS neuropathology.

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Abstract Background Global treatment budgets, i.e. predefined budgets for patients treated in hospital independent of the setting within the hospital, together with flexible and integrated treatment (FIT) have been introduced in some German psychiatric hospitals since 2013. We investigated pooled changes in inpatient, day-care, outpatient treatment, and continuity of care for patients with mental disorders in 12 FIT-hospitals. Methods We conducted a series of 12 controlled cohort studies regarding FIT hospitals using anonymized patient claims data from more than 70 German statutory health insurance funds. Each study compared one FIT-hospital to matched patients from equivalent non-FIT-hospitals (routine care). We included only those patients without treatment in the respective hospital within two years prior to first hospital treatment (either FIT or routine care). We contrasted results between the year prior to with the first and second year after patient’s first treatment (treatment continuity: only group comparison) using multivariate multi-level models. To approximate the difference-in-difference effect in the meta-analysis, we used the interaction terms group (FIT hospital vs. routine care) x time (year before vs. first or second patient year after study inclusion) in the Poisson models. Results The 12 studies included 36,069 patients with 2,358 patients from a Department of child and adolescent psychiatry. The pooled effect revealed a 5.1 days lower increase in inpatient treatment in FIT-hospitals during the first patient year compared to routine care. Results were statistically significant for adult care FIT-hospitals but not for child and adolescent FIT-hospitals. Utilization of day-care treatment increased more in most FIT-hospitals during the first year, while outpatient contacts increased in some and decreased in others. The odds of treatment continuity increased by 1.4 in FIT-hospitals compared to non-FIT-hospitals. Conclusions Global treatment budgets lead to the intended changes in mental health care in the majority of FIT-hospitals compared to routine care in this large real-world evidence study from Germany. For child and adolescent psychiatry, more evidence is needed to draw firm conclusions. Trial registration This study was registered in the database “Health Services Research Germany” (trial number: VVfD_EVA64_15_003713).

Abstract Background Data on resource use are frequently required for healthcare assessments. Studies on healthcare utilization (HCU) in individuals with mental disorders have analyzed both self-reports and administrative data. Source of data may affect the quality of analysis and compromise the accuracy of results. We sought to ascertain the degree of agreement between self-reports and statutory health insurance (SHI) fund claims data from patients with mental disorders. Methods Claims data from six German SHI and self-reports were obtained along with a cost-effectiveness analysis performed as a part of a controlled prospective multicenter cohort study conducted in 18 psychiatric hospitals in Germany (PsychCare), including patients with pre-defined psychiatric disorders. Self-reports were collected using the German adaption of the Client Sociodemographic and Service Receipt Inventory (CSSRI) questionnaire with a 6-month recall period. Data linkage was performed using a unique pseudonymized identifier. Missing responses were coded as non-use for all analyses. HCU was calculated for inpatient and outpatient care, day-care services, home treatment, and pharmaceuticals. Concordance was measured using Cohen’s Kappa (κ) and intraclass correlation coefficient (ICC). Regression approaches were used to investigate the effect of independent variables on the agreements. Results In total 274 participants (mean age 47.8 [SD = 14.2] years; 47.08% women) were included in the analysis. No significant differences were observed between the linked and unlinked patients in terms of baseline characteristics. Total agreements values were 63.9% (κ = 0.03; PABAK = 0.28) for outpatient contacts, 69.3% (κ = 0.25; PABAK = 0.39) for medication use, 81.0% (κ = 0.56; PABAK = 0.62) for inpatient days and 86.1% (κ = 0.67; PABAK = 0.72) for day-care services. There was varied quantitative agreement between data sources, with the poorest agreement for outpatient care (ICC [95% CI] = 0.22 [0.10–0.33]) and the best for psychiatric day-care services (ICC [95% CI] = 0.72 [0.66–0.78]). Marital status and time since first treatment positively affected the chance of agreement on utilization of outpatient services. Conclusions Although there were high levels of absolute agreement, the measures of concordance between administrative records and self-reports were generally minimal to moderate. Healthcare investigations should consider using linked or at least different data sources to estimate HCU for specific utilization areas, where unbiased information can be expected. Trial registration This study was part of the multi-center controlled PsychCare trial (German Clinical Trials Register No. DRKS00022535; Date of registration: 2020–10-02).

Wire arc additive manufacturing (WAAM) and laser-based powder bed fusion (L-PBF) are additive manufacturing (AM) processes that allow the manufacturing of complex part geometries. The manufacturing of AM parts does not result in high-quality functional surfaces; therefore, postprocessing such as milling is usually required. For L-PBF parts, the support structures and, for WAAM parts, the undulating surface are usually removed after AM processes. These two application-related cases are investigated in this work, with the conclusion that support structure milling and the milling of the surface of WAAM parts lead to the dimensionally increased wear of milling tools in comparison to milling of solid material.

Abstract Background Approximately 25% of so-called high utilizers of medical care are estimated to suffer from depression. A large proportion of these individuals remain undiagnosed and untreated. This study aims to examine the effects of a systematic screening and collaborative treatment program on depression severity in small primary care practices of the German outpatient health care system. Method High utilizers of primary care who screened positive for depressive symptoms on the Brief Psychiatric Health Questionnaire (B-PHQ) were further diagnosed using the DIA-X, a standardized diagnostic interview, performed by trained and supervised interviewers. Patients with major depression were randomized (cluster randomization by practice) to (a) a six-month treatment program of pharmacotherapy, standardized patient and provider education, and physician and patient counseling or (b) six months of usual medical care. All subjects were followed for a 12-month observation period using the 17-item Hamilton Depression Rating scale (HAMD-17) rated by the treating physicians and the B-PHQ-9 rated by the patients. Results A total of 63 high utilizer patients were included in the trial (17 male, 46 female), 19 randomized to intervention, 44 to usual care. The mean age was 49.7 (SD 13.8). Most patients had one or more somatic co-morbidities. There was no significant difference in response (defined as a decrease in the HAMD-17 sum score of at least 50%) after six months of treatment (50% vs. 42%, p = 0.961, all analyses adjusted for age) and after 12 months of treatment (83% vs. 54%, p = 0.282) between groups. Using patient self-rating assessments with the B-PHQ-9 questionnaire the intervention was superior to treatment as usual at six months (83% vs. 16%, p = 0.000). There was no significant difference in HAMD-17 depression severity at six months between the groups (10.5 (SD 7.6) vs. 12.3 (SD 7.8), p = 0.718), but a trend at 12 months (4.7 (SD 8.0) vs. 11.2 (SD 7.4), p = 0.083). Again, using B-PHQ-9 sum scores depression severity was significantly lower in the intervention group than in the treatment as usual group after six months (6.4 (SD 5.2) vs. 11.5 (SD 5.8), p = 0.020), but not at 12 months (7.9 (SD 8.7) vs. 9.0 (SD 5.2), p = 0.858). Conclusion A systematic collaborating treatment program for depression in high utilizers in primary care showed superiority to treatment as usual only in terms of patients´ self-assessment but not according to physicians´ assessment. The advance of the intervention group at 6 months was lost after 12 months of follow-up. Overall, positive results from similar trials in the US health care systems could not be confirmed in a German primary care setting.

Abstract Background Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection. Discussion To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population. Summary We propose a list of measures to be taken to improve the external validity of double-blind, placebo-controlled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself.