Diffusion barriers imposed by tissue topology shape morphogen gradients.

Animals use a small number of morphogens to pattern tissues, but it is unclear how evolution modulates morphogen signaling range to match tissues of varying sizes. Here, we used single molecule imaging in reconstituted morphogen gradients and in tissue explants to determine that Hedgehog diffused extra-cellularly as a monomer, and rapidly transitioned between membrane-confined and -unconfined states. Unexpectedly, the vertebrate-specific protein SCUBE1 expanded Hedgehog gradients by accelerating the transition rates between states without affecting the relative abundance of molecules in each state. This observation could not be explained under existing models of morphogen diffusion. Instead, we developed a topology-limited diffusion model in which cell-cell gaps create diffusion barriers, and morphogens can only overcome the barrier by passing through a membrane-unconfined state. Under this model, SCUBE1 promotes Hedgehog secretion and diffusion by allowing it to transiently overcome diffusion barriers. This multiscale understanding of morphogen gradient formation unified prior models and discovered novel knobs that nature can use to tune morphogen gradient sizes across tissues and organisms.

HER2-targeted, enzyme-activated liposomes show superior in vivo efficacy in an ovarian cancer model.

Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes.

Patient satisfaction with clinical services provided by chiropractic students under supervision compared to licensed chiropractors: An observational study.

OBJECTIVE: This study investigated patient satisfaction with care provided by chiropractic students under supervision vs supervisors in a Danish hospital setting. METHODS: A cross-sectional observational study of patient satisfaction was conducted at the Spine Center of Southern Denmark, where chiropractic students from the University of Southern Denmark complete an 8-week internship in their final year of pregraduate training. Patients were assigned to students or supervisors based on administrative convenience (ie, natural allocation). Blinded from the aim of the study, all patients seen by a chiropractor (with or without a student) were invited to answer a questionnaire rating satisfaction with the clinical encounter. Results were analyzed using ordinal logistic regression with group allocation blinded by the investigators. RESULTS: Results from 438 participants (response rate = 88%) showed no significant difference in patient satisfaction between the student and supervisor groups. Although a small difference favored the supervisor group, the student group had a higher proportion of high and very high satisfaction combined. CONCLUSION: Satisfaction differed minimally whether patient care was administered by students under the supervision of a licensed chiropractor or by licensed chiropractors alone. Our findings suggest that patients do not negatively view student involvement in clinical consultations at a Danish hospital.

Detailed operational building data for six office rooms in Denmark: Occupancy, indoor environment, heating, ventilation, lighting and room control monitoring with sub-hourly temporal resolution.

The operational building data presented in this paper has been collected from six office rooms located in an office building (research and educational purposes) located on the main campus of Aalborg University in Denmark. The dataset consists of measurements of occupancy, indoor environmental quality, room-level and system-level heating, ventilation and lighting operation at a 5 min resolution. The indoor environmental quality and building system data were collected from the building management system. The occupancy level in each monitored room is established from the computer vision-based analysis of wall-mounted camera footage of each office. The number of people present in the room is estimated using the YOLOv5s image recognition algorithm. The present dataset can be used for occupancy analysis, indoor environmental quality investigations, machine learning, and model predictive control.

LeGenD: determining N-glycoprofiles using an explainable AI-leveraged model with lectin profiling.

Glycosylation affects many vital functions of organisms. Therefore, its surveillance is critical from basic science to biotechnology, including biopharmaceutical development and clinical diagnostics. However, conventional glycan structure analysis faces challenges with throughput and cost. Lectins offer an alternative approach for analyzing glycans, but they only provide glycan epitopes and not full glycan structure information. To overcome these limitations, we developed LeGenD, a lectin and AI-based approach to predict N-glycan structures and determine their relative abundance in purified proteins based on lectin-binding patterns. We trained the LeGenD model using 309 glycoprofiles from 10 recombinant proteins, produced in 30 glycoengineered CHO cell lines. Our approach accurately reconstructed experimentally-measured N-glycoprofiles of bovine Fetuin B and IgG from human sera. Explanatory AI analysis with SHapley Additive exPlanations (SHAP) helped identify the critical lectins for glycoprofile predictions. Our LeGenD approach thus presents an alternative approach for N-glycan analysis.

Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation.

Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but the underlying structures and mechanisms remain controversial. Here, we investigate a boundary that typically insulates fibroblast growth factor (FGF) oncogenes but is disrupted by DNA hypermethylation in gastrointestinal stromal tumors (GISTs). The boundary contains an array of CTCF sites that enforce adjacent TADs, one containing FGF genes and the other containing ANO1 and its putative enhancers, which are specifically active in GIST and its likely cell of origin. We show that coordinate disruption of four CTCF motifs in the boundary fuses the adjacent TADs, allows the ANO1 enhancer to contact FGF3, and causes its robust induction. High-resolution micro-C maps reveal specific contact between transcription initiation sites in the ANO1 enhancer and FGF3 promoter that quantitatively scales with FGF3 induction such that modest changes in contact frequency result in strong changes in expression, consistent with a causal relationship.

Eradication of Staphylococcus aureus in Implant-Associated Osteomyelitis by an Injectable in situ-Forming Depot Antibiotics Delivery System.

BACKGROUND: Bone infections from Staphylococcus aureus are notoriously difficult to treat and have high recurrence rates. Local antibiotic delivery systems hold the potential to achieve high in situ antibiotic concentrations, which are otherwise challenging to achieve via systemic administration. Existing solutions have been shown to confer suboptimal drug release and distribution. Here we present and evaluate an injectable in situ-forming depot system termed CarboCell. The CarboCell technology provides sustained and tuneable release of local high-dose antibiotics. METHODS: CarboCell formulations of levofloxacin or clindamycin with or without antimicrobial adjuvants cis-2-decenoic acid or cis-11-methyl-2-dodecenoic acid were tested in experimental rodent and porcine implant-associated osteomyelitis models. In the porcine models, debridement and treatment with CarboCell-formulated antibiotics was carried out without systemic antibiotic administration. The bacterial burden was determined by quantitative bacteriology. RESULTS: CarboCell formulations eliminated S. aureus in infected implant rat models. In the translational implant-associated pig model, surgical debridement, and injection of clindamycin-releasing CarboCell formulations resulted in pathogen-free bone tissues and implants in 9/12, and full eradication in 5/12 pigs. CONCLUSIONS: Sustained release of antimicrobial agents mediated by the CarboCell technology demonstrated promising therapeutic efficacy in challenging translational models and may be beneficial in combination with the current standard of care.

Brain and cancer associated binding domain mutations provide insight into CTCF's relationship with chromatin and its ability to act as a chromatin organizer.

Although only a fraction of CTCF motifs are bound in any cell type, and few occupied sites overlap cohesin, the mechanisms underlying cell-type specific attachment and ability to function as a chromatin organizer remain unknown. To investigate the relationship between CTCF and chromatin we applied a combination of imaging, structural and molecular approaches, using a series of brain and cancer associated CTCF mutations that act as CTCF perturbations. We demonstrate that binding and the functional impact of WT and mutant CTCF depend not only on the unique binding properties of each protein, but also on the genomic context of bound sites and enrichment of motifs for expressed TFs abutting these sites. Our studies also highlight the reciprocal relationship between CTCF and chromatin, demonstrating that the unique binding properties of WT and mutant proteins have a distinct impact on accessibility, TF binding, cohesin overlap, chromatin interactivity and gene expression programs, providing insight into their cancer and brain related effects.

Enhancer selectivity in space and time: from enhancer-promoter interactions to promoter activation.

The primary regulators of metazoan gene expression are enhancers, originally functionally defined as DNA sequences that can activate transcription at promoters in an orientation-independent and distance-independent manner. Despite being crucial for gene regulation in animals, what mechanisms underlie enhancer selectivity for promoters, and more fundamentally, how enhancers interact with promoters and activate transcription, remain poorly understood. In this Review, we first discuss current models of enhancer-promoter interactions in space and time and how enhancers affect transcription activation. Next, we discuss different mechanisms that mediate enhancer selectivity, including repression, biochemical compatibility and regulation of 3D genome structure. Through 3D polymer simulations, we illustrate how the ability of 3D genome folding mechanisms to mediate enhancer selectivity strongly varies for different enhancer-promoter interaction mechanisms. Finally, we discuss how recent technical advances may provide new insights into mechanisms of enhancer-promoter interactions and how technical biases in methods such as Hi-C and Micro-C and imaging techniques may affect their interpretation.

Carving out a Glycoside Hydrolase Active Site for Incorporation into a New Protein Scaffold Using Deep Network Hallucination.

Enzymes are indispensable biocatalysts for numerous industrial applications, yet stability, selectivity, and restricted substrate recognition present limitations for their use. Despite the importance of enzyme engineering in overcoming these limitations, success is often challenged by the intricate architecture of enzymes derived from natural sources. Recent advances in computational methods have enabled the de novo design of simplified scaffolds with specific functional sites. Such scaffolds may be advantageous as platforms for enzyme engineering. Here, we present a strategy for the de novo design of a simplified scaffold of an endo-α-N-acetylgalactosaminidase active site, a glycoside hydrolase from the GH101 enzyme family. Using a combination of trRosetta hallucination, iterative cycles of deep-learning-based structure prediction, and ProteinMPNN sequence design, we designed proteins with 290 amino acids incorporating the active site while reducing the molecular weight by over 100 kDa compared to the initial endo-α-N-acetylgalactosaminidase. Of 11 tested designs, six were expressed as soluble monomers, displaying similar or increased thermostabilities compared to the natural enzyme. Despite lacking detectable enzymatic activity, the experimentally determined crystal structures of a representative design closely matched the design with a root-mean-square deviation of 1.0 Å, with most catalytically important side chains within 2.0 Å. The results highlight the potential of scaffold hallucination in designing proteins that may serve as a foundation for subsequent enzyme engineering.

Interest in mHealth Among Patients With Low Back Pain: Cross-Sectional Study.

BACKGROUND: Digitally supported self-management tailored to an individual's need, in addition to usual care, may reduce pain-related disability compared to usual care alone, and patients with low back pain (LBP) using mobile health (mHealth) solutions express positive experiences. Hence, implementing mHealth solutions designed to support self-management is desirable from a clinical and patient perspective. Easily accessible mHealth solutions that can support the self-management of patients with LBP are available, but interest may be subgroup specific. Understanding the characteristics and preferences of patients with LBP labeled as interested may help to reach relevant LBP patient groups and inform the development and implementation of effective interventions with mHealth for patients with LBP. OBJECTIVE: This study aims to explore the proportion of patients with LBP labeled as interested in testing an mHealth solution designed to support self-management in addition to usual care and to assess how these patients differ from those who were labeled as not interested. METHODS: This exploratory cross-sectional study analyzed demographic and patient-reported outcomes from the SpineData registry, a Danish registry of patients with LBP in an outpatient setting. Between February and December 2019, the SpineData registry was used to assess the preliminary eligibility of patients for a clinical trial (selfBACK). Patients were labeled as interested or uninterested depending on if they responded to an invitation to be tested for eligibility for the trial Outcomes were selected from the International Classification of Functioning core set of LBP using a clinical approach. Associations were assessed in a backward selection process, and the proportion of variance explained was assessed with pseudo-R2 statistic. RESULTS: This study included 843 patients, with 181 (21%) individuals labeled as interested in participating in the selfBACK trial. Notably, the cohort labeled as interested differed from their uninterested counterparts in two key aspects: age (36-65 years: 116/181, 64.1% vs 347/662, 52.4%; P=.003) and smoking status (smokers: 22/181, 12.5% vs 174/662, 26.6%; P<.001). Those aged 36-65 years had higher odds of being labeled as interested compared to individuals aged 18-35 years (odds ratio [OR] 0.43, 95% CI 0.26-0.71) and those 65 years or older (OR 0.77, 95% CI 0.53-1.15). Nevertheless, age accounted for only a modest proportion of variance (R2=0.014). Smokers demonstrated lower odds of being labeled as interested (OR 0.39, 95% CI 0.24-0.64), with smoking status explaining a similarly small proportion of variance (R2=0.019). Collectively, age and smoking status accounted for 3.3% of the variance. CONCLUSIONS: Our investigation revealed that 181 (21%) individuals with LBP invited to participate in the mHealth solution trial for self-management expressed interest. Generally, the characteristics of those labeled as interested and uninterested were comparable. Of note, patients aged 36-65 years had a higher frequency of being labeled as interested compared to their younger and older counterparts.

Study protocol for the Screen-Free Time with Friends Feasibility Trial.

BACKGROUND: Children are spending less leisure time with their friends in person and an increasing amount of time with digital screens. These changes may negatively affect children's physical and mental health. The Screen-Free Time with Friends Feasibility Trial will test the feasibility, including acceptability and compliance, of an intervention designed to reduce screen media usage and encourage physical interaction with friends during leisure time in 9-11-year-old children. METHODS: A non-randomized single-group feasibility trial will be conducted from March to October 2023 including approximately 75 children (aged 9-11 years) and 75 parents (at least 1 per child) from 3 different schools recruited from 3 different municipalities in Denmark. The Screen-Free Time with Friends intervention is a multicomponent intervention targeting families, afterschool clubs, and local communities. It has been developed using a systematic process guided by the Medical Research Council UK's framework for developing and evaluating complex interventions. With a systems perspective in mind, the intervention and implementation approach has been designed to facilitate adaptation to the specific needs of diverse local communities while maintaining the core components of the intervention. Feasibility and acceptability of the intervention will be assessed during the intervention using process evaluation inspired by the RE-AIM framework including questionnaires and interviews with the municipality project managers, research team members, local ambassadors and stakeholders, parents and school, and afterschool club personnel. In addition, participation, recruitment, retention rate, and compliance to the outcome measurements will be investigated and presented. DISCUSSION: The trial will investigate the feasibility and acceptability of the Screen-Free Time with Friends intervention, the recruitment strategy, and the planned outcome measurements. This feasibility study will investigate necessary refinements before the implementation of the intervention program in a larger cluster randomized controlled trial to evaluate its impact. CLINICALTRIALS: gov, ID: NCT05480085. Registered 29 July 2022. https://clinicaltrials.gov/ct2/show/NCT05480085?cond=Screen+free+time+with+friends&draw=2&rank=1.

Two-Year Results of 0.01% Atropine Eye Drops and 0.1% Loading Dose for Myopia Progression Reduction in Danish Children: A Placebo-Controlled, Randomized Clinical Trial.

We investigated the two-year safety and efficacy of 0.1% loading dose and 0.01% low-dose atropine eye drops in Danish children for reduction in myopia progression in an investigator-initiated, placebo-controlled, double-masked, randomized clinical trial. Ninety-seven six- to twelve-year old myopic participants were randomized to 0.1% loading dose for six months and then 0.01% for eighteen months (loading dose group, N = 33), 0.01% for two years (0.01% group, N = 32) or placebo for two years (placebo, N = 32). Axial length (AL) and spherical equivalent refraction (SER) were primary outcomes. Secondary outcomes included adverse events and reactions, choroidal thickness, and other ocular biometrical measures. Outcomes were measured from baseline and at six-month intervals. Individual eyes nested by participant ID were analyzed with linear-mixed model analysis. Data were analyzed with intention-to-treat. Mean AL was 0.08 mm less (95% confidence interval (CI): -0.01; 0.17, p-value = 0.08) in the 0.1% loading dose and 0.10 mm less (95% CI: 0.01; 0.19, p-value = 0.02) in the 0.01% group after two years of treatment compared to placebo. Mean SER progression was 0.12 D (95% CI: -0.10; 0.33) less in the loading dose and 0.26 D (95% CI: 0.04; 0.48) less in the 0.01% groups after two years of treatment compared to placebo (p-value = 0.30 and 0.02, respectively). In total, 17 adverse events were reported in the second-year follow-up, and all were rated as mild. Adjusting for iris color did not affect treatment effect estimates. Intra-ocular pressure increased over two years comparably between all groups but remained within normal limits. Two-year treatment with 0.01% low-dose atropine eye drops is a safe and moderately efficacious intervention in Danish children for reducing myopia progression.

Morphological and genetic evidence suggest gene flow among native and naturalized mint species.

PREMISE: Cultivation and naturalization of plants beyond their natural range can bring previously geographically isolated taxa together, increasing the opportunity for hybridization, the outcomes of which are not predictable. Here, we explored the phenotypic and genomic effects of interspecific gene flow following the widespread cultivation of Mentha spicata (spearmint), M. longifolia, and M. suaveolens. METHODS: We morphologically evaluated 155 herbarium specimens of three Mentha species and sequenced the genomes of a subset of 93 specimens. We analyzed the whole genomes in a population and the phylogenetic framework and associated genomic classifications in conjunction with the morphological assessments. RESULTS: The allopolyploid M. spicata, which likely evolved in cultivation, had altered trichome characters, that is possibly a product of human selection for a more palatable plant or a byproduct of selection for essential oils. There were signs of genetic admixture between mints, including allopolyploids, indicating that the reproductive barriers between Mentha species with differences in ploidy are likely incomplete. Still, despite gene flow between species, we found that genetic variants associated with the cultivated trichome morphology continue to segregate. CONCLUSIONS: Although hybridization, allopolyploidization, and human selection during cultivation can increase species richness (e.g., by forming hybrid taxa), we showed that unless reproductive barriers are strong, these processes can also result in mixing of genes between species and the potential loss of natural biodiversity.

Social media shaping autism perception and identity.

LAY ABSTRACT: This study suggested that social media can provide important information about autism to autistic people. We interviewed 12 autistic adults (aged 18-49 years) and talked to them about the use of social media to find both general information and content specifically about autism, autism identity and online autistic communities. There is little research exploring how autistic people find information about autism on social media and how that makes them feel. Therefore, it is important to ask autistic people about their experiences with using social media to obtain content about autism. The 12 participants explained that when they searched for information about autism on the official health pages, they often felt that the information they found was insufficient and could not answer their questions. In addition, they searched on social media platforms for information about autism despite that they perceived social media as an unreliable source. On the social media platforms, many found content that was positive in relation to their autistic identities. The participants also found comfort in some of the forums and social media groups and received helpful advice. Nevertheless, some of the discussions were aggressive and the participants felt alienated, which did not provide a sense of community online. The findings from the study may advice on what is missing in the official pages about autism, and highlight the need to involve the autistic community in writing the content on such platforms.

Population genomics of post-glacial western Eurasia.

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

Inter seasonal validation of non-contact NIR spectroscopy for measurement of total soluble solids in high tunnel strawberries.

Autonomous field robots are being developed for picking of fruit, where each fruit needs to be individually graded and handled. There is therefore a need for rapid and non-destructive sensing to measure critical fruit quality parameters. In this article we report how total soluble solids (TSS), a measure for total sugar content, can be measured in strawberries in the field by non-contact near-infrared (NIR) interaction spectroscopy. A specially designed prototype system working in the wavelength range 760-1080 nm was tested for this purpose. This novel instrument was compared with a commercial handheld NIR reflection instrument working in the range 900-1600 nm. The instruments were calibrated in the lab using data collected from 200 strawberries of two varieties and tested in a strawberry field on 50 berries in 2022 and 100 berries in 2023. Both systems performed well during calibration with root mean square errors of cross validation for TSS around 0.49 % and 0.57 %, for interaction and reflection, respectively. For prediction of TSS in new berries in 2023, the interaction system was superior, with a prediction error of 1.0 % versus 8.1 % for the reflection system, most likely because interaction probes deeper into the berries. The results suggest that interaction measurements of average TSS are more robust and would most likely require less calibration maintenance compared to reflection measurements. The non-contact feature is important since it reduces the spread of diseases and physical damage to the berries.

Testing walking performance in patients with low back pain: will two minutes do instead of six minutes?

PURPOSE: The six-minute walk test (6MWT) can assess walking function but is time-consuming. We investigate the correlation of performance over the first two minutes of the 6MWT (2MWT#) and the 6MWT. We also evaluate the 2MWT#'s ability to predict 6MWT results, assess correlations to secondary explanatory outcomes, and assess the ability to discriminate between clinical subgroups. MATERIAL AND METHODS: A cross-sectional study of 124 participants with LBP. Correlations between the 2MWT# and 6MWT and secondary outcomes were evaluated using the Pearson product-moment correlation coefficient. The predictive ability of the 2MWT# was defined as the residual distance between the observed 6MWT and three times the 2MWT#. Differences between clinical subgroups were evaluated using the Wilcoxon rank test. RESULTS: The 2MWT# and 6MWT correlated highly (r = 83, 95% CI 0.76 - 0.87). The 2MWT# overestimated 6MWT results with 46.8 meters (SD 67.0). Both tests correlated with secondary outcomes and discriminated similarly between clinical subgroups. CONCLUSIONS: The 2MWT# correlates highly with 6MWT but overestimates the observed 6MWT by 9%. Because it is shorter, possibly less burdensome, and with little or no loss of discriminatory ability, we consider it a legitimate alternative to the 6MWT in patients with LBP.Implications for rehabilitationWalking function is often affected in patients with low back pain (LBP).The six-minute walk test (6MWT) is frequently used to assess walking function but is time-consuming.A shorter two-minute walk test is a legitimate alternative in patients with LBP as it correlates highly with the 6MWT and has little or no loss of discriminatory ability between clinical subgroups.

Redefining effect size interpretations for psychotherapy RCTs in depression.

INTRODUCTION: Effect sizes are often used to interpret the magnitude of a result and in power calculations when planning research studies. However, as effect size interpretations are context-dependent, Jacob Cohen's suggested guidelines for what represents a small, medium, and large effect are unlikely to be suitable for a diverse range of research populations and interventions. Our objective here is to determine empirically-derived effect size thresholds associated with psychotherapy randomized controlled trials (RCTs) in depression by calculating the effect size distribution. METHODS: We extracted effect sizes from 366 RCTs provided by the systematic review of Cuijpers and colleagues (2020) on psychotherapy for depressive disorders across all age groups. The 50th percentile effect size, as this represents a medium effect size, and the 25th (small) and 75th (large) percentile effect sizes were calculated to determine empirically-derived effect size thresholds. RESULTS: After adjusting for publication bias, 0.27, 0.53, and 0.86 represent small, medium, and large effect sizes, respectively, for psychotherapy treatment for depressive disorders. DISCUSSION: The effect size distribution for psychotherapy treatment of depression indicates that observed effect size thresholds are larger than Cohen's suggested effect size thresholds (0.2, 0.5, and 0.8). These results have implications for the interpretation of study effects and the planning of future studies via power analyses, which often use effect size thresholds.