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Depression is one of the leading causes of disability worldwide. Cognitive behavioral therapy (CBT) is an effective treatment, but it is difficult to access due to clinician shortages, waitlists, and logistical barriers. Smartphone-based CBT interventions offer a scalable alternative to traditional face-to-face care, but few provide transparency regarding how closely they adhere to evidence-based therapeutic principles. Understanding what therapeutic components are included in interventions helps clinicians and patients determine whether they follow CBT principles and how they might help reduce depressive symptoms. This study aimed to characterize the therapeutic content of Mindset (Koa Health), a therapist-guided smartphone intervention for depression, by identifying the core CBT techniques it delivers and the specific behavioral strategies the app uses to put those techniques into practice. A qualitative content analysis was conducted on all 393 unique intervention pages of Mindset. Using established CBT strategy definitions and the behavior change technique (BCT) Taxonomy version 1 (BCTTv1), coders independently evaluated each page using a collaborative consensus approach. Interrater agreement was 93.75% for CBT and 93.62% for BCT coding. Descriptive statistics (frequency, mean, and SD) and overlap between the two were calculated. All 16 core CBT techniques were identified. CBT techniques were used a total of 528 times (mean per module 66.0, SD 56.0). The most frequently used techniques included psychoeducation (164/325, 50.5% of pages), skill building (110/325, 33.8%), cognitive restructuring (46/325, 14.2%), activity scheduling (42/325, 12.9%), and self-monitoring (39/325, 12%). Across modules, 37 of 93 possible BCTs were coded 878 times (mean per module 109.8, SD 92.0) across 13 of 16 BCTTv1 categories. The most frequently applied BCT categories were shaping knowledge (205/325, 63.1% of pages), repetition and substitution (138/325, 42.5%), and feedback and monitoring (113/325, 34.8%). Overlap between the 2 frameworks was common, with the most frequent CBT-BCT pairings being psychoeducation (CBT technique)×Shaping knowledge (BCT category; appearing together on 119 pages), skill building×Shaping knowledge (80 pages), activity scheduling×Shaping knowledge (42 pages), and activity scheduling×Repetition and substitution (42 pages). Mindset demonstrates coverage of CBT techniques and alignment with evidence-based BCTs. This study is the first to introduce mechanism mapping, a dual-coding approach that describes the presence of therapeutic strategies and how they are behaviorally operationalized, addressing a gap in digital mental health transparency. Unlike existing content evaluations that use presence or absence checklists, our framework captures implementation depth through systematic documentation of behavioral scaffolding. This replicable methodology enables researchers to evaluate therapeutic fidelity, supports clinicians in making evidence-informed recommendations for digital mental health treatments, and provides a foundation for the development of adaptive interventions that can enhance real-world treatment outcomes for individuals with depression.

Abstract Introduction: Body dysmorphic disorder (BDD) is severe, chronic, and undertreated. Apps could substantially improve treatment access. Objective: We provide an initial test of the usability and efficacy of coach-supported app-based cognitive behavioral therapy (CBT) for BDD. The Perspectives app covers core treatment components: psychoeducation, cognitive restructuring, exposure with response prevention, mindfulness, attention retraining, and relapse prevention. Methods: A randomized waitlist-controlled trial was conducted. Adults (N = 80) with primary BDD were assigned to 12 weeks of Perspectives or waitlist. Coaches promoted engagement and answered questions via in-app messaging and phone calls. BDD severity was measured at baseline, mid-treatment, and end of treatment by blinded independent evaluators (Yale-Brown Obsessive Compulsive Scale Modified for BDD; BDD-YBOCS). Secondary outcomes included BDD-related insight, depression, quality of life, and functioning. Results: App uptake and satisfaction were high. In intent-to-treat analyses, Perspectives app-based CBT was associated with significantly lower BDD-YBOCS severity at end of treatment (M [SD]: 16.8 [7.5]) compared to the waitlist (26.7 [6.2]; p < 0.001, d = 1.44). App-based CBT was associated with greater improvements across all secondary measures, with medium to large effects. Conclusions: Perspectives, supported by a bachelor’s-level coach, is an efficacious, scalable treatment for adults with BDD.

Skin microbes interact with the immune system to aid wound healing The immune system acts as a formidable guardian of health, protecting and restoring tissue function during infectious and environmental challenges. To date, our understanding of host immunity stems from models of inflammation and infection with pathogenic microbes. However, the vast majority of microbial-immune encounters occur as a symbiotic relationship with the commensal microbiota, the trillions of microorganisms that inhabit our barrier tissues, including the gastrointestinal tract and skin. Indeed, far from being ignored by the host, commensal microbes promote the development, education, and function of the mammalian immune system ( 1 ). In return, immune responses to commensal microbes, particularly those mediated by the adaptive immune system, act to bolster epithelial fortifications for antimicrobial function, restraining systemic translocation of both commensal and pathogenic microbes ( 2 ).

Invasive fungal infections pose an important threat to public health and are an under-recognized component of antimicrobial resistance, an emerging crisis worldwide. Across a period of profound global environmental change and expanding at-risk populations, human-infecting pathogenic fungi are evolving resistance to all licensed systemic antifungal drugs. In this Review, we highlight the main mechanisms of antifungal resistance and explore the similarities and differences between bacterial and fungal resistance to antimicrobial control. We discuss the research and innovation topics that are needed for risk reduction strategies aimed at minimizing the emergence of resistance in pathogenic fungi. These topics include links between the environment and One Health, surveillance, diagnostics, routes of transmission, novel therapeutics and methods to mitigate hotspots for fungal adaptation. We emphasize the global efforts required to steward our existing antifungal armamentarium, and to direct the research and development of future therapies and interventions.The impacts of fungal infections on human health are of increasing concern, and resistance of pathogenic fungi to all licensed systemic antifungals has been documented. In this Review, Fisher, Verweij and colleagues discuss the research and innovation topics that are needed to understand and minimize the occurrence and impact of antifungal resistance.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide with 5-FU still the primary chemotherapeutic of choice. With the increasing use of immunotherapies, much research is focused on the ability to make tumours more immunogenic, thereby rationalising combination with immunotherapy. Here we investigate whether NUC-3373, a phosphoramidate transformation of 5-fluorodeoxyuridine (FUDR), enhances immunogenicity in CRC cell lines and facilitates lymphocyte mediated cell death in vitro . At sub IC 50 doses NUC-3373 upregulates damage associate molecular patterns (DAMPs) in both HCT116 and SW480 cells and increases surface expression of MHCII and PD-L1. Pre-treatment with NUC-3373 and subsequent coculture with NK-92 MI natural killer cells caused an increase in LAMP1 expression (degranulation), production of IFN-γ, and NK-mediated cytotoxicity compared to vehicle controls. Cocultures with patient-derived PBMCs with heterologous CRC cells pre-treated with NUC-3373 demonstrated increased cell death compared to both vehicle controls and monocultures of CRC cells exposed to NUC-3373. Lastly, the PD-1 immune checkpoint inhibitor nivolumab showed synergistic activity when HCT116 cells were pre-treated with NUC-3373. To conclude, we show that NUC-3373 can modulate immune signaling and may therefore facilitate immune mediated tumour cell death in vitro .

The timely identification of patients who are at risk of a mental health crisis can lead to improved outcomes and to the mitigation of burdens and costs. However, the high prevalence of mental health problems means that the manual review of complex patient records to make proactive care decisions is not feasible in practice. Therefore, we developed a machine learning model that uses electronic health records to continuously monitor patients for risk of a mental health crisis over a period of 28 days. The model achieves an area under the receiver operating characteristic curve of 0.797 and an area under the precision-recall curve of 0.159, predicting crises with a sensitivity of 58% at a specificity of 85%. A follow-up 6-month prospective study evaluated our algorithm’s use in clinical practice and observed predictions to be clinically valuable in terms of either managing caseloads or mitigating the risk of crisis in 64% of cases. To our knowledge, this study is the first to continuously predict the risk of a wide range of mental health crises and to explore the added value of such predictions in clinical practice. Machine learning applied on electronic health records can predict mental health crises 28 days in advance and become a clinically valuable tool for managing caseloads and mitigating the risk of crisis.

Mildly irradiated mini-Neptunes have densities potentially consistent with them hosting substantial liquid-water oceans (“Hycean” planets). The presence of CO2 and simultaneous absence of ammonia (NH3) in their atmospheres has been proposed as a fingerprint of such worlds. JWST observations of K2-18b, the archetypal Hycean, have found the presence of CO2 and the depletion of NH3 to <100 ppm; hence, it has been inferred that this planet may host liquid-water oceans. In contrast, climate modeling suggests that many of these mini-Neptunes, including K2-18b, may likely be too hot to host liquid water. We propose a solution to this discrepancy between observation and climate modeling by investigating the effect of a magma ocean on the atmospheric chemistry of mini-Neptunes. We demonstrate that atmospheric NH3 depletion is a natural consequence of the high solubility of nitrogen species in magma at reducing conditions; precisely the conditions prevailing where a thick hydrogen envelope is in communication with a molten planetary surface. The magma ocean model reproduces the present JWST spectrum of K2-18b to ≲3σ, suggesting this is as credible an explanation for current observations as the planet hosting a liquid-water ocean. Spectral areas that could be used to rule out the magma ocean model include the >4 μm region, where CO2 and CO features dominate: magma ocean models suggest a systematically lower CO2/CO ratio than estimated from free-chemistry retrieval, indicating that deeper observations of this spectral region may be able to distinguish between oceans of liquid water and magma on mini-Neptunes.

Desmosomes are intercellular adhesive junctions that impart strength to vertebrate tissues. Their dense, ordered intercellular attachments are formed by desmogleins (Dsgs) and desmocollins (Dscs), but the nature of trans-cellular interactions between these specialized cadherins is unclear. Here, using solution biophysics and coated-bead aggregation experiments, we demonstrate family-wise heterophilic specificity: All Dsgs form adhesive dimers with all Dscs, with affinities characteristic of each Dsg:Dsc pair. Crystal structures of ectodomains from Dsg2 and Dsg3 and from Dsc1 and Dsc2 show binding through a strand-swap mechanism similar to that of homophilic classical cadherins. However, conserved charged amino acids inhibit Dsg:Dsg and Dsc:Dsc interactions by same-charge repulsion and promote heterophilic Dsg:Dsc interactions through opposite-charge attraction. These findings show that Dsg:Dsc heterodimers represent the fundamental adhesive unit of desmosomes and provide a structural framework for understanding desmosome assembly.

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5–46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells. Genetic and phenotypic analysis reveals expression quantitative trait loci in human induced pluripotent stem cell lines associated with cancer and disease. Mapping variations in human induced pluripotent stem cells The Human Induced Pluripotent Stem Cells Initiative (HipSci) has resulted in the generation, genotyping and phenotyping of more than 700 human induced pluripotent stem (iPS) cell lines derived from 300 healthy individuals. Although analysis of these data indicates that most of the variations in phenotypes between cells arise from variations between individuals, the authors also assess the consequences of the rare genetic defects that are recurrently seen in iPS cells after reprogramming and provide a map of the common regulatory variants that can change the transcriptome of human pluripotent cells. This resource will be useful for genetic studies of complex traits and cancer.