Publications

Importance Physician burnout and retention problems are threatening workforce stability and patient care. Objective To compare physician well-being in multiple European countries and the US to inform physician well-being interventions and evaluate whether modifiable aspects of hospital care environments are associated with physician job outcomes. Design, Setting, and Participants This cross-sectional study was conducted at 49 hospitals in 6 European countries (Belgium, England, Germany, Ireland, Sweden, and Norway) and 56 US hospitals. European data from physicians and nurses were collected in 2023; US data were collected in 2021. Data were analyzed from February through August 2025. Exposures Three explanatory variables were measured at the hospital level: nurse staffing adequacy, clinical care environment, and physician and nurse teamwork. Main Outcomes and Measures Primary outcomes include individual-level measures of physician well-being and job outcomes (eg, high burnout, job dissatisfaction, intention to leave employer, and willingness to recommend employer). Results Among a total of 21 396 physicians and nurses, 1149 European physicians (mean [SD] age, 41.3 [10.6] years; 536 female [46.5%] and 609 male [52.9%]) and 5334 US physicians (mean [SD] age, 44.5 [11.8] years; 1861 female [34.9%] and 2373 male [44.5%]) reported on their well-being and 3044 European nurses and 11 869 US nurses reported on hospital care environments. Poor well-being was common among hospital physicians in the US and Europe; for example, 324 of 1083 physicians in Europe with responses to the question (29.9%) and 1178 of 4959 physicians with responses to the question (23.8%) intended to leave their job within a year. Improvements in nurse staffing adequacy, clinical care environments, and clinician teamwork were associated with favorable physician job outcomes in the US and Europe. For example, among US hospitals, a 10% increase in favorable care environments was associated with lower odds of physicians intending to leave (odds ratio [OR], 0.78; 95% CI, 0.68-0.90), not recommending their hospital (OR, 0.75; 95% CI, 0.61-0.92), experiencing high burnout (OR, 0.90; 95% CI, 0.83-0.98), and having job dissatisfaction (OR, 0.81; 95% CI, 0.69-0.95). Among European hospitals, a 10% increase in hospital-level reports of nurse staffing adequacy was associated with lower odds of physicians intending to leave (OR, 0.80; 95% CI, 0.71-0.91), not recommending their hospital (OR, 0.73; 95% CI, 0.61-0.88), reporting high burnout (OR, 0.88; 95% CI, 0.78-0.99), and reporting job dissatisfaction (OR, 0.85; 95% CI, 0.73-0.98). Conclusions and Relevance In this study, improved hospital nurse work environments were associated with more favorable physician outcomes, and modifiable features of the hospital environment, including having adequate numbers of direct care nurses and strong physician and nurse teamwork, were associated with greater physician well-being. These findings may inform the development and implementation of evidence-based interventions to improve physician well-being and retention.

Supplementary Data from Transcriptome Profile of Human Colorectal Adenomas

Many pathogenic viruses that affect man display species specificity, limiting the use of animal models. Studying viral biology and identifying potential treatments therefore benefits from the development of in vitro cell systems that closely mimic human physiology. In the current COVID-19 pandemic, rapid scientific insights are of the utmost importance to limit its impact on public health and society. Organoids are emerging as versatile tools to progress the understanding of SARS-CoV-2 biology and to aid in the quest for novel treatments.

The gastric epithelium consists of tubular glandular units each containing several differentiated cells types, and populations of stem cells, which enable the stomach to secrete the acid, mucus and various digestive enzymes required for its function. Cell signalling provides cues to regulate development and homeostasis of adult tissues, however very little is known about which cell signalling pathways are required for homeostasis of the gastric epithelium. Many diseases, such as cancer, arise as a result of deregulation to signalling pathways that regulate homeostasis of the diseased organ. Therefore it is important to understand the biology of how normal conditions are maintained in a tissue to help inform the mechanisms driving disease in that same tissue, and identify potential points of therapeutic intervention. Wnt signalling regulates several cell functions including proliferation, differentiation and migration, and plays a critical role during homeostasis of several tissues, including the intestinal epithelium. Wnt3a is required in the culture medium of gastric organoids, suggesting it is also important for the homeostasis of the gastric epithelium, but this has not been investigated in vivo. Here we show that the Wnt receptor Frizzled7 (Fzd7), which is required for the homeostasis of the intestine, is expressed in the gastric epithelium and is required for gastric organoid growth. Gastric specific loss of Fzd7 in the adult gastric epithelium of mice is deleterious and triggers rapid epithelial repopulation, which we believe is the first observation of this novel function for this tissue. Taken together these data provide functional evidence of a critical role for Wnt signalling, via the Fzd7 receptor, during homeostasis of the gastric epithelium.

Cross-talk in the mammary gland Macrophages engulf damaged and dead cells to clear infection, but they also participate in tissue regeneration. Chakrabarti et al. expand the macrophage repertoire for mammary gland development (see the Perspective by Kannan and Eaves). Mammary gland stem cells secrete the Notch ligand Dll1 and activate Notch signaling, which promotes survival of adjacent macrophages. This stimulates production of Wnt ligands, which signal back to the mammary gland stem cells. This cross-talk plays an important role in coordinating mammary gland development, tissue homeostasis, and, not least, breast cancer. Science , this issue p. eaan4153 ; see also p. 1401

The Human Cell Atlas (HCA) will be made up of comprehensive reference maps of all human cells - the fundamental units of life - as a basis for understanding fundamental human biological processes and diagnosing, monitoring, and treating disease. It will help scientists understand how genetic variants impact disease risk, define drug toxicities, discover better therapies, and advance regenerative medicine. A resource of such ambition and scale should be built in stages, increasing in size, breadth, and resolution as technologies develop and understanding deepens. We will therefore pursue Phase 1 as a suite of flagship projects in key tissues, systems, and organs. We will bring together experts in biology, medicine, genomics, technology development and computation (including data analysis, software engineering, and visualization). We will also need standardized experimental and computational methods that will allow us to compare diverse cell and tissue types - and samples across human communities - in consistent ways, ensuring that the resulting resource is truly global. This document, the first version of the HCA White Paper, was written by experts in the field with feedback and suggestions from the HCA community, gathered during recent international meetings. The White Paper, released at the close of this yearlong planning process, will be a living document that evolves as the HCA community provides additional feedback, as technological and computational advances are made, and as lessons are learned during the construction of the atlas.

Abstract RNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been sufficiently characterized. In this study we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 (KRC) in exocrine cells. We demonstrate that Rnf43 loss results in an increased incidence of high-grade cystic lesions of the pancreas and PDAC. Importantly, KRC mice have a significantly decreased survival compared to mice containing only an oncogenic Kras mutation. By use of single cell RNA sequencing we demonstrated that KRC tumor progression is accompanied by a decrease in macrophages, as well as an increase in T and B lymphocytes with evidence of increased immune checkpoint molecule expression and affinity maturation, respectively. This was in stark contrast to the tumor immune microenvironment observed in the Kras / Tp53 driven PDAC GEMM. Furthermore, expression of the chemokine, CXCL5, was found to be specifically decreased in KRC cancer cells by means of epigenetic regulation and emerged as a putative candidate for mediating the unique KRC immune landscape. This GEMM establishes RNF43 as a bona fide tumor suppressor gene in PDAC and puts forth a rationale for an immunotherapy approach in this subset of PDAC cases.

<p>Extension of the methods related to the scRNA-seq data analysis</p>

Patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are currently treated with surgery and/or radio- and chemotherapy. Despite these therapeutic interventions, 40% of patients relapse, urging the need for more effective therapies. In photodynamic therapy (PDT), a light-activated photosensitizer produces reactive oxygen species that ultimately lead to cell death. Targeted PDT, using a photosensitizer conjugated to tumor-targeting molecules, has been explored as a more selective cancer therapy. Organoids are self-organizing three-dimensional structures that can be grown from both normal and tumor patient-material and have recently shown translational potential. Here, we explore the potential of a recently described HNSCC–organoid model to evaluate Epidermal Growth Factor Receptor (EGFR)-targeted PDT, through either antibody- or nanobody-photosensitizer conjugates. We find that EGFR expression levels differ between organoids derived from different donors, and recapitulate EGFR expression levels of patient material. EGFR expression levels were found to correlate with the response to EGFR-targeted PDT. Importantly, organoids grown from surrounding normal tissues showed lower EGFR expression levels than their tumor counterparts, and were not affected by the treatment. In general, nanobody-targeted PDT was more effective than antibody-targeted PDT. Taken together, patient-derived HNSCC organoids are a useful 3D model for testing in vitro targeted PDT.