Julkaisuarkisto

Healthcare professionals (HCPs) play a key role in improving pain outcomes in hospitalized children. Knowledge gaps can significantly hinder the ability of HCPs to provide optimal pain care. Developing targeted educational interventions to address these gaps requires a clear understanding of priority areas for training on essential pain-related topics. Against this background, this study aimed to establish consensus on topics for a pediatric pain educational program (PPEP) for continuing professional education among HCPs. A two-stage modified e-Delphi study was conducted among experts in pediatric care, health education, and pain research. The researchers developed 35 topics by reviewing the Core Content of the Pediatric Pain PRN Curriculum. In the first and second rounds, experts rated the topics and suggested additional topics. Ratings were done on a four-point Likert scale with options ranging from 1 (not important at all) to 4 (very important). The outcomes from both rounds were analyzed based on the level of consensus. Consensus on a topic was set at a threshold of ≥ 70. A response rate of 88% (n = 22/25) and 100% (n = 22/22) was achieved for the first and second rounds, respectively. Experts rated 35 topics and 5 topics (the topic that failed to achieve consensus in the first round and four new ones generated from expert comments) in the first and second rounds, respectively. In the first round, experts agreed on 34 of the 35 topics (72.7%–90.9%) while all five topics achieved consensus (90.9%–100%) in the second round. Thus, 39 topics under the domains of pain theories, pediatric chronic pain, pain assessment, opioid risk evaluation and mitigation strategies (REMS), biobehavioural strategies, procedural pain, acute pain management and reorientation were agreed on for inclusion in the PPEP. A high level of consensus was achieved among a multidisciplinary panel of experts on the content of the PPEP. This can serve as a valuable resource for interprofessional pain continuing education in low-resource settings. The topics can also be integrated into curricula for preregistration healthcare professionals in such settings.

The global decline of biodiversity demands transformative change that realigns human activity with planetary processes. Regenerative development may facilitate systemic transformation but remains underexamined in relation to biodiversity. We explore the relationship between biodiversity and place regeneration, conceptually aligning biodiversity enhancement and regenerative development. This requires adopting a refocused concept of biodiversity as a dynamic, relational attribute of life that engenders biocultural diversity. Similarly, regenerative development promotes co-evolving, life-affirming relationships within and between human and natural systems. Regenerative design may catalyse regenerative development capacity in communities by engaging participants in regenerative dynamics, potentially increasing biodiversity. However, the intentional incorporation of actions explicitly aimed at enhancing biodiversity remains necessary. Challenges persist due to entrenched anthropocentric worldviews and the difficulty of including human expressions within biodiversity. The refocused biodiversity concept offers a feasible leverage point for fostering transformative change within the narrowing timeframes to halt biodiversity decline.

Recessively inherited loss-of-function mutations in excision repair cross-complementing 6–like 2 (ERCC6L2) cause a bone marrow failure (BMF) syndrome characterized by moderate cytopenias, frequent somatic TP53 mutations, and a propensity to develop myeloid malignancies. The pathophysiology and molecular mechanisms underlying the BMF syndrome as well as its association with TP53-mutant clonal hematopoiesis and myeloid malignancies have remained poorly understood. Using novel preclinical in vitro and in vivo model systems, we demonstrate that Ercc6l2 maintains the competitive fitness of hematopoietic stem and progenitor cells (HSPCs) by mitigating replication stress. Sustained replication stress and DNA damage in Ercc6l2-deficient HSPCs cause p53 pathway activation followed by cell cycle arrest and apoptosis. Moreover, Ercc6l2 deficiency results in decreased expression of master hematopoietic regulators Runx1 and Gata1 in HSPCs. Altogether, loss of Ercc6l2 leads to reduced HSPC numbers, bone marrow hypocellularity, and cytopenias. Notably, somatic Trp53 mutations restore cellular fitness of Ercc6l2-deficient HSPCs by abrogating p53 pathway activation and restoring Runx1 and Gata1 expression, thereby correcting the BMF phenotype. However, p53 loss fails to normalize replication stress, allowing for the accumulation of DNA damage over time, which increases the likelihood for leukemic transformation. Our data uncover the pathogenesis of ERCC6L2 disease and provide a prototypic example of clonal compensation in BMF syndromes, in which somatic mutations in leukemia-associated genes, in this case TP53, transiently improve blood cell production at, however, the expense of increasing leukemogenic potential.