Ribosomes are specialized entities that participate in regulation of gene expression through their rRNAs carrying ribozyme activity. Ribosome biogenesis is overactivated in p53-inactivated cancer ...cells, although involvement of p53 on ribosome quality is unknown. Here, we show that p53 represses expression of the rRNA methyl-transferase fibrillarin (FBL) by binding directly to FBL. High levels of FBL are accompanied by modifications of the rRNA methylation pattern, impairment of translational fidelity, and an increase of internal ribosome entry site (IRES)-dependent translation initiation of key cancer genes. FBL overexpression contributes to tumorigenesis and is associated with poor survival in patients with breast cancer. Thus, p53 acts as a safeguard of protein synthesis by regulating FBL and the subsequent quality and intrinsic activity of ribosomes.
Display omitted
•p53 directly represses transcription of the rRNA methyl-transferase fibrillarin•rRNA methylation pattern is altered in response to p53 inactivation•p53 inactivation promotes IRES-dependent translation in an FBL-dependent manner•High FBL mRNA levels are a marker of poor prognosis in breast cancer
The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly ...understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.
Aim(s)
To assess the effectiveness of sub‐epidermal moisture (SEM) assessment technology in the detection of early‐stage pressure damage in a critical care unit (CCU) and dark skin tone patients and ...its impact on hospital‐acquired pressure injury (HAPI) incidence.
Design
Quality improvement study employing Kurt Lewin's change model emphasizing planning, implementation, evaluation and sustainable change.
Methods
The study evaluated 140 adult patients admitted to the CCU over a 24‐week period, from July to December 2022. Retrospective analysis of standard PI care pathways was performed in 90 patients admitted during a 12‐week pre‐implementation period. Fifty patients were admitted through the subsequent 12‐week implementation period. SEM assessments were performed daily at the sacrum and heels and interventions were applied based on SEM assessments; SEM delta ≥0.6 indicating localized oedema or persistent focal oedema. Statistical analyses were performed on anonymized data.
Results
Pre‐implementation HAPI incidence was 8.9% (N = 8/90). All eight patients were African American with varying skin tones. A 100% reduction in HAPI incidence was achieved in the implementation period which included 35 African American patients. The relative risk of HAPI incidence was 1.6 times higher in the pre‐implementation group.
Conclusion
Implementing SEM assessment technology enabled equitable PI care for all population types and resulted in a 100% reduction of PIs in our CCU. Objective SEM assessments detected early‐stage PIs, regardless of skin tone and enabled providing interventions to specific anatomies developing tissue damage as opposed to universal preventive interventions.
Implications
PI care pathways relying on visual and tactile skin assessments are inherently biased in providing equitable care for dark skin tone patients. Implementing SEM assessments empowers healthcare practitioners in driving objective clinical interventions, eliminates bias and enables positive PI health outcomes.
Impact
Implementing SEM assessment technology had three main effects: it detected early tissue damage regardless of skin tone (detection effect), enabled anatomy‐specific interventions (treatment effect) and prevented PIs across all population types (prevention effect).
The authors have adhered to the Standards for Quality Improvement Reporting Excellence (SQUIRE) 2.0 guidelines.
Patient or Public Contribution
No patient or public contribution.
What does this paper contribute to the wider global clinical community? Addressing health inequities in pressure injury prevention; Demonstrated effectiveness across patient populations; Resource optimization and enhanced patient safety.
Single particle tracking is a powerful technique for investigating the dynamic behavior of biological molecules. However, many of the analytical tools are prone to generate results that can lead to ...mistaken interpretations of the underlying transport process. Here, we explore the effects of localization error and confinement on the velocity autocorrelation function, Cυ. We show that calculation of Cυ across a range of discretizations can distinguish the effects of localization error, confinement, and medium elasticity. Thus, under certain regimes, Cυ can be used as a diagnostic tool to identify the underlying mechanism of anomalous diffusion. Finally, we apply our analysis to experimental data sets of chromosomal loci and RNA-protein particles in Escherichia coli.
Rising mortality in the United States due to alcoholic liver disease (ALD) and the dearth of effective treatments for ALD have led to increased research in this area, particularly in alcoholic ...hepatitis. To understand the burden of illness and potential economic value of effective treatments, we conducted a health care claims analysis of over 15,000 commercially insured adults who were hospitalized with alcoholic hepatitis (AH) between 2006 and 2013 and followed for up to 5 years. Their average age was 54 years and 68% were male. Over 5 years, about two-thirds of these adults died (44% in the first year), and fewer than 500 received liver transplants. There were nearly 40,000 re-hospitalizations, with over 50% of the survivors re-hospitalized within a year and nearly 75% through the second year. The total costs were nearly $145,000 per patient, with costs decreasing over time from over $50,000 in the first year (including the index hospitalization) to about $10,000 per year in the later years. Total costs for the cohort over 5 years were $2.2 billion. Patients who received a liver transplant averaged about $300,000 in transplant-related costs and over $1,000,000 in total health care costs over 5 years. Average costs in years following the index hospitalization were similar to diabetes. AH has a high mortality and is a high-cost condition.
•There is an increasing rate of hospitalizations due to alcohol-related conditions.•Medical treatment for AH has limited efficacy. Only transplantation is life-saving, but it is not widely accepted.•The total average annual per-patient costs for AH are higher than for heart failure or diabetes.•Patients with the condition tend to be people of middle age in their prime working years.
1. The rapid increase of human activity in wild and developed areas presents novel challenges for wildlife. Some species may use human-dominated landscapes because of favourable resources (e.g. high ...prey availability along roadsides); however, use of these areas may increase exposure to anthropogenic stressors, such as human disturbance or noise, which can negatively affect reproduction or survival. In this case, human-dominated landscapes may act as an ecological trap. 2. We evaluated whether American kestrel Falco sparverius reproductive failure was associated with human disturbance (traffic conditions and land development) or other common predictors of reproductive outcome, such as habitat and clutch initiation date. Also, we examined relationships among human disturbance, corticosterone (CORT) concentrations and nest abandonment to explore potential mechanisms for stress-induced reproductive failure. 3. Twenty-six (36%) of 73 kestrel nesting attempts failed and 88% of failures occurred during incubation. Kestrels nesting in higher disturbance areas were 9·9 times more likely to fail than kestrels nesting in lower disturbance areas. Habitat and clutch initiation date did not explain reproductive outcome. 4. Females in higher disturbance areas had higher CORT and were more likely to abandon nests than females in lower disturbance areas. There was no relationship between male CORT and disturbance or abandonment. Females spent more time incubating than males and may have had more exposure to anthropogenic stressors. Specifically, traffic noise may affect a cavity-nesting bird's perception of the outside environment by masking auditory cues. In response, incubating birds may perceive a greater predation risk, increase vigilance behaviour, decrease parental care, or both. 5. Synthesis and applications. Proximity to large, busy roads and developed areas negatively affected kestrel reproduction by causing increased stress hormones that promoted nest abandonment. These results demonstrate that species presence in a human-dominated landscape does not necessarily indicate a tolerance for anthropogenic stressors. Managers should carefully consider or discourage projects that juxtapose favourable habitat conditions with areas of high human activity to decrease risk of ecological traps. Noise mitigation, while locally effective, may not protect widespread populations from the pervasive threat of traffic noise. Innovative engineering that decreases anthropogenic noise at its source is necessary.
Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic ...resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease.
Abstract
The Human Phenotype Ontology (HPO)—a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases—is used by thousands of researchers, clinicians, informaticians and ...electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO’s interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.
This quality improvement project implemented job-related education for registered nurses (RNs) completing preoperative anesthesia interviews (PAIs) to increase their knowledge and confidence, improve ...completeness of documented preoperative interviews, and decrease day of surgery (DOS) cancellations.
Pre/post implementation design and retrospective chart review.
An educational module on PAIs was created and RNs working in the pre-admission testing (PAT) clinic were asked to complete the module. Pre and post implementation data was collected on RN knowledge and confidence, assessment completeness, and DOS cancellations.
Knowledge and confidence increases were not statistically significant, although several interview components within PAI documentation improved with statistical significance. Overall DOS cancellations, although not statistically significant, were found to decrease, 1.3% to 1.2%.
Registered nurses’ knowledge, confidence and PAI completeness improved after completing the educational module with anesthetic considerations. Patients seen at the PAT clinic for PAIs before the DOS allowed for patient optimization and education leading to decreased preventable DOS cancellations.
PDF
