Abstract In addition to intellectual disability, individuals with Down syndrome (DS) exhibit dementia by the third or fourth decade of life, due to the early onset of neuropathological changes ...typical of Alzheimer's disease (AD). Deficient ontogenetic neurogenesis contributes to the brain hypoplasia and hypocellularity evident in fetuses and children with DS. A murine model of DS and AD (the Ts65Dn mouse) exhibits key features of these disorders, notably deficient ontogenetic neurogenesis, degeneration of basal forebrain cholinergic neurons (BFCNs), and cognitive deficits. Adult hippocampal (HP) neurogenesis is also deficient in Ts65Dn mice and may contribute to the observed cognitive dysfunction. Herein, we demonstrate that supplementing the maternal diet with additional choline (approximately 4.5 times the amount in normal rodent chow) dramatically improved the performance of the adult trisomic offspring in a radial arm water maze task. Ts65Dn offspring of choline-supplemented dams performed significantly better than unsupplemented Ts65Dn mice. Furthermore, adult hippocampal neurogenesis was partially normalized in the maternal choline supplemented (MCS) trisomic offspring relative to their unsupplemented counterparts. A significant correlation was observed between adult hippocampal neurogenesis and performance in the water maze, suggesting that the increased neurogenesis seen in the supplemented trisomic mice contributed functionally to their improved spatial cognition. These findings suggest that supplementing the maternal diet with additional choline has significant translational potential for DS.
Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed ...RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation.
Background
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with hepatic morbidity and mortality and extra-hepatic comorbidities. Published NASH cost-effectiveness models ...(CEMs) are heterogeneous and consistently omit comorbid conditions that frequently co-exist alongside NASH. We aimed to develop a de novo CEM framework that incorporates extra-hepatic disease states and outcomes alongside hepatic components to enable future estimation of the cost-effectiveness of NASH interventions.
Methods
Patient-level simulation and cohort-level Markov models were implemented in the same framework. Model inputs included fibrosis progression; late-stage liver disease outcomes; comorbidity outcomes for cardiovascular disease, type 2 diabetes, and obesity; mortality; health-related quality of life; and direct medical costs. The prototype analysis assessed the cost-effectiveness of obeticholic acid versus standard of care from a US payer perspective over a lifetime horizon with costs and effects discounted at 3% per annum. However, the CEM was designed for easy adaptation to other countries, time horizons, and other considerations. Efficacy and adverse event parameters were obtained from the 18-month interim analysis of the REGENERATE trial. Outputs include total and incremental costs, total life years, and quality-adjusted life years.
Results
In this model, total costs, total life years, and quality-adjusted life years were all higher with obeticholic acid compared with standard of care. Cross-validation of this model with the 2016 and 2020 Institute for Clinical and Economic Review models revealed marked differences, mainly driven by mortality inputs, transition probability estimates, and incorporation of the effect of treatment and comorbidities.
Conclusion
This is the first CEM in NASH to incorporate the clinical consequences of several comorbidities. The flexible yet standardized framework permits estimation of the cost-effectiveness of NASH interventions in a variety of settings. The model currently includes several assumptions and will be further developed as more relevant data become available.
Infographic
In May of 2001, thirteen experts on computerized provider order entry (CPOE) from around the world gathered at a 2-day conference to develop a consensus statement on successful CPOE implementation. A ...qualitative research approach was used to generate and validate a list of categories and considerations to guide CPOE implementation.
The 2013 Breast Cancer Campaign gap analysis established breast cancer research priorities without a specific focus on surgical research or the role of surgeons on breast cancer research. This Review ...aims to identify opportunities and priorities for research in breast surgery to complement the 2013 gap analysis. To identify these goals, research-active breast surgeons met and identified areas for breast surgery research that mapped to the patient pathway. Areas included diagnosis, neoadjuvant treatment, surgery, adjuvant therapy, and attention to special groups (eg, those receiving risk-reducing surgery). Section leads were identified based on research interests, with invited input from experts in specific areas, supported by consultation with members of the Association of Breast Surgery and Independent Cancer Patients' Voice groups. The document was iteratively modified until participants were satisfied that key priorities for surgical research were clear. Key research gaps included issues surrounding overdiagnosis and treatment; optimising treatment options and their selection for neoadjuvant therapies and subsequent surgery; reducing rates of re-operations for breast-conserving surgery; generating evidence for clinical effectiveness and cost-effectiveness of breast reconstruction, and mechanisms for assessing novel interventions; establishing optimal axillary management, especially post-neoadjuvant treatment; and defining and standardising indications for risk-reducing surgery. We propose strategies for resolving these knowledge gaps. Surgeons are ideally placed for a central role in breast cancer research and should foster a culture of engagement and participation in research to benefit patients and health-care systems. Development of infrastructure and surgical research capacity, together with appropriate allocation of research funding, is needed to successfully address the key clinical and translational research gaps that are highlighted in this Review within the next two decades.
Since 2012, second-year English and Drama undergraduates at the University of Exeter have had the opportunity to take a course called “Theatrical Cultures”. This option introduces students to plays ...and entertainments that were popular between the 1580s and the 1640s, with a view to opening an understanding of the period that is deeply informed by theatre history. In this essay, we share and reflect on our teaching of Christopher Marlowe’s Tamburlaine, Parts One and Two, which examines the plays as productions by the Lord Admiral’s Men in the Rose playhouse. We start by explaining the learning context for the blocking workshop we use as a practical teaching method. We then share instructions for setting up the workshop and outline our “learning-by-doing” methodology, which involves placing the bodies of our students and the properties necessary to perform a scene within the dimensions of the first Rose stage. The intended learning outcomes of the workshop include a practical understanding of the affordances of the early modern playhouse and the ability to translate this understanding into a critical interpretation of Marlowe’s drama. As students deliver lines, wield swords and crowns, and try to imagine how a chariot navigates the stage space available, they recognise moments of potential bathos and physical comedy in the plays, hinting at those “fond and frivolous gestures” that Marlowe’s publisher, Richard Jones, sought to remove from the 1590 play-text. In the third section of the essay, we evaluate these insights and the workshop’s pedagogical value by sharing reflections by tutors and students who have participated in the blocking workshop.
An outbreak of over 1,000 COVID-19 cases in Provincetown, Massachusetts (MA), in July 2021—the first large outbreak mostly in vaccinated individuals in the US—prompted a comprehensive public health ...response, motivating changes to national masking recommendations and raising questions about infection and transmission among vaccinated individuals. To address these questions, we combined viral genomic and epidemiological data from 467 individuals, including 40% of outbreak-associated cases. The Delta variant accounted for 99% of cases in this dataset; it was introduced from at least 40 sources, but 83% of cases derived from a single source, likely through transmission across multiple settings over a short time rather than a single event. Genomic and epidemiological data supported multiple transmissions of Delta from and between fully vaccinated individuals. However, despite its magnitude, the outbreak had limited onward impact in MA and the US overall, likely due to high vaccination rates and a robust public health response.
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•Large Delta outbreak in a highly vaccinated population changed US indoor masking policy•Outbreak included multiple Delta introductions; one introduction led to 83% of cases•Spread from and between vaccinated cases contributed, a picture resolved by genomic data•Outbreak was successfully contained; it did not drive the rise of Delta in MA or the US
Rapid integration of epidemiological and genomic data was used to support the public health response during a large outbreak of the SARS-CoV-2 Delta variant. The outbreak stemmed primarily from a single source spreading the virus at multiple locations, and while numerous likely transmissions from and between vaccinated individuals were observed, the downstream impact of the outbreak was minimized with robust intervention and community engagement.
Children's nurses require a wide range of skills and knowledge to enable them to provide the best care for children and families, thus nurse educators must continually strive to ensure they create ...appropriate and meaningful learning for students in their journey to become children's nurses. Museum visits have been utilized previously within nurse education, but no evidence as to any added value of such visits on the learning of children's nursing students has been reported. This article highlights an innovative teaching strategy that was introduced to a group of year 1 children's nursing students-a field visit to the Museum of Childhood in London-and demonstrates the potential value to their learning. Students worked together in small groups within the museum exploring topics relevant to children's nursing. They had an opportunity to reflect and research further and then worked together to present their learning to their peers. Subsequent evaluation of both the visit and the presentation helped unravel the extent of student learning and highlighted that a range of different learning had taken place. Not without its challenges, the museum visit seemed to provide a meaningful learning experience for students, and suggestions for improving the learning for future similar groups have been explored.
Background
Cancer patients are often malnourished pre‐operatively. The present study aimed to establish whether current screening was appropriate for use in prehabilitation and investigate any ...association between nutritional risk, functionality and quality of life (QoL).
Methods
This cohort study used routinely collected data from September 2020 to August 2021 from patients in a Prehab4cancer programme. Included patients were aged ≥ 18 years, had colorectal, lung or oesophago‐gastric cancer and were scheduled for surgery. Nutritional assessment included Patient‐Generated Subjective Global Assessment (PG‐SGA) Short‐Form and QoL with a sit‐to‐stand test. Association between nutritional risk and outcomes was analysed using adjusted logistic regression.
Results
From 928 patients referred to Prehab4Cancer service over 12 months, data on nutritional risk were collected from 526 patients. Pre‐operatively, 233 out of 526 (44%) patients were at nutritional risk (score ≥ 2). During prehabilitation, 31% of patients improved their PG‐SGA and 74% of patients maintained or improved their weight. Odds ratios (OR) with confidence intervals (CI) showed that patients with better QoL using EuroQol‐5 Dimensions (OR = 0.05, 95% CI = 0.01, 0.45, p = 0.01), EuroQol Visual Analogue Scale (OR = 0.96, 95% CI = 0.93, 1.00, p = 0.04) or sit‐to‐stand (OR = 0.96, 95% 0.93, 1.00, p = 0.04) were less likely to be nutritional at risk.
Conclusions
Almost half of patients in Prehab4Cancer programme assessed using PG‐SGA were at risk of malnutrition. However, almost half of the sample did not have their risk assessed. Patients at risk of malnutrition were more likely to have a poorer QoL and sit‐to‐stand test than those who were not at risk.
Key points
Colorectal, lung or oesopho‐gastric cancer patients referred to the Prehab4Cancer service underwent a nutritional assessment. Almost half of patients assessed using the Patient‐Generated Subjective Global Assessment (i.e., PG‐SGA) were at risk of malnutrition. Patients at risk of malnutrition were more likely to have a worse quality of life and sit‐to‐stand test indicating reduced physical function than those who were not at risk of malnutrition. This indicates that optimising the nutritional status of cancer patients in the prehabilitation period can maximise the nutritional status, functionality and quality of life of patients.
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