Views of newly-qualified GPs about their training and preparedness: Lessons for extended generalist training

©British Journal of General Practice. Background: General practice is becoming increasingly complex due to an ageing population with multiple morbidities and the shift of services from secondary to primary care, yet GP training remains largely the same. Extended training is now recommended, initially proposed as a fourth GP specialty trainee year, but more recently as a broad-based 4-year specialty training programme. Aim: To explore the views of newly-qualified GPs about their training and preparedness for specific aspects of the GP's role. Design and setting Qualitative study with newly-qualified GPs who qualified with Severn Deanery between 2007 and 2010. Method: Semi-structured interviews with 18 GPs between November 2011 and April 2012. Results: Gaining experience in a variety of primary care environments widens insight into patient populations as well as helping GPs develop adaptability and confidence, although this is not routinely part of GP training. However, alongside variety, having continuity with patients in practice remains important. Opportunities to be involved in the management of a practice or to take on substantial leadership roles also vary widely and this may limit preparedness and development of generalist skills. Conclusion: Extended training could help prepare GPs for the current challenges of general practice. It could ensure all trainees are exposed to a greater variety of primary care settings including those outside GP practice, as well as experience of business, finance, and leadership roles. Collectively, these changes have the potential to produce GPs with both generalist and enhanced skills, who are better prepared to work collaboratively across the organisational boundaries between primary, secondary, and community care

Cofilin and drebrin mediated regulation of the neuronal cytoskeleton in development and disease

The brain is a highly complex structure; neurons extend axons which follow precise paths to make connections with their targets. This extension is guided by a specialised and highly motile structure at the axon tip -the growth cone- which integrates guidance cues to steer the axon through the environment. Aberrant pathfinding is likely to result in developmental impairments causing disruption to brain functions underlying emotion learning and memory. Furthermore, pre-existing connections are constantly remodelled, the ability to do so declines with age, and can have huge impacts on quality of life and well-being. Examining how changes in growth cone behaviour triggered by external cues occurs is crucial for understanding processes in both development and disease. Controlled reorganisation of growth cone cytoskeletal components, such as actin filaments, generate membrane protrusions forming lamellipodia and filopodia. Filopodium formation is commonly associated with sensing the mechanical and chemical environment of the cell. Despite our understanding of the guidance choices that can be made, how filopodia transmit information at a molecular level leading to profound changes in morphology, motility and directionality remains largely unknown. Various actin-binding proteins regulate the number, stability and branching of filopodia. They may therefore have a key role in priming or abrogating the ability of the growth cone to respond to a given guidance cue. I have shown that the actin binding proteins drebrin and cofilin, whilst displaying opposing molecular activities on actin filaments, work synergistically in a temporally regulated manner. A fluorescent membrane marker combined with tagged cofilin and drebrin enabled accurate correlation of cofilin and drebrin dynamics with growth cone morphology and filopodial turnover in live neurons. In contrast to previous in vitro experiments, cofilin was found to enhance the effect of drebrin to promote filopodia formation in intact neurons, and that growth cone spread was significantly constrained when cofilin was knocked down. Importantly, this adds to our understanding of how the two actin binding proteins contribute to directed motility in neuronal growth cone filopodia during guidance. Furthermore, following acute treatment with low concentrations of the repulsive guidance cue semaphorin-3A, neuronal growth cones expressing cofilin displayed increased morphological complexity and filopodial stability. This suggests that traditional collapse signals may serve as pause signals allowing neurons to increase the surface area to sense the environment adequately and enable precise wiring decisions. Remodeling of the cytoskeleton is perturbed in a number of degenerative diseases including Alzheimer's, Huntington's, and Amyotrophic Lateral Sclerosis. These conditions are associated with widespread synaptic loss, resulting in memory loss, cognitive impairment, and movement disorders which leads to severe deterioration in quality of life for those afflicted in addition to wider negative socioeconomic impacts. How widespread synaptic loss occurs is poorly understood. One common characteristic is neuronal stress which can be initiated through different conditions such as neuroinflammation, energetic stress, glutamate excitotoxicity, and accumulation of misfolded proteins, all of which have been associated with perturbation of the actin cytoskeleton and the initiation of the cofilin-actin rod stress response. Dysfunction of the cytoskeleton can lead to the disruption of synaptic activity by blocking the delivery of elements such as organelles and proteins required for maintenance of the synapse. Modulating this stress response offers an approach to protecting the integrity of normal synaptic function. Actin interacting protein-1 is a conserved actin binding protein that enhances the filament disassembly activity of cofilin. I have discovered that AIP-1 has a potent ability to prevent the formation of cofilin rods which are thought to contribute to the neuronal dysfunction in several neurodegenerative disorders, even when they are treated with amyloid-β or subjected to metabolic stress. This is the first study to demonstrate a molecular mechanism for preventing rod formation in the presence of a neuronal stressor and has the potential to protect against rod formation by other stressors associated with disease such as inflammation and excitotoxicity. AIP-1 offers the exciting possibility of a means to reverse cofilin rod formation and the subsequent cytoskeletal pathology associated with dementia and has potential for therapeutic exploitation in human disease. Furthermore, it is the first study to demonstrate that AIP-1 localises to areas of rapid actin remodeling in neuronal growth cones. Exploiting the action of AIP-1 therefore represents an exciting and novel therapeutic avenue to tackle neurodegeneration.University of Exeter Medical Schoo

Nancy Meleski Collection - Accession 1566

The Nancy Meleski Collection contains a family bible with names of people who got married, were born, and died, a family dictionary that contains names of people and towns, and a collection of sheet music for vocals, violin, and piano. Names and places listed in the family bible are: Moses F. Hardy, Amanda Kineeskern, Seward Valley, New York, Stefhen P. Brewster, Julia Holly, Amanda Hardy, William Eben Hardy, Parley Elmer Hardy, Katharine Melinda Brewster, and Rhoby Jennings. People and places listed in the family dictionary are: Volney, New York, Schroeppel, New York, Chauncy Morgan, Palermo Morgan, Albert Morgan, Richard Holly, and Marie Holly Woods.https://digitalcommons.winthrop.edu/manuscriptcollection_findingaids/2625/thumbnail.jp

Exposure to the rxr agonist sr11237 in early life causes disturbed skeletal morphogenesis in a rat model

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation in EO. Rats given SR11237 from post-natal day 5 to post-natal day 15 were harvested for micro-computed tomography (microCT) scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole-mount evaluation. RXR agonist-treated rats had shorter long bones than the controls and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape, in correspondence with p57 immunostaining. Additionally, SOX9-positive cells were found surrounding the calcified tissue. The epiphysis of SR11237-treated bones showed increased TRAP staining and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of the treated animals. This study suggests that stimulation of RXR causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models

Aircraft Cost Index and the Future of Carbon Emissions from Air Travel

Air travel accounts for 2% of global CO2 emissions and this proportion is set to grow in the future. There are currently no large scale solutions to drastically reduce the industry’s dependence on oil. Therefore, airlines are looking to use a basket of measures to reduce fuel consumption. Optimisation of the use of cost index (CI) could be a valuable addition to this. By balancing time-dependent costs with the cost of fuel, it controls the speed of the aircraft to achieve the most economic flight time. This has a direct impact on the CO2 emissions from the aircraft, with higher speeds resulting in higher fuel consumption. The aim of this study is to assess the impact that CI has on CO2 emissions for six different aircraft models on a flight-by-flight basis and to evaluate how the CI could be affected by future impacts on the industry for a representative aircraft. Results show that a range of representative CI values for different aircraft models exist and suggest that the maximum benefit for optimising CI values occurs for long range flights. The average saving in CO2 emissions is 1%. Results show that time-related costs have the greatest effect on the optimum CI values, particularly delay costs. On the fuel side of the equation it is notable that a carbon price resulting from the implementation of a market based mechanism has little impact on the optimum CI and only reduces CO2 emissions by 0.01% in this case. The largest savings in CO2 emissions result from the use of biofuels, with reductions of between 9% and 44% for 10% and 50% blends respectively. This study also highlights the need for further research into crew and maintenance costs, cumulative costs and delay induced by congestion and climate change events, as well as policy considerations to ensure that there is a reduction in CO2 emissions. The study concludes that CI should be seen as a valuable tool in both helping to reduce CO2 emissions, as well to assess the impact of future events on the industry

Socioeconomic conditions across life related to multiple measures of the endocrine system in older adults:Longitudinal findings from a British birth cohort study

AbstractBackgroundLittle is known about how socioeconomic position (SEP) across life impacts on different axes of the endocrine system which are thought to underlie the ageing process and its adverse consequences. We examined how indicators of SEP across life related to multiple markers of the endocrine system in late midlife, and hypothesized that lower SEP across life would be associated with an adverse hormone profile across multiple axes.MethodsData were from a British cohort study of 875 men and 905 women followed since their birth in March 1946 with circulating free testosterone and insulin-like growth factor-I (IGF-I) measured at both 53 and 60–64 years, and evening cortisol at 60–64 years. Indicators of SEP were ascertained prospectively across life—paternal occupational class at 4, highest educational attainment at 26, household occupational class at 53, and household income at 60–64 years. Associations between SEP and hormones were investigated using multiple regression and logistic regression models.ResultsLower SEP was associated with lower free testosterone among men, higher free testosterone among women, and lower IGF-I and higher evening cortisol in both sexes. For example, the mean standardised difference in IGF-I comparing the lowest with the highest educational attainment at 26 years (slope index of inequality) was −0.4 in men (95% CI -0.7 to −0.2) and −0.4 in women (−0.6 to −0.2). Associations with each hormone differed by SEP indicator used and sex, and were particularly pronounced when using a composite adverse hormone score. For example, the odds of having 1 additional adverse hormone concentration in the lowest compared with highest education level were 3.7 (95% CI: 2.1, 6.3) among men, and 1.6 (1.0, 2.7) among women (P (sex interaction) = 0.02). We found no evidence that SEP was related to apparent age-related declines in free testosterone or IGF-I.ConclusionsLower SEP was associated with an adverse hormone profile across multiple endocrine axes. SEP differences in endocrine function may partly underlie inequalities in health and function in later life, and may reflect variations in biological rates of ageing. Further studies are required to assess the likely functional relevance of these associations

Characterizing Diophantine Henselian valuation rings and valuation ideals

We give a characterization, in terms of the residue field, of those henselian valuation rings and those henselian valuation ideals that are diophantine. This characterization gives a common generalization of all the positive and negative results on diophantine henselian valuation rings and diophantine valuation ideals in the literature. We also treat questions of uniformity and we apply the results to show that a given field can carry at most one diophantine nontrivial equicharacteristic henselian valuation ring or valuation ideal