Project description:BackgroundInsulin shares a limited physiological concentration range with other endocrine hormones. Not only too low, but also too high systemic insulin levels are detrimental for body functions.Main bodyThe physiological function and clinical relevance of insulin are usually seen in association with its role in maintaining glucose homeostasis. However, insulin is an anabolic hormone which stimulates a large number of cellular responses. Not only too low, but also excess insulin concentrations are detrimental to the physiological balance. Although the glucoregulatory activity of insulin is mitigated during hyperinsulinemia by dampening the efficiency of insulin signaling ("insulin resistance"), this is not the case for most other hormonal actions of insulin, including the promotion of protein synthesis, de novo lipogenesis, and cell proliferation; the inhibition of lipolysis, of autophagy-dependent cellular turnover, and of nuclear factor E2-related factor-2 (Nrf2)-dependent antioxidative; and other defense mechanisms. Hence, there is no general insulin resistance but selective impairment of insulin signaling which causes less glucose uptake from the blood and reduced activation of endothelial NO synthase (eNOS). Because of the largely unrestricted insulin signaling, hyperinsulinemia increases the risk of obesity, type 2 diabetes, and cardiovascular disease and decreases health span and life expectancy. In epidemiological studies, high-dose insulin therapy is associated with an increased risk of cardiovascular disease. Randomized controlled trials of insulin treatment did not observe any effect on disease risk, but these trials only studied low insulin doses up to 40 IU/day. Proof for a causal link between elevated insulin levels and cardiovascular disease risk comes from Mendelian randomization studies comparing individuals with genetically controlled low or high insulin production.ConclusionsThe detrimental actions of prolonged high insulin concentrations, seen also in cell culture, argue in favor of a lifestyle that limits circadian insulin levels. The health risks associated with hyperinsulinemia may have implications for treatment regimens used in type 2 diabetes.
Project description:Traditionally the management of any chronic condition starts with its diagnosis. The labelling of disease can be beneficial in terms of defining appropriate treatment such as in coronary artery disease. However, sometimes it may be detrimental such as when x-rays are used to diagnose lumbar spondylosis leading to patients inappropriately limiting their activity. Chronic knee pain in the elderly is another example where applying labels is problematical. A common diagnosis in this situation is osteoarthritis, but this label can be applied in two ways: as a radiological diagnosis, or as a clinical one. The x-ray diagnosis, however, does not equate with the clinical syndrome, and vice versa. In addition, diagnosing knee pain as osteoarthritis does not necessarily help in management, since a patient's debility is more dependent upon their clinical signs and symptoms than the presence of radiographic osteoarthritis, and by the same token its clinical counterpart. GPs are consistent in their management of knee pain, but in attempting to diagnose the pain as osteoarthritis, these plans can alter and become more dependent on the actual diagnosis than the clinical picture. As a result management may well diverge from what the current best evidence supports. Diagnosis for diagnosis sake, should therefore be discouraged, and chronic knee pain gives us one example of why this is the case. GPs would be better placed to manage this condition if it was considered more as a regional pain syndrome, perhaps defining it simply as 'chronic knee pain in older people'. This example suggests that there is a pressing need in primary care to carefully consider in chronic disease when it is appropriate to be definitive in diagnosis such that when using disease specific labels, there is definite benefit for the patient and doctor.
Project description:Acquired resistance to targeted inhibitors remains a major, and inevitable, obstacle in the treatment of oncogene-addicted cancers. Newer-generation inhibitors may help overcome resistance mutations, and inhibitor combinations can target parallel pathways, but durable benefit to patients remains elusive in most clinical scenarios. Now, recent studies suggest a third approach may be available in some cases-exploitation of oncogene overexpression that may arise to promote resistance. Here, we discuss the importance of maintaining oncogenic signaling at "just-right" levels in cells, with too much signaling, or oncogene overdose, being potentially as detrimental as too little. This is highlighted in particular by recent studies of mutant-BRAF in melanoma and the fusion kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in anaplastic large cell lymphoma. Oncogene overdose may be exploitable to prolong tumor control through intermittent dosing in some cases, and studies of acute lymphoid leukemias suggest that it may be specifically pharmacologically inducible.
Project description:ObjectiveTo explore how out-of-hours primary healthcare services (OOHS) are represented in UK national newspapers, focusing on content and tone of reporting and the use of personal narratives to frame stories.DesignA retrospective cross-sectional quantitative content analysis of articles published in 2005, 2010 and 2015.Data sourcesNexis database used to search 10 UK national newspapers covering quality, middle-market and tabloid publications.Inclusion/exclusion criteriaAll articles containing the terms 'out-of-hours' (≥3 mentions per article) or ('NHS 24' OR 'NHS 111' OR 'NHS Direct') AND 'out-of-hours' (≥1 mention per article) were included. Letters, duplicate news items, opinion pieces and articles without a substantial portion of the story (>50% of an article's word count, as judged by researchers) concerning OOHS were excluded.Results332 newspaper articles were identified: 113 in 2005 (34.1%), 140 in 2010 (42.2%) and 79 in 2015 (23.8%). Of these, 195 (58.7%) were in quality newspapers, 99 (29.8%) in middle-market and 38 (11.3%) in tabloids. The most commonly reported themes were OOHS organisation, personal narratives and telephone triage. Stories about service-level crises and personal tragedy, including unsafe doctors and missed or delayed identification of rare conditions, predominated. The majority of articles (252, 75.9%) were negative in tone. This was observed for all included newspapers and by publication genre; middle-market newspapers had the highest percentage of negative articles (Pearson χ2=35.72, p<0.001). Articles presented little supporting contextual information, such as call rates per annum, or advice on how to access OOHS.ConclusionIn this first reported analysis of UK national newspaper coverage of OOHS, media representation is generally negative in tone, with frequent reports of 'negative exemplars' of OOHS crises and fatal individual patient cases with little or no contextualisation. We present recommendations for the future reporting of OOHS, which could apply to the reporting of healthcare services more generally.
Project description:To describe the resilience and emotional intelligence of Registered Practical Nurses working in Home and Community Care during the COVID-19 pandemic. Specifically, to determine if there was a relationship between resilience and emotional intelligence based on whether a nurse: (1) left the sector, (2) considered leaving, or (3) took a leave of absence during the pandemic. An online cross-sectional survey was used to capture respondents' demographic information and scores on the Connor-Davidson Resilience Scale, Resilience at Work Scale®, and Wong and Law Emotional Intelligence Scale. Registered Practical Nurses working, or who had worked, in Home and Community Care January 2020 to September 2022 were eligible to participate. The Checklist for Reporting Results of Internet E-Surveys was used. The survey was available June to September 2022 and advertised by the Registered Practical Nurses Association of Ontario to approximately 2105 members. Descriptive statistics and independent samples t-tests were used to analyze results at a level of P < .05 was used for all analyses. A total of 672 respondents participated (completion rate = 92.8%). There were no differences on resilience or emotional intelligence scores based on whether a nurse left, or considered leaving, the Home and Community Care sector during the pandemic. However, nurses who took a leave of absence scored significantly higher on resilience and emotional intelligence measures when compared to those who did not. Results suggest that a leave of absence for these nurses during the pandemic may have been a supportive coping strategy.
Project description:Air pollution contributes to poor respiratory and cardiovascular health. Susceptible individuals may be advised to mitigate effects of air pollution through actions such as reducing outdoor physical activity on days with high pollution. Our analysis identifies the extent to which susceptible individuals changed activities due to bad air quality. This cross-sectional study included 10,898 adults from the National Health and Nutrition Examination Survey (NHANES) 2007-2010. Participants reported if they did something differently when air quality was bad. Susceptible categories included respiratory conditions, cardiovascular conditions and older age (≥ 65 years). Analyses accounted for complex survey design; logistic regression models controlled for gender, race, education, smoking, and body mass index. 1305 individuals reported doing something differently (12.0%, 95% confidence interval (CI): 10.9, 13.1). This percentage was 14.2% (95% CI: 11.6, 16.8), 25.1% (95% CI: 21.7, 28.6), and 15.5% (95% CI: 12.2, 18.9) among older adults, those with a respiratory condition, and those with a cardiovascular condition, respectively. In adjusted regression models the following were significantly more likely to have changed activity compared to those who did not belong to any susceptible group: respiratory conditions (adjusted odds ratio (aOR): 2.61, 95% CI: 2.03, 3.35); respiratory and cardiovascular conditions (aOR: 4.36, 95% CI: 2.47, 7.69); respiratory conditions and older age (aOR: 3.83; 95% CI: 2.47, 5.96); or all three groups (aOR: 3.52; 95% CI: (2.33, 5.32). Having cardiovascular conditions alone was not statistically significant. Some individuals, especially those with a respiratory condition, reported changing activities due to poor air quality. However, efforts should continue to educate the public about air quality and health.
Project description:FliL is a bacterial flagellar protein demonstrated to associate with, and regulate ion flow through, the stator complex in a diverse array of bacterial species. FliL is also implicated in additional functions such as stabilizing the flagellar rod, modulating rotor bias, sensing the surface, and regulating gene expression. How can one protein do so many things? Its location is paramount to understanding its numerous functions. This review will look at the evidence, attempt to resolve some conflicting findings, and offer new thoughts on FliL.