Background and Aims
Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD.
Approach and Results
We ...generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high‐fat, high‐fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond.
Conclusions
This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication.
BackgroundThe pathophysiology of COVID-19 remains poorly understood. We aimed to estimate the contribution of intrapulmonary shunting and ventilation-to-perfusion (VA/Q) mismatch using a mathematical ...model to construct oxygen-haemoglobin dissociation curves (ODCs).MethodsODCs were constructed using transcutaneous pulse oximetry at two different fractions of inspired oxygen (FiO2). 199 patients were included from two large district general hospitals in the South East of England from 1st to 14th January 2021. The study was supported by the National Institute of Health Research (NIHR) Clinical Research Network.ResultsOverall mortality was 29%. Mean age was 68.2 years (SEM 1·2) with 46% female. Median shunt on admission was 17% (IQR 8-24.5); VA/Q was 0.61 (IQR 0.52-0.73). Shunt was 37.5% higher in deaths (median 22%, IQR 9-29) compared to survivors (16%, 8-21; p = 0.0088) and was a predictor of mortality (OR 1.04; 95% CI 1.01-1.07). Admission oxygen saturations were more strongly predictive of mortality (OR 0.91, 95% CI 0.87-0.96). There was no difference in VA/Q mismatch between deaths (0.60; IQR 0.50-0.73) and survivors (0.61; IQR 0.52-0.73; p = 0.63) and it was not predictive of mortality (OR 0.68; 95% CI 0.18-2.52; p = 0.55). Shunt negatively correlated with admission oxygen saturation (R -0.533; p<0.0001) whereas VA/Q was not (R 0.1137; p = 0.12).InterpretationShunt, not VA/Q mismatch, was associated with worsening hypoxia, though calculating shunt was not of prognostic value. This study adds to our understanding of the pathophysiology of hypoxaemia in COVID-19. Our inexpensive and reliable technique may provide further insights into the pathophysiology of hypoxia in other respiratory diseases.
The pathophysiology of COVID-19 remains poorly understood. We aimed to estimate the contribution of intrapulmonary shunting and ventilation-to-perfusion (VA/Q) mismatch using a mathematical model to ...construct oxygen-haemoglobin dissociation curves (ODCs).
ODCs were constructed using transcutaneous pulse oximetry at two different fractions of inspired oxygen (FiO2). 199 patients were included from two large district general hospitals in the South East of England from 1st to 14th January 2021. The study was supported by the National Institute of Health Research (NIHR) Clinical Research Network.
Overall mortality was 29%. Mean age was 68.2 years (SEM 1·2) with 46% female. Median shunt on admission was 17% (IQR 8-24.5); VA/Q was 0.61 (IQR 0.52-0.73). Shunt was 37.5% higher in deaths (median 22%, IQR 9-29) compared to survivors (16%, 8-21; p = 0.0088) and was a predictor of mortality (OR 1.04; 95% CI 1.01-1.07). Admission oxygen saturations were more strongly predictive of mortality (OR 0.91, 95% CI 0.87-0.96). There was no difference in VA/Q mismatch between deaths (0.60; IQR 0.50-0.73) and survivors (0.61; IQR 0.52-0.73; p = 0.63) and it was not predictive of mortality (OR 0.68; 95% CI 0.18-2.52; p = 0.55). Shunt negatively correlated with admission oxygen saturation (R -0.533; p<0.0001) whereas VA/Q was not (R 0.1137; p = 0.12).
Shunt, not VA/Q mismatch, was associated with worsening hypoxia, though calculating shunt was not of prognostic value. This study adds to our understanding of the pathophysiology of hypoxaemia in COVID-19. Our inexpensive and reliable technique may provide further insights into the pathophysiology of hypoxia in other respiratory diseases.
Learn about alternative ways of managing the change experience to make it doable, energising and transformative. The process of change in all organizations - corporate, public sector and ...not-for-profit - can be fraught, overwhelming and unpredictable, both for those experiencing change and for those charged with its implementation. Relational Change presents a refreshingly readable and accessible alternative to the normal rhetoric of mechanistic, top-down change. Instead, Liz Wiggins and Harriet Hunter show how paying closer attention to personal interactions and relationships lies at the very heart of effective and sustainable change in organizations. Exploring issues of power, politics, emotions and the way people and systems can become stuck in unhelpful patterns, this book will help you work practically with the messiness of change. The dynamic new ways discussed are highly relevant for life in organizations today and will apply to your life outside work too. Integrating research and theory from a wide range of sources, as well sharing their own extensive experience of leading change, the authors present a stimulating and thought-provoking people-centred and relational approach that focuses on doing with others, rather than doing to them. Relational Change combines academically-grounded, theoretically-robust thinking that explains the rationale for relational change with real-world stories that will resonate with your own experience of change, whether as a seasoned or novice leader.
...the methotrexate is making him very sick; despite taking ondansetron, he is violently ill after each weekly methotrexate dose, often vomiting to the point of epistaxis. ACR, American College of ...Rheumatology; ADA, adalimumab; CHAQ, Childhood Health Assessment Questionnaire; ETA, etanercept; IL, interleukin; JADAS, Juvenile Arthritis Disease Activity Score; JIA, juvenile idiopathic arthritis; pJIA, polyarticular JIA; QALY, quality-adjusted life year; RR, relative risk; TNF, tumour necrosis factor; RCT, randomised controlled trial. Rather than traditional RCTs, these are both withdrawal trials; all participants receive the drug during an intial ‘lead-in’ phase, then only those showing a response enter the double-blind phase and randomised to either drug or placebo. Since the trial phase is thus targeted to known responders, the outcome is not diluted by refractory cases. ADA is also an effective treatment for inflammatory bowel disease,13 whereas ETA is not.14 On the other hand, in certain settings, clinicians may favour ETA due to a lower risk of tuberculosis.15 Clinical bottom line Both etanercept and adalimumab are safe and effective drugs in the treatment of juvenile idiopathic arthritis (Grade A).
The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however there is a low conversion rate from success in animals to ...humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any established therapies and a major field of animal research. We performed a meta-analysis with meta-regression of 603 interventional rodent studies (10,364 animals) in NAFLD to assess which variables influenced treatment response. Weight loss and alleviation of insulin resistance were consistently associated with improvement in NAFLD. Multiple drug classes that do not affect weight in humans caused weight loss in animals. Other study design variables, such as age of animals and dietary composition, influenced the magnitude of treatment effect. Publication bias may have increased effect estimates by 37-79%. These findings help to explain the challenge of reproducibility and translation within the field of metabolism.
Metastatic neuroendocrine tumour of the orbit Hunter, Harriet; Thomas, Mike
Diagnostic histopathology (Oxford, England : 2008),
March 2024, 2024-03-00, Letnik:
30, Številka:
3
Journal Article
Recenzirano
A 64-year-old patient presented with a tumour of the orbit. A biopsy showed an infiltrative tumour with coarse “salt-and-pepper” chromatin, showing strong expression of AE1/3, CD56, synaptophysin, ...chromogranin, and CDX2 on immunohistochemistry. The Ki67 proliferation index was low (<1%). The diagnosis of metastatic neuroendocrine tumour, most likely of gastrointestinal origin was favoured over a primary neuroendocrine tumour of the orbit.
Abstract Both catchment geology and land use surrounding a stream will affect the degree of fine sediment deposition from erosion and its consequent impacts on stream macroinvertebrate communities. ...While geology and land use have been shown to impact stream communities individually, their interaction has received less attention. We investigated the interaction between geology and land use on stream macroinvertebrate communities in the Tairāwhiti Region, New Zealand. The region has streams that drain harder sandstones and softer shales and mudstones, the latter having some of the highest erosion rates in the world. Macroinvertebrates were sampled each year between 2016 and 2018 at 80 sites in exotic forest, indigenous forest and pasture streams that drained hard or soft geology catchments. Conductivity in pasture and exotic forest streams was nearly twice as high as in indigenous forest streams and higher in soft than hard sediment streams. Deposited sediment cover was greater in soft than hard sediment streams, and greater in pasture and exotic forest streams than in indigenous forest streams. Periphyton cover did not differ between land uses but was higher in soft sediment streams. Ecological health was higher in the indigenous forest sites, intermediate in exotic forest sites and lowest in pasture streams. Biological indices were also higher within each land use in streams draining hard than soft sediment streams. Invertebrate communities appear to be determined primarily by the amount of deposited fine sediment and conductivity, both of which are higher in soft than in hard bottom streams, and in exotic forest and pasture streams. Synthesis and applications : Our results illustrate a complex and strong interaction between geology and land use and the consequent impact on stream macroinvertebrate communities. The combination of soft bottom streams with pasture or exotic forest land use is more detrimental than in similar hard bottom streams. Therefore, regulations for the management of any given land use need to be much stricter in catchments dominated by soft sediment geology.
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