Lynchhudson9076
Recent progress in deep learning has greatly improved the prediction of RNA splicing from DNA sequence. Here, we present Pangolin, a deep learning model to predict splice site strength in multiple tissues. Pangolin outperforms state-of-the-art methods for predicting RNA splicing on a variety of prediction tasks. Pangolin improves prediction of the impact of genetic variants on RNA splicing, including common, rare, and lineage-specific genetic variation. In addition, Pangolin identifies loss-of-function mutations with high accuracy and recall, particularly for mutations that are not missense or nonsense, demonstrating remarkable potential for identifying pathogenic variants.
Current hyponatraemia guidelines are divided on the use of tolvaptan in hospitalised patients with moderate to severe hyponatraemia, due to an uncertain risk-benefit ratio. We will conduct a randomised trial to test the hypothesis that early use of tolvaptan improves the rate of serum sodium correction and clinical outcomes compared with current standard first-line therapy, restriction of fluid intake, without increasing the risk of serum sodium overcorrection.
We will enrol hospitalised patients with euvolaemic or hypervolaemic hyponatraemia and serum sodium of 115-130 mmol/L at Austin Health, a tertiary care centre in Melbourne, Australia. Participants will be randomised 11 to receive either tolvaptan (initial dose 7.5 mg) or fluid restriction (initial limit 1000 ml per 24 h), with titration of therapy based on serum sodium response according to a pre-determined protocol over a 72-h intervention period. The primary endpoint will be the between-group change in serum sodium over time, from study day 1 to ur findings, we will have established an evidence-based framework for tolvaptan initiation and monitoring to guide its use.
Australia and New Zealand Clinical Trials Registry ACTRN12619001683123 . Registered on December 2 2019.
Australia and New Zealand Clinical Trials Registry ACTRN12619001683123 . Registered on December 2 2019.
Among esophagogastric cancer patients, the probability of having undergone treatment with curative intent has been shown to vary, depending on the hospital of diagnosis. However, little is known about the factors that contribute to this variation. In this study, we sought to understand the organization of clinical pathways and their association with variation in practice.
A mixed-method study using quantitative and qualitative data was conducted. Quantitative data were obtained from the Netherlands Cancer Registry (e.g., outpatient clinic consultations and diagnostic procedures). For qualitative data, thematic content analysis was performed using semi-structured interviews (n = 30), observations of outpatient clinic consultations (n = 26), and multidisciplinary team meetings (MDTM, n = 16) in eight hospitals, to assess clinicians' perspectives regarding the clinical pathways.
Quantitative analyses showed that patients more often underwent surgical consultation prior to the MDTM in hospitals associated with a low probability of receiving such treatment.
Surgical consultation prior to MDTM was more often conducted in hospitals associated with a high probability of receiving treatment with curative intent, whereas a geriatrician was consulted more often in hospitals associated with a low probability of receiving such treatment.
Clinical research should provide reliable evidence to clinicians, health policy makers, and researchers. The reliability of evidence will be assured once study planning, conducting, and reporting of results are transparent. The present research investigates publication rates, time until publication, and characteristics of clinical trials on medicinal products associated with timely publication of results, measures of scientific impact, authorship, and open access publication.
Clinical trials authorized in Hungary in 2012 were followed until publication and/or June 2020. Corresponding scientific publications were searched via clinical trial registries, PubMed (MEDLINE), and Google.
Overall, 330 clinical trials were authorized in 2012 of which 232 trials were completed for more than 1 year in June 2020. The proportion of industry initiation was high (97%). Time to publication was 21 (22) months [median (IQR)]. Time to publication was significantly shorter when trials involved both European and non-Europea of information of clinical trial results. c-Met inhibitor Publications with domestic co-authors contribute to the research output of a country. Measurable domestic scientific impact of trials on medicinal products needs further improvement.
Glycoengineering, in the biotechnology workhorse bacterium, Escherichia coli, is a rapidly evolving field, particularly for the production of glycoconjugate vaccine candidates (bioconjugation). Efficient production of glycoconjugates requires the coordinated expression within the bacterial cell of three components a carrier protein, a glycan antigen and a coupling enzyme, in a timely fashion. Thus, the choice of a suitable E. coli host cell is of paramount importance. Microbial chassis engineering has long been used to improve yields of chemicals and biopolymers, but its application to vaccine production is sparse.
In this study we have engineered a family of 11 E. coli strains by the removal and/or addition of components rationally selected for enhanced expression of Streptococcus pneumoniae capsular polysaccharides with the scope of increasing yield of pneumococcal conjugate vaccines. Importantly, all strains express a detoxified version of endotoxin, a concerning contaminant of therapeutics produced inli Falcon, Peregrine and Sparrowhawk all showed increased production of S. pneumoniae serotype 4 capsule. Eagle (a strain without enterobacterial common antigen, containing a GalNAc epimerase and PglB expressed from the chromosome) and Sparrowhawk (a strain without enterobacterial common antigen, O-antigen ligase and chain length determinant, containing a GalNAc epimerase and chain length regulators from Streptococcus pneumoniae) respectively produced an AcrA-SP4 conjugate with 4 × and 14 × more glycan than that produced in the base strain, W3110. Beyond their application to the production of pneumococcal vaccine candidates, the bank of 11 new strains will be an invaluable resource for the glycoengineering community.
Chronic kidney disease (CKD) is a very common long-term condition and powerful risk factor for cardiovascular disease (CVD). Low-dose aspirin is of proven benefit in the secondary prevention of myocardial infarction (MI) and stroke in people with pre-existing CVD. However, in people without CVD, the rates of MI and stroke are much lower, and the benefits of aspirin in the primary prevention of CVD are largely balanced by an increased risk of bleeding. People with CKD are at greatly increased risk of CVD and so the absolute benefits of aspirin are likely to be greater than in lower-risk groups, even if the relative benefits are the same. Post hoc evidence suggests the relative benefits may be greater in the CKD population but the risk of bleeding may also be higher. A definitive study of aspirin for primary prevention in this high-risk group, recommended by the National Institute for Health and Care Excellence (NICE) in 2014, has never been conducted. The question has global significance given the rising burased in those randomised to take aspirin. The key consideration is then whether and to what extent the benefits of aspirin from the expected reduction in CVD events exceed the risks of major bleeding.
This will be the first definitive trial of aspirin for primary CVD prevention in CKD patients. The research will be of great interest to clinicians, guideline groups and policy-makers, in the UK and globally, particularly given the high and rising prevalence of CKD that is driven by population ageing and epidemics of obesity and diabetes. The low cost of aspirin means that a positive result would be of relevance to low- and middle-income countries and the impact in the developed world less diluted by any inequalities in health care access.
ISRCTN ISRCTN40920200 . EudraCT 2018-000644-26 .
gov NCT03796156.
gov NCT03796156.
Signs of disorder in neighbourhoods (e.g., litter, graffiti) are thought to influence the behaviour of residents, potentially leading to violations of rules and petty criminal behaviour. Recently, these premises have been applied to the hospital context, with physical and social disorder found to have a negative association with patient safety. Building on these results, the present study investigates whether physical and social disorder differ between hospitals, and their relationship to safety culture.
We conducted a cross sectional survey with Likert-style and open response questions administered in four Australian hospitals. All staff were invited to participate in the pilot study from May to September 2018. An analysis of variance (ANOVA) was used to examine differences in disorder by hospital, and hierarchical linear regression assessed the relationship of physical and social disorder to key aspects of safety culture (safety climate, teamwork climate). Open responses were analysed using thematic anapting to holistically understand a hospital's safety culture. Interventions that target aspects of physical and social disorder in a hospital may hold value in improving safety culture and patient safety.
Epidemiological studies have suggested that elevated concentrations of particulate matter (PM) are strongly associated with the incidence of atherosclerosis, however, the underlying cellular and molecular mechanisms of atherosclerosis by PM exposure and the components that are mainly responsible for this adverse effect remain to be established. In this investigation, we evaluated the effects of ambient PM on vascular smooth muscle cell (VSMC) behavior. Furthermore, the effects of polycyclic aromatic hydrocarbons (PAHs), major components of PM, on VSMC migration and the underlying mechanisms were examined.
VSMC migration was significantly increased by treatment with organic matters extracted from ambient PM. The total amount of PAHs contained in WPM was higher than that in SPM, leading to higher ROS generation and VSMC migration. The increased migration was successfully inhibited by treatment with the anti-oxidant, N-acetyl-cysteine (NAC). The levels of matrix metalloproteinase (MMP) 2 and 9 were significathe activation of the focal adhesion complex.
PAHs, including oxy-PAHs, in ambient PM may have dual effects that lead to an increase in VSMC migration. One is the generation of oxidative stress followed by MMP upregulation, and the other is actin reorganization that results from the activation of the focal adhesion complex.
Despite the widespread adoption of interprofessional simulation-based education (IPSE) in healthcare as a means to optimize interprofessional teamwork, data suggest that IPSE may not achieve these intended goals due to a gap between the ideals and the realities of implementation.
We conducted a qualitative case study that used the framework method to understand what and how core principles from guidelines for interprofessional education (IPE) and simulation-based education (SBE) were implemented in existing in situ IPSE programs. We observed simulation sessions and interviewed facilitators and directors at seven programs.
We found considerable variability in how IPSE programs apply and implement core principles derived from IPE and SBE guidelines with some principles applied by most programs (e.g., "active learning", "psychological safety", "feedback during debriefing") and others rarely applied (e.g., "interprofessional competency-based assessment", "repeated and distributed practice"). Through interviews we identified that buy-in, resources, lack of outcome measures, and power discrepancies influenced the extent to which principles were applied.
