342 research outputs found
Adherence barriers to antimicrobial treatment guidelines in teaching hospital, the Netherlands
Full text linkTo optimize appropriate antimicrobial use in a university hospital and identify barriers hampering implementation strategies, physicians were interviewed regarding their opinions on antimicrobial policies. Results indicated that effective strategies should include regular updates of guidelines that incorporate the views of relevant departments and focus on addressing senior staff and residents because residents do not make independent decisions in a teaching-hospital setting
Eligibility for sotagliflozin in a real-world heart failure population based on the SOLOIST-WHF trial enrolment criteria: Data from the swedish heart failure registry
Full text linkAims: The SOLOIST-WHF trial demonstrated efficacy of sotagliflozin in patients with type 2 diabetes mellitus (T2DM) and recent worsening heart failure (HF) regardless of ejection fraction (EF). Selection criteria in trials may limit their generalizability. Therefore, we aimed to investigate eligibility for sotagliflozin based on the SOLOIST-WHF criteria in a real-world HF population. Methods and results: SOLOIST-WHF criteria were applied to patients stabilized after HF hospitalization in the Swedish HF Registry according to 1) literal scenario (all inclusion/exclusion criteria) or 2) pragmatic scenario (only criteria likely to influence treatment decisions). Of 5453 inpatients with T2DM and recent worsening HF, 51.4% had reduced EF (HFrEF), 19.1% mildly reduced (HFmrEF), and 29.5% preserved EF (HFpEF). Eligibility (literal) was: 27.2% (32.4% in HFrEF, 24.7% in HFmrEF, 19.7% in HFpEF) and eligibility (pragmatic) was 62.8% (69.1%, 60.3%, 53.4%, respectively). In the literal scenario, criteria limiting eligibility were HF duration 85 years, acute coronary syndrome < 3 months, and insufficiently high N-terminal pro-B-type natriuretic peptide levels. Eligible vs. non-eligible patients had more severe HF, higher cardiovascular (CV) comorbidity burden, higher use of HF treatments, and higher event rates (all-cause death 30.8 vs. 27.2 per 100 patient-years, CV death 19.1 vs. 16.6, and HF hospitalization 36.7 vs. 24.0). Conclusion: In this large, real-world HF cohort with T2DM, ∼1/3 of patients were eligible for sotagliflozin in the literal and ∼2/3 of patients in the pragmatic scenario. Eligible patients had more severe HF and higher event rates, in particular CV and HF events
Determination of the molecular and physiological basis of citric acid tolerance in spoilage yeast
No full textThe ability of yeasts to grow and adapt under extreme environmental conditions including within the presence of weak organic acid preservatives has led to substantial economic losses through manufactured food and beverage spoilage. The food industry has employed the use of various weak organic acids such as sorbic, benzoic and acetic acid as preservatives to help prevent spoilage by yeasts and moulds. The mechanisms by which S. cerevisiae is able to adapt to these weak organic acids have been extensively studied. A lesser studied weak organic acid preservative is citric acid. The aim of this study was to gain further information on the mechanisms of citric acid adaptation and through this identify potential targets for new preservation strategies.
Current knowledge indicates the involvement of the HOG pathway in citric acid adaptation. A citric acid sensitivity screen from a previous study also isolated a SR protein kinase Sky1p, involved in polyamine metabolism, which has been connected with other crucial cellular processes including modulation of ion homeostasis and osmotic shock.
In this study we have undertaken a systematic screen for genes that confer increased sensitivity to citric acid paying particular attention to those involved in polyamine metabolism and those known to encode proteins which have evidence of interactions with Sky1p. Many of the deletion strains tested exhibited hypersensitivity to citric acid including Δsky1. Protein-protein interaction maps for Sky1p highlighted an interesting secondary interacting protein Nmd5p, an importin crucial for the nuclear localization of Hog1p. This information suggested there may be the possibility of linkage between Sky1p and Hog1p and their roles in citric acid tolerance, perhaps through Nmd5p. This provided an incentive to perform a range of experiments to test this theory.
Proteomic and phosphoproteomic analyses were carried out to study protein expression and phosphorylation changes in response to citric acid stress. Comparative proteomic analyses for Δsky1, Δhog1 and BY4741a with and without citric acid identified four instances of analogous protein expression responses in both Δsky1 and Δhog1, suggesting functional overlap upon exposure to citric acid.
Epistasis studies of Δhog1Δsky1 suggested that the two protein kinases do not function on the same pathway. However, overexpression analyses did suggest some functional interaction between Hog1p and Sky1p in mediating citric acid resistance since overexpression of Sky1p in Δhog1 resulted in partial rescue of growth. Further supporting evidence for some functional interaction or linkage was provided by Hog1p phosphorylation and localisation studies. Δsky1 exhibited dual phosphorylation of Hog1p in the absence of citric acid stress; implying that loss of SKY1 results in dual phosphorylation of Hog1p by either prompting phosphorylation or perhaps by interfering with dephosphorylation of Hog1p. Localisation studies of Hog1p proved that like osmotic stress, citric acid stress results in nuclear translocation of Hog1p and deletion of SKY1 seemed to interfere with this localisation to some extent.
In light of the results attained in this study we believe we have evidence to propose a novel role for Sky1p in mediating resistance to citric acid and that there is also substantial evidence to suggest that Sky1p shares some functional redundancy and perhaps functional linkage with Hog1p in citric acid adaptation
Medication Related Problems in Cardio-Metabolic Disease Management in Sub-Saharan Africa: A Systematic Review
No full textHundreds of variants clustered in genomic loci and biological pathways affect human height
Full text linkMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits(1), but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait(2,3). The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways
Emerg Infect Dis
No full textTo optimize appropriate antimicrobial use in a university hospital and identify barriers hampering implementation strategies, physicians were interviewed regarding their opinions on antimicrobial policies. Results indicated that effective strategies should include regular updates of guidelines that incorporate the views of relevant departments and focus on addressing senior staff and residents because residents do not make independent decisions in a teaching-hospital setting
Safety-Related Drug Label Changes Following Large Post-Marketing Cardiometabolic Trials: A Review of European Public Assessment Reports
Full text linkSelective safety data collection may simplify late-stage clinical trials and improve their feasibility. However, the impact on increasing overall drug safety knowledge is unknown. The aim of this study is to evaluate how much safety information is added to the drug label based on large trials after initial authorization. Changes made to the “undesirable effects” section of the drug label of cardiometabolic agents approved between 2000 and 2020 based on the results of large (> 1,000 patient) clinical trials submitted to the European Medicines Agency (EMA) were evaluated. The study focused on glucose lowering, antithrombotic, and lipid-modifying agents. The primary outcome was the number of changes in adverse drug reactions in the drug label. The EMA reviewed 55 large trials concerning 25 cardiometabolic agents after the initial marketing authorization, which included 402,444 patients. Ultimately, 38 trials (69%) resulted in a safety section update, whereas 17 trials (31%) did not. Changes in listed adverse drug reactions were made following 19 trials (35%) for 12 agents: 77 adverse drug reactions were added, 11 were deleted, and the frequencies of 43 were changed. Most changes in adverse drug reactions arose from trials with antithrombotic agents (88%) and trials performed in a new population (92%). Large trials for cardiometabolic agents reported after authorization add limited new safety information on adverse drug reactions, especially when performed in the population studied prior to approval. This suggests that selective safety data collection does not reduce learnings from late stage cardiometabolic trials in populations comprehensively studied before
A full-document analysis of the semantic relation between European Public Assessment Reports and EMA guidelines using a BERT language model
Full text linkIn the European Union, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) develop guidelines to guide drug development, supporting development of efficacious and safe medicines. A European Public Assessment Report (EPAR) is published for every medicine application that has been granted or refused marketing authorisation within the EU. In this work, we study the use of text embeddings and similarity metrics to investigate the semantic similarity between EPARs and EMA guidelines. All 1024 EPARs for initial marketing authorisations from 2008 to 2022 was compared to the 669 current EMA scientific guidelines. Documents were converted to plain text and split into overlapping chunks, generating 265,757 EPAR and 27,649 guideline text chunks. Using a Sentence BERT language model, the chunks were transformed into embeddings and fed into an in-house piecewise matching algorithm to estimate the full-document semantic distance. In an analysis of the document distance scores and product characteristics using a linear regression model, EPARs of anti-virals for systemic use (ATC code J05) and antihemorrhagic medicines (B02) present with statistically significant lower overall semantic distance to guidelines compared to other therapeutic areas, also when adjusting for product age and EPAR length. In conclusion, we believe our approach provides meaningful insight into the interplay between EMA scientific guidelines and the assessment made during regulatory review, and could potentially be used to answer more specific questions such as which therapeutic areas could benefit from additional regulatory guidance
Medication Related Problems in Cardio-Metabolic Disease Management in Sub-Saharan Africa:A Systematic Review
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