Literature Watch
Prospective Assessment of Inpatient Boxed Warning Prescriber Adherence.
Prospective Assessment of Inpatient Boxed Warning Prescriber Adherence.
J Patient Saf. 2017 Mar;13(1):25-30
Authors: Kloet MA, Lohr BR, Smithburger PL, Seybert AL, Kane-Gill SL
Abstract
OBJECTIVE: To evaluate medication boxed warning nonadherence in the inpatient setting.
METHODS: This was a prospective cohort quality improvement project approved by our institution's Total Quality Council. General medicine and ICU patients 18 years and older were included if they were cared for by a prescriber-led multidisciplinary team that included a pharmacist. Patients were evaluated for medication orders with an actionable boxed warning; if boxed warning nonadherence occurred, the physician's reason was determined. Patients with boxed warning nonadherence were monitored for adverse drug reactions until discharge.
RESULTS: A total of 393 patients (224 general medicine and 169 ICU) were evaluated for nonadherence to 149 actionable boxed warnings. There were 293 drugs (175 general medicine and 118 ICU) with boxed warnings prescribed, and more than 50% of these were medications restarted from home. A total of 23 boxed warning nonadherences occurred in general medicine patients, and NSAIDs accounted for 81% of these events. ICU patients experienced 11 boxed warning nonadherences, with nearly 54% from anti-infectives and immunosuppressants. Antipsychotics were the most commonly ordered boxed warning medication class in ICU patients. Reasons for nonadherence included knowledge deficit and an acceptable risk-to-benefit ratio. Two adverse drug reactions occurred from boxed warning nonadherences, both because of a drug-drug interaction.
CONCLUSIONS: Boxed warning nonadherence is a concern in the inpatient setting, specifically with NSAID use in general medicine patients and antipsychotic use in ICU patients. More than half of boxed warning nonadherence occurred in medications restarted from home, which emphasizes the need for medication evaluation during transitions of care.
PMID: 24647270 [PubMed - indexed for MEDLINE]
"systems biology"; +39 new citations
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These pubmed results were generated on 2017/06/01
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Notice To Add Acceptance of Revisions to: Initiative to Maximize Research Education in Genomics: Diversity Action Plan (R25)
Partnerships for the Development of Vaccines and Immunophrophylactics Targeting Multiple Antimicrobial-Resistant Bacteria (R01)
Notice of Change in Application Due date and Eligibility Requirements for PAR-17-001 "Emerging Global Leader Award (K43)"
Socioeconomic Disparities in Health and Mortality at Older Ages (R01)
Notice of Correction to Developmental Core Other Attachments Instruction for Application Submission for PAR-17-237 "Centers for AIDS Research (P30)"
NHLBI Policy for Submission of Investigator-Initiated Single-Site Clinical Trials (Phase II and beyond)
Reminder: Authentication of Key Biological and/or Chemical Resources
Notice of Modification of the Data Submission and Sharing Policies for the Federal Interagency Traumatic Brain Injury Research (FITBIR) Informatics System
"systems biology"; +24 new citations
24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2017/05/31
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Identification of a functional enhancer variant within the chronic pancreatitis-associated SPINK1 c.101A>G (p.Asn34Ser)-containing haplotype.
Identification of a functional enhancer variant within the chronic pancreatitis-associated SPINK1 c.101A>G (p.Asn34Ser)-containing haplotype.
Hum Mutat. 2017 May 29;:
Authors: Boulling A, Masson E, Zou WB, Paliwal S, Wu H, Issarpu P, Bhaskar S, Génin E, Cooper DN, Li ZS, Chandak GR, Liao Z, Chen JM, Férec C
Abstract
The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser) variant (also known as rs17107315:T>C) represents the most important heritable risk factor for idiopathic chronic pancreatitis identified to date. The causal variant contained within this risk haplotype has however remained stubbornly elusive. Herein we set out to resolve this enigma by employing a hypothesis-driven approach. Firstly, we searched for variants in strong linkage disequilibrium with rs17107315:T>C using HaploReg v4.1. Secondly, we identified two candidate SNPs by visual inspection of sequences spanning all 25 SNPs found to be in linkage disequilibrium with rs17107315:T>C, guided by prior knowledge of pancreas-specific transcription factors and their cognate binding sites. Thirdly, employing a novel cis-regulatory module-guided approach to further filter the two candidate SNPs yielded a solitary candidate causal variant. Finally, combining data from phylogenetic conservation and chromatin accessibility, co-transfection transactivation experiments and population genetic studies, we suggest that rs142703147:C>A, which disrupts a PTF1L binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module located ∼4 kb upstream of the SPINK1 promoter, contributes to the aforementioned chronic pancreatitis risk haplotype. Further studies are required not only to improve the characterization of this functional SNP but also to identify other functional components that might contribute to this high-risk haplotype. This article is protected by copyright. All rights reserved.
PMID: 28556356 [PubMed - as supplied by publisher]
Redeployment of a conserved gene regulatory network during Aedes aegypti development.
Redeployment of a conserved gene regulatory network during Aedes aegypti development.
Dev Biol. 2016 Aug 15;416(2):402-13
Authors: Suryamohan K, Hanson C, Andrews E, Sinha S, Scheel MD, Halfon MS
Abstract
Changes in gene regulatory networks (GRNs) underlie the evolution of morphological novelty and developmental system drift. The fruitfly Drosophila melanogaster and the dengue and Zika vector mosquito Aedes aegypti have substantially similar nervous system morphology. Nevertheless, they show significant divergence in a set of genes co-expressed in the midline of the Drosophila central nervous system, including the master regulator single minded and downstream genes including short gastrulation, Star, and NetrinA. In contrast to Drosophila, we find that midline expression of these genes is either absent or severely diminished in A. aegypti. Instead, they are co-expressed in the lateral nervous system. This suggests that in A. aegypti this "midline GRN" has been redeployed to a new location while lost from its previous site of activity. In order to characterize the relevant GRNs, we employed the SCRMshaw method we previously developed to identify transcriptional cis-regulatory modules in both species. Analysis of these regulatory sequences in transgenic Drosophila suggests that the altered gene expression observed in A. aegypti is the result of trans-dependent redeployment of the GRN, potentially stemming from cis-mediated changes in the expression of sim and other as-yet unidentified regulators. Our results illustrate a novel "repeal, replace, and redeploy" mode of evolution in which a conserved GRN acquires a different function at a new site while its original function is co-opted by a different GRN. This represents a striking example of developmental system drift in which the dramatic shift in gene expression does not result in gross morphological changes, but in more subtle differences in development and function of the late embryonic nervous system.
PMID: 27341759 [PubMed - indexed for MEDLINE]
Old and new applications of non-anticoagulant heparin.
Old and new applications of non-anticoagulant heparin.
Int J Cardiol. 2016 Jun;212 Suppl 1:S14-21
Authors: Cassinelli G, Naggi A
Abstract
The aim of this chapter is to provide an overview of non-anticoagulant effects of heparins and their potential use in new therapeutic applications. Heparin and heparin derivatives have been tested in inflammatory, pulmonary and reproductive diseases, in cardiovascular, nephro- and neuro-tissue protection and repair, but also as agents against angiogenesis, atheroschlerosis, metastasis, protozoa and viruses. Targeting and inhibition of specific mediators involved in the inflammatory process, promoting some of the above mentioned pathologies, are reported along with recent studies of heparin conjugates and oral delivery systems. Some reports from the institute of the authors, such as those devoted to glycol-split heparins are also included. Among the members and derivatives of this class, several are undergoing clinical trials as antimetastatic and antimalarial agents and for the treatment of labour pain and severe hereditary anaemia. Other heparins, whose therapeutic targets are non-anticoagulant such as nephropathies, retinopathies and cystic fibrosis are also under investigation.
PMID: 27264866 [PubMed - indexed for MEDLINE]
Adverse Drug Reactions in Children: The Double-Edged Sword of Therapeutics.
Adverse Drug Reactions in Children: The Double-Edged Sword of Therapeutics.
Clin Pharmacol Ther. 2017 Jun;101(6):725-735
Authors: Elzagallaai AA, Greff M, Rieder MJ
Abstract
Adverse drug reactions (ADRs) represent a major health problem worldwide, with high morbidity and mortality rates. ADRs are classified into Type A (augmented) and Type B (bizarre) ADRs, with the former group being more common and the latter less common but often severe and clinically more problematic due to their unpredictable nature and occurrence at any dose. Pediatric populations are especially vulnerable to ADRs due to the lack of data for this age group from the drug development process and because of the wide use of off-label and unlicensed use of drugs. Children are more prone to specific types of ADRs because of the level of maturity of body systems involved in absorption, metabolism, transportation, and elimination of drugs. This state-of-the-art review provides an overview of definitions, classifications, epidemiology, and pathophysiology of ADRs and discusses the available evidence for related risk factors and causes of ADRs in the pediatric population.
PMID: 28295234 [PubMed - indexed for MEDLINE]
The Influence of Genotype Information on Psychiatrists' Treatment Recommendations: More Experienced Clinicians Know Better What to Ignore.
The Influence of Genotype Information on Psychiatrists' Treatment Recommendations: More Experienced Clinicians Know Better What to Ignore.
Value Health. 2017 Jan;20(1):126-131
Authors: McMichael AJ, Boeri M, Rolison JJ, Kane J, O'Neill FA, Scarpa R, Kee F
Abstract
BACKGROUND: This study applies attribute nonattendance to medical decision making. We aimed to demonstrate how this type of analysis can be used in medical decision making to assess whether psychiatrists were influenced in their treatment recommendations by information on the genotype of a patient, despite knowing the patient's response to treatment as measured by the Positive and Negative Syndrome Scale. A patient's genetic information may be used to predict their response to therapy; such information, however, becomes redundant, and should not influence decisions, once a clinician knows the patient's actual response to treatment.
METHODS: Sixty-seven psychiatrists were presented with patients' pre- or post-treatment scores on the Positive and Negative Syndrome Scale for two hypothetical treatments for schizophrenia. Psychiatrists were also informed whether the patient possessed a genotype linked to hyper-responsiveness to one of the treatments, and were asked to recommend one of these two treatments. Attribute nonattendance assessed whether the information on genotype influenced psychiatrists' treatment recommendations.
RESULTS: Years of experience predicted whether psychiatrists were influenced by the genetic information. Psychiatrists with 1 year or less of experience had a 46% probability of considering genetic information, whereas psychiatrists with at least 15 years of experience had a lower probability (7%).
CONCLUSIONS: Psychiatrists and other clinicians should be cautious about allowing a patient's genetic information to carry unnecessary weight in their clinical decision making.
PMID: 28212953 [PubMed - indexed for MEDLINE]
Spatial regulation of the KH domain RNA-binding protein Rnc1 mediated by a Crm1-independent nuclear export system in Schizosaccharomyces pombe.
Spatial regulation of the KH domain RNA-binding protein Rnc1 mediated by a Crm1-independent nuclear export system in Schizosaccharomyces pombe.
Mol Microbiol. 2017 May;104(3):428-448
Authors: Satoh R, Matsumura Y, Tanaka A, Takada M, Ito Y, Hagihara K, Inari M, Kita A, Fukao A, Fujiwara T, Hirai S, Tani T, Sugiura R
Abstract
RNA-binding proteins (RBPs) play important roles in the posttranscriptional regulation of gene expression, including mRNA stability, transport and translation. Fission yeast rnc1(+) encodes a K Homology (KH)-type RBP, which binds and stabilizes the Pmp1 MAPK phosphatase mRNA thereby suppressing the Cl(-) hypersensitivity of calcineurin deletion and MAPK signaling mutants. Here, we analyzed the spatial regulation of Rnc1 and discovered a putative nuclear export signal (NES)Rnc1 , which dictates the cytoplasmic localization of Rnc1 in a Crm1-independent manner. Notably, mutations in the NESRnc1 altered nucleocytoplasmic distribution of Rnc1 and abolished its function to suppress calcineurin deletion, although the Rnc1 NES mutant maintains the ability to bind Pmp1 mRNA. Intriguingly, the Rnc1 NES mutant destabilized Pmp1 mRNA, suggesting the functional importance of the Rnc1 cytoplasmic localization. Mutation in Rae1, but not Mex67 deletion or overproduction, induced Rnc1 accumulation in the nucleus, suggesting that Rnc1 is exported from the nucleus to the cytoplasm via the mRNA export pathway involving Rae1. Importantly, mutations in the Rnc1 KH-domains abolished the mRNA-binding ability and induced nuclear localization, suggesting that Rnc1 may be exported from the nucleus together with its target mRNAs. Collectively, the functional Rae1-dependent mRNA export system may influence the cytoplasmic localization and function of Rnc1.
PMID: 28142187 [PubMed - indexed for MEDLINE]
Genetic Mechanisms Leading to Sex Differences Across Common Diseases and Anthropometric Traits.
Genetic Mechanisms Leading to Sex Differences Across Common Diseases and Anthropometric Traits.
Genetics. 2017 Feb;205(2):979-992
Authors: Traglia M, Bseiso D, Gusev A, Adviento B, Park DS, Mefford JA, Zaitlen N, Weiss LA
Abstract
Common diseases often show sex differences in prevalence, onset, symptomology, treatment, or prognosis. Although studies have been performed to evaluate sex differences at specific SNP associations, this work aims to comprehensively survey a number of complex heritable diseases and anthropometric traits. Potential genetically encoded sex differences we investigated include differential genetic liability thresholds or distributions, gene-sex interaction at autosomal loci, major contribution of the X-chromosome, or gene-environment interactions reflected in genes responsive to androgens or estrogens. Finally, we tested the overlap between sex-differential association with anthropometric traits and disease risk. We utilized complementary approaches of assessing GWAS association enrichment and SNP-based heritability estimation to explore explicit sex differences, as well as enrichment in sex-implicated functional categories. We do not find consistent increased genetic load in the lower-prevalence sex, or a disproportionate role for the X-chromosome in disease risk, despite sex-heterogeneity on the X for several traits. We find that all anthropometric traits show less than complete correlation between the genetic contribution to males and females, and find a convincing example of autosome-wide genome-sex interaction in multiple sclerosis (P = 1 × 10(-9)). We also find some evidence for hormone-responsive gene enrichment, and striking evidence of the contribution of sex-differential anthropometric associations to common disease risk, implying that general mechanisms of sexual dimorphism determining secondary sex characteristics have shared effects on disease risk.
PMID: 27974502 [PubMed - indexed for MEDLINE]
Human blood cell levels of 5-hydroxymethylcytosine (5hmC) decline with age, partly related to acquired mutations in TET2.
Human blood cell levels of 5-hydroxymethylcytosine (5hmC) decline with age, partly related to acquired mutations in TET2.
Exp Hematol. 2016 Nov;44(11):1072-1084
Authors: Buscarlet M, Tessier A, Provost S, Mollica L, Busque L
Abstract
Epigenetic alteration may play a role in age-associated dysfunction of stem cells and predispose to the development of hematological cancers. We analyzed global levels of hematopoietic 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in a cross-sectional study comprising 198 unrelated individuals from four age categories (neonates, 25-30, 70-75, and >90 years old) by liquid chromatography-electrospray ionization-tandem mass spectrometry with multiple reaction monitoring. X-chromosome inactivation (XCI) ratios and telomere length (TL) were measured in all individuals by polymerase chain reaction. Sequencing of epigenetic regulator genes (including TET2, DNMT3A, ASXL1, IDH1, IDH2, and WT1) was performed in the two older subcohorts. We found that global 5hmC levels declined with age in human blood cells (27.5% reduction from birth to old age, p < 0.0005). The levels of 5mC underwent a more modest reduction (2.4% drop) between newborns and the elderly (p < 0.0005). Low 5hmC was associated with increased skewing of XCI (age-adjusted p = 0.0304) and reduced TL (age-adjusted p = 0.0354), both surrogate markers of clonal dominance. Of the 100 individuals over the age of 70, 16 had somatic mutations in TET2, 14 in DNMT3A, and none in IDH1, IDH2, or WT1. Individuals with TET2 mutations had significantly lower 5hmC (relative to unmutated individuals), whereas DNMT3A-mutated subjects did not. However, mutations in TET2 cannot account solely for the decline in 5hmC levels observed with aging because unmutated older individuals also had lower 5hmC levels compared with younger individuals. This suggests that the age-associated decline in 5hmC is multifactorial. Larger prospective studies are needed to determine whether 5hmC reduction is a biomarker of hematological cancer development.
PMID: 27475703 [PubMed - indexed for MEDLINE]
A randomised control trial of atorvastatin in bronchiectasis patients infected with Pseudomonas aeruginosa- a proof of concept study.
A randomised control trial of atorvastatin in bronchiectasis patients infected with Pseudomonas aeruginosa- a proof of concept study.
Chest. 2017 May 26;:
Authors: Bedi P, Chalmers JD, Graham C, Clarke A, Donaldson S, Doherty C, Govan JR, Davidson DJ, Rossi AG, Hill AT
Abstract
INTRODUCTION: There are no randomised control trials of statin therapy in patients with severe bronchiectasis, chronically infected with Pseudomonas aeruginosa.
METHODS: 32 patients chronically infected with P. aeruginosa were recruited in this double blind cross over RCT. 16 patients were recruited in each arm, given atorvastatin 80mg or placebo for 3months, followed by a washout period for 6weeks, crossed over and administered the alternative therapy for 3months.
RESULTS: 27 patients completed the study. Atorvastatin did not significantly improve the primary endpoint of cough as measured by Leicester Cough Questionnaire [mean difference=1.92, 95% CI for difference (-0.57, 4.41), p=0.12]. However, atorvastatin treatment resulted in improved St Georges Respiratory Questionnaire (-5.62points, p=0.016), reduced serum CXCL8 (p=0.04), TNF (p=0.01) and ICAM1 (p=0.04). There was a trend towards improvement in serum CRP and serum neutrophil counts (p=0.07 and p=0.06 respectively). In vitro, we demonstrated that atorvastatin 10μM reduced fMLF induced upregulation of CD11b expression and changes in calcium flux reflecting an ability to decrease neutrophil activation.
CONCLUSION: We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in bronchiectasis patients infected with P. aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation.
PMID: 28554732 [PubMed - as supplied by publisher]
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