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Co-Prescription of QT-Interval Prolonging Drugs: An Analysis in a Large Cohort of Geriatric Patients.

PLoS One. 2016;11(5):e0155649

Authors: Schächtele S, Tümena T, Gaßmann KG, Fromm MF, Maas R

Abstract
BACKGROUND: Drug-induced QT-interval prolongation is associated with occurrence of potentially fatal Torsades de Pointes arrhythmias (TdP). So far, data regarding the overall burden of QT-interval prolonging drugs (QT-drugs) in geriatric patients are limited.
OBJECTIVE: This study was performed to assess the individual burden of QT-interval prolonging drugs (QT-drugs) in geriatric polymedicated patients and to identify the most frequent and risky combinations of QT-drugs.
METHODS: In the discharge medication of geriatric patients between July 2009 and June 2013 from the Geriatrics in Bavaria-Database (GiB-DAT) (co)-prescriptions of QT-drugs were investigated. QT-drugs were classified according to a publicly available reference site (CredibleMeds®) as ALL-QT-drugs (associated with any QT-risk) or High-risk-QT-drugs (corresponding to QT-drugs with known risk of Torsades de Pointes according to CredibleMeds®) and in addition as SmPC-high-risk-QT-drugs (according to the German prescribing information (SmPC) contraindicated co-prescription with other QT-drugs).
RESULTS: Of a cohort of 130,434 geriatric patients (mean age 81 years, 67% women), prescribed a median of 8 drugs, 76,594 patients (58.7%) received at least one ALL-QT-drug. Co-prescriptions of two or more ALL-QT-drugs were observed in 28,768 (22.1%) patients. Particularly risky co-prescriptions of High-risk-QT-drugs or SmPC-high-risk-QT-drugs with at least on further QT-drug occurred in 55.9% (N = 12,633) and 54.2% (N = 12,429) of these patients, respectively. Consideration of SmPCs (SmPC-high-risk-QT-drugs) allowed the identification of an additional 15% (N = 3,999) patients taking a risky combination that was not covered by the commonly used CredibleMeds® classification. Only 20 drug-drug combinations accounted for more than 90% of these potentially most dangerous co-prescriptions.
CONCLUSION: In a geriatric study population co-prescriptions of two and more QT-drugs were common. A considerable proportion of QT-drugs with higher risk only could be detected by using more than one classification-system. Local adaption of international classifications can improve identification of patients at risk.

PMID: 27192430 [PubMed - indexed for MEDLINE]

Related Articles

Predictive Factors of Spontaneous Reporting of Adverse Drug Reactions among Community Pharmacists.

PLoS One. 2016;11(5):e0155517

Authors: Yu YM, Lee E, Koo BS, Jeong KH, Choi KH, Kang LK, Lee MS, Choi KH, Oh JM, Shin WG

Abstract
PURPOSE: To evaluate the association between spontaneous reporting (SR) and the knowledge, attitude, and needs of community pharmacists (CPs), using a questionnaire following a conceptual model known as the mixed model of knowledge-attitude-practices and the satisfaction of needs.
METHODS: Self-administered questionnaires were used with a nationwide convenience sample of CPs between September 1, 2014 and November 25, 2014 in Korea. The association between SR and the predictive factors was evaluated using multivariate logistic regression analysis.
RESULTS: In total, 1,001 questionnaires were analyzed. The mean age of the respondents and the number of years spent in community pharmacy practice were 45.6 years and 15.3 years, respectively. CPs with experience of SR was 29.4%. Being older than 60 (ORadj, 0.16; 95% CI, 0.06-0.42), having prior experience with adverse drug reactions (ADR) (ORadj, 6.46; 95% CI, 2.46-16.98), having higher specific knowledge of SR (ORadj, 3.58; 95% CI, 1.96-6.56), and having less concern about the obstacles to SR (ORadj, 0.36; 95% CI, 0.23-0.57) were significant contributing factors to SR. The main obstacles to SR included perception of ADRs as 'not serious ADR' (77.9%), 'already well known ADR' (81.5%), and 'uncertain about causality' (73.3%). CPs without reporting experience had greater concerns related to the reporting method and the liability of the pharmacy than those with reporting experience (p<0.05).
CONCLUSIONS: Findings from our study showed around one in three CPs had ADR reporting experience in Korea, while 87.1% had prior experience with ADR cases. The knowledge of SR, prior experience of ADR, and less concern about the obstacles to SR were contributing factors for reporting levels.

PMID: 27192159 [PubMed - indexed for MEDLINE]

Related Articles

Patterns of adverse drug reaction signals in NAFDAC Pharmacovigilance activities from September to November, 2014.

Int J Risk Saf Med. 2016 Mar 16;28(1):13-23

Authors: Awodele O, Ibrahim A, Orhii P

Abstract
BACKGROUND: Adverse drug reaction signals are reported information on possible causal relationships between an adverse event and a drug. The National Pharmacovigilance Centre (NPC) in Nigeria has over 3,000 reported adverse drug reaction cases which have been adequately entered into the ADR data bank.
OBJECTIVE: Data mining of ADR reports from September to November, 2014 were carried out in this present study with the intention to describe the pattern of ADRs and generate possible signals.
METHODS: A total of about 100 reported cases with arrays of adverse drug reactions were reported between September and November, 2014 and the data were analyzed using SPSS version 17.
RESULTS: Efavirenz/Tenofovir/Lamivudine combination was the highest reported drugs (24.2%) while efavirenz alone was reported in 8 times (8.8%) and HIV (63.3%) was the highest reported indication of drug use. Efavirenz caused central nervous system adverse reactions as revealed in the ADRs analyses. Zidovudine/Lamivudine/Nevirapine combination in concomitant use with Cotrimoxazole were reported 8 times with generalized maculopapular rashes on the trunk with some area of hyper pigmentation with intense itching documented twice and big/swollen rashes all over the faces. Zidovudine was also reported four times to cause severe anaemia.
CONCLUSION: More surveillance is advocated so as to ascertain the consistency of the observed ADRs and thereafter establish appropriate signals.

PMID: 27176753 [PubMed - indexed for MEDLINE]

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Illuminating drug action by network integration of disease genes: a case study of myocardial infarction.

Mol Biosyst. 2016 Apr 26;12(5):1653-66

Authors: Wang RS, Loscalzo J

Abstract
Drug discovery has produced many successful therapeutic agents; however, most of these drugs were developed without a deep understanding of the system-wide mechanisms of action responsible for their indications. Gene-disease associations produced by molecular and genetic studies of complex diseases provide great opportunities for a system-level understanding of drug activity. In this study, we focused on acute myocardial infarction (MI) and conducted an integrative network analysis to illuminate drug actions. We integrated MI drugs, MI drug interactors, drug targets, and MI disease genes into the human interactome and showed that MI drug targets are significantly proximate to MI disease proteins. We then constructed a bipartite network of MI-related drug targets and MI disease proteins and derived 12 drug-target-disease (DTD) modules. We assessed the biological relevance of these modules and demonstrated the benefits of incorporating disease genes. The results indicate that DTD modules provide insights into the mechanisms of action of MI drugs and the cardiovascular (side) effects of non-MI drugs.

PMID: 27004607 [PubMed - indexed for MEDLINE]

Funding Opportunity RFA-HD-18-013 from the NIH Guide for Grants and Contracts. The goal of this funding opportunity announcement (FOA) is to advance the field of population dynamics research by increasing research impact, innovation, and productivity; developing junior scientists; and maximizing the efficiency of research support.

Notice NOT-OD-17-094 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-17-334 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites applications to conduct research to advance the understanding and application of synthetic biology for human health. It will support 1) the development of innovative tools and technologies in synthetic biology and 2) their application in biomedical research and human health. An integrative research plan based on collaborations of synthetic biologists with computational scientists, cell biologists, engineers, and/or physician scientists is strongly recommended. Early stage investigators in Synthetic Biology are especially encouraged to apply.

Related Articles

Antistaphylococcal Activity of Selected Thiourea Derivatives.

Pol J Microbiol. 2017 Jan 02;65(4):451-460

Authors: Stefańska J, Stępień K, Bielenica A, Wrzosek M, Struga M

Abstract
Five of thiourea derivatives were prepared using as a starting compound 3-(trifluoromethyl)aniline, 4-chloro-3-nitroaniline, 1,3-thiazol-2-amine, 2H-1,2,3-triazol-4-amine and commercial isothiocyanates. All compounds were evaluated in vitro for antimicrobial activity. Derivatives 2 and 3 showed the highest inhibition against Gram-positive cocci (standard and hospital strains). The observed MIC values were in the range of 0.5-8 μg/ml. The products effectively inhibited the formation of biofilms of methicillin-resistant and standard strains of Staphylococcus epidermidis. Inhibitory activity of thioureas 2 and 3 against Staphylococcus aureus topoisomerase IV was studied. The examined compounds were nongenotoxic.

PMID: 28735329 [PubMed - in process]

Related Articles

Identification of the first dominant mutation of LAMA5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix.

J Med Genet. 2017 Jul 22;:

Authors: Sampaolo S, Napolitano F, Tirozzi A, Reccia MG, Lombardi L, Farina O, Barra A, Cirillo F, Melone MAB, Gianfrancesco F, Iorio GD, Esposito T

Abstract
BACKGROUND: The laminin alpha 5 gene (LAMA5) plays a master role in the maintenance and function of the extracellular matrix (ECM) in mammalian tissues, which is critical in developmental patterning, stem cell niches, cancer and genetic diseases. Its mutations have never been reported in human disease so far. The aim of this study was to associate the first mutation in LAMA5 gene to a novel multisystem syndrome.
METHODS: A detailed characterisation of a three-generation family, including clinical, biochemical, instrumental and morphological analysis, together with genetics and expression (WES and RNAseq) studies, was performed.
RESULTS: The heterozygous LAMA5 mutation c.9418G>A (p.V3140M) was associated with skin anomalies, impaired scarring, night blindness, muscle weakness, osteoarthritis, joint and internal organs ligaments laxity, malabsorption syndrome and hypothyroidism. We demonstrated that the mutation alters the amount of LAMA5 peptides likely derived from protein cleavage and perturbs the activation of the epithelial-mesenchymal signalling, producing an unbalanced expression of Sonic hedgehog and GLI1, which are upregulated in cells from affected individuals, and of ECM proteins (COL1A1, MMP1 and MMP3), which are strongly inhibited. Studies carried out using human skin biopsies showed alteration of dermal papilla with a reduction of the germinative layer and an early arrest of hair follicle downgrowth. The knock-in mouse model, generated in our laboratory, shows similar changes in the tissues studied so far.
CONCLUSIONS: This is the first report of a disease phenotype associated with LAMA5 mutation in humans.

PMID: 28735299 [PubMed - as supplied by publisher]

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An update on the genetics of dementia with Lewy bodies.

Parkinsonism Relat Disord. 2017 Jul 13;:

Authors: Vergouw LJM, van Steenoven I, van de Berg WDJ, Teunissen CE, van Swieten JC, Bonifati V, Lemstra AW, de Jong FJ

Abstract
The genetic architecture of dementia with Lewy bodies (DLB) is increasingly taking shape. Initially, genetic research focused mainly on linkage and candidate gene studies in small series of DLB patients. More recently, association and exome sequencing studies in larger groups have been conducted, and have shown that several variants in GBA and the APOE ε4 allele are important genetic risk factors for DLB. However, genetic research in DLB is still in its infancy. So far, many genetic studies have been biased and performed in clinically and pathologically heterogeneous populations. Therefore, it is likely that multiple DLB-specific genetic determinants still have to be identified. To further our understanding of the role of genetics in DLB, future genetic studies should be unbiased and performed in large series of DLB patients, ideally with both a clinical diagnosis and pathological confirmation. The combination of genomic techniques with other research modalities, such as proteomic research, is a promising approach to identify novel genetic determinants. More knowledge about the genetics of DLB will increase our understanding of the pathophysiology of the disease and its relation with Parkinson's Disease and Alzheimer's Disease, and may eventually lead to the development of disease modifying treatments.

PMID: 28734699 [PubMed - as supplied by publisher]

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Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.

Lancet Oncol. 2017 Jul 19;:

Authors: Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, André T

Abstract
BACKGROUND: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer.
METHODS: In this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged ≥18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188.
FINDINGS: Of the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12·0 months (IQR 8·6-18·0), 23 (31·1%, 95% CI 20·8-42·9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57-79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (event rate 86%, 95% CI 62-95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator.
INTERPRETATION: Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients.
FUNDING: Bristol-Myers Squibb.

PMID: 28734759 [PubMed - as supplied by publisher]

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Notice NOT-HS-17-018 from the NIH Guide for Grants and Contracts

Notice NOT-OD-17-095 from the NIH Guide for Grants and Contracts

Notice NOT-OD-17-096 from the NIH Guide for Grants and Contracts

Notice NOT-MH-17-039 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-17-335 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) intends to support investigators who have interest and capability to join efforts for the discovery of cell-based chemical probes for novel brain targets. It is expected that applicants will have in hand the starting compounds (validated hits) for chemical optimization and bioassays for testing new analog compounds. Through this FOA, NIH wishes to stimulate research in: 1) discovery and development of novel, small molecules for their potential use in understanding biological processes relevant to the missions of NIMH, NIA, and/or NIDCD; and 2) discovery and/or validation of novel, biological targets that will inform studies of brain disease mechanisms. Emphasis will be placed on projects that provide new insight into important disease-related biological targets and biological processes. The main emphasis of projects submitted under this FOA should be in the discovery of cell-based chemical probes. Applicants interested in developing in vivo chemical probes may wish to apply using the companion R01 mechanism (PAR-17-336).

Funding Opportunity PAR-17-336 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) intends to support investigators who have interest and capability to join efforts for the discovery of in vivo chemical probes for novel brain targets. It is expected that applicants will have in hand the starting compounds (validated hits) for chemical optimization and bioassays for testing new analog compounds. Through this FOA, NIH wishes to stimulate research in 1) discovery and development of novel, small molecules for their potential use in understanding biological processes relevant to the missions of NIMH, NEI, NIAAA, NIDA, NIA and/or NIDCD and 2) discovery and/or validation of novel, biological targets that will inform studies of brain disease mechanisms. Emphasis will be placed on projects that provide new insight into important disease-related biological targets and biological processes.

Related Articles

Identification of a rare COCH mutation by whole-exome sequencing : Implications for personalized therapeutic rehabilitation in an Austrian family with non-syndromic autosomal dominant late-onset hearing loss.

Wien Klin Wochenschr. 2017 Jul 21;:

Authors: Parzefall T, Frohne A, Koenighofer M, Kirchnawy A, Streubel B, Schoefer C, Gstoettner W, Frei K, Lucas T

Abstract
BACKGROUND: Non-syndromic autosomal dominant hearing impairment is characteristically postlingual in onset. Genetic diagnostics are essential for genetic counselling, disease prognosis and understanding of the molecular mechanisms of disease. To date, 36 causative genes have been identified, many in only individual families. Gene selection for genetic screening by traditional methods and genetic diagnosis in autosomal dominant patients has therefore been fraught with difficulty. Whole-exome sequencing provides a powerful tool to analyze all protein-coding genomic regions in parallel, thus allowing the comprehensive screening of all known genes and associated alterations.
METHODS: In this study, a previously undiagnosed late-onset progressive autosomal dominant hearing loss in an Austrian family was investigated by means of whole-exome sequencing. Results were confirmed by Sanger sequencing.
RESULTS: A previously described c.151C>T missense (p.Pro51Ser) mutation in the LCCL (limulus factor C, cochlin, late gestation lung protein Lgl1) domain of the cochlin gene (COCH) was identified as causative and segregated with disease in five members of the family. Molecular diagnostics led to the decision to perform cochlear implantation in an index patient who subsequently showed excellent postoperative auditory performance. The c.151C>T mutation was not found in 18 screened Austrian families with autosomal dominant hearing loss but was represented alongside other known pathogenic mutant COCH alleles in the Genome Aggregation Database (gnomAD) in European populations. A combined allele frequency of 0.000128 implies an orphan disease frequency for COCH-induced hearing loss of 1:3900 in Europe.
CONCLUSIONS: Exome sequencing successfully resolved the genetic diagnosis in a family suffering from autosomal dominant hearing impairment and allowed prediction of purported auditory outcome after cochlear implantation in an index patient. Personalized treatment approaches based on the molecular mechanisms of disease may become increasingly important in the future.

PMID: 28733840 [PubMed - as supplied by publisher]

Related Articles

Biological age is better than chronological as predictor of 3-month outcome in ischemic stroke.

Neurology. 2017 Jul 21;:

Authors: Soriano-Tárraga C, Mola-Caminal M, Giralt-Steinhauer E, Ois A, Rodríguez-Campello A, Cuadrado-Godia E, Gómez-González A, Vivanco-Hidalgo RM, Fernández-Cadenas I, Cullell N, Roquer J, Jiménez-Conde J

Abstract
OBJECTIVE: To analyze the effect of age-related DNA methylation changes in multiple cytosine-phosphate-guanine (CpG) sites (biological age [b-age]) on patient outcomes at 3 months after an ischemic stroke.
METHODS: We included 511 patients with first-ever acute ischemic stroke assessed at Hospital del Mar (Barcelona, Spain) as the discovery cohort. Demographic and clinical data, including chronological age (c-age), vascular risk factors, initial stroke severity, recanalization treatment, and previous and 3-month modified Rankin Scale (p-mRS and 3-mRS, respectively) were registered. B-age was estimated with an algorithm, based on DNA methylation in 71 CpGs. Bivariate analysis determined variables associated with 3-mRS for inclusion in ordinal multivariate analysis.
RESULTS: After ordinal regressions for 3-month ischemic stroke outcome (3-mRS), b-age was associated with outcome (odds ratio 1.04 [95% confidence interval 1.01-1.07]), nullifying c-age. Stepwise regression kept b-age, basal NIH Stroke Scale, sex, p-mRS, and recanalization treatment as better explanatory variables, instead of c-age. These results were successfully replicated in an independent cohort.
CONCLUSIONS: B-age, estimated by DNA methylation, is an independent predictor of ischemic stroke outcome regardless of chronological years.

PMID: 28733340 [PubMed - as supplied by publisher]