Donor support for quality assurance and pharmacovigilance of anti-malarials in malaria-endemic countries.

Malar J. 2017 Jul 11;16(1):282

Authors: Kovacs SD, Mills BM, Stergachis A

Abstract
BACKGROUND: Malaria control efforts have been strengthened by funding from donor groups and government agencies. The Global Fund to Fight AIDS, Tuberculosis and the Malaria (Global Fund), the US President's Malaria Initiative (PMI) account for the majority of donor support for malaria control and prevention efforts. Pharmacovigilance (PV), which encompasses all activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem, is a necessary part of efforts to reduce drug resistance and improve treatment outcomes. This paper reports on an analysis of PV plans in the Global Fund and PMI and World Bank's grants for malaria prevention and control.
METHODS: All active malaria grants as of September 2015 funded by the Global Fund and World Bank, and fiscal year 2015 and 2016 PMI Malaria Operational Plans (MOP) were identified. The total amount awarded for PV-related activities and drug quality assurance was abstracted. A Key-Word-in-Context (KWIC) analysis was conducted for the content of each grant. Specific search terms consisted of pharmacovigilance, pregn*, registry, safety, adverse drug, mass drug administration, primaquine, counterfeit, sub-standard, and falsified. Grants that mentioned PV activities identified in the KWIC search, listed PV in their budgets, or included the keywords: counterfeit, sub-standard, falsified, mass drug administration, or adverse event were thematically coded using Dedoose software version 7.0.
RESULTS: The search identified 159 active malaria grants including 107 Global Fund grants, 39 fiscal year 2015 and 2016 PMI grants and 13 World Bank grants. These grants were primarily awarded to low-income countries (57.2%) and in sub-Saharan Africa (SSA) (70.4%). Thirty-seven (23.3%) grants included a budget line for PV- or drug quality assurance-related activities, including 21 PMI grants and 16 Global Fund grants. Only 23 (14.5%) grants directly mentioned PV. The primary focus area was improving drug quality monitoring, especially among the PMI grants.
CONCLUSIONS: The results of the analysis demonstrate that funding for PV has not been sufficiently prioritized by either the key malaria donor organizations or by the recipient countries, as reflected in their grant proposal submissions and MOPs.

PMID: 28693488 [PubMed - in process]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/07/12

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33 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2017/07/12

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.

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2017/07/11

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.

MTRR rs1801394 and its interaction with MTHFR rs1801133 in colorectal cancer: a case-control study and meta-analysis.

Pharmacogenomics. 2017 Jul 10;:

Authors: Haerian MS, Haerian BS, Molanaei S, Kosari F, Sabeti S, Bidari-Zerehpoosh F, Abdolali E

Abstract
AIM: This study aims to evaluate the association between the MTRR rs1801394 alone or in interaction with the MTHFR rs1801133 and susceptibility to colorectal cancer (CRC) and its characteristics in Iranian population. Additionally, both a systematic review and meta-analysis were performed to derive a more precise assessment of this association.
MATERIALS & METHODS: Genomic DNA of 2332 subjects was genotyped for rs1801394. These data were pooled with 17 eligible studies for meta-analysis.
RESULTS: No significant association was found between the rs1801394 or rs1801394-rs1801133 and CRC risk. Meta-analysis results also demonstrated no significant relationship between the rs1801394 and CRC risk.
CONCLUSION: Results of this study showed that the rs1801394 alone or together with the rs1801133 is not a risk factor for CRC in Iranian population.

PMID: 28691890 [PubMed - as supplied by publisher]

Feasibility of clinical pharmacist-led CYP2C19 genotyping for patients receiving non-emergent cardiac catheterization in an integrated health system.

Pharm Pract (Granada). 2017 Apr-Jun;15(2):946

Authors: Johnson SG, Shaw PB, Delate T, Kurz DL, Gregg D, Darnell JC, Aquilante CL

Abstract
OBJECTIVE: To assess the feasibility of clinical pharmacist-led CYP2C19 genotype-guided P2Y12 inhibitor antiplatelet drug therapy recommendations to cardiologists in an outpatient cardiology practice.
METHODS: This was a prospective, open-labeled, single-arm study conducted in an integrated healthcare delivery system between March 1, 2013 and January 23, 2014. Patients requiring non-emergent cardiac catheterization were included. A clinical pharmacist provided interpretation and recommendations from genotyping results. The feasibility of implementing CYP2C19 genotype-guided antiplatelet therapy was assessed by the: 1) percentage of patients approached who consented to CYP2C19 genotyping, 2) percentage of patients with CYP2C19 genotyping results available prior to cardiac catheterization, and 3) percentage of clinical pharmacist CYP2C19 genotype-based antiplatelet recommendations accepted by cardiologists.
RESULTS: Of the 43 patients identified for potential recruitment, 22 of these were eligible for study enrollment and 6 (27%) patients consented and received CYP2C19 genotyping. All patients had genotyping results available prior to catheterization and all clinical pharmacists' antiplatelet therapy recommendations were accepted by the patients' cardiologists. Three patients had the CYP2C19 wild-type (*1/*1) genotype and the clinical pharmacist recommended clopidogrel therapy. CYP2C19 variant genotypes (i.e., *1/*2, *1/*17, and *2/*17) were found in the other three patients; alternative antiplatelet therapy was recommended for the patient with the *1/*2 genotype, while clopidogrel was recommended for those with *1/*17 and *2/*17 genotypes.
CONCLUSION: A relatively small proportion of patients undergoing non-emergent cardiac catheterization consented to pharmacogenetic testing; however, their cardiologists were receptive to clinical pharmacists conducting such testing and providing corresponding pharmacotherapy recommendations. Future studies should identify patient barriers to pharmacogenetic testing.

PMID: 28690699 [PubMed - in process]

Role of Genetic Testing in Patients undergoing Percutaneous Coronary Intervention.

Expert Rev Clin Pharmacol. 2017 Jul 10;:

Authors: Moon JY, Franchi F, Rollini F, Rivas Rios JR, Kureti M, Cavallari LH, Angiolillo DJ

Abstract
INTRODUCTION: Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered: The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert Commentary: The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes.

PMID: 28689434 [PubMed - as supplied by publisher]

[Chinese expert consensus for non-antiinfective effects and clinical use of macrolides].

Zhonghua Nei Ke Za Zhi. 2017 Jul 01;56(7):546-557

Authors: Lin JT, Zhang YM, Zhou X, Wang CZ, Huang M, Liu CT, Wu CG, Wan HY, Yu WC, Dai YR

Abstract
Important/potential value of macrolides has been proved in the management of chronic respiratory diseases by increasing basic and clinical trials.Through three face-to-face discussions, 10 experts examined important data and drafted this consensus related to macrolides: (1) mechanism of non-antiinfective effects; (2) clinical use in chronic respiratory diseases; (3) cautions of long-term use.The mechanism out of non-antiinfective effects includes anti-inflammatory effect, modifying airway secretion, immune-regulation related to antibacterial effect, corticoid saving effect and anti-viral effect.The efficacy of long-term use of low-dose macrolides is definitely confirmed in diffuse panbronchiolitis, chronic rhinosinusitis. It is considerably used in bronchiectasia, cystic fibrosis, severe asthma and chronic obstructive pulmonary disease. Further studies should be conducted in cryptogenic organizing pneumonia and respiratory viral infection. It should be paid attention to its possible adverse effects (including drug interactions, cardiac toxicity, ototoxicity and disturbance of intestinal flora) and drug resistance in long-term use.A Chinese consensus for non-antiinfective effects and clinical use of macrolides is developed for the first time, which aims to expand their rational use and the further research.

PMID: 28693067 [PubMed - in process]

Diversity, Prevalence, and Longitudinal Occurrence of Type II Toxin-Antitoxin Systems of Pseudomonas aeruginosa Infecting Cystic Fibrosis Lungs.

Front Microbiol. 2017;8:1180

Authors: Andersen SB, Ghoul M, Griffin AS, Petersen B, Johansen HK, Molin S

Abstract
Type II toxin-antitoxin (TA) systems are most commonly composed of two genes encoding a stable toxin, which harms the cell, and an unstable antitoxin that can inactivate it. TA systems were initially characterized as selfish elements, but have recently gained attention for regulating general stress responses responsible for pathogen virulence, formation of drug-tolerant persister cells and biofilms-all implicated in causing recalcitrant chronic infections. We use a bioinformatics approach to explore the distribution and evolution of type II TA loci of the opportunistic pathogen, Pseudomonas aeruginosa, across longitudinally sampled isolates from cystic fibrosis lungs. We identify their location in the genome, mutations, and gain/loss during infection to elucidate their function(s) in stabilizing selfish elements and pathogenesis. We found (1) 26 distinct TA systems, where all isolates harbor four in their core genome and a variable number of the remaining 22 on genomic islands; (2) limited mutations in core genome TA loci, suggesting they are not under negative selection; (3) no evidence for horizontal transmission of elements with TA systems between clone types within patients, despite their ability to mobilize; (4) no gain and limited loss of TA-bearing genomic islands, and of those elements partially lost, the remnant regions carry the TA systems supporting their role in genomic stabilization; (5) no significant correlation between frequency of TA systems and strain ability to establish as chronic infection, but those with a particular TA, are more successful in establishing a chronic infection.

PMID: 28690609 [PubMed - in process]

Investigating the variation in the incidence of new Pseudomonas aeruginosa infection between paediatric cystic fibrosis centres.

J Cyst Fibros. 2017 Jul 06;:

Authors: Gilchrist FJ, Jones AM, Smyth AR, Southern KW, Webb AK, Lenney W

PMID: 28690130 [PubMed - as supplied by publisher]

Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis.

J Clin Invest. 2017 Jul 10;:

Authors: Zang S, Li J, Yang H, Zeng H, Han W, Zhang J, Lee M, Moczygemba M, Isgandarova S, Yang Y, Zhou Y, Rao A, You MJ, Sun D, Huang Y

Abstract
Angioimmunoblastic T cell lymphoma (AITL) represents a distinct, aggressive form of peripheral T cell lymphoma with a dismal prognosis. Recent exome sequencing in patients with AITL has revealed the frequent coexistence of somatic mutations in the Rho GTPase RhoA (RhoAG17V) and loss-of-function mutations in the 5-methylcytosine oxidase TET2. Here, we have demonstrated that TET2 loss and RhoAG17V expression in mature murine T cells cooperatively cause abnormal CD4+ T cell proliferation and differentiation by perturbing FoxO1 gene expression, phosphorylation, and subcellular localization, an abnormality that is also detected in human primary AITL tumor samples. Reexpression of FoxO1 attenuated aberrant immune responses induced in mouse models adoptively transferred with T cells and bearing genetic lesions in both TET2 and RhoA. Our findings suggest a mutational cooperativity between epigenetic factors and GTPases in adult CD4+ T cells that may account for immunoinflammatory responses associated with AITL patients.

PMID: 28691928 [PubMed - as supplied by publisher]

Integrating Next-Generation Genomic Sequencing and Mass Spectrometry to Estimate Allele-Specific Protein Abundance in Human Brain.

J Proteome Res. 2017 Jul 10;:

Authors: Wingo TS, Duong DM, Zhou M, Dammer EB, Wu H, Cutler DJ, Lah JJ, Levey AI, Seyfried NT

Abstract
Gene expression contributes to phenotypic traits and human disease. To date, comparatively less is known about regulators of protein abundance, which is also under genetic control and likely influences clinical phenotypes. However, identifying and quantifying allele-specific protein abundance by bottom-up proteomics is challenging since single nucleotide variants (SNVs) that alter protein sequence are not considered in standard human protein databases. To address this, we developed the GenPro software and used it to create personalized protein databases (PPDs) to identify single amino acid variants (SAAVs) at the protein level from whole exome sequencing. In silico assessment of PPDs generated by GenPro revealed only a 1% increase in tryptic search space compared to a direct translation of all human transcripts and an equivalent search space compared to the UniProtKB reference database. To identify a large unbiased number of SAAV peptides, we performed high-resolution mass spectrometry-based proteomics for two human post-mortem brain samples and searched the collected MS/MS spectra against their respective PPD. We found an average of ~117,000 unique peptides mapping to ~9,300 protein groups for each sample and of these 977 were unique variant peptides. We found that over 400 reference and SAAV peptide pairs were, on average, equally abundant in human brain by label-free ion intensity measurements and confirmed the absolute levels of three reference and SAAV peptide pairs using heavy labeled peptides standards coupled with parallel reaction monitoring (PRM). Our results highlight the utility of integrating genomic and proteomic sequencing data to identify sample-specific SAAV peptides and support the hypothesis that most alleles are equally expressed in human brain.

PMID: 28691493 [PubMed - as supplied by publisher]

Next generation sequencing and array-based comparative genomic hybridization for molecular diagnosis of pediatric endocrine disorders.

Ann Pediatr Endocrinol Metab. 2017 Jun;22(2):90-94

Authors: Fukami M, Miyado M

Abstract
Next-generation sequencing (NGS) and array-based comparative genomic hybridization (array CGH) have enabled us to perform high-throughput mutation screening and genome-wide copy number analysis, respectively. These methods can be used for molecular diagnosis of pediatric endocrine disorders. NGS has determined the frequency and phenotypic variation of mutations in several disease-associated genes. Furthermore, whole exome analysis using NGS has successfully identified several novel causative genes for endocrine disorders. Array CGH is currently used as the standard procedure for molecular cytogenetic analysis. Array CGH can detect various submicroscopic genomic rearrangements involving exons or enhancers of disease-associated genes. This review introduces some examples of the use of NGS and array CGH for the molecular diagnosis of pediatric endocrine disorders.

PMID: 28690986 [PubMed]

Whole-exome sequencing analysis of Waardenburg syndrome in a Chinese family.

Hum Genome Var. 2017;4:17027

Authors: Chen D, Zhao N, Wang J, Li Z, Wu C, Fu J, Xiao H

Abstract
Waardenburg syndrome (WS) is a dominantly inherited, genetically heterogeneous auditory-pigmentary syndrome characterized by non-progressive sensorineural hearing loss and iris discoloration. By whole-exome sequencing (WES), we identified a nonsense mutation (c.598C>T) in PAX3 gene, predicted to be disease causing by in silico analysis. This is the first report of genetically diagnosed case of WS PAX3 c.598C>T nonsense mutation in Chinese ethnic origin by WES and in silico functional prediction methods.

PMID: 28690861 [PubMed - in process]

The detection of a novel insertion mutation in exon 2 of the MEFV gene associated with familial mediterranean fever in a moroccan family.

Hum Genome Var. 2017;4:17023

Authors: Mejtoute T, Sayel H, El-Akhal J, Moufid FZ, Bouguenouch L, El Bouchikhi I, Hida M, Couissi D, Ouldim K

Abstract
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease that is inherited in an autosomal recessive manner and is caused by mutations in the MEFV gene. As the name indicates, FMF occurs within families and is more common in individuals of Mediterranean descent than in persons of any other ethnicity. To date, 314 mutations have been reported. We studied a Moroccan family with a total of five members, including a mother who was presenting with symptoms of FMF, while her four children remained asymptomatic. The five patients were screened by DNA sequencing of exon 2 and exon 10 of the MEFV gene. Then, complete exome sequencing analysis of the MEFV gene was done for the patients in whom a novel mutation was detected. This analysis identified a novel single base Cytosine (C) insertion mutation in the coding region of the MEFV gene, named c.441dupC (p. Glu148Argfs*5 or E148RfsX5), which resulted in a mutated Pyrin/Marenostrin protein. This is the first report of a new mutation in exon 2 of the MEFV gene in a Moroccan family. This novel insertion mutation may provide important information for further studies of FMF pathogenesis.

PMID: 28690860 [PubMed - in process]

[Drug induced angioedema: a rare side effect of simvastatin].

Pan Afr Med J. 2017;26:213

Authors: El Mekki AB, Chaib A

PMID: 28690728 [PubMed - in process]