Principles and applications of pharmacometrics in drug evaluation in children.

Therapie. 2018 Feb 16;:

Authors: Leroux S, Elie V, Zhao W, Magreault S, Jacqz-Aigrain E

Abstract
Drug evaluation in children is difficult for many well-identified reasons and many drugs are still used off-label. Innovative approaches are particularly adapted to the paediatric and neonatal populations, as clinical trials are difficult to conduct, need adapted designs in order to define the optimal dosage regimen in many diseases and therapeutic areas. Population approaches to define pharmacokinetics and pharmacokinetic/pharmacodynamics are now more currently used to define dosing regimens, adapted to the different paediatric and neonatal age groups, that allow to increase efficacy and reduce toxicity, by taking into account factors explaining variability in drug response. Such approaches are presented and the evaluation of vancomycin in neonates is detailed as different steps allowed validation of the optimal strategy to administer vancomycin in neonates.

PMID: 29605146 [PubMed - as supplied by publisher]

Six-minute walk test as a determinant of the functional capacity of children and adolescents with cystic fibrosis: A systematic review.

Respir Med. 2018 Apr;137:83-88

Authors: Andrade Lima C, Dornelas de Andrade A, Campos SL, Brandão DC, Mourato IP, Britto MCA

Abstract
Cystic Fibrosis (CF) is a multisystem disorder. The involvement of the respiratory system is frequent and culminates in dyspnea and exercise intolerance. Functional capacity is an important diagnostic tool, because it reflects the cardiorespiratory status, quality of life and prognosis. This systematic review aims to assess the reproducibility and validity of the six minute walk test (6MWT) to reflect the functional capacity of children and adolescents with cystic fibrosis, and also the correlation between 6MWT and lung function. Searches for articles were performed in eight databases using MeSH/DeCS keywords. A total of 695 articles were found and, after verifying all eligibility criteria, six articles were included for analysis and scoring regarding the methodological quality according to the QUADAS scale (Quality Assessment of Diagnostic Accuracy Studies). All articles had good methodology (QUADAS between 9 and 11 points). The 6MWT is not correlated with lung function. There is a strong indication that the 6MWT is a reproducible test to assess the functional capacity of children and adolescents with CF. The validity assessment could not be reached because the studies included in this systematic review did not use adequate statistical tools to carry out such an evaluation.

PMID: 29605218 [PubMed - in process]

Burden of pneumococcal community-acquired pneumonia in adults across Europe: A literature review.

Respir Med. 2018 Apr;137:6-13

Authors: Torres A, Cillóniz C, Blasi F, Chalmers JD, Gaillat J, Dartois N, Schmitt HJ, Welte T

Abstract
BACKGROUND: The burden of community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae (pneumococcus) among adults in Europe is poorly defined.
METHODS: Structured searches of PubMed were conducted to identify the incidence of pneumococcal CAP among adults across Europe.
RESULTS: The overall incidence rates for CAP was 68-7000 per 100,000 and the incidence in hospitalised CAP cases of all causes was 16-3581 per 100,000. In general the incidence of CAP increased consistently with age. Available data indicated higher burdens of pneumococcal CAP caused in groups with more comorbidities. Most cases of pneumococcal CAP (30%-78%) were caused by serotypes covered by PCV13 vaccine; the incidence of PCV13-related pneumonia decreased after the introduction of childhood vaccination.
CONCLUSIONS: We observed a high burden adult pneumococcal CAP in Europe despite use of the 23-valent pneumococcal polysaccharide vaccine, particularly in elderly patients with comorbidities. CAP surveillance presented wide variations across Europe. Pneumococcal CAP has to be monitored very carefully due to the possible effect of current vaccination strategies.

PMID: 29605214 [PubMed - in process]

A review of the etiology and clinical presentation of non-cystic fibrosis bronchiectasis: A tertiary care experience.

Respir Med. 2018 Apr;137:35-39

Authors: Satırer O, Mete Yesil A, Emiralioglu N, Tugcu GD, Yalcın E, Dogru D, Kiper N, Ozcelik U

Abstract
INTRODUCTION: Non-cystic fibrosis(CF) bronchiectasis has been recognized in children for the past 200 years. Early childhood pneumonia and underlying conditions such as immunodeficiency, primary ciliary dyskinesia(PCD), and congenital lung pathology should be considered in the etiology. The aim of our study was to describe the clinical characteristics, laboratory, and radiological findings of a large population of patients with non-CF bronchiectasis at a tertiary center.
METHODS: We analyzed the clinical findings of 187 patients diagnosed with non-CF bronchiectasis over a period of 10 years (January 2005-December 2015) at the Hacettepe University Faculty of Medicine Department of Pediatric Pulmonology.
RESULTS: The median age at the time of diagnosis of non-CF bronchiectasis was 8 years (1-18 years). Consanguinity was positive in 59.4% (n = 111) of patients and 19.8% (n = 37) of patients had a positive family history for non-CF bronchiectasis. Common causes were PCD in 51.3% (n = 96), immunodeficiency in 15% (n = 28), history of tuberculosis in 5.9% (n = 11), post-infectious complication in 3.2% (n = 6) and other anomalies in 2.1% (n = 4) of patients. The frequency of pulmonary lobe involvement was as follows: 71.1% left-lower lobe, 59.4% right lower lobe, 54% right-middle lobe, 26.8% left lingula, 13.9% right upper lobe, and 9.6% left upper lobe.
CONCLUSIONS: Diagnosis of non-CF bronchiectasis is often delayed because of a failure to recognize the significance of symptoms. Through clinical investigation, including a HRCT scan of the chest, sweat test, studies of immune function, and ciliary function in a child with a prolonged suppurative cough, remains important. In Turkey, the most common causes of non-CF bronchiectasis are PCD and immunodeficiency, related to a high frequency of consanguinity.

PMID: 29605210 [PubMed - in process]

Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.

Lancet. 2018 Mar 28;:

Authors: Männikkö R, Wong L, Tester DJ, Thor MG, Sud R, Kullmann DM, Sweeney MG, Leu C, Sisodiya SM, FitzPatrick DR, Evans MJ, Jeffrey IJM, Tfelt-Hansen J, Cohen MC, Fleming PJ, Jaye A, Simpson MA, Ackerman MJ, Hanna MG, Behr ER, Matthews E

Abstract
BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS.
METHODS: We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system.
FINDINGS: Four (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057).
INTERPRETATION: Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths.
FUNDING: UK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

PMID: 29605429 [PubMed - as supplied by publisher]

Flexible Protein-Protein Docking with SwarmDock.

Methods Mol Biol. 2018;1764:413-428

Authors: Moal IH, Chaleil RAG, Bates PA

Abstract
The atomic structures of protein complexes can provide useful information for drug design, protein engineering, systems biology, and understanding pathology. Obtaining this information experimentally can be challenging. However, if the structures of the subunits are known, then it is often possible to model the complex computationally. This chapter provide practical guidelines for docking proteins using the SwarmDock flexible protein-protein docking method, providing an overview of the factors that need to be considered when deciding whether docking is likely to be successful, the preparation of structural input, generation of docked poses, analysis and ranking of docked poses, and the validation of models using external data.

PMID: 29605931 [PubMed - in process]

Automated Computational Inference of Multi-protein Assemblies from Biochemical Co-purification Data.

Methods Mol Biol. 2018;1764:391-399

Authors: Goebels F, Hu L, Bader G, Emili A

Abstract
Biology has amassed a wealth of information about the function of a multitude of protein-coding genes across species. The challenge now is to understand how all these proteins work together to form a living organism, and a crucial step for gaining this knowledge is a complete description of the molecular "wiring circuits" that underlie cellular processes. In this chapter, we describe a general computational framework for predicting multi-protein assemblies from biochemical co-fractionation data.

PMID: 29605929 [PubMed - in process]

Biochemical Identification of Nonmethylated DNA by BioCAP-Seq.

Methods Mol Biol. 2018;1766:15-29

Authors: Long HK, Rose NR, Blackledge NP, Klose RJ

Abstract
CpG islands are regions of vertebrate genomes that often function as gene regulatory elements and are associated with most gene promoters. CpG island elements usually contain nonmethylated CpG dinucleotides, while the remainder of the genome is pervasively methylated. We developed a biochemical approach called biotinylated CxxC affinity purification (BioCAP) to unbiasedly isolate regions of the genome that contain nonmethylated CpG dinucleotides. The resulting highly pure nonmethylated DNA is easily analyzed by quantitative PCR to interrogate specific loci or via massively parallel sequencing to yield genome-wide profiles.

PMID: 29605845 [PubMed - in process]

Trypanosomatids Are Much More than Just Trypanosomes: Clues from the Expanded Family Tree.

Trends Parasitol. 2018 Mar 28;:

Authors: Lukeš J, Butenko A, Hashimi H, Maslov DA, Votýpka J, Yurchenko V

Abstract
Trypanosomes and leishmanias are widely known parasites of humans. However, they are just two out of several phylogenetic lineages that constitute the family Trypanosomatidae. Although dixeny - the ability to infect two hosts - is a derived trait of vertebrate-infecting parasites, the majority of trypanosomatids are monoxenous. Like their common ancestor, the monoxenous Trypanosomatidae are mostly parasites or commensals of insects. This review covers recent advances in the study of insect trypanosomatids, highlighting their diversity as well as genetic, morphological and biochemical complexity, which, until recently, was underappreciated. The investigation of insect trypanosomatids is providing an important foundation for understanding the origin and evolution of parasitism, including colonization of vertebrates and the appearance of human pathogens.

PMID: 29605546 [PubMed - as supplied by publisher]

Compensation of Signal Spillover in Suspension and Imaging Mass Cytometry.

Cell Syst. 2018 Mar 23;:

Authors: Chevrier S, Crowell HL, Zanotelli VRT, Engler S, Robinson MD, Bodenmiller B

Abstract
The advent of mass cytometry increased the number of parameters measured at the single-cell level while decreasing the extent of crosstalk between channels relative to dye-based flow cytometry. Although reduced, spillover still exists in mass cytometry data, and minimizing its effect requires considerable expert knowledge and substantial experimental effort. Here, we describe a novel bead-based compensation workflow and R-based software that estimates and corrects for interference between channels. We performed an in-depth characterization of the spillover properties in mass cytometry, including limitations defined by the linear range of the mass cytometer and the reproducibility of the spillover over time and across machines. We demonstrated the utility of our method in suspension and imaging mass cytometry. To conclude, our approach greatly simplifies the development of new antibody panels, increases flexibility for antibody-metal pairing, opens the way to using less pure isotopes, and improves overall data quality, thereby reducing the risk of reporting cell phenotype artifacts.

PMID: 29605184 [PubMed - as supplied by publisher]

Systematic Evaluation of Molecular Networks for Discovery of Disease Genes.

Cell Syst. 2018 Mar 26;:

Authors: Huang JK, Carlin DE, Yu MK, Zhang W, Kreisberg JF, Tamayo P, Ideker T

Abstract
Gene networks are rapidly growing in size and number, raising the question of which networks are most appropriate for particular applications. Here, we evaluate 21 human genome-wide interaction networks for their ability to recover 446 disease gene sets identified through literature curation, gene expression profiling, or genome-wide association studies. While all networks have some ability to recover disease genes, we observe a wide range of performance with STRING, ConsensusPathDB, and GIANT networks having the best performance overall. A general tendency is that performance scales with network size, suggesting that new interaction discovery currently outweighs the detrimental effects of false positives. Correcting for size, we find that the DIP network provides the highest efficiency (value per interaction). Based on these results, we create a parsimonious composite network with both high efficiency and performance. This work provides a benchmark for selection of molecular networks in human disease research.

PMID: 29605183 [PubMed - as supplied by publisher]

Physical-chemical mechanisms of pattern formation during gastrulation.

J Chem Phys. 2018 Mar 28;148(12):123302

Authors: Bozorgui B, Kolomeisky AB, Teimouri H

Abstract
Gastrulation is a fundamental phase during the biological development of most animals when a single layer of identical embryo cells is transformed into a three-layer structure, from which the organs start to develop. Despite a remarkable progress in quantifying the gastrulation processes, molecular mechanisms of these processes remain not well understood. Here we theoretically investigate early spatial patterning in a geometrically confined colony of embryonic stem cells. Using a reaction-diffusion model, a role of Bone-Morphogenetic Protein 4 (BMP4) signaling pathway in gastrulation is specifically analyzed. Our results show that for slow diffusion rates of BMP4 molecules, a new length scale appears, which is independent of the size of the system. This length scale separates the central region of the colony with uniform low concentrations of BMP molecules from the region near the colony edge where the concentration of signaling molecules is elevated. The roles of different components of the signaling pathway are also explained. Theoretical results are consistent with recent in vitro experiments, providing microscopic explanations for some features of early embryonic spatial patterning. Physical-chemical mechanisms of these processes are discussed.

PMID: 29604871 [PubMed - in process]

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Niclosamide, a drug with many (re)purposes.

ChemMedChem. 2018 Mar 30;:

Authors: Kadri H, Lambourne OA, Mehellou Y

Abstract
Niclosamide is an anthelmintic drug that has mainly been used for over 50 years to treat tapeworm infections. However, with the increase in drug repurposing initiatives, niclosamide has emerged as a true hit in many screens against various diseases. Indeed, from being an anthelmintic drug, it has now shown potential in treating Parkinson's disease, diabetes, viral and microbial infections as well as various cancers. Such diverse pharmacological activities are a result of niclosamide's ability to uncouple mitochondrial phosphorylation and modulate a selection of signaling pathways, such as Wnt/β-catenin, mTOR and JAK/STAT3, which are implicated many diseases. In this highlight, we will discuss the plethora of diseases that niclosamide has shown promise in treating.

PMID: 29603892 [PubMed - as supplied by publisher]

Osmolality predictive models of different Polymers as tools in parenteral and ophthalmic formulation development.

Int J Pharm. 2018 Mar 28;:

Authors: Camargo DA, Carreras MR, Montoya EG, Lozano PP, Carmona MM, Grau JRT, Negre JMS

Abstract
During the development of parenteral dosage forms, different physicochemical studies are required to ensure stable, effective and safe formulations. The osmolality of this kind of dosage form should bear a close similarity to the body fluids to prevent local irritation, pain or even more significant side effects like endothelial damage. The osmotic studies performed in Polyethylene glycol 400 (PEG 400), Polyethylene glycol 4000 (PEG 4000), Poloxamer 407 (P407), Sodium Hyaluronate (SH), Chondroitin Sulphate Sodium (CS), Cremophor RH 40 (CRE40) and Polyvinyl alcohol (PVA) aqueous solutions, showed that the theoretical determination of the osmolality based on their molecular weight as the only determinant factor did not agree with the values obtained by the measurement of colligative properties such as the freezing point depression. The data obtained from this study and its analysis, provided predictive equations that can be used as tools in the primary development to estimate formulatiońs osmolality at different concentrations; and its evolution over a period at the hypothetical worst-case scenario of storage temperature.

PMID: 29604368 [PubMed - as supplied by publisher]

A new vaccine targeting RANKL, prepared by incorporation of an unnatural Amino acid into RANKL, prevents OVX-induced bone loss in mice.

Biochem Biophys Res Commun. 2018 Mar 28;:

Authors: Li F, Li H, Zhai Q, Li F, Wu T, Sha X, Zhang B, Yang W, Lu Z, Tao H

Abstract
Bone homeostasis is maintained by a dynamic balance between osteoblastic bone formation and osteoclastic bone resorption. The receptor activator of nuclear-κB ligand (RANKL) is essential for the function of the bone-resorbing osteoclasts, and targeting RANKL has been proved highly successful in osteoporosis patients. This study aimed to design a novel vaccine targeting RANKL and evaluate its therapeutic effects in OVX-induced bone loss model. Anti-RANKL vaccine was generated by incorporating the unnatural amino acid p-nitrophenylalanine (pNO2Phe) into selected sites in the murine RANKL (mRANKL) molecule. Specifically, mutation of a single tyrosine residue Tyr234 (Y234) or Tyr240 (Y240) of mRANKL to pNO2Phe (thereafter named as Y234pNO2Phe or Y240pNO2Phe) induced a high titer antibody response in mice, whereas no significant antibody response was observed for the wild type mRANKL (WT mRANKL). The antiserum induced by Y234pNO2Phe or Y240pNO2Phe could efficiently prevent osteoclastogenesis in vitro. Moreover, immunization with Y234pNO2Phe or Y240pNO2Phe could also prevent OVX-induced bone loss in mice, suggesting that selected pNO2Phe-substituted mRANKL may pave the way for creating a novel vaccine to treat osteoporosis.

PMID: 29604276 [PubMed - as supplied by publisher]

Implementation of a pharmacist-led pharmacogenomics service for the Program of All-Inclusive Care for the Elderly (PHARM-GENOME-PACE).

J Am Pharm Assoc (2003). 2018 Mar 27;:

Authors: Bain KT, Schwartz EJ, Knowlton OV, Knowlton CH, Turgeon J

Abstract
OBJECTIVES: To determine the feasibility of implementing a pharmacist-led pharmacogenomics (PGx) service for the Program of All-Inclusive Care for the Elderly (PACE).
SETTING: A national centralized pharmacy providing PGx services to community-based PACE centers.
PRACTICE DESCRIPTION: Individuals 55 years of age and older enrolled in PACE who underwent PGx testing as part of their medical care (n = 296).
PRACTICE INNOVATION: Pharmacist-led PGx testing, interpreting, and consulting.
EVALUATION: Implementation processes and roles were ascertained by reviewing policies and procedures for the PGx service and documented observations made by pharmacists providing the service. Genetic variants and drug-gene interactions (DGIs) were determined by interpretations of PGx test results. Types of recommendations provided by pharmacists were ascertained from PGx consultations. Prescribers' acceptance of recommendations were ascertained by documented responses or drug changes made after PGx consultations.
RESULTS: Challenges to implementation included lack of systems interoperability, limited access to medical electronic health records, determining prescribers' responses, and knowledge and competency gaps in PGx. Pharmacist roles most essential to overcoming challenges were interpreting and applying PGx data, determining how to disseminate those data to prescribers, advocating for appropriate PGx testing, and educating about the application of test results to clinical practice. Participants frequently used drugs posing DGI risks, with the majority (73.6%) reporting more than 1 interaction. The overwhelming majority (89.0%) of pharmacists' recommendations to mitigate risks were accepted by referring prescribers.
CONCLUSION: Implementing a pharmacist-led PGx service for PACE is feasible. Implementation of this service highlights the leadership role of pharmacists in moving PGx from research to practice.

PMID: 29602745 [PubMed - as supplied by publisher]

Pediatric pharmacology.

Therapie. 2018 Feb 21;:

Authors: Kaguelidou F, Kassai Koupai B, Durrieu G

PMID: 29602602 [PubMed - as supplied by publisher]

FMR1 premutation frequency in a large, ethnically diverse population referred for carrier testing.

Am J Med Genet A. 2018 Mar 31;:

Authors: Owens KM, Dohany L, Holland C, DaRe J, Mann T, Settler C, Longman RE

Abstract
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is caused by an expansion of cytosine-guanine-guanine (CGG) repeats in the FMR1 gene. Female premutation allele carriers (55-200 CGG repeats) are at risk to have an affected child. Currently, specific population-based carrier screening for FXS is not recommended. Previous studies exploring female premutation carrier frequency have been limited by size or ethnicity. This retrospective study provides a pan-ethnic estimate of the Fragile X premutation carrier frequency in a large, ethnically diverse population of women referred for routine carrier screening during a specified time period at Progenity, Inc. Patient ethnicity was self-reported and categorized as: African American, Ashkenazi Jewish, Asian, Caucasian, Hispanic, Native American, Other/Mixed/Unknown, or Sephardic Jewish. FXS test results were stratified by ethnicity and repeat allele category. Total premutation carrier frequency was calculated and compared against each ethnic group. A total of 134,933 samples were included. The pan-ethnic premutation carrier frequency was 1 in 201. Only the Asian group differed significantly from this frequency. Using the carrier frequency of 1 in 201, a conservative pan-ethnic risk estimate for a male fetus to have FXS can be calculated as 1 in 2,412. This risk is similar to the highest ethnic-based fetal risks for cystic fibrosis and spinal muscular atrophy, for which population-wide screening is currently recommended. This study adds to the literature and supports further evaluation into specific population-wide screening recommendations for FXS.

PMID: 29603880 [PubMed - as supplied by publisher]

Defining chronic Pseudomonas aeruginosa infection in cystic fibrosis.

J Cyst Fibros. 2018 Mar 27;:

Authors: Waters V, Grimwood K

PMID: 29602718 [PubMed - as supplied by publisher]