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("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/06/12

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.

Cascade Ligand- and Structure-Based Virtual Screening to Identify New Trypanocidal Compounds Inhibiting Putrescine Uptake.

Front Cell Infect Microbiol. 2018;8:173

Authors: Alberca LN, Sbaraglini ML, Morales JF, Dietrich R, Ruiz MD, Pino Martínez AM, Miranda CG, Fraccaroli L, Alba Soto CD, Carrillo C, Palestro PH, Talevi A

Abstract
Chagas disease is a neglected tropical disease endemic to Latin America, though migratory movements have recently spread it to other regions. Here, we have applied a cascade virtual screening campaign combining ligand- and structure-based methods. In order to find novel inhibitors of putrescine uptake in Trypanosoma cruzi, an ensemble of linear ligand-based classifiers obtained by has been applied as initial screening filter, followed by docking into a homology model of the putrescine permease TcPAT12. 1,000 individual linear classifiers were inferred from a balanced dataset. Subsequently, different schemes were tested to combine the individual classifiers: MIN operator, average ranking, average score, average voting, with MIN operator leading to the best performance. The homology model was based on the arginine/agmatine antiporter (AdiC) from Escherichia coli as template. It showed 64% coverage of the entire query sequence and it was selected based on the normalized Discrete Optimized Protein Energy parameter and the GA341 score. The modeled structure had 96% in the allowed area of Ramachandran's plot, and none of the residues located in non-allowed regions were involved in the active site of the transporter. Positivity Predictive Value surfaces were applied to optimize the score thresholds to be used in the ligand-based virtual screening step: for that purpose Positivity Predictive Value was charted as a function of putative yields of active in the range 0.001-0.010 and the Se/Sp ratio. With a focus on drug repositioning opportunities, DrugBank and Sweetlead databases were subjected to screening. Among 8 hits, cinnarizine, a drug frequently prescribed for motion sickness and balance disorder, was tested against T. cruzi epimastigotes and amastigotes, confirming its trypanocidal effects and its inhibitory effects on putrescine uptake. Furthermore, clofazimine, an antibiotic with already proven trypanocidal effects, also displayed inhibitory effects on putrescine uptake. Two other hits, meclizine and butoconazole, also displayed trypanocidal effects (in the case of meclizine, against both epimastigotes and amastigotes), without inhibiting putrescine uptake.

PMID: 29888213 [PubMed - in process]

Learning Opportunities for Drug Repositioning via GWAS and PheWAS Findings.

AMIA Jt Summits Transl Sci Proc. 2018;2017:237-246

Authors: Yin W, Gao C, Xu Y, Li B, Ruderfer DM, Chen Y

Abstract
Drug repositioning for available medications can be preferred over traditional drug development, which requires substantially more effort to uncover new insights into medications and diseases. Genome-Wide Association Studies (GWAS) and Phenome-Wide Association Studies (PheWAS) are two complimentary methods for finding novel associations between genes and diseases. We hypothesize that discoveries from these studies could be leveraged to find new targets for existing drugs. Thus, we propose a framework to learn opportunities for inferring such relationships via overlapped genes between disease-associated genes (e.g. GWAS and PheWAS findings) and drugtargeted genes. We use drug indications found in Medication Indication Resource (MEDI) as a gold standard to evaluate if drug indications learned from GWAS and PheWAS findings have clinical indications. We examined 151,011 <drug, GWAS phenotype> pairs from 987 drugs across 153 diseases and 763 pairs were statistically significant. Out of these 763 pairs, 16 of them were found to have clinical indications.

PMID: 29888080 [PubMed]

A Network-Biology Informed Computational Drug Repositioning Strategy to Target Disease Risk Trajectories and Comorbidities of Peripheral Artery Disease.

AMIA Jt Summits Transl Sci Proc. 2018;2017:108-117

Authors: Shameer K, Dow G, Glicksberg BS, Johnson KW, Ze Y, Tomlinson MS, Readhead B, Dudley JT, Kullo IJ

Abstract
Currently, drug discovery approaches focus on the design of therapies that alleviate an index symptom by reengineering the underlying biological mechanism in agonistic or antagonistic fashion. For example, medicines are routinely developed to target an essential gene that drives the disease mechanism. Therapeutic overloading where patients get multiple medications to reduce the primary and secondary side effect burden is standard practice. This single-symptom based approach may not be scalable, as we understand that diseases are more connected than random and molecular interactions drive disease comorbidities. In this work, we present a proof-of-concept drug discovery strategy by combining network biology, disease comorbidity estimates, and computational drug repositioning, by targeting the risk factors and comorbidities of peripheral artery disease, a vascular disease associated with high morbidity and mortality. Individualized risk estimation and recommending disease sequelae based therapies may help to lower the mortality and morbidity of peripheral artery disease.

PMID: 29888052 [PubMed]

Incorporating Protein Dynamics Through Ensemble Docking in Machine Learning Models to Predict Drug Binding.

AMIA Jt Summits Transl Sci Proc. 2018;2017:26-34

Authors: Alghamedy F, Bopaiah J, Jones D, Zhang X, Weiss HL, Ellingson SR

Abstract
Drug discovery is an expensive, lengthy, and sometimes dangerous process. The ability to make accurate computational predictions of drug binding would greatly improve the cost-effectiveness and safety of drug discovery and development. This study incorporates ensemble docking, the use of multiple protein conformations extracted from a molecular dynamics trajectory to perform docking calculations, with additional biomedical data sources and machine learning algorithms to improve the prediction of drug binding. We found that we can greatly increase the classification accuracy of an active vs a decoy compound using these methods over docking scores alone. The best results seen here come from having an individual protein conformation that produces binding features that correlate well with the active vs. decoy classification, in which case we achieve over 99% accuracy. The ability to confidently make accurate predictions on drug binding would allow for computational polypharamacological networks with insights into side-effect prediction, drug-repurposing, and drug efficacy.

PMID: 29888034 [PubMed]

Lethal cerebral hemorrhage after ticagrelor intoxication: a specific antidote is urgently needed.

Clin Toxicol (Phila). 2018 Jun 11;:1-4

Authors: Willeman T, Marlu R, Böhle H, Francony G, Jourdil JF, Fonrose X, Stanke-Labesque F

Abstract
BACKGROUND: Ticagrelor is a direct and reversible competitive antagonist of the P2Y12 receptor and inhibits platelet activation. Although adverse bleeding is common, fatal intoxication has never been documented.
CASE DESCRIPTION: A 47-year-old man died from a severe cerebral hemorrhage secondary to a fall and cranial trauma 4 d after the massive intake of ticagrelor. Iterative platelet transfusions did not improve his condition. Toxicological analyses by liquid chromatography tandem mass spectrometry (LC-MS/MS) revealed high plasma concentrations of ticagrelor (3343 µg/L) and its active metabolite AR-C124910XX (656 µg/L) 10 h after intake. The approximate ingested dose was extrapolated to 1677 mg. Assessment of ADP-induced platelet aggregation and platelet Vasodilator Stimulated Phosphoprotein phosphorylation (VASP), 2 and 3 d after admission, respectively, showed the persistence of platelet inhibition.
DISCUSSION: To the best of our knowledge, no prior fatal cases have been reported and documented with both ticagrelor and AR-C124910XX concentrations. Our findings highlight the need for a specific antidote to manage such complications resulting from ticagrelor overdose.

PMID: 29889575 [PubMed - as supplied by publisher]

Pharmacogenomic studies of hypertension: paving the way for personalized antihypertensive treatment.

Expert Rev Precis Med Drug Dev. 2018;3(1):33-47

Authors: Eadon MT, Kanuri SH, Chapman AB

Abstract
Introduction: Increasing clinical evidence supports the implementation of genotyping for anti-hypertensive drug dosing and selection. Despite robust evidence gleaned from clinical trials, the translation of genotype guided therapy into clinical practice faces significant challenges. Challenges to implementation include the small effect size of individual variants and the polygenetic nature of antihypertensive drug response, a lack of expert consensus on dosing guidelines even without genetic information, and proper definition of major antihypertensive drug toxicities. Balancing clinical benefit with cost, while overcoming these challenges, remains crucial.
Areas covered: This review presents the most impactful clinical trials and cohorts which continue to inform and guide future investigation. Variants were selected from among those identified in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR), the Genetic Epidemiology of Responses to Antihypertensives study (GERA), the Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study, the SOPHIA study, the Milan Hypertension Pharmacogenomics of hydro-chlorothiazide (MIHYPHCTZ), the Campania Salute Network, the International Verapamil SR Trandolapril Study (INVEST), the Nordic Diltiazem (NORDIL) Study, GenHAT, and others.
Expert Commentary: The polygenic nature of antihypertensive drug response is a major barrier to clinical implementation. Further studies examining clinical effectiveness are required to support broad-based implementation of genotype-based prescribing in medical practice.

PMID: 29888336 [PubMed]

Whole-Exome Sequencing Identifies One De Novo Variant in the FGD6 Gene in a Thai Family with Autism Spectrum Disorder.

Int J Genomics. 2018;2018:8231547

Authors: Thongnak C, Hnoonual A, Tangviriyapaiboon D, Silvilairat S, Puangpetch A, Pasomsub E, Chantratita W, Limprasert P, Sukasem C

Abstract
Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques.

PMID: 29888248 [PubMed]

CATCH-KB: Establishing a Pharmacogenomics Variant Repository for Chemotherapy-Induced Cardiotoxicity.

AMIA Jt Summits Transl Sci Proc. 2018;2017:168-177

Authors: Morash M, Mitchell H, Yu A, Campion T, Beltran H, Elemento O, Pathak J

Abstract
The Cardiotoxicity of Chemotherapy Knowledgebase (CATCH-KB) contains information extracted from articles investigating an association between germline genetic polymorphisms and the development of chemotherapy-induced cardiotoxicity (CIC) in cancer patients receiving antineoplastic treatments. CATCH-KB also contains integrated gene and drug information from open biomedical resources such as PharmGKB1 and SIDER2. Furthermore, the genetic polymorphisms, drugs, and cancer types detailed in CATCH-KB are standardized according to appropriate biomedical ontologies, such as SNOMED-CT3 and RxNorm4. CATCH-KB currently contains information on 49 research papers published between 2004 and 2017 investigating a total of 2,210 variants in over 280 genes for an association with CIC. By centralizing this information and linking it to external open-access biomedical resources, CATCH-KB will facilitate hypothesis generation and meta-analysis efforts and will ultimately accelerate the use of genetic screening in preventing CIC. CATCH-KB is publicly accessible via http://catchkb.org.

PMID: 29888066 [PubMed]

A single intraperitoneal injection of bovine fetuin-A attenuates bone resorption in a murine calvarial model of particle-induced osteolysis.

Bone. 2017 Dec;105:262-268

Authors: Jablonski H, Polan C, Wedemeyer C, Hilken G, Schlepper R, Bachmann HS, Grabellus F, Dudda M, Jäger M, Kauther MD

Abstract
Particle-induced osteolysis, which by definition is an aseptic inflammatory reaction to implant-derived wear debris eventually leading to local bone destruction, remains the major reason for long-term failure of orthopedic endoprostheses. Fetuin-A, a 66kDa glycoprotein with diverse functions, is found to be enriched in bone. Besides being an important inhibitor of ectopic calcification, it has been described to influence the production of mediators of inflammation. Furthermore, a regulatory role in bone metabolism has been assigned. In the present study, the influence of a single dose of bovine fetuin-A, intraperitoneally injected in mice subjected to particle-induced osteolysis of the calvaria, was analyzed. Twenty-eight male C57BL/6 mice, twelve weeks of age, were randomly divided into four groups. Groups 2 and 4 were subjected to ultra-high molecular weight polyethylene (UHMWPE) particles placed on their calvariae while groups 1 and 3 were sham-operated. Furthermore, groups 3 and 4 received a single intraperitoneal injection of 20mg bovine fetuin-A while groups 1 and 2 were treated with physiologic saline. After 14days calvarial bone was qualitatively and quantitatively assessed using microcomputed tomography (μCT) and histomorphometrical approaches. Application of fetuin-A led to a reduction of particle-induced osteolysis in terms of visible osteolytic lesions and eroded bone surface. The reduction of bone thickness and bone volume, as elicited by UHMWPE, was alleviated by fetuin-A. In conclusion, fetuin-A was found to exert an anti-resorptive effect on particle-induced osteolysis in-vivo. Thus, fetuin-A could play a potentially osteoprotective role in the treatment of bone metabolic disorders.

PMID: 28942123 [PubMed - indexed for MEDLINE]

Polymorphisms in CYP2C9 are associated with response to indomethacin among neonates with patent ductus arteriosus.

Pediatr Res. 2017 Nov;82(5):776-780

Authors: Smith CJ, Ryckman KK, Bahr TM, Dagle JM

Abstract
BackgroundPatent ductus arteriosus (PDA) is a common complication seen in preterm infants. Indomethacin is routinely used to treat PDA. Evidence suggests that the response of indomethacin is highly heritable. This study investigated the association between single-nucleotide polymorphisms (SNPs) in CYP2C9 and the closure of PDA in response to indomethacin.MethodsSix SNPs in CYP2C9 were analyzed for association with indomethacin response. A case-control analysis was performed among neonates who responded to indomethacin (responders) and among those who required surgical ligation (non-responders). Independent transmission disequilibrium tests were performed among parent-child trios of responders and non-responders.ResultsThe G allele of rs2153628 was associated with increased odds of response to indomethacin in the case-control analysis (odds ratios (OR): 1.918, 95% confidence interval (CI): 1.056, 3.483). Among indomethacin responders, the G allele of rs2153628 and the T allele of rs1799853 were overtransmitted from the parents to their child (OR: 2.667, 95% CI: 1.374, 5.177 and OR: 2.375, 95% CI: 1.040, 5.425, respectively), consistent with the case-control analysis.ConclusionWe identified an association between two SNPs in CYP2C9, rs2153628 and rs1799853, and indomethacin response for the treatment of PDA. These findings suggest that response to indomethacin in the closure of PDA may be influenced by polymorphisms associated with altered indomethacin metabolism.

PMID: 28609430 [PubMed - indexed for MEDLINE]

Impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations and incidence of rejection in Japanese renal transplant recipients receiving different tacrolimus formulations.

Clin Exp Nephrol. 2017 Oct;21(5):787-796

Authors: Niioka T, Kagaya H, Saito M, Inoue T, Numakura K, Yamamoto R, Habuchi T, Satoh S, Miura M

Abstract
BACKGROUND: We investigated the impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations (C 0h/D) and the incidence of rejection in Japanese recipients taking twice-daily (Tac-BID, n = 140) or modified-release once-daily (Tac-QD, n = 80) tacrolimus formulations for 1 year after renal transplantation.
METHODS: Logistic regression analysis was carried out to estimate the distinction rate of CYP3A5 genotypes based on the C 0h/D of Tac-BID or Tac-QD. The coefficients of variation (%CVs) were compared in each recipient to estimate the stability of tacrolimus C 0h/D between formulations or CYP3A5 genotypes.
RESULTS: Recipients with at least one CYP3A5*1 wild-type allele (EMs) and recipients with homozygous expression of the variant allele CYP3A5*3 (PMs) were significantly identified using the tacrolimus C 0h/D cut-off values of 2.77 and 0.85 ng/mL/mg, respectively, and discrimination rates of 75.3 and 85.4%, respectively, for Tac-BID and Tac-QD groups. The %CV of the tacrolimus C 0h/D in CYP3A5 EMs taking Tac-QD was significantly lower than that in those taking Tac-BID (20.4 versus 23.3%, P = 0.003). The %CV of the tacrolimus C 0h/D was an independent risk factor for rejection (odds ratio = 1.028, P = 0.033).
CONCLUSIONS: The tacrolimus C 0h/D values with definite cut-offs for CYP3A5 genotypes were specifically identified in Japanese renal transplant recipients taking Tac-QD. In addition, a larger %CV for the tacrolimus C 0h/D correlated with the incidence of rejection. Consequently, the stability of the C 0h/D achieved using Tac-QD, which was clearly influenced by the CYP3A5 polymorphism, may prevent the development of rejection.

PMID: 28271256 [PubMed - indexed for MEDLINE]

Carbon nanofiber-based multiplexed immunosensor for the detection of survival motor neuron 1, cystic fibrosis transmembrane conductance regulator and Duchenne Muscular Dystrophy proteins.

Biosens Bioelectron. 2018 May 28;117:84-90

Authors: Eissa S, Alshehri N, Abduljabbar M, Rahman AMA, Dasouki M, Nizami IY, Al-Muhaizea MA, Zourob M

Abstract
Simultaneous and point-of-care detection of multiple protein biomarkers has significant impact on patient care. Spinal Muscular Atrophy (SMA), Cystic Fibrosis (CF) and Duchenne Muscular Dystrophy (DMD) are well known progressive hereditary disorders associated with increased morbidity as well as mortality. Therefore, rapid detection of biomarkers specific for these three disorders in newborns offers new opportunities for early diagnosis, delaying symptoms and effective treatment. Here, we report the development of a disposable carbon nanofiber (CNF)-based electrochemical immunosensor for simultaneous detection of survival motor neuron 1 (SMN1), cystic fibrosis transmembrane conductance regulator (CFTR) and DMD proteins. The CNF-modified array electrodes were first functionalized by electroreduction of carboxyphenyl diazonium salt. Then, the immunosensor was fabricated by the covalent immobilization of the three antibodies on the working electrodes of the array sensor via carbodiimide (EDC/NHS) chemistry. Simultaneous detection of CFTR, DMD and SMN1 was achieved with high sensitivity and detection limits of 0.9 pg/ml, 0.7 pg/ml and 0.74 pg/ml, respectively. The multiplexed immunosensor has also shown strong selectivity against non-specific proteins. Moreover, high recovery percentage was obtained when the immunosensor was applied in spiked whole blood samples. This voltammetric immunosensor offers cost effective, easy to use, rapid and high throughput potential screening method for these three hereditary disorders using only few drops of blood.

PMID: 29890394 [PubMed - as supplied by publisher]

Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis: The Optimize Randomized Trial.

Am J Respir Crit Care Med. 2018 Jun 11;:

Authors: Mayer-Hamblett N, Retsch-Bogart G, Kloster M, Accurso F, Rosenfeld M, Albers G, Black P, Brown P, Cairns A, Davis SD, Graff GR, Kerby GS, Orenstein D, Buckingham R, Ramsey BW, OPTIMIZE Study Group

Abstract
RATIONALE: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach complementing traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation (PEx) and inflammation may ultimately prolong time to Pa recurrence.
OBJECTIVES: To test the hypothesis that the addition of azithromycin to TIS in children with CF and early Pa decreases the risk of PEx and prolongs time to Pa recurrence.
METHODS: The OPTIMIZE trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF ages 6 months-18 years with early Pa. Azithromycin or placebo was given 3x weekly with standardized TIS.
MEASUREMENTS: The primary endpoint was time to PEx requiring antibiotics and secondary endpoint time to Pa recurrence, in addition to other clinical and safety outcomes.
MAIN RESULTS: 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the National Heart, Lung, and Blood Institute (NHLBI) because the trial had reached the pre-specified interim boundary for efficacy. The risk of PEx was reduced by 44% in the azithromycin group as compared to placebo (hazard ratio [HR]: 0.56, 95% CI:0.37,0.83, p=0.004). Weight increased by 1.27 kg in the azithromycin group compared to placebo (95% CI:0.01,2.52, p=0.046). No significant differences were seen in microbiologic, clinical, or safety endpoints.
CONCLUSIONS: Azithromycin was associated with a significant reduction in risk of PEx and sustained improvement in weight but had no impact on microbiologic outcomes in children with early Pa. Clinical trial registered with ClinicalTrials.gov (NCT02054156).

PMID: 29890086 [PubMed - as supplied by publisher]

Transcriptional profiling of Scedosporium apiospermum enzymatic antioxidant gene battery unravels the involvement of thioredoxin reductases against chemical and phagocytic cells oxidative stress.

Med Mycol. 2018 Jun 08;:

Authors: Staerck C, Tabiasco J, Godon C, Delneste Y, Bouchara JP, Fleury MJJ

Abstract
Scedosporium species rank the second, after Aspergillus fumigatus, among the filamentous fungi colonizing the airways of patients with cystic fibrosis (CF). Development of microorganisms in the respiratory tract depends on their capacity to evade killing by the host immune system, particularly through the oxidative response of macrophages and neutrophils, with the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS). This is particularly true in the airways of CF patients which display an exacerbated inflammatory reaction. To protect themselves, pathogens have developed various enzymatic antioxidant systems implicated in ROS degradation, including superoxide dismutases, catalases, cytochrome C peroxidases, chloroperoxidases and enzymes of the glutathione and thioredoxin systems, or in RNS degradation, that is, flavohemoglobins, nitrate reductases, and nitrite reductases. Here we investigated the transcriptional regulation of the enzymatic antioxidant gene battery in 24-h-old hyphae of Scedosporium apiospermum in response to oxidative stress induced chemically or by exposure to activated phagocytic cells. We showed that 21 out of the 33 genes potentially implicated in the oxidative or nitrosative stress response were overexpressed upon exposure of the fungus to various chemical oxidants, while they were only 13 in co-cultures with macrophages or neutrophils. Among them, genes encoding two thioredoxin reductases and to a lesser extent, a peroxiredoxin and one catalase were found to be overexpressed after chemical oxidative stress as well as in co-cultures. These results suggest that thioredoxin reductases, which are known to be virulence factors in other pathogenic fungi, play a key role in pathogenesis of scedosporiosis, and may be new drug targets.

PMID: 29889264 [PubMed - as supplied by publisher]

Diagnosis and treatment of pancreatic exocrine insufficiency.

Curr Opin Gastroenterol. 2018 Jun 07;:

Authors: Dominguez-Muñoz JE

Abstract
PURPOSE OF REVIEW: Pancreatic exocrine insufficiency (PEI), defined as a secretion of pancreatic enzymes and bicarbonate insufficient to maintain a normal digestion, is a frequent but frequently underdiagnosed and undertreated condition. PEI may be secondary to different pancreatic diseases and extrapancreatic conditions. Recent data support the high clinical relevance of PEI and its treatment.
RECENT FINDINGS: Together with symptoms of maldigestion, PEI is associated with nutritional deficiencies leading to osteoporosis, low-trauma fractures, sarcopenia and increased mortality. No single widely available test allows to diagnose PEI accurately. Diagnosis of PEI requires the evaluation of symptoms, nutritional markers and a noninvasive pancreatic function test in the appropriate clinical context. Pancreatic enzyme replacement therapy (PERT) improves digestion, symptoms, nutritional status and quality of life of patients with PEI. In addition, PERT is associated with a longer survival in patients with unresectable pancreatic cancer and after surgery for pancreatic cancer or chronic pancreatitis.
SUMMARY: Awareness of PEI in different clinical conditions is required. Nutritional advice and appropriate PERT are mandatory to reduce the morbidity and mortality associated with PEI. Further studies on the clinical impact of PEI and its treatment are needed, especially in diseases other than chronic pancreatitis and cystic fibrosis.

PMID: 29889111 [PubMed - as supplied by publisher]

Benchmark Evaluation of True Single Molecular Sequencing to Determine Cystic Fibrosis Airway Microbiome Diversity.

Front Microbiol. 2018;9:1069

Authors: Hahn A, Bendall ML, Gibson KM, Chaney H, Sami I, Perez GF, Koumbourlis AC, McCaffrey TA, Freishtat RJ, Crandall KA

Abstract
Cystic fibrosis (CF) is an autosomal recessive disease associated with recurrent lung infections that can lead to morbidity and mortality. The impact of antibiotics for treatment of acute pulmonary exacerbations on the CF airway microbiome remains unclear with prior studies giving conflicting results and being limited by their use of 16S ribosomal RNA sequencing. Our primary objective was to validate the use of true single molecular sequencing (tSMS) and PathoScope in the analysis of the CF airway microbiome. Three control samples were created with differing amounts of Burkholderia cepacia, Pseudomonas aeruginosa, and Prevotella melaninogenica, three common bacteria found in cystic fibrosis lungs. Paired sputa were also obtained from three study participants with CF before and >6 days after initiation of antibiotics. Antibiotic resistant B. cepacia and P. aeruginosa were identified in concurrently obtained respiratory cultures. Direct sequencing was performed using tSMS, and filtered reads were aligned to reference genomes from NCBI using PathoScope and Kraken and unique clade-specific marker genes using MetaPhlAn. A total of 180-518 K of 6-12 million filtered reads were aligned for each sample. Detection of known pathogens in control samples was most successful using PathoScope. In the CF sputa, alpha diversity measures varied based on the alignment method used, but similar trends were found between pre- and post-antibiotic samples. PathoScope outperformed Kraken and MetaPhlAn in our validation study of artificial bacterial community controls and also has advantages over Kraken and MetaPhlAn of being able to determine bacterial strains and the presence of fungal organisms. PathoScope can be confidently used when evaluating metagenomic data to determine CF airway microbiome diversity.

PMID: 29887843 [PubMed]

Ivacaftor CFTR Potentiator Therapy is Efficient for Pancreatic Manifestations in Cystic Fibrosis.

Am J Gastroenterol. 2018 Jun 11;:

Authors: Kounis I, Lévy P, Rebours V

PMID: 29887601 [PubMed - as supplied by publisher]