Related Articles

TDRD6 is associated with oligoasthenoteratozoospermia by sequencing the patient from a consanguineous family.

Gene. 2018 Jun 15;659:84-88

Authors: Sha YW, Wang X, Su ZY, Wang C, Ji ZY, Mei LB, Zhang L, Deng BB, Huang XJ, Yan W, Chen J, Li P, Cui YQ, Qu QL, Yin C, He XM

Abstract
Oligoasthenoteratozoospermia (OAT) is characterized as low sperm count, decreased sperm motility and structural abnormalities of the sperm head in the same patient. However, very few studies reported the genetic alterations associated with OAT. Here we report a 38-year-old patient with OAT from a consanguineous family, with 2-6 million/mL sperm density, 2.1-3.8% normal sperm morphology and immotile sperm. Whole-exome sequencing (WES) identified homozygous variant c.1259A>G:p.Y420C in the TDRD6 gene. TDRD6 is a testis-specific expressed protein that was localized to the chromatoid bodies in germ cells and played an important role in the nonsense-mediated decay pathway. This rare variant co-segregated with the OAT phenotype in this family. Bioinformatic analysis also suggested the variant a pathogenic mutation. Two intracytoplasmic sperm injection (ICSI) cycles were carried out in the patient's wife, but she did not become pregnant after embryo transfer. So the mutations in TDRD6 may be associated with human male infertility and early embryonic lethality.

PMID: 29551503 [PubMed - indexed for MEDLINE]

Related Articles

New role of LRP5, associated with nonsyndromic autosomal-recessive hereditary hearing loss.

Hum Mutat. 2017 Oct;38(10):1421-1431

Authors: Xia W, Hu J, Liu F, Ma J, Sun S, Zhang J, Jin K, Huang J, Jiang N, Wang X, Li W, Ma Z, Ma D

Abstract
Human hearing loss is a common neurosensory disorder about which many basic research and clinically relevant questions are unresolved. At least 50% of hearing loss are due to a genetic etiology. Although hundreds of genes have been reported, there are still hundreds of related deafness genes to be found. Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual nonsyndromic sensorineural hearing loss. Whole-exome sequencing (WES) identified lipoprotein receptor-related protein 5 (LRP5), a member of the low-density lipoprotein receptor family, as the causative gene in this family. In the zebrafish model, lrp5 downregulation using morpholinos led to significant abnormalities in zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance. Rescue experiments showed that LRP5 mutation is associated with hearing loss. Knocking down lrp5 in zebrafish results in reduced expression of several genes linked to Wnt signaling pathway and decreased cell proliferation when compared with those in wild-type zebrafish. In conclusion, the LRP5 mutation influences cell proliferation through the Wnt signaling pathway, thereby reducing the number of supporting cells and hair cells and leading to nonsyndromic hearing loss in this Chinese family.

PMID: 28677207 [PubMed - indexed for MEDLINE]

Funding Opportunity PA-18-780 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages formative research, intervention development, and pilot-testing of interventions. Primary scientific areas of focus include the feasibility, tolerability, acceptability and safety of novel or adapted interventions that target HIV prevention, treatment or services research. For the purposes of this FOA, "intervention" may include behavioral, social, or structural approaches, as well as combination biomedical and behavioral approaches that prevent the acquisition and transmission of HIV infection, or improve clinical outcomes for persons who are HIV infected.

Notice NOT-MD-18-005 from the NIH Guide for Grants and Contracts

23 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 2018/05/10

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.

Related Articles

Repurposing drugs to fast-track therapeutic agents for the treatment of cryptococcosis.

PeerJ. 2018;6:e4761

Authors: Truong M, Monahan LG, Carter DA, Charles IG

Abstract
Many infectious diseases disproportionately affect people in the developing world. Cryptococcal meningitis is one of the most common mycoses in HIV-AIDS patients, with the highest burden of disease in sub-Saharan Africa. Current best treatment regimens still result in unacceptably high mortality rates, and more effective antifungal agents are needed urgently. Drug development is hampered by the difficulty of developing effective antifungal agents that are not also toxic to human cells, and by a reluctance among pharmaceutical companies to invest in drugs that cannot guarantee a high financial return. Drug repurposing, where existing drugs are screened for alternative activities, is becoming an attractive approach in antimicrobial discovery programs, and various compound libraries are now commercially available. As these drugs have already undergone extensive optimisation and passed regulatory hurdles this can fast-track their progress to market for new uses. This study screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The anthelminthic agent flubendazole, and L-type calcium channel blockers nifedipine, nisoldipine and felodipine, appeared particularly promising and were tested in additional strains and species. Flubendazole was very active against all pathogenic Cryptococcus species, with minimum inhibitory concentrations of 0.039-0.156 μg/mL, and was equally effective against isolates that were resistant to fluconazole. While nifedipine, nisoldipine and felodipine all inhibited Cryptococcus, nisoldipine was also effective against Candida, Saccharomyces and Aspergillus. This study validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.

PMID: 29740519 [PubMed]

Related Articles

Inhalational Gentamicin Treatment Is Effective Against Pneumonic Plague in a Mouse Model.

Front Microbiol. 2018;9:741

Authors: Gur D, Glinert I, Aftalion M, Vagima Y, Levy Y, Rotem S, Zauberman A, Tidhar A, Tal A, Maoz S, Ber R, Pass A, Mamroud E

Abstract
Pneumonic plague is an infectious disease characterized by rapid and fulminant development of acute pneumonia and septicemia that results in death within days of exposure. The causative agent of pneumonic plague, Yersinia pestis (Y. pestis), is a Tier-1 bio-threat agent. Parenteral antibiotic treatment is effective when given within a narrow therapeutic window after symptom onset. However, the non-specific "flu-like" symptoms often lead to delayed diagnosis and therapy. In this study, we evaluated inhalational gentamicin therapy in an infected mouse model as a means to improve antibiotic treatment efficacy. Inhalation is an attractive route for treating lung infections. The advantages include directly dosing the main infection site, the relative accessibility for administration and the lack of extensive enzymatic drug degradation machinery. In this study, we show that inhalational gentamicin treatment administered 24 h post-infection, prior to the appearance of symptoms, protected against lethal intranasal challenge with the fully virulent Y. pestis Kimberley53 strain (Kim53). Similarly, a high survival rate was demonstrated in mice treated by inhalation with another aminoglycoside, tobramycin, for which an FDA-approved inhaled formulation is clinically available for cystic fibrosis patients. Inhalational treatment with gentamicin 48 h post-infection (to symptomatic mice) was also successful against a Y. pestis challenge dose of 10 i.n.LD50. Whole-body imaging using IVIS technology demonstrated that adding inhalational gentamicin to parenteral therapy accelerated the clearance of Y. pestis from the lungs of infected animals. This may reduce disease severity and the risk of secondary infections. In conclusion, our data suggest that inhalational therapy with aerosolized gentamicin may be an effective prophylactic treatment against pneumonic plague. We also demonstrate the benefit of combining this treatment with a conventional parenteral treatment against this rapidly progressing infectious disease. We suggest the inhalational administration route as a clinically relevant treatment modality against pneumonic plague and other respiratory bacterial pathogens.

PMID: 29740404 [PubMed]

Related Articles

User Needs in the Development of a Health App Ecosystem for Self-Management of Cystic Fibrosis: User-Centered Development Approach.

JMIR Mhealth Uhealth. 2018 May 08;6(5):e113

Authors: Floch J, Zettl A, Fricke L, Weisser T, Grut L, Vilarinho T, Stav E, Ascolese A, Schauber C

Abstract
BACKGROUND: Digital self-management in cystic fibrosis (CF) is foreseen as a means toward better understanding of the disease and its treatment and better adherence to the treatment. Mobile apps hold the potential to provide access to information, motivate, and strengthen compliance. However, to deliver high-quality apps, the development should be based on thorough knowledge about user needs. Empirical research on the user-centered development of mobile apps for health care is, however, still limited.
OBJECTIVE: The aim of this research is to develop and evaluate an app ecosystem for self-management in CF. It targets not only those directly affected by CF but also parents and health care professionals involved in the treatment. This paper covers the first step of the design process that aims to analyze the context and the user requirements. The primary research question is as follows: what digital support has the potential to usefully support persons with CF and their caregivers in the CF care? To answer this question, we address two preliminary questions: what important factors in everyday life affect the care of persons with CF? and how is the CF care delivered today and what are the limitations of CF care services?
METHODS: The overall research adopts a user-centered design approach in which future users are involved in the development process from the very beginning to ensure that the apps developed best suit the potential users. The research presented in the paper follows an interpretative case study research strategy seeking to understand the concerns and needs of persons with CF and their caregivers. Data were collected through semistructured qualitative interviews involving 74 participants in seven European countries and from internet forums.
RESULTS: The results of the analysis phase show a strong need for individuality of the digital support, as well as for its adaptability to different contexts. The paper presents the concerns and needs of the participants in the study and extracts a set of relevant features for a self-management app ecosystem. Education, enzyme dosage calculation, nutrition management, treatment organization, health diary, treatment follow-up, practical guidelines for treatment, communication with doctors, and communication with peers are foreseen as useful features.
CONCLUSIONS: The results indicate the readiness for self-management in the CF care even in countries that provide well-functioning health care services for CF care. The large diversity of user requirements identified reflects the crucial role user integration plays in developing apps for a chronic condition such as CF. The need for personalization stemming from the individuality of the patients and the need for communication with health care professionals support the idea of an app ecosystem for the self-management of CF.

PMID: 29739742 [PubMed]

Modern Approaches for the Discovery of Anti-Infectious Drugs for the Treatment of Neglected Diseases.

Curr Top Med Chem. 2018 May 09;:

Authors: Bellera CL, Sbaraglini ML, Talevi A

Abstract
Neglected diseases comprise a number of infectious diseases historically endemic to low- and middle-income countries, though recently they have spread to high-income countries due to human migrations. In the past, pharmaceutical companies have shown hesitant to invest in these health conditions, due to the limited return on investment. As a result, the role of the academic sector and non-for-profit organizations in the discovery of new drugs for neglected diseases has been particularly relevant. <p> Here, we review recent applications of modern drug discovery technologies in the field of neglected diseases, including high-throughput screening, in silico screening and computer-aided drug design. The suitability and perspectives of each approach is discussed depending on the context, along with the technology and translational gaps influencing them.

PMID: 29741140 [PubMed - as supplied by publisher]

Related Articles

High-content drug screening for rare diseases.

J Inherit Metab Dis. 2017 Jul;40(4):601-607

Authors: Bellomo F, Medina DL, De Leo E, Panarella A, Emma F

Abstract
Per definition, rare diseases affect only a small number of subjects within a given population. Taken together however, they represent a considerable medical burden, which remains poorly addressed in terms of treatment. Compared to other diseases, obstacles to the development of therapies for rare diseases include less extensive physiopathology knowledge, limited number of patients to test treatments, and poor commercial interest from the industry. Recently, advances in high-throughput and high-content screening (HTS and HCS) have been fostered by the development of specific routines that use robot- and computer-assisted technologies to automatize tasks, allowing screening of a large number of compounds in a short period of time, using experimental model of diseases. These approaches are particularly relevant for drug repositioning in rare disease, which restricts the search to compounds that have already been tested in humans, thereby reducing the need for extensive preclinical tests. In the future, these same tools, combined with computational modeling and artificial neural network analyses, may also be used to predict individual clinical responses to drugs in a personalized medicine approach.

PMID: 28593466 [PubMed - indexed for MEDLINE]

Related Articles

Development of a database to record orofacial manifestations in patients with rare diseases: a status report from the ROMSE (recording of orofacial manifestations in people with rare diseases) database.

Br J Oral Maxillofac Surg. 2017 Jun;55(5):500-503

Authors: Hanisch M, Hanisch L, Benz K, Kleinheinz J, Jackowski J

Abstract
The aim of this working group was to establish a ROMSE (recording of orofacial manifestations in people with rare diseases) database to provide clinicians, patients, and their families with better information about these diseases. In 2011, we began to search the databases Orphanet, OMIM® (Online Mendelian Inheritance in Man®), and PubMed, for rare diseases with orofacial symptoms, and since 2013, the collected information has been incorporated into a web-based, freely accessible database. To date, 471 rare diseases with orofacial signs have been listed on ROMSE, and 10 main categories with 99 subcategories of signs such as different types of dental anomalies, changes in the oral mucosa, dysgnathia, and orofacial clefts, have been defined. The database provides a platform for general clinicians, orthodontists, and oral and maxillofacial surgeons to work on the best treatments.

PMID: 28238524 [PubMed - indexed for MEDLINE]

Exploratory Application of Neuropharmacometabolomics in Severe Childhood Traumatic Brain Injury.

Crit Care Med. 2018 May 07;:

Authors: Hagos FT, Empey PE, Wang P, Ma X, Poloyac SM, Bayır H, Kochanek PM, Bell MJ, Clark RSB

Abstract
OBJECTIVES: To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity of combination therapy with probenecid and N-acetylcysteine to impact glutathione-related and other pathways and networks, relative to placebo treatment.
DESIGN: Analysis of cerebrospinal fluid obtained from children enrolled in an Institutional Review Board-approved, randomized, placebo-controlled trial of a combination of probenecid and N-acetylcysteine after severe traumatic brain injury (Trial Registration NCT01322009).
SETTING: Thirty-six-bed PICU in a university-affiliated children's hospital.
PATIENTS AND SUBJECTS: Twelve children 2-18 years old after severe traumatic brain injury and five age-matched control subjects.
INTERVENTION: Probenecid (25 mg/kg) and N-acetylcysteine (140 mg/kg) or placebo administered via naso/orogastric tube.
MEASUREMENTS AND MAIN RESULTS: The cerebrospinal fluid metabolome was analyzed in samples from traumatic brain injury patients 24 hours after the first dose of drugs or placebo and control subjects. Feature detection, retention time, alignment, annotation, and principal component analysis and statistical analysis were conducted using XCMS-online. The software "mummichog" was used for pathway and network analyses. A two-component principal component analysis revealed clustering of each of the groups, with distinct metabolomics signatures. Several novel pathways with plausible mechanistic involvement in traumatic brain injury were identified. A combination of metabolomics and pathway/network analyses showed that seven glutathione-centered pathways and two networks were enriched in the cerebrospinal fluid of traumatic brain injury patients treated with probenecid and N-acetylcysteine versus placebo-treated patients. Several additional pathways/networks consisting of components that are known substrates of probenecid-inhibitable transporters were also identified, providing additional mechanistic validation.
CONCLUSIONS: This proof-of-concept neuropharmacometabolomics assessment reveals alterations in known and previously unidentified metabolic pathways and supports therapeutic target engagement of the combination of probenecid and N-acetylcysteine treatment after severe traumatic brain injury in children.

PMID: 29742587 [PubMed - as supplied by publisher]

Analyzing the clinical actionability of germline pharmacogenomic findings in oncology.

Cancer. 2018 May 09;:

Authors: Wellmann R, Borden BA, Danahey K, Nanda R, Polite BN, Stadler WM, Ratain MJ, O'Donnell PH

Abstract
BACKGROUND: Germline and tumor pharmacogenomics impact drug responses, but germline markers less commonly guide oncology prescribing. The authors hypothesized that a critical number of clinically actionable germline pharmacogenomic associations exist, representing clinical implementation opportunities.
METHODS: In total, 125 oncology drugs were analyzed for positive germline pharmacogenomic associations in journals with impact factors ≥5. Studies were assessed for design and genotyping quality, clinically relevant outcomes, statistical rigor, and evidence of drug-gene effects. Associations from studies of high methodologic quality were deemed potentially clinically actionable, and translational summaries were written as point-of-care clinical decision support (CDS) tools and formally evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument.
RESULTS: The authors identified germline pharmacogenomic results for 56 of 125 oncology drugs (45%) across 173 publications. Actionable associations were detected for 12 drugs, including 6 that had germline pharmacogenomic information within US Food and Drug Administration labels or published guidelines (capecitabine/fluorouracil/dihydropyrimidine dehydrogenase [DPYD], irinotecan/uridine diphosphate glucuronosyltransferase family 1 member A1 [UGT1A1], mercaptopurine/thioguanine/thiopurine S-methyltransferase [TPMT], tamoxifen/cytochrome P450 [CYP] family 2 subfamily D member 6 [CYP2D6]), and 6 others were novel (asparaginase/nuclear factor of activated T-cells 2 [NFATC2]/human leukocyte antigen D-related β1 [HLA-DRB1], cisplatin/acylphosphatase 2 [ACYP2], doxorubicin/adenosine triphosphate-binding cassette subfamily C member 2/Rac family small guanosine triphosphatase 2/neutrophil cytosolic factor 4 [ABCC2/RAC2/NCF4], lapatinib/human leukocyte antigen DQ α1 [HLA-DQA1], sunitinib/cytochrome P450 family 3 subfamily A member 5 [CYP3A5], vincristine/centrosomal protein 72 [CEP72]). By using AGREE II, the developed CDS summaries had high mean ± standard deviation scores (maximum score, 100) for scope and purpose (92.7 ± 5.1) and rigour of development (87.6 ± 7.4) and moderate yet robust scores for clarity of presentation (58.6 ± 25.1) and applicability (55.9 ± 24.6). The overall mean guideline quality score was 5.2 ± 1.0 (maximum score, 7). Germline pharmacogenomic CDS summaries for these 12 drugs were recommended for implementation.
CONCLUSIONS: Several oncology drugs have actionable germline pharmacogenomic information, justifying their delivery through institutional pharmacogenomic implementations to determine clinical utility. Cancer 2018. © 2018 American Cancer Society.

PMID: 29742281 [PubMed - as supplied by publisher]

Genomics and electronic health record systems.

Hum Mol Genet. 2018 May 01;27(R1):R48-R55

Authors: Ohno-Machado L, Kim J, Gabriel RA, Kuo GM, Hogarth MA

Abstract
Several reviews and case reports have described how information derived from the analysis of genomes are currently included in electronic health records (EHRs) for the purposes of supporting clinical decisions. Since the introduction of this new type of information in EHRs is relatively new (for instance, the widespread adoption of EHRs in the United States is just about a decade old), it is not surprising that a myriad of approaches has been attempted, with various degrees of success. EHR systems undergo much customization to fit the needs of health systems; these approaches have been varied and not always generalizable. The intent of this article is to present a high-level view of these approaches, emphasizing the functionality that they are trying to achieve, and not to advocate for specific solutions, which may become obsolete soon after this review is published. We start by broadly defining the end goal of including genomics in EHRs for healthcare and then explaining the various sources of information that need to be linked to arrive at a clinically actionable genomics analysis using a pharmacogenomics example. In addition, we include discussions on open issues and a vision for the next generation systems that integrate whole genome sequencing and EHRs in a seamless fashion.

PMID: 29741693 [PubMed - in process]

Inter-individual variation in imatinib disposition: any role for prevalent variants of CYP1A2, CYP2C8, CYP2C9, and CYP3A5 in Nigerian CML patients?

Leuk Lymphoma. 2018 May 09;:1-6

Authors: Adehin A, Adeagbo BA, Kennedy MA, Bolaji OO, Olugbade TA, Bolarinwa RA, Durosinmi MA

Abstract
Imatinib has been successful in the management of chronic myeloid leukemia (CML) but some patients experience adverse reactions or develop resistance to its use. The roles of some polymorphisms in genes encoding enzymes critical for the biotransformation of imatinib have been previously examined. This study, hence, evaluated some other unstudied functionally significant polymorphisms in CYP1A2, CYP2C8, CYP2C9, and CYP3A5. Trough imatinib blood levels and genotypes were determined in 42 CML patients by an HPLC-UV technique and a Sequenom iPLEX assay, respectively. Statistical analysis of the influence of genetic polymorphisms on standardized trough level detected no significant relationship. However, higher trough levels were observed in two homozygous carriers of CYP2C8*2 while diminished imatinib levels were seen in two homozygous carriers of CYP3A5*7. The study findings suggest that polymorphisms in drug metabolizing enzymes may be significant for imatinib therapy only in instances where all copies of the relevant studied genes are functionally impaired.

PMID: 29741432 [PubMed - as supplied by publisher]

Overexpression of Fn14 in gliomas: tumor progression and poor prognosis.

Future Oncol. 2018 May 09;:

Authors: Tan D, Pang FM, Li D, Zhang L, Wu J, Liu ZQ, Li X, Yan H

Abstract
AIM: To confirm whether the expression level of Fn14 could affect progression or prognosis of glioma patients.
METHODS: Glioma cohorts in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas databases were comprehensively analyzed.
RESULTS: Low-grade patients had lower expression level of Fn14, while patients with higher expression of Fn14 tended to harbor shorter overall survival and disease-free survival. The expression level of Fn14 was downregulated by IDH1/IDH2 mutations while its gene body methylation was upregulated. After adjusting age, the expression level of Fn14 was still significantly associated with overall survival and disease-free survival in low-grade gliomas. In a cell line data analysis, Fn14 expression was positively correlated with temozolomide dosage.
CONCLUSION: Fn14 was an independent predictive biomarker for the progression and prognosis in low-grade gliomas.

PMID: 29741404 [PubMed - as supplied by publisher]

Related Articles

Race and Beta-Blocker Survival Benefit in Patients With Heart Failure: An Investigation of Self-Reported Race and Proportion of African Genetic Ancestry.

J Am Heart Assoc. 2018 May 08;7(10):

Authors: Luzum JA, Peterson E, Li J, She R, Gui H, Liu B, Spertus JA, Pinto YM, Williams LK, Sabbah HN, Lanfear DE

Abstract
BACKGROUND: It remains unclear whether beta-blockade is similarly effective in black patients with heart failure and reduced ejection fraction as in white patients, but self-reported race is a complex social construct with both biological and environmental components. The objective of this study was to compare the reduction in mortality associated with beta-blocker exposure in heart failure and reduced ejection fraction patients by both self-reported race and by proportion African genetic ancestry.
METHODS AND RESULTS: Insured patients with heart failure and reduced ejection fraction (n=1122) were included in a prospective registry at Henry Ford Health System. This included 575 self-reported blacks (129 deaths, 22%) and 547 self-reported whites (126 deaths, 23%) followed for a median 3.0 years. Beta-blocker exposure (BBexp) was calculated from pharmacy claims, and the proportion of African genetic ancestry was determined from genome-wide array data. Time-dependent Cox proportional hazards regression was used to separately test the association of BBexp with all-cause mortality by self-reported race or by proportion of African genetic ancestry. Both sets of models were evaluated unadjusted and then adjusted for baseline risk factors and beta-blocker propensity score. BBexp effect estimates were protective and of similar magnitude both by self-reported race and by African genetic ancestry (adjusted hazard ratio=0.56 in blacks and adjusted hazard ratio=0.48 in whites). The tests for interactions with BBexp for both self-reported race and for African genetic ancestry were not statistically significant in any model (P>0.1 for all).
CONCLUSIONS: Among black and white patients with heart failure and reduced ejection fraction, reduction in all-cause mortality associated with BBexp was similar, regardless of self-reported race or proportion African genetic ancestry.

PMID: 29739794 [PubMed - in process]

Related Articles

Analytical validation of a psychiatric pharmacogenomic test.

Per Med. 2018 Feb 07;:

Authors: Jablonski MR, King N, Wang Y, Winner JG, Watterson LR, Gunselman S, Dechairo BM

Abstract
AIM: The aim of this study was to validate the analytical performance of a combinatorial pharmacogenomics test designed to aid in the appropriate medication selection for neuropsychiatric conditions.
MATERIALS & METHODS: Genomic DNA was isolated from buccal swabs. Twelve genes (65 variants/alleles) associated with psychotropic medication metabolism, side effects, and mechanisms of actions were evaluated by bead array, MALDI-TOF mass spectrometry, and/or capillary electrophoresis methods (GeneSight Psychotropic, Assurex Health, Inc.).
RESULTS: The combinatorial pharmacogenomics test has a dynamic range of 2.5-20 ng/μl of input genomic DNA, with comparable performance for all assays included in the test. Both the precision and accuracy of the test were >99.9%, with individual gene components between 99.4 and 100%.
CONCLUSION: This study demonstrates that the combinatorial pharmacogenomics test is robust and reproducible, making it suitable for clinical use.

PMID: 29739269 [PubMed - as supplied by publisher]

Pharmacokinetic Monitoring Of Vancomycin In Cystic Fibrosis: Is It Time To Move Past Trough Concentrations?

Pediatr Infect Dis J. 2018 May 04;:

Authors: Fusco NM, Prescott WA, Meaney CJ

Abstract
BACKGROUND: A correlation between vancomycin trough concentrations (VTC) and area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio (AUC/MIC) has not been established in children/adolescents with cystic fibrosis (CF). The primary objective of this study was to determine the correlation between measured VTCs and AUC/MIC using population-based pharmacokinetics.
METHODS: A retrospective cohort study of children/adolescents diagnosed with CF, age 6 to < 18 years, treated with vancomycin (VAN) for methicillin-resistant Staphylococcus aureus (MRSA) infection was conducted. The relationship between final VTCs and calculated AUC/MIC, using models established by Le et al and Stockmann et al, was assessed using Pearson and Spearman correlations. All tests were two-tailed with alpha set at 0.05.
RESULTS: Thirty children/adolescents, age 7 to 17 years (median age 15 [IQR 9-17] years), were included. The mean final VAN dose was 58.03±18.58 mg/kg/day and the median final VTC was 12.6 (11-13.6) mg/L. The mean AUC/MIC was 355.34±138.46 (Le model) versus 426.79±178.92 (Stockmann model) (p=0.089). No correlation existed between VTCs and AUC/MIC using either the model by Le (r=0.140, p=0.461) or Stockmann (r=0.115; p=0.564). Using the Stockmann model: VAN dose (mg/kg/dose) was found to have a strong positive correlation with AUC (r=0.8874, p<0.0001) and AUC/MIC (r=0.7877, p<0.0001).
CONCLUSIONS: VTCs did not correlate with AUC or AUC/MIC. Further research is needed to determine which estimate of VAN treatment efficacy is most appropriate for children and adolescents with CF infected with MRSA.

PMID: 29742643 [PubMed - as supplied by publisher]

IL-9 and Mast Cells Are Key Players of Candida albicans Commensalism and Pathogenesis in the Gut.

Cell Rep. 2018 May 08;23(6):1767-1778

Authors: Renga G, Moretti S, Oikonomou V, Borghi M, Zelante T, Paolicelli G, Costantini C, De Zuani M, Villella VR, Raia V, Del Sordo R, Bartoli A, Baldoni M, Renauld JC, Sidoni A, Garaci E, Maiuri L, Pucillo C, Romani L

Abstract
Candida albicans is implicated in intestinal diseases. Identifying host signatures that discriminate between the pathogenic versus commensal nature of this human commensal is clinically relevant. In the present study, we identify IL-9 and mast cells (MCs) as key players of Candida commensalism and pathogenicity. By inducing TGF-β in stromal MCs, IL-9 pivotally contributes to mucosal immune tolerance via the indoleamine 2,3-dioxygenase enzyme. However, Candida-driven IL-9 and mucosal MCs also contribute to barrier function loss, dissemination, and inflammation in experimental leaky gut models and are upregulated in patients with celiac disease. Inflammatory dysbiosis occurs with IL-9 and MC deficiency, indicating that the activity of IL-9 and MCs may go beyond host immunity to include regulation of the microbiota. Thus, the output of the IL-9/MC axis is highly contextual during Candida colonization and reveals how host immunity and the microbiota finely tune Candida behavior in the gut.

PMID: 29742432 [PubMed - in process]