Funding Opportunity PA-18-673 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) will support students at institutions without formal NIH-funded institutional predoctoral dual-degree training programs. The purpose of the Kirschstein-NRSA, dual-doctoral degree, predoctoral fellowship (F30) is to enhance the integrated research and clinical training of promising predoctoral students, who are matriculated in a combined MD/PhD or other dual-doctoral degree training program (e.g., DO/PhD, DDS/PhD, AuD/PhD, DVM/PhD), and who intend careers as physician/clinician-scientists. Applicants must propose an integrated research and clinical training plan and a dissertation research project in scientific health-related fields relevant to the missions of the participating NIH Institutes and Centers. The fellowship experience is expected to clearly enhance the individuals potential to develop into a productive, independent physician/clinician-scientist. This Funding Opportunity Announcement (FOA) is designed specifically for applicants proposing research that does not involve leading an independent clinical trial, a clinical trial feasibility study, or an ancillary study to a clinical trial, but does allow applicants to propose research experience in a clinical trial led by a sponsor or co-sponsor.

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Related Articles

Leveraging the Learning Health Care Model to Improve Equity in the Age of Genomic Medicine.

Learn Health Syst. 2018 Jan;2(1):

Authors: Blizinsky KD, Bonham VL

Abstract
To fully achieve the goals of a genomics-enabled learning health care system, purposeful efforts to understand and reduce health disparities and improve equity of care are essential. This paper highlights three major challenges facing genomics-enabled learning health care systems, as they pertain to ancestrally diverse populations: inequality in the utility of genomic medicine; lack of access to pharmacogenomics in clinical care; and inadequate incorporation of social and environmental data into the electronic health care record (EHR). We advance a framework that can not only be used to directly improve care for all within the learning health system, but can also be used to focus on the needs to address racial and ethnic health disparities and improve health equity.

PMID: 29457138 [PubMed]

Funding Opportunity PA-18-672 from the NIH Guide for Grants and Contracts. The National Institutes of Health (NIH) awards senior individual research training fellowships to experienced scientists who wish to make major changes in the direction of their research careers or who wish to broaden their scientific background by acquiring new research capabilities as independent investigators in research fields relevant to the missions of participating NIH Institutes and Centers. This Funding Opportunity Announcement (FOA) is designed specifically for applicants proposing research that does not involve leading an independent clinical trial, a clinical trial feasibility study, or an ancillary study to a clinical trial, but does allow applicants to propose research experience in a clinical trial led by a sponsor or co-sponsor.

Notice NOT-MH-18-023 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-133 from the NIH Guide for Grants and Contracts

Notice NOT-HL-18-598 from the NIH Guide for Grants and Contracts

Related Articles

Multimodality imaging-based evaluation of Rosai-Dorfman disease in the head and neck: A retrospective observational study.

Medicine (Baltimore). 2017 Dec;96(51):e9372

Authors: Xu Q, Fu L, Liu C

Abstract
Rosai-Dorfman disease (RDD) is an uncommon benign entity characterized histologically by lymphatic sinus dilatation due to histiocyte proliferation. This study was performed to delineate its imaging features, reviewed retrospectively in 12 patients (8 women and 4 men, mean age 58.2 years [range 27-84]) with pathologically confirmed RDD in the head and neck. The location, involvement, and imaging characteristics (CT, magnetic resonance imaging (MRI), and PET/CT) of all lesions were evaluated. Signal intensity on MRI images was compared to gray matter (orbital RDD) and adjacent muscle (sinonasal and cervical RDD). RDD in the head and neck involved multiple sites, primarily the sinonasal cavity (n = 7), neck (n = 3), and orbit (n = 1), with one case of simultaneous involvement of the sinonasal cavity, orbit, and neck. With sinonasal involvement, MRI signal intensity of the involved areas was isointense or slightly hyperintense relative to adjacent muscle on T1WI images and heterogeneous on T2WI images; with lacrimal involvement, it was isointense relative to gray matter on T1- and T2-weighted images; and with neck involvement, it was isointense relative to muscle on T1WI images and relatively hyperintense on T2WI images, with homogenous postcontrast enhancement in all sites of involvement. The lesions on CT were observed as enhancing masses with or without bony destruction. PET/CT showed hypermetabolism in one lesion in the neck. RDD is a rare disorder with multiple sites of involvement in the head and neck. Concomitant cervical lymphadenopathy with extranodal masses assisted by multimodal imaging may be useful in the diagnosis of RDD.

PMID: 29390533 [PubMed - indexed for MEDLINE]

Related Articles

Dexmedetomidine-based monitored conscious sedation combined local anesthesia for levator resection in a 10-year-old child with Marcus Gunn jaw-winking synkinesis: A case report.

Medicine (Baltimore). 2017 Dec;96(51):e9369

Authors: Tu Y, Gao F

Abstract
RATIONALE: Levator resection has become a routine procedure for patients with severe Marcus Gunn jaw-winking synkinesis (MGJWS). To optimize the surgical outcome, adult patients need to be kept awake, or easily aroused and responsive to verbal commands during the operation. However, levator resection is commonly performed under general anesthesia in pediatric patients. In the present case, we described a successful anesthetic protocol of conscious sedation with local anesthesia for levator resection in a child.
PATIENT CONCERNS: A 10-year-old boy with MGJWS was admitted to our hospital and scheduled for levator resection. The patient was born through a normal delivery and had no previous history of allergy, no comorbidity, and no history of receiving anesthesia or operation. The laboratory tests of the patient were unremarkable.
DIAGNOSES: The diagnosis of MGJWS was made by two experienced ophthalmologists.
INTERVENTIONS: A 10-year-old boy with MGJWS was admitted to our hospital and scheduled for levator resection. The levator resection was performed under monitored conscious sedation with dexmedetomidine and local anesthesia.
OUTCOMES: Patient with spontaneous breathing responded normally to verbal commands throughout the operation, and no adverse events occurred. The patient and ophthalmologist reported high satisfaction with anesthesia management.
LESSONS: Dexmedetomidine-based monitored conscious sedation with local anesthesia is a feasible alternative to general anesthesia for levator resection in collaborative patients.

PMID: 29390531 [PubMed - indexed for MEDLINE]

Related Articles

Solitary fibrous tumor of the ilium: A case report.

Medicine (Baltimore). 2017 Dec;96(51):e9355

Authors: Ge X, Liao J, Choo RJ, Yan J, Zhang J

Abstract
RATIONALE: Solitary fibrous tumors (SFTs) are rare spindle cell tumors that are most commonly found in the mediastinal pleura. Although there are increasingly more reports of extra-pleural SFTs, reports of SFTs in bone are very rare. To our knowledge, a SFT of the ilium has not yet been reported. With low specificity on computer tomograpy and magnetic resonance imaging, SFTs are easily misdiagnosed.
PATIENT CONCERNS: A 33-year-old man visited our hospital due to repeated right ilium pain for 3 months. The pain was dull and bearable, with no hip joint dyskinesia. The relevant physical examinations are negative. The patient was healthy before and had a negative family history. Radiologically, a large mass with inhomogeneous attenuation and intensity and obvious heterogeneous enhancement was misdiagnosed as a giant cell tumor of ilium.
DIAGNOSES: The man was diagnosed as the solitary fibrous tumor of right ilium.
INTERVENTIONS: The patient was performed an "incision biopsy of the right ilium" and "extended resection of tumor".
OUTCOMES: The pathology and immunohistochemistry was confirmed as the solitary fibrous tumors. The patient was followed-up by computed tomography of pelvis in local hospital every 6 mouths, and there is no recurrence and any symptoms.
LESSONS: We learned that the solitary fibrous tumor could locate in the ilium, and when we see imaging manifestations like this case, we should think it may be SFT.

PMID: 29390521 [PubMed - indexed for MEDLINE]

Related Articles

Cervical digit in a child: A case report.

Medicine (Baltimore). 2017 Dec;96(51):e9348

Authors: Tong MJ, Xiang GH, He ZL, Xu HZ, Tian NF

Abstract
BACKGROUND: A "digit-like" bone is a rare developmental anomaly that is usually seen in the pelvic or thoracic regions. Such an anomaly in the cervical spine is extremely rare and few cases have been reported. We present a patient with an anomalous bone posterior to a cervical vertebra. The patient was admitted to our hospital with a gradually growing hard neck mass and esthetic complaints. Physical examination, radiographs, reconstructed computed tomography, and magnetic resonance imaging revealed a digit-like bone posterior to the cervical spine. The patient was diagnosed with a "cervical digit." Through a posterior midline approach, the anomalous bone was excised because of its gradually increasing size and esthetic complaints.
RESULTS: Intraoperatively, the bony mass was found to have a pseudoarticulation with the spinous process of C5 (the fifth cervical vertebra). The specimen consisted of normal bone and cartilage. The child returned to a normal life postoperatively with no symptoms. There was no recurrence at the 2-year follow-up.
CONCLUSION: A congenital cervical digit is a rare deformity. A detailed clinical workup and advanced imaging examinations are useful for diagnosing such conditions. Esthetic complaints contribute to surgical indications. This is the first cervical digit managed with surgical excision of the anomalous bone and had a favorable outcome.

PMID: 29390517 [PubMed - indexed for MEDLINE]

Effects of Cytochrome P450 Single Nucleotide Polymorphisms on Methadone Metabolism and Pharmacodynamics.

Biochem Pharmacol. 2018 Feb 16;:

Authors: Ahmad T, Valentovic MA, Rankin GO

Abstract
Methadone is a synthetic, long-acting opioid with a single chiral center forming two enantiomers, (R)-methadone and (S)-methadone, each having specific pharmacological actions. Concentrations of (R)- and (S)-methadone above therapeutic levels have the ability to cause serious, life-threatening, and fatal side effects. This toxicity can be due in part to the pharmacogenetics of an individual, which influences the pharmacokinetic and pharmacodynamic properties of the drug. Methadone is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, predominately by CYP2B6, followed by CYP3A4, 2C19, 2D6, and to a lesser extent, CYP2C18, 3A7, 2C8, 2C9, 3A5, and 1A2. Single nucleotide polymorphisms (SNPs) located within CYPs have the potential to play an important role in altering methadone metabolism and pharmacodynamics. Several SNPs in the CYP2B6, 3A4, 2C19, 2D6, and 3A5 genes result in increases in methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance. In particular, carriers of CYP2B6∗6/∗6 may have a greater risk for detrimental adverse effects, as methadone metabolism and clearance are diminished in these individuals. CYP2B6∗4, on the other hand, has been observed to decrease plasma concentrations of methadone due to increased methadone clearance. The involvement, contribution, and understanding the role of SNPs in CYP2B6, and other CYP genes, in methadone metabolism can improve the therapeutic uses of methadone in patient outcome and the development of personalized medicine.

PMID: 29458047 [PubMed - as supplied by publisher]

Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation.

Br J Clin Pharmacol. 2018 Feb 19;:

Authors: Ueshima S, Hira D, Kimura Y, Fujii R, Tomitsuka C, Yamane T, Tabuchi Y, Ozawa T, Itoh H, Ohno S, Horie M, Terada T, Katsura T

Abstract
AIMS: This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolising enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban.
METHODS: Data were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2, and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using non-linear mixed effect modelling (NONMEM™) program.
RESULTS: The non-linear relationship between oral clearance (CL/F) of apixaban and creatinine clearance (Ccr) was observed. The population mean of CL/F for a typical patient (Ccr value of 70 mL/min) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06 L/h. When Ccr values were set to the typical value, the population mean of CL/F was 1.52 times higher in patients with the CYP3A5*1/*1 genotype compared with patients with the CYP3A5*1/*3 or *3/*3 genotype, while the population mean of CL/F was 1.49 times higher in patients with the ABCG2 421C/C or C/A genotype compared with patients with the ABCG2 421A/A genotype. However, no covariates affected the population mean of the apparent volume of distribution (Vd/F) of apixaban. The population mean of Vd/F was estimated to be 24.7 L.
CONCLUSION: The present study suggests that the ABCG2 421A/A and CYP3A5*3 genotypes and renal function are considered to be intrinsic factors affecting apixaban pharmacokinetics. These findings may provide useful information for precision medicine using apixaban, to avoid the risk of adverse reactions.

PMID: 29457840 [PubMed - as supplied by publisher]

Novel approach for CES1 genotyping: integrating single nucleotide variants and structural variation.

Pharmacogenomics. 2018 Feb 19;:

Authors: Bjerre D, Berg Rasmussen H

Abstract
AIM: Development of a specific procedure for genotyping of CES1A1 (CES1) and CES1A2, a hybrid of CES1A1  and the pseudogene CES1P1.
MATERIALS & METHODS: The number of CES1A1 and CES1A2  copies and that of CES1P1  were determined using real-time PCR. Long range PCRs followed by secondary PCRs allowed sequencing of single nucleotide variants in CES1A1 and CES1A2. Results & conlusion: A procedure consisting of two main steps was developed. Its first main step, the copy number determination, informed about presence of CES1A2 . This information enabled choice of PCR in the second main step, which selectively amplified CES1A1 and, if present, also CES1A2, for subsequent sequencing. Examination of 501 DNA samples suggested that our procedure is specific with potential for personalization of drug treatments.

PMID: 29457755 [PubMed - as supplied by publisher]

Related Articles

Kinase-targeted cancer therapies: progress, challenges and future directions.

Mol Cancer. 2018 Feb 19;17(1):48

Authors: Bhullar KS, Lagarón NO, McGowan EM, Parmar I, Jha A, Hubbard BP, Rupasinghe HPV

Abstract
The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.

PMID: 29455673 [PubMed - in process]

Related Articles

Systematic Cell-Based Phenotyping of Missense Alleles.

Methods Mol Biol. 2017;1601:215-228

Authors: Thormählen AS, Runz H

Abstract
Sequencing of the protein-coding genome, the exome, has proven powerful to unravel links between genetic variation and disease for both Mendelian and complex conditions. Importantly, however, the increasing number of sequenced human exomes and mapping of disease-associated alleles is accompanied by a simultaneous, yet exponential increase in the overall number of rare and low frequency alleles identified. For most of these novel alleles, biological consequences remain unknown since reliable experimental approaches to better characterize their impact on protein function are only slowly emerging.Here we review a scalable, cell-based strategy that we have recently established to systematically profile the biological impact of rare and low frequency missense variants in vitro. By applying this approach to missense alleles identified through cohort-level exome sequencing in the low-density lipoprotein receptor (LDLR) we are able to distinguish rare alleles that predispose to familial hypercholesterolemia and myocardial infarction from alleles without obvious impact on LDLR levels or functions. We propose that systematic implementation of such and similar strategies will significantly advance our understanding of the protein-coding human genome and how rare and low frequency genetic variation impacts on health and disease.

PMID: 28470529 [PubMed - indexed for MEDLINE]

Impact of home spirometry on medication adherence among adolescents with cystic fibrosis.

Pediatr Pulmonol. 2018 Feb 19;:

Authors: Shakkottai A, Kaciroti N, Kasmikha L, Nasr SZ

Abstract
OBJECTIVE: Medication adherence among adolescents with cystic fibrosis (CF) is often suboptimal and this has significant impact on their health and quality of life. The purpose of the study was to evaluate the impact of frequent home pulmonary function (PFT) monitoring on medication adherence among adolescents with CF.
HYPOTHESIS: We hypothesized that weekly home PFT monitoring will improve adherence while not significantly adding to the treatment burden.
METHODS: Individuals aged 12-21 years with CF were provided a spirometer to measure PFTs weekly for 1 year. Results were reviewed weekly via telephone. PFT data were downloaded from the device during quarterly clinic visits. Adherence was calculated from prescription refill data and compared to the previous year. Perceptions of treatment burden were assessed using the CF questionnaire-revised (CFQ-R) quality of life measure. Health outcome measures including nutritional status and PFTs from clinic were collected for the study period and the year prior.
RESULTS: Thirty-nine subjects participated in the study. Mean age was 15.89 ± 2.18 years and 54% were female. Mean adherence to weekly spirometry monitoring was 59.47 ± 24.60%. Values generated on the device showed good correlation with those obtained in clinic. Mean medication possession ratio (MPR) was 60% in the previous year and 65% during the study (P = 0.04). Mean treatment burden scaled score on the CFQ-R was 68 at enrollment and 66 at study completion (P = 0.14).
CONCLUSIONS: Frequent home PFT monitoring is feasible in CF adolescents and could successfully improve medication adherence without significantly impacting treatment burden.

PMID: 29457700 [PubMed - as supplied by publisher]

Related Articles

Assessment of pulmonary structure-function relationships in young children and adolescents with cystic fibrosis by multivolume proton-MRI and CT.

J Magn Reson Imaging. 2018 Feb 19;:

Authors: Pennati F, Roach DJ, Clancy JP, Brody AS, Fleck RJ, Aliverti A, Woods JC

Abstract
BACKGROUND: Lung disease is the most frequent cause of morbidity and mortality in patients with cystic fibrosis (CF), and there is a shortage of sensitive biomarkers able to regionally monitor disease progression and to assess early responses to therapy.
PURPOSE: To determine the feasibility of noncontrast-enhanced multivolume MRI, which assesses intensity changes between expiratory and inspiratory breath-hold images, to detect and quantify regional ventilation abnormalities in CF lung disease, with a focus on the structure-function relationship.
STUDY TYPE: Retrospective.
POPULATION: Twenty-nine subjects, including healthy young children (n = 9, 7-37 months), healthy adolescents (n = 4, 14-22 years), young children with CF lung disease (n = 10, 7-47 months), and adolescents with CF lung disease (n = 6, 8-18 years) were studied.
FIELD STRENGTH/SEQUENCE: 3D spoiled gradient-recalled sequence at 1.5T.
ASSESSMENT: Subjects were scanned during breath-hold at functional residual capacity (FRC) and total lung capacity (TLC) through noncontrast-enhanced MRI and CT. Expiratory-inspiratory differences in MR signal-intensity (Δ1 H-MRI) and CT-density (ΔHU) were computed to estimate regional ventilation. MR and CT images were also evaluated using a CF-specific scoring system.
STATISTICAL TESTS: Quadratic regression, Spearman's correlation, one-way analysis of variance (ANOVA).
RESULTS: Δ1 H-MRI maps were sensitive to ventilation heterogeneity related to gravity dependence in healthy lung and to ventilation impairment in CF lung disease. A high correlation was found between MRI and CT ventilation maps (R2  = 0.79, P < 0.001). Globally, Δ1 H-MRI and ΔHU decrease with increasing morphological score (respectively, R2  = 0.56, P < 0.001 and R2  = 0.31, P < 0.001). Locally, Δ1 H-MRI was higher in healthy regions (median 15%) compared to regions with bronchiectasis, air trapping, consolidation, and to segments fed by airways with bronchial wall thickening (P < 0.001).
DATA CONCLUSION: Multivolume noncontrast-enhanced MRI, as a nonionizing imaging modality that can be used on nearly any MRI scanner without specialized equipment or gaseous tracers, may be particularly valuable in CF care, providing a new imaging biomarker to detect early alterations in regional lung structure-function.
LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018.

PMID: 29457316 [PubMed - as supplied by publisher]

Related Articles

Improvement in Exophiala dermatitidis airway persistence and respiratory decline in response to interferon-gamma therapy in a patient with cystic fibrosis.

J Cyst Fibros. 2018 Feb 15;:

Authors: Eades CP, Armstrong-James DPH, Periselneris J, Jones A, Simmonds N, Kelleher P, Shah A

PMID: 29456196 [PubMed - as supplied by publisher]

Related Articles

Mast cell tryptase changes with Aspergillus fumigatus - Host crosstalk in cystic fibrosis patients.

J Cyst Fibros. 2018 Feb 15;:

Authors: Gomez C, Carsin A, Gouitaa M, Reynaud-Gaubert M, Dubus JC, Mège JL, Ranque S, Vitte J

Abstract
Pulmonary and systemic antifungal immunity influences quality of life and survival of people with cystic fibrosis. Aspergillus fumigatus (Af) induces specific IgG and IgE. Mast cells respond to IgE, IgG and direct interactions with Af. Mast cells are the source of the protease tryptase. We aimed at evaluating serum baseline tryptase as a potential biomarker of the Af-host interaction in cystic fibrosis patients. Serum baseline tryptase, IgE and IgG directed to Af extract and Af molecular allergens were measured in 76 cystic fibrosis patients. The main findings were (i) lower levels of serum baseline tryptase in patients displaying specific IgE to Af (p < 0.0001) and (ii) an association between tryptase levels and IgE or IgG responses to Af and ribotoxin (Asp f 1). These findings suggest that serum baseline tryptase is influenced by Af-host interactions and thus might be a marker for mast cell regulation and pulmonary immune defenses.

PMID: 29456195 [PubMed - as supplied by publisher]