Literature Watch
Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis.
Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis.
Antimicrob Agents Chemother. 2018 Jun 18;:
Authors: Park AYJ, Wang J, Jayne J, Fukushima L, Rao AP, D'Argenio DZ, Beringer PM
Abstract
Over the past decade, the prevalence of infections involving Methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics has shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate 200 mg PO or IV once daily for 3 doses, with minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetics was performed using maximum-likelihood, expectation maximization method, and the disposition of TZD was described by a 2-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean (%CV) sputum-to-unbound plasma penetration ratio of 2.88 (50.3). The estimated population mean ± standard deviation of total clearance, central volume of distribution, and bioavailability were 9.72 ± 1.62 L/h, 61.6 ± 6.94 L, and 1.04 ± 0.232 respectively. The total clearance is higher in CF patients when compared with healthy volunteers; however, it is similar to published data in patients with complicated skin and skin structure infections (cSSSI). This study demonstrates the oral bioavailability of tedizolid is excellent in patients with CF, and the plasma pharmacokinetics are similar to that reported for patients with cSSSI.
PMID: 29914949 [PubMed - as supplied by publisher]
Ready, Steady, Go - Achieving successful transition in cystic fibrosis.
Ready, Steady, Go - Achieving successful transition in cystic fibrosis.
Paediatr Respir Rev. 2018 May 18;:
Authors: Connett GJ, Nagra A
Abstract
Successful transfer to adult services is the paediatric team's anticipated endpoint for the care they provide to their patients. The preceding transition process needs to be well planned and designed to address young peoples' psycho-social, educational and vocational as well as their medical needs. Ready, Steady, Go is a generic programme that has been successfully implemented to make the transition process an integral part of the routine care of young people with cystic fibrosis. Used in combination with other initiatives, the programme helps achieve the more seamless transfer of young people better prepared to meet their ongoing needs.
PMID: 29914748 [PubMed - as supplied by publisher]
Royal society of medicine cystic fibrosis symposium 2017.
Royal society of medicine cystic fibrosis symposium 2017.
Paediatr Respir Rev. 2018 May 18;:
Authors: Jones AM
PMID: 29914747 [PubMed - as supplied by publisher]
Multi-resistant Pseudomonas aeruginosa ST235 in cystic fibrosis.
Multi-resistant Pseudomonas aeruginosa ST235 in cystic fibrosis.
Paediatr Respir Rev. 2018 May 18;:
Authors: Lee AC, Jones AL
Abstract
Chronic Pseudomonas aeruginosa infection is associated with a decline in lung function and overall poorer prognosis in the cystic fibrosis population. Molecular typing of P. aeruginosa has identified multiple clonal strains with increased virulence and transmissibility. P. aeruginosa ST235 is an emerging clonal strain with multi-drug resistance and is associated with more virulent infections. Novel cephalosporins, which have recently been introduced to clinical practice, may have higher efficacy against multi-drug resistant bacteria.
PMID: 29914746 [PubMed - as supplied by publisher]
The use of lumacaftor/ivacaftor to treat acute deterioration in paediatric cystic fibrosis.
The use of lumacaftor/ivacaftor to treat acute deterioration in paediatric cystic fibrosis.
Paediatr Respir Rev. 2018 May 19;:
Authors: Hammond JA, Connett GJ
Abstract
Lumacaftor/ivacaftor is a precision medicine targeting the defective cystic fibrosis transmembrane regulator (CFTR) protein in cystic fibrosis (CF) patients homozygous for Phe508del genotype. Whilst there is evidence for efficacy in children aged 6-11 years who are stable with good lung function, there are little data about the use of this medication for children with acute deterioration in this age group. We describe the use of this drug to treat a child with an unusually severe exacerbation of CF lung disease and review the potential of lumacaftor/ivacaftor as a rescue therapy in the paediatric CF population.
PMID: 29914743 [PubMed - as supplied by publisher]
Progressive Hearing Loss among Patients with Cystic Fibrosis and Parenteral Aminoglycoside Treatment.
Progressive Hearing Loss among Patients with Cystic Fibrosis and Parenteral Aminoglycoside Treatment.
Otolaryngol Head Neck Surg. 2018 Jun 01;:194599818782444
Authors: Zettner EM, Gleser MA
Abstract
Objective Hearing loss is a significant and growing problem as patients with cystic fibrosis (CF) live longer and experience frequent courses of intravenous aminoglycoside antibiotics (hereafter, "IVs"). This study seeks to document that risk in a large adult population with CF, accounting for age and aminoglycoside exposure. Study Design Retrospective case review of patients with CF who had multiple audiograms over years. Setting Tertiary care cystic fibrosis setting. Subject and Methods The first and last audiograms recorded over a 10-year period were compared for 165 adult patients with CF. Patients were divided into 3 study groups: 34 patients with no intervening aminoglycoside IVs (0 IVs), 103 patients with 1 to 9 IVs, and 28 patients with ≥10 IVs. Threshold shift (TS) between the audiograms were examined for the 3 groups before and after age/sex adjustments. Two new hearing loss metrics were tested. Results At first examination, 48% of patients (average age, 30.0 years) already had hearing loss. At last examination (average, 4.4 years later), 64% of the patients had hearing loss even with age/sex adjustment. Use of the age/sex hearing threshold adjustment eliminated the TS in the 0 IVs group. Two new metrics calculated for each patient demonstrated that 48% of patients who had 1 to 9 IVs had ototoxic scores, while almost 80% of the ≥10 IV group had ototoxic scores. Conclusion The majority of adult patients with CF are (often repeatedly) exposed to parenteral aminoglycosides and lose hearing at a rate that far exceeds that predicted from aging alone.
PMID: 29914288 [PubMed - as supplied by publisher]
Genomic insights into the causes of type 2 diabetes.
Genomic insights into the causes of type 2 diabetes.
Lancet. 2018 Jun 16;391(10138):2463-2474
Authors: Langenberg C, Lotta LA
Abstract
Genome-wide association studies have implicated around 250 genomic regions in predisposition to type 2 diabetes, with evidence for causal variants and genes emerging for several of these regions. Understanding of the underlying mechanisms, including the interplay between β-cell failure, insulin sensitivity, appetite regulation, and adipose storage has been facilitated by the integration of multidimensional data for diabetes-related intermediate phenotypes, detailed genomic annotations, functional experiments, and now multiomic molecular features. Studies in diverse ethnic groups and examples from population isolates have shown the value and need for a broad genomic approach to this global disease. Transethnic discovery efforts and large-scale biobanks in diverse populations and ancestries could help to address some of the Eurocentric bias. Despite rapid progress in the discovery of the highly polygenic architecture of type 2 diabetes, dominated by common alleles with small, cumulative effects on disease risk, these insights have been of little clinical use in terms of disease prediction or prevention, and have made only small contributions to subtype classification or stratified approaches to treatment. Successful development of academia-industry partnerships for exome or genome sequencing in large biobanks could help to deliver economies of scale, with implications for the future of genomics-focused research.
PMID: 29916387 [PubMed - in process]
Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.
Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.
Genet Med. 2018 Jun 18;:
Authors: Sun M, Johnson AK, Nelakuditi V, Guidugli L, Fischer D, Arndt K, Ma L, Sandford E, Shakkottai V, Boycott K, Chardon JW, Li Z, Del Gaudio D, Burmeister M, Gomez CM, Waggoner DJ, Das S
Abstract
PURPOSE: To examine the impact of a targeted exome approach for the molecular diagnosis of patients nationwide with a wide range of ataxia-related phenotypes.
METHODS: One hundred and seventy patients with ataxia of unknown etiology referred from clinics throughout the United States and Canada were studied using a targeted exome approach. Patients ranged in age from 2 to 88 years. Analysis was focused on 441 curated genes associated with ataxia and ataxia-like conditions.
RESULTS: Pathogenic and suspected diagnostic variants were identified in 88 of the 170 patients, providing a positive molecular diagnostic rate of 52%. Forty-six different genes were implicated, with the six most commonly mutated genes being SPG7, SYNE1, ADCK3, CACNA1A, ATP1A3, and SPTBN2, which accounted for >40% of the positive cases. In many cases a diagnosis was provided for conditions that were not suspected and resulted in the broadening of the clinical spectrum of several conditions.
CONCLUSION: Exome sequencing with targeted analysis provides a high-yield approach for the genetic diagnosis of ataxia-related conditions. This is the largest targeted exome study performed to date in patients with ataxia and ataxia-like conditions and represents patients with a wide range of ataxia phenotypes typically encountered in neurology and genetics clinics.
PMID: 29915382 [PubMed - as supplied by publisher]
The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy.
The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy.
J Hum Genet. 2018 Jun 18;:
Authors: Yin X, Tang B, Mao X, Peng J, Zeng S, Wang Y, Jiang H, Li N
Abstract
Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a family of enzymes that play critical roles in protein biosynthesis. Mutations in mt-aaRSs are associated with various diseases. As a member of the mt-aaRS family, PARS2 encoding prolyl-tRNA synthetase 2 was recently shown to be associated with Alpers syndrome and certain infantile-onset neurodegenerative disorders in four patients. Here, we present two patients in a pedigree with early developmental delay, epileptic spasms, delayed myelination combined with cerebellar white matter abnormalities, and progressive cortical atrophy. Whole-exome sequencing revealed pathogenic compound heterozygous variants [c.283 G > A (p.95 V > I)] and [c.604 G > C (p.202 R > G)] in PARS2. Nearly all patients had epileptic spasms with early response to treatment, early developmental delay and/or regression followed by generalized hypotonia, postnatal microcephaly, elevated lactate levels, and progressive cerebral atrophy. Our study provides further evidence for validating the role of PARS2 in the pathology of related infantile-onset encephalopathy, contributing to the phenotypic features of this condition, and providing clinical and molecular insight for the diagnosis of this disease entity.
PMID: 29915213 [PubMed - as supplied by publisher]
Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma.
Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma.
BMC Cancer. 2017 Jul 24;17(1):497
Authors: Dwight T, Na U, Kim E, Zhu Y, Richardson AL, Robinson BG, Tucker KM, Gill AJ, Benn DE, Clifton-Bligh RJ, Winge DR
Abstract
BACKGROUND: Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with the development of pheochromocytoma (PC) and/or paraganglioma (PGL). As assembly factors have been identified as playing a role in maturation of individual SDH subunits and assembly of the functioning SDH complex, we hypothesized that SDHAF3 variants may be associated with PC/PGL and functionality of SDH.
METHODS: DNA was extracted from the blood of 37 individuals (from 23 families) with germline SDH mutations and 18 PC/PGL (15 sporadic, 3 familial) and screened for mutations using a custom gene panel, containing SDHAF3 (SDH assembly factor 3) as well as eight known PC/PGL susceptibility genes. Molecular and functional consequences of an identified sequence variant of SDHAF3 were assessed in yeast and mammalian cells (HEK293).
RESULTS: Using massively parallel sequencing, we identified a variant in SDHAF3, c.157 T > C (p.Phe53Leu), associated with increased prevalence in familial and sporadic PC/PGL (6.6%) when compared to normal populations (1.2% [1000 Genomes], p = 0.003; 2.1% [Exome Aggregation Consortium], p = 0.0063). In silico prediction tools suggest this variant is probably damaging to protein function, hence we assessed molecular and functional consequences of the resulting amino acid change (p.Phe53Leu) in yeast and human cells. We showed that introduction of SDHAF3 p.Phe53Leu into Sdh7 (ortholog of SDHAF3 in humans) null yeast resulted in impaired function, as observed by its failure to restore SDH activity when expressed in Sdh7 null yeast relative to WT SDHAF3. As SDHAF3 is involved in maturation of SDHB, we tested the functional impact of SDHAF3 c.157 T > C and various clinically relevant SDHB mutations on this interaction. Our in vitro studies in human cells show that SDHAF3 interacts with SDHB (residues 46 and 242), with impaired interaction observed in the presence of the SDHAF3 c.157 T > C variant.
CONCLUSIONS: Our studies reveal novel insights into the biogenesis of SDH, uncovering a vital interaction between SDHAF3 and SDHB. We have shown that SDHAF3 interacts directly with SDHB (residue 242 being key to this interaction), and that a variant in SDHAF3 (c.157 T > C [p.Phe53Leu]) may be more prevalent in individuals with PC/PGL, and is hypomorphic via impaired interaction with SDHB.
PMID: 28738844 [PubMed - indexed for MEDLINE]
Generalizability of clinical trials of advanced melanoma in the real-world, population-based setting.
Generalizability of clinical trials of advanced melanoma in the real-world, population-based setting.
Med Oncol. 2018 Jun 18;35(7):110
Authors: Sam D, Gresham G, Abdel-Rahman O, Cheung WY
Abstract
Results from novel therapeutics trials are not always generalizable to real-world patients. We aimed to determine the pattern in which trial findings are applied in a population-based setting of melanoma patients and consequent treatment outcomes. Patients with unresectable disease during 2011-2014 and referred to cancer centers in a large Canadian province were retrospectively reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified patients into trial-eligible and ineligible and those treated and untreated with these agents. We identified 290 patients with known BRAF status for the Vem analysis and 212 patients previously treated with first-line agents for the Ipi analysis. For the Vem cohort, a total of 49 patients were considered trial-eligible, of whom 36 (73%) received treatment. For the Ipi cohort, there were 119 trial-eligible cases of whom 43 (36%) received therapy. Factors other than eligibility criteria most frequently associated with non-treatment in these cohorts included concerns regarding treatment harm and patient preferences. In multivariable analysis, overall survival was improved in Vem cohort patients considered trial-eligible and treated compared to those who were ineligible. Within the Ipi cohort, survival was improved in trial-eligible patients regardless of whether they received Ipi compared to ineligible patients. Real-world uptake of new melanoma treatments was suboptimal, and non-use in trial-eligible patients was frequent. Future clinical trials that are more pragmatically designed to include participants who better reflect the real-world population may facilitate increased uptake of novel therapeutics into routine clinical practice.
PMID: 29915956 [PubMed - in process]
pharmacogenomics; +20 new citations
20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2018/06/20
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.
"systems biology"; +25 new citations
25 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2018/06/20
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.
Notice of Clarification of NIA intent to fund awards for RFA-HL-18-023 "Stimulating Access to Research in Residency (StARR) (R38)"
Modeling and Simulation to Optimize HIV Prevention Research (MS OPR) (R01 Clinical Trial not allowed)
Global Brain and Nervous System Disorders Research Across the Lifespan (R01 Clinical Trials Optional)
Global Brain and Nervous System Disorders Research Across the Lifespan (R21 Clinical Trial Optional)
Notice to Extend the Expiration Date for PAR-15-359 "Novel Approaches to Diagnosing Alzheimer's Disease and Predicting Progression (R01)"
Notice of Pre-Submission Webinars for RFA-TR-18-020: Rare Diseases Clinical Research Consortia (RDCRC) for the Rare Diseases Clinical Research Network (RDCRN) (U54 Clinical Trial Optional) and RFA-TR-18-021: Data Management and Coordinating Center (DMCC)
Notice of Correction to NOT-OD-18-174 "Notice of Intent to Publish a Funding Opportunity Announcement for the Predoctoral Training in Advanced Data Analytics for Behavioral and Social Sciences Research (BSSR) Institutional Research Training Program [T32]"
Pages
