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Identifying genetically driven clinical phenotypes using linear mixed models.

Nat Commun. 2016 04 25;7:11433

Authors: Mosley JD, Witte JS, Larkin EK, Bastarache L, Shaffer CM, Karnes JH, Stein CM, Phillips E, Hebbring SJ, Brilliant MH, Mayer J, Ye Z, Roden DM, Denny JC

Abstract
We hypothesized that generalized linear mixed models (GLMMs), which estimate the additive genetic variance underlying phenotype variability, would facilitate rapid characterization of clinical phenotypes from an electronic health record. We evaluated 1,288 phenotypes in 29,349 subjects of European ancestry with single-nucleotide polymorphism (SNP) genotyping on the Illumina Exome Beadchip. We show that genetic liability estimates are primarily driven by SNPs identified by prior genome-wide association studies and SNPs within the human leukocyte antigen (HLA) region. We identify 44 (false discovery rate q<0.05) phenotypes associated with HLA SNP variation and show that hypothyroidism is genetically correlated with Type I diabetes (rG=0.31, s.e. 0.12, P=0.003). We also report novel SNP associations for hypothyroidism near HLA-DQA1/HLA-DQB1 at rs6906021 (combined odds ratio (OR)=1.2 (95% confidence interval (CI): 1.1-1.2), P=9.8 × 10(-11)) and for polymyalgia rheumatica near C6orf10 at rs6910071 (OR=1.5 (95% CI: 1.3-1.6), P=1.3 × 10(-10)). Phenome-wide application of GLMMs identifies phenotypes with important genetic drivers, and focusing on these phenotypes can identify novel genetic associations.

PMID: 27109359 [PubMed - indexed for MEDLINE]

LY2495655, an antimyostatin antibody, in pancreatic cancer: a randomized, phase 2 trial.

J Cachexia Sarcopenia Muscle. 2018 Jul 27;:

Authors: Golan T, Geva R, Richards D, Madhusudan S, Lin BK, Wang HT, Walgren RA, Stemmer SM

Abstract
BACKGROUND: Cachexia is a formidable clinical challenge in pancreatic cancer. We assessed LY2495655 (antimyostatin antibody) plus standard-of-care chemotherapy in pancreatic cancer using cachexia status as a stratifier.
METHODS: In this randomized, phase 2 trial, patients with stage II-IV pancreatic cancer were randomized to 300 mg LY2495655, 100 mg LY2495655, or placebo, plus physician-choice chemotherapy from a prespecified list of standard-of-care regimens for first and later lines of care. Investigational treatment was continued during second-line treatment. The primary endpoint was overall survival.
RESULTS: Overall, 125 patients were randomized. In August 2014, 300 mg LY2495655 was terminated due to imbalance in death rates between the treatment arms; in January 2015, 100 mg LY2495655 treatment was terminated due to futility. LY2495655 did not improve overall survival: the hazard ratio was 1.70 (90% confidence interval, 1.1-2.7) for 300 mg vs. placebo and 1.3 (0.82-2.1) for 100 mg vs. placebo (recommended doses). Progression-free survival results were consistent with the overall survival results. A numerically higher hazard ratio was observed in patients with weight loss (WL) of ≥5% (cachexia) than with <5% WL within 6 months before randomization. Subgroup analyses for patients stratified by WL in the 6 months preceding enrollment suggested that functional responses to LY2495655 (either dose) may have been superior in patients with <5% WL vs. patients with ≥5% WL. Among possibly drug-related adverse events, fatigue, diarrhoea, and anorexia were more common in LY2495655-treated than in placebo-treated patients.
CONCLUSIONS: In the intention-to-treat analysis, LY2495655 did not confer clinical benefit in pancreatic cancer. Our data highlight the importance of assessing survival when investigating therapeutic management of cachexia and support the use of WL as a stratifier (independent of performance status).

PMID: 30051975 [PubMed - as supplied by publisher]

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Trends in reporting drug-associated liver injuries in Taiwan: a focus on amiodarone.

Int J Clin Pharm. 2018 Jul 26;:

Authors: Ye JH, Ho YF, On AW, Chen WW, Huang YM, Huang WI, Tang YW

Abstract
Background A pharmacovigilance database of real-world adverse drug reaction (ADR) reports is helpful for characterising adverse events and identifying new signals after drug approval. Objective This study aimed to analyse trends of ADR reporting in relation to liver injury and to delineate critical factors for suspected drug-related hepatotoxicity with a focus on reports associated with amiodarone. Setting The 2000-2014 Taiwan pharmacovigilance database. Method Relevant Standardized Medical Dictionary for Regulatory Activities queries were used to identify reports associated with liver injury. Information on ADR, patient characteristics, and the verbatim pertaining to amiodarone prescriptions, liver injury, comedications, and comorbidities were extracted and evaluated. Group comparisons between Hy's Law cases and Temple's Corollary cases of suspected amiodarone-related hepatotoxicity were performed. Main outcome measure Number and nature of drug-related liver injuries, particularly those associated with amiodarone. Results Of the 98,777 ADR reports over a 15-year period, 4261 (4.3%) were related to liver injury. Sixty-eight reports contained amiodarone prescriptions, but only 49 (1.1%) were eligible for further analysis. Hepatotoxic cases associated with amiodarone mostly occurred within 1 week, exhibited a hepatocellular pattern, and were more common among elderly individuals. Among 23 discernible cases, four (17.4%) recovered fully from liver injury. The critical Hy's Law cases were associated with shorter height, lower body surface area, and higher average daily doses. Conclusion This study substantiates the importance of ADR reporting. Data pertaining to drug-associated liver injury and factors associated with suspected amiodarone-related hepatotoxicity warrants continual attention in pharmacovigilance for those at risk, especially the elderly.

PMID: 30051228 [PubMed - as supplied by publisher]

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"No pain, No gain" still true with immunotherapy: When the finger shows the moon, look at the moon!

Crit Rev Oncol Hematol. 2018 Jul;127:1-5

Authors: Milano G, Innocenti F, Lacarelle B, Ciccolini J

Abstract
There is a rising evidence that the proverbial statement "No pain, No gain" first coined at the light of pioneering clinical experiences with canonical chemotherapy still holds true in the era of modern treatments of cancer. This close relationship between the occurrence of specific drug-related toxicity and treatment outcome has been confirmed since then with a large variety of treatments, ranging from cytotoxics, hormonotherapy, targeted therapy and much interestingly even with the latest immune checkpoint inhibitors. In the current context of precision medicine, and along with the constant quest for identifying predictive biomarkers, close monitoring of treatment-related toxicities could therefore be convenient to help predicting therapeutic response, but presents several caveats. The purpose of this review is to briefly describe these relationships across the different treatments, to comment on possible underlying mechanisms and to comment on possible strategies aiming at exploiting this relationship while keeping the maximal safety ensured in patients with cancer. In particular, this review will investigate on how drug exposure along with germinal and somatic genetic issues does impact on the "No Pain, No Gain" aphorism, and why the temptation to use treatment-related toxicities as a cheap and convenient way to predict clinical outcome or to adapt dosing should be resisted. We do advocate instead for developing comprehensive genomic support along with extensive biomathematical modeling to better customize dosing and shift towards a new "No Pain, Maximal Gain" paradigm.

PMID: 29891106 [PubMed - indexed for MEDLINE]

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Adverse events of Dupilumab in adults with moderate-to-severe atopic dermatitis: A meta-analysis.

Int Immunopharmacol. 2018 Jan;54:303-310

Authors: Ou Z, Chen C, Chen A, Yang Y, Zhou W

Abstract
BACKGROUND: Dupilumab, a fully human monoclonal antibody against interleukin-4 receptor alpha, inhibits the signals of interleukin-4 and interleukin-13, and has also shown significant efficacy in patients with moderate-to-severe atopic dermatitis (AD), while the effect of it on adverse events remains controversial.
OBJECTIVE: To assess the influence of dupilumab on adverse events in adults with moderate-to-severe AD.
METHOD: Randomised controlled trials (RCTs) that compared dupilumab with a placebo for patients with moderate-to-severe AD were searched in the MEDLINE, EMBASE, Web of Science and Cochrane databases. The outcome of the study was the incidence of adverse events during the observation period.
RESULTS: Eight RCTs were analysed in this study. Meta-analysis showed that patients treated with dupilumab had a lower risk of skin infection (risk ratio [RR] 0.54; 95% confidence interval [CI] 0.42-0.69) and exacerbation of AD (RR 0.44, 95% CI 0.34-0.59), but had a higher risk of injection-site reaction (RR 2.24, 95% CI 1.68-2.99), headache (RR 1.47, 95% CI 1.05-2.06), and conjunctivitis (RR 2.64, 95% CI 1.79-3.89) than did patients treated with a placebo. Nasopharyngitis, urinary tract infection, upper respiratory tract infection, and herpes virus infection were found balanced in dupilumab groups and placebo groups.
CONCLUSION: Dupilumab moderately reduced the risk of skin infection and the exacerbation of AD, slightly increased the risk of headache, and moderately increased the risk of injection-site reaction and conjunctivitis, but had little effect on other infections in adults with moderate-to-severe AD.

PMID: 29182975 [PubMed - indexed for MEDLINE]

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Strategies for Avoiding Benzopyrone Hepatotoxicity in Lymphedema Management-The Role of Pharmacogenetics, Metabolic Enzyme Gene Identification, and Patient Selection.

Lymphat Res Biol. 2017 Dec;15(4):317-323

Authors: Hu M, Piller NB

Abstract
INTRODUCTION: Benzopyrones are plant-derived chemicals which have an evidenced degree of clinical efficacy in lymphedema management indicated in past trials. Unfortunately, in some of these cases idiosyncratic hepatotoxicity have been documented in a minority of patients. This review aims to tackle the problem of benzopyrone (particularly coumarin) toxicity by considering their metabolic pathways and identifying relevant alleles needed to take a targeted pharmacogenetic approach in its future use.
METHODS AND RESULTS: The nontoxic 7-hydroxylation and the toxic heterocyclic "ring-splitting" epoxidation pathways are the two main detoxification pathways in the hepatometabolism of coumarin, the former catalyzed by CYP2A6 and the latter by possibly CYP1A and CYP2E. Acetaldehyde dehydrogenase (ALDH) clears toxic aldehyde intermediates. CYP2A6 polymorphism screening methods, including genotyping, by real-time polymerase chain reaction and chromatography-mass spectroscopy functional metabolite assays; efficiency of these techniques are continually improving. ALDH polymorphisms have also been implicated, with clinically viable screening tests, rapid genotyping, and sensitive questionnaires already available for ALDH2*1/ALDH2*2. Dysfunctional polymorphisms of the above genes and others are significantly more prevalent in Eastern Asian populations, uncommon in Caucasian populations. The role of other enzymes/genes in the pathway is yet to be clarified.
CONCLUSION: Although screening techniques are becoming increasingly clinically feasible, uncertainty remains on the link between the genotype, metabolic phenotype, and the exact gene products involved. These must be elucidated further before a targeted pharmacogenomic approach is fully viable. In the meantime, treatment should be avoided in those with vulnerable familial and ethnic descents if used.

PMID: 29087786 [PubMed - indexed for MEDLINE]

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Predicting the Risk of Phospholipidosis with in Silico Models and an Image-Based in Vitro Screen.

Mol Pharm. 2017 Dec 04;14(12):4346-4352

Authors: Fusani L, Brown M, Chen H, Ahlberg E, Noeske T

Abstract
The drug-induced accumulation of phospholipids in lysosomes of various tissues is predominantly observed in regular repeat dose studies, often after prolonged exposure, and further investigated in mechanistic studies prior to candidate nomination. The finding can cause delays in the discovery process inflicting high costs to the affected projects. This article presents an in vitro imaging-based method for early detection of phospholipidosis liability and a hybrid approach for early detection and risk mitigation of phospolipidosis utilizing the in vitro readout with in silico model prediction. A set of reference compounds with phospolipidosis annotation was used as an external validation set yielding accuracies between 77.6% and 85.3% for various in vitro and in silico models, respectively. By means of a small set of chemically diverse known drugs with in vivo phospholipidosis annotation, the advantages of combining different prediction methods to reach an overall improved phospholipidosis prediction will be discussed.

PMID: 29077420 [PubMed - indexed for MEDLINE]

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Limitations in Clinical Translation of Nanoparticle-Based Gene Therapy.

Trends Biotechnol. 2017 Dec;35(12):1124-1125

Authors: Wong JKL, Mohseni R, Hamidieh AA, MacLaren RE, Habib N, Seifalian AM

Abstract
Organic nanoparticle-based (ONP) gene therapy is a potential strategy to cure human cancer. However, there are still many practical barriers before the promising results from in vitro and preclinical studies can be translated to clinical success. We discuss the reasons behind the hesitant uptake by the clinic.

PMID: 28822599 [PubMed - indexed for MEDLINE]

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[Deprescription, what are we talking about?]

Farm Hosp. 2017 Jul 01;41(4):567-568

Authors: Gutiérrez-Valencia M, Martínez-Velilla N

PMID: 28683712 [PubMed - indexed for MEDLINE]

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Using the diffusion of innovations theory to assess socio-technical factors in planning the implementation of an electronic health record alert across multiple primary care clinics.

J Innov Health Inform. 2016 04 15;23(1):450-8

Authors: Lin CP, Guirguis-Blake J, Keppel GA, Dobie S, Osborn J, Cole AM, Baldwin LM

Abstract
BACKGROUND: Adverse drug events (ADEs) are a leading cause of death in the United States. Patients with stage 3 and 4 chronic kidney disease (CKD) are at particular risk because many medications are cleared by the kidneys. Alerts in the electronic health record (EHR) about drug appropriateness and dosing at the time of prescription have been shown to reduce ADEs for patients with stage 3 and 4 CKD in inpatient settings, but more research is needed about the implementation and effectiveness of such alerts in outpatient settings.
OBJECTIVE: To explore factors that might inform the implementation of an electronic drug-disease alert for patients with CKD in primary care clinics, using Rogers' diffusion of innovations theory as an analytic framework.
METHODS: Interviews were conducted with key informants in four diverse clinics using various EHR systems. Interviews were audio recorded and transcribed. results Although all clinics had a current method for calculating glomerular filtration rate (GFR), clinics were heterogeneous with regard to current electronic decision support practices, quality improvement resources, and organizational culture and structure.
CONCLUSION: Understanding variation in organizational culture and infrastructure across primary care clinics is important in planning implementation of an intervention to reduce ADEs among patients with CKD.

PMID: 27348488 [PubMed - indexed for MEDLINE]

28 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 2018/07/28

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.

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Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism.

Res Pract Thromb Haemost. 2018 Jan;2(1):69-76

Authors: Albisetti M, Schlosser A, Brueckmann M, Gropper S, Glund S, Tartakovsky I, Brandão LR, Reilly PA

Abstract

Background: The incidence of venous thromboembolism (VTE) in children has been increasing. Anticoagulants are the mainstay of treatment but are associated with bleeding events that may be life-threatening. Idarucizumab is a fragment antigen-binding (fab) that provides immediate, complete, and sustained reversal of dabigatran's anticoagulant effects in adults.
Objective and Methods: This phase III, open-label, single-arm, multicenter, multinational trial will assess the safety of idarucizumab in children participating in two ongoing trials investigating dabigatran etexilate. Eligible patients will be children with VTE (aged 0-≤18 years; n = ~5) with life-threatening or uncontrolled bleeding (group A), and children who require emergency surgery/urgent procedures for a condition other than bleeding (group B). Patients will receive idarucizumab up to 5 g as two consecutive intravenous infusions over 5-10 minutes each, as two 10-15-minute drips or as two bolus injections (15 minutes apart) and will be monitored for 30 days. The primary endpoint will be the safety of idarucizumab assessed by the occurrence of drug-related adverse events (including immune reactions) and all-cause mortality. Secondary endpoints will be the reversal of dabigatran anticoagulant effects assessed by changes in diluted thrombin time and ecarin clotting time, time to achieve complete reversal and the duration of the reversal and bleeding severity (group A). The formation of antidrug antibodies at 30 days post-dose and cessation of bleeding will also be assessed.
Conclusion: This study will report the safety of idarucizumab in children with VTE who require rapid reversal of the anticoagulant effects of dabigatran. Clinical trial registration: NCT02815670.

PMID: 30046708 [PubMed]

Funding Opportunity RFA-HL-19-020 from the NIH Guide for Grants and Contracts. The National Heart, Lung, and Blood Institute invites cooperative agreement (U01) applications to serve as the Research Center (RC) for the Molecular Atlas of Lung Development Program (LungMAP), Phase 2. The overall objective of LungMAP is to better understand human lung development through building an open-access reference resource of a comprehensive, dynamic, 3-D molecular atlas of the late-stage developing human lung with data and reagents available to the research community. Phase 2 of LungMAP will continue to generate and integrate high-resolution, multiscale molecular profiles associated with spatial information to provide molecular characterizations of functionally and anatomically defined cell types in the developing human lung. Phase 2 of LungMAP will focus on human lung only and will extend the scope to cover normal lung development into early adulthood (up to 25 years old), as well as abnormal lung development in selected neonatal and pediatric rare lung diseases. The purpose of the LungMAP RCs will be to generate the molecular profiling data of the developing human lung. Applicants are not required to have been funded in Phase 1 (RFA-HL-14-008) in order to submit applications for Phase 2.

Funding Opportunity RFA-HL-19-021 from the NIH Guide for Grants and Contracts. The National Heart, Lung, and Blood Institute invites cooperative agreement (U01) applications to serve as the Research Center (RC) for the Molecular Atlas of Lung Development Program (LungMAP), Phase 2. The overall objective of LungMAP is to better understand human lung development through building an open-access reference resource of a comprehensive, dynamic, 3-D molecular atlas of the late-stage developing human lung with data and reagents available to the research community. Phase 2 of LungMAP will continue to generate and integrate high-resolution, multiscale molecular profiles associated with spatial information to provide molecular characterizations of functionally and anatomically defined cell types in the developing human lung. Phase 2 of LungMAP will focus on human lung only and will extend the scope to cover normal lung development into early adulthood (up to 25 years old), as well as abnormal lung development in selected neonatal and pediatric rare lung diseases. The purpose of the LungMAP RCs will be to generate the molecular profiling data of the developing human lung. Applicants are not required to have been funded in Phase 1 (RFA-HL-14-008) in order to submit applications for Phase 2.

Funding Opportunity RFA-HL-19-022 from the NIH Guide for Grants and Contracts. The National Heart, Lung, and Blood Institute invites cooperative agreement (U24) applications to serve as the Data Coordinating Center (DCC) for the Molecular Atlas of Lung Development Program (LungMAP), Phase 2. The overall objective of LungMAP is to better understand human lung development through building an open-access reference resource of a comprehensive, dynamic, 3-D molecular atlas of the late-stage developing human lung with data and reagents available to the research community. Phase 2 of LungMAP will continue to generate and integrate high-resolution, multiscale molecular profiles associated with spatial information to provide molecular characterizations of functionally and anatomically defined cell types in the developing human lung. Phase 2 of LungMAP will focus on human lung only and will extend the scope to cover normal lung development into early adulthood (up to 25 years old), as well as abnormal lung development in selected neonatal and pediatric rare lung diseases. The DCC will perform data collection, integration, and analysis; develop and maintain the LungMAP database and website; and coordinate research activities of the Human Tissue Core (HTC) and the Research Centers (RCs). Applicants are not required to have been funded in Phase 1 (RFA-HL-14-009) in order to submit applications for Phase 2.

Notice NOT-TR-18-027 from the NIH Guide for Grants and Contracts

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/07/27

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.

14 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 2018/07/27

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

Diagnostic accuracy of NUDT15 gene variants for thiopurine-induced leukopenia: a systematic review and meta-analysis.

Pharmacol Res. 2018 Jul 23;:

Authors: Cargnin S, Genazzani AA, Canonico PL, Terrazzino S

Abstract
We herein conducted a systematic review and meta-analysis of published studies to estimate diagnostic accuracy of NUDT15 gene polymorphisms for detection of thiopurine-induced leukopenia. Eligible studies were identified through a comprehensive search on PubMed, Web of Knowledge, Cochrane and OpenGrey datasets up to April 2018. The methodological quality of eligible studies was assessed using the QUADAS-2 criteria. The diagnostic odds ratio (DOR) was used as a single measure of diagnostic performance. Sixteen studies including a total of 3538 thiopurine-treated patients fulfilled inclusion criteria for the systematic review. Among these, 16 studies were available for the meta-analysis of rs116855232, 6 studies for rs186364861 and 5 studies for rs554405994 of NUDT15. A higher DOR was found for rs116855232 (8.44, 95% CI: 5.46-13.03), as compared to rs554405994 (4.336, 95% CI 2.924-6.429) or rs186364861 (2.742, 95% CI 1.453-5.175). Results of meta-regression analysis showed that incidence of leukopenia (relative DOR: 0.96; 95%CI: 0.93-1.00, p = 0.037) and leukopenia onset (late vs early leukopenia, relative DOR: 0.41, 95% CI 0.20-0.85, p = 0.0189) significantly influenced diagnostic accuracy of rs116855232. Subgroup analysis for rs186364861 and rs554405994 revealed a significant DOR for early-onset leukopenia (rs186364861: 4.04, 95% CI 1.78-9.20; rs554405994: 2.94, 95% CI 1.74-4.95), but not for late-onset leukopenia (rs186364861: 1.52, 95% CI 0.52-4.43; rs554405994: 2.02, 95% CI 0.93-4.40). The present meta-analysis points to rs116855232, rs554405994 and rs186364861 of NUDT15 as clinically relevant predictors of thiopurine-induced leukopenia. Nevertheless, prospective studies of genotype-guided dosing of thiopurines are warranted to prove clinical benefit and cost-effectiveness of pretreatment NUDT15 gene testing across different populations.

PMID: 30048756 [PubMed - as supplied by publisher]

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Cardiopulmonary, biomarkers, and vascular responses to acute hypoxia following cardiac transplantation.

Clin Transplant. 2018 Jul 26;:e13352

Authors: Sanz-de la Garza M, Iannino N, Finnerty V, Mansour A, Blondeau L, Gayda M, Chaar D, Sirois MG, Racine N, de Denus S, Harel F, White M

Abstract
Previous studies have suggested good adaptation of cardiac transplant (CTx) recipients to exposure to a high altitude. No studies have investigated the cardiopulmonary and biomarker responses to acute hypoxic challenges following CTx. Thirty-six CTx recipients and seventeen age-matched healthy controls (HC) were recruited. Sixteen (16) patients (42%) had cardiac allograft vasculopathy (CAV). Cardiopulmonary responses to maximal and submaximal exercise at 21% O2 , 20-min hypoxia (11.5% O2 ), and following a 10-minute exposure to 11.5% O2 using 30% of peak power output were completed. Vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), suppression of tumorigenicity 2 (ST2) were measured at baseline and at peak stress. Endothelial peripheral function was assessed using near-infrared spectroscopy. Compared with HC, CTx presented a lesser O2 desaturation both at rest (-19.4±6.8 [CTx] versus -24.2±6.0% O2 [HC], P<0.05) and following exercise (-23.2 ±4.9 [CTx] versus -26.2±4.7% O2 [HC], P<0.05). CTx patients exhibited a significant decrease in peak oxygen uptake. IL-6 and VEGF levels were significantly higher in CTx recipients in basal conditions but did not change in response to acute stress. CTx patients exhibit a favorable ventilatory and overall response to hypoxic stress. These data provide further insights on the good adaptability of CTx to exposure to high altitude. This article is protected by copyright. All rights reserved.

PMID: 30047602 [PubMed - as supplied by publisher]