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Acute Lidocaine Toxicity; a Case Series.

Emerg (Tehran). 2018;6(1):e38

Authors: Rahimi M, Elmi M, Hassanian-Moghaddam H, Zamani N, Soltaninejad K, Forouzanfar R, Shadnia S

Abstract
Introduction: Parenteral form of lidocaine is the best-known source of lidocaine poisoning. This study aimed to evaluate the characteristics of acute lidocaine toxicity .
Methods: In this retrospective cross-sectional study, demographics, clinical presentation, laboratory findings, and outcome of patients intoxicated with lidocaine (based on ICD10 codes) admitted to Loghman Hakim Hospital, during April 2007 to March 2014 were analyzed.
Results: 30 cases with the mean age of 21.83 ± 6.57 year were studied (60% male). All subjects had used either 6.5% lidocaine spray or 2% topical formulations of lidocaine. The mean consumed dose of lidocaine was 465 ± 318.17 milligrams. The most frequent clinical presentations were nausea and vomiting (50%), seizure (33.3%), and loss of consciousness (16.7%). 22 (73.3%) cases had normal sinus rhythm, 4 (13.3%) bradycardia, 2 (6.7%) ventricular tachycardia, and 2 (6.7%) had left axis deviation. 11 (36.6%) cases were intubated and admitted to intensive care unit (ICU) for 6.91 ± 7.16 days. Three patients experienced status epilepticus that led to cardiac arrest, and death (all cases with suicidal intention).
Conclusion: Based on the results of this study, most cases of topical lidocaine toxicity were among < 40-year-old patients with a male to female ratio of 1.2, with suicidal attempt in 90%, need for intensive care in 36.6%, and mortality rate of 10%.

PMID: 30009240 [PubMed]

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Evaluation of preventable adverse drug reactions by implementation of the nationwide network of prospective drug utilization review program in Korea.

PLoS One. 2018;13(4):e0195434

Authors: Lee J, Noh Y, Lee S

Abstract
BACKGROUND: A prospective Drug Utilization Review (DUR) program has been implemented in Korea to improve the quality and safety of medication use.
OBJECTIVE: To evaluate the influence of the DUR program in reducing incidence of preventable adverse drug reactions (pADRs).
METHODS: This study was performed using administrative data from the Health Insurance Review and Assessment Service (HIRA). The claims data for all adult patients with adverse drug events (ADE)-related diagnoses from 2009 to 2014 were obtained. Incidence rates of first-time and repeat pADRs prior to and after DUR program implementation were evaluated. Quarterly trends in incidence rates of overall ADE, allergic reactions, and ADRs were analyzed.
RESULTS: Data extraction covering the period from 2009 to 2014 led to the identification of 3,927,662 records. First-time pADR rates decreased gradually after implementation of the DUR program (change in slope: -0.016, p = 0.02). The program had a similar influence on repeat pADR rates (change in slope: -0.006, p≤0.01). The program did not decrease rates of first-time or repeat allergic reactions (change in slope: 0.018, p = 0.07 and 0.003, p = 0.04, respectively). In the cohort aged ≤65 years, first-time pADR rate reduction was significant (28.2% [27.1-29.3] in ≤18 years, and 19.8% [18.1-21.5] in 19-64 years). In contrast, first-time pADR rate was increased by 0.6% [-0.7-1.9] in patients ≥65 years.
CONCLUSION: Implementation of the prospective DUR program effectively reduced the number of pADRs. In the future, to reduce non-preventable ADRs such as allergic reactions, provision of clinical information including allergy history should be added to the DUR program.

PMID: 29641617 [PubMed - indexed for MEDLINE]

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Drug-related problems and changes in drug utilization after medication reviews in nursing homes in Oslo, Norway.

Scand J Prim Health Care. 2017 Dec;35(4):329-335

Authors: Fog AF, Kvalvaag G, Engedal K, Straand J

Abstract
OBJECTIVE: We describe the drug-related problems (DRPs) identified during medication reviews (MRs) and the changes in drug utilization after MRs at nursing homes in Oslo, Norway. We explored predictors for the observed changes.
DESIGN: Observational before-after study.
SETTING: Forty-one nursing homes.
INTERVENTION: MRs performed by multidisciplinary teams during November 2011 to February 2014.
SUBJECTS: In all, 2465 long-term care patients.
MAIN OUTCOME MEASURES: DRPs identified by explicit criteria (STOPP/START and NORGEP) and drug-drug interaction database; interventions to resolve DRPs; drug use changes after MR.
RESULTS: A total of 6158 DRPs were identified, an average of 2.6 DRPs/patient, 2.0 for regular and 0.6 for pro re nata (prn) drugs. Of these patients, 17.3% had no DRPs. The remaining 82.7% of the patients had on average 3.0 DRPs/patient. Use of unnecessary drugs (43.5%), excess dosing (12.5%) and lack of monitoring of the drug use (11%) were the most frequent DRPs. Opioids and psychotropic drugs were involved in 34.4% of all DRPs. The mean number of drugs decreased after the MR from 6.8 to 6.3 for regular drugs and from 3.0 to 2.6 for prn drugs. Patients with DRPs experienced a decrease of 1.1 drugs after MR (0.5 for regular and 0.6 for prn drugs). The reduction was most pronounced for the regular use of antipsychotics, antidepressants, hypnotics/sedatives, diuretics, antithrombotic agents, antacid drugs; and for prn use of anxiolytics, opioids, hypnotics/sedatives, metoclopramide and NSAIDs.
CONCLUSION: The medication review resulted in less drug use, especially opioids and psychotropic drugs.

PMID: 29096573 [PubMed - indexed for MEDLINE]

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Drug-, herb- and dietary supplement-induced liver injury.

Arch Argent Pediatr. 2017 Dec 01;115(6):e397-e403

Authors: Cavalieri ML, D'Agostino D

Abstract
Drug- and substance-induced liver injury accounts for approximately 20% of pediatric cases of acute liver failure. It is caused by two mechanisms: direct and idiosyncratic hepatotoxicity. Direct hepatotoxicity is the result of the administration of a drug with intrinsic toxicity and is dose-dependent (e.g., acetaminophen). Idiosyncratic hepatotoxicity is unpredictable, uncommon, variable in presentation, and doseindependent. The clinical, histological, and laboratory manifestations include hepatitis, which is generally asymptomatic but with a significant increase of liver enzymes; cholestasis, accompanied with jaundice, pruritus, prominent elevation of alkaline phosphatase, and mild elevation of aminotransferases; or mixed, with elements of both hepatitis and cholestasis. Time to recovery is variable, depending on the type of liver injury. Early detection and discontinuation of the causative drug is the most effective and important step for the fast resolution of histological and clinical changes, thus reducing severe liver injury.

PMID: 29087122 [PubMed - indexed for MEDLINE]

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Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

Ann Oncol. 2017 Jul 01;28(suppl_4):iv119-iv142

Authors: Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K, ESMO Guidelines Committee

PMID: 28881921 [PubMed - indexed for MEDLINE]

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Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines.

Ann Oncol. 2017 Jul 01;28(suppl_4):iv100-iv118

Authors: Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K, ESMO Guidelines Committee

PMID: 28881914 [PubMed - indexed for MEDLINE]

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Predictors on admission of functional decline among older patients hospitalised for acute care: A prospective observational study.

Australas J Ageing. 2017 Dec;36(4):E57-E63

Authors: Basic D, Ní Chróinín D, Conforti D, Shanley C

Abstract
OBJECTIVE: We sought to investigate the incidence of, and factors associated with, in-hospital functional decline among older acute hospital patients.
METHODS: We conducted a prospective observational study of consecutive patients admitted under geriatric medicine over 5 years. The primary outcome measure was functional decline between admission and discharge, representing deterioration in any of the following: Modified Barthel Index (MBI), independence in Timed Up and Go test or walking, and/or need for walking aid.
RESULTS: Overall, 56% (950/1693) patients (mean age 81.9 years) exhibited in-hospital functional decline. Premorbid MBI (odds ratio (OR) 1.05 per unit increase, P < 0.001), adverse drug reaction (OR 1.50, P = 0.001) and in-hospital consultation as the referral source (OR 1.57, P = 0.001) were independently associated with functional decline, adjusting for age, dementia and nursing home residence.
CONCLUSION: These factors may aid identification of vulnerable patients who might particularly benefit from targeted multidisciplinary intervention. Further studies validating this, and exploring the impact of focussed management, are needed.

PMID: 28856791 [PubMed - indexed for MEDLINE]

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The Interplay between Pharmacokinetics and Pharmacodynamics.

Pediatr Rev. 2017 May;38(5):195-206

Authors: Sandritter TL, McLaughlin M, Artman M, Lowry J

PMID: 28461611 [PubMed - indexed for MEDLINE]

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Common and Rare Ocular Side-effects of the Dexamethasone Implant.

Ocul Immunol Inflamm. 2017 Dec;25(6):834-840

Authors: Fassbender Adeniran JM, Jusufbegovic D, Schaal S

Abstract
PURPOSE: Expanding indications for use, and overall increased use of the slow-release dexamethasone (DEX) implant yields an opportunity to study the reported ocular side-effects and adverse events associated with this drug.
METHODS: A PubMed.gov (US National Library of Medicine, National Institutes of Health) review of literature for the search terms, "Ozurdex and complication," through December 2015.
RESULTS: Ocular hypertension and cataract are the main long-term sequelae identified in large, randomized clinical trials. Case reports have emerged regarding implant migration, complications with implantation, infection, and posterior segment sequelae, including vitreomacular traction.
CONCLUSION: DEX implant overall is well-tolerated and, with careful monitoring, can be a useful adjunct to treating macular edema associated with diabetes, retinal vein occlusion, and chronic uveitis.

PMID: 27379861 [PubMed - indexed for MEDLINE]

Funding Opportunity RFA-MH-19-147 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) solicits applications to develop informatics tools for analyzing, visualizing, and integrating data related to the BRAIN Initiative or to enhance our understanding of the brain.

Funding Opportunity RFA-MH-19-145 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) solicits applications to develop web-accessible data archives to capture, store, and curate data related to BRAIN Initiative activities. The data archives will work with the research community to incorporate tools that allow users to analyze and visualize the data, but the creation of such tools is not part of this FOA. The data archives will use appropriate standards to describe the data, but the creation of such standards is not part of this FOA. A goal of this program is to advance research by creating a community resource data archive with appropriate standards and summary information that is broadly available and accessible to the research community for furthering research.

Funding Opportunity RFA-MH-19-146 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) solicits applications to develop standards that describe experimental protocols that are being conducted as part of the BRAIN Initiative.It is expected that applications will solicit community input at all stages of the process. It is recommended that the first step of standard development will involve sharing data between different key groups in the experimental community in order to ensure that the developing standard will cover the way that all of those groups are collecting data. The developed standard is expected to be made widely available.

Funding Opportunity PAR-18-857 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages innovative research to enhance the quality of measurements of dietary intake and physical activity. Applications submitted to this FOA may include development of: novel assessment approaches; better methods to evaluate instruments; assessment tools for culturally diverse populations or various age groups, including children and older adults; improved technology or applications of existing technology; statistical methods/modeling to improve assessment and/or to correct for measurement errors or biases; methods to investigate the multidimensionality of diet and physical activity behavior through pattern analysis; or integrated measurement of diet and physical activity along with the environmental context of such behaviors.

Funding Opportunity PA-18-856 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages innovative research to enhance the quality of measurements of dietary intake and physical activity. Applications submitted to this FOA may include development of: novel assessment approaches; better methods to evaluate instruments; assessment tools for culturally diverse populations or various age groups, including children and older adults; improved technology or applications of existing technology; statistical methods/modeling to improve assessment and/or to correct for measurement errors or biases; methods to investigate the multidimensionality of diet and physical activity behavior through pattern analysis; or integrated measurement of diet and physical activity along with the environmental context of such behaviors.

Notice NOT-DA-18-018 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-210 from the NIH Guide for Grants and Contracts

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Pluripotent Stem Cell Platforms for Drug Discovery.

Trends Mol Med. 2018 Jul 10;:

Authors: Chen KG, Mallon BS, Park K, Robey PG, McKay RDG, Gottesman MM, Zheng W

Abstract
Use of human pluripotent stem cells (hPSCs) and their differentiated derivatives have led to recent proof-of-principle drug discoveries, defining a pathway to the implementation of hPSC-based drug discovery (hPDD). Current hPDD strategies, however, have inevitable conceptual biases and technological limitations, including the dimensionality of cell-culture methods, cell maturity and functionality, experimental variability, and data reproducibility. In this review, we dissect representative hPDD systems via analysis of hPSC-based 2D-monolayers, 3D culture, and organoids. We discuss mechanisms of drug discovery and drug repurposing, and roles of membrane drug transporters in tissue maturation and hPDD using the example of drugs that target various mutations of CFTR, the cystic fibrosis transmembrane conductance regulator gene, in patients with cystic fibrosis.

PMID: 30006147 [PubMed - as supplied by publisher]

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GATA3 as a master regulator and therapeutic target in ovarian high-grade serous carcinoma stem cells.

Int J Cancer. 2018 Jul 14;:

Authors: Chen HJ, Huang RL, Liew PL, Su PH, Chen LY, Weng YC, Chang CC, Wang YC, Chan MW, Lai HC

Abstract
Ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy. Prevailing evidences suggest that drug resistance and recurrence of ovarian HGSC are caused by the presence of cancer stem cells. Therefore, targeting cancer stems is appealing, however, all attempts to date, have failed. To circumvent this limit, we analyzed differential transcriptomes at early differentiation of ovarian HGSC stem cells and identified the developmental transcription factor GATA3 as highly expressed in stem, compared to progenitor cells. GATA3 expression associates with poor prognosis of ovarian HGSC patients, and was found to recruit the histone H3, lysine 27 (H3K27) demethylase, UTX, activate stemness markers, and promote stem-like phenotypes in ovarian HGSC cell lines. Targeting UTX by its inhibitor, GSKJ4, impeded GATA3-driven stemness phenotypes, and enhanced apoptosis of GATA3-expressing cancer cells. Combinations of gemcitabine or paclitaxel with GSKJ4, resulted in a synergistic cytotoxic effect. Our findings provide evidence for a new role for GATA3 in ovarian HGSC stemness, and demonstrate that GATA3 may serve as a biomarker for precision epigenetic therapy in the future. This article is protected by copyright. All rights reserved.

PMID: 30006927 [PubMed - as supplied by publisher]

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ACGH detects distinct genomic alterations of primary intrahepatic cholangiocarcinomas and matched lymph node metastases and identifies a poor prognosis subclass.

Sci Rep. 2018 Jul 13;8(1):10637

Authors: Jansen R, Moehlendick B, Bartenhagen C, Tóth C, Lehwald N, Stoecklein NH, Knoefel WT, Lachenmayer A

Abstract
Lymph node metastases (LNM) are an important prognostic factor for patients with intrahepatic cholangiocarcinoma, but underlying genetic alterations are poorly understood. Whole genome array comparative genomic hybridization (aCGH) was performed in 37 tumors and 14 matched LNM. Genomic analyses of tumors confirmed known and identified new (gains in 19q) copy number alterations (CNA). Tumors with LNM (N1) had more alterations and exclusive gains (3p, 4q, 5p, 13q) and losses (17p and 20p). LNM shared most alterations with their matched tumors (86%), but 79% acquired new isolated gains [12q14 (36%); 1p13, 2p23, 7p22, 7q11, 11q12, 13q13 and 14q12 (>20%)]. Unsupervised clustering revealed a poor prognosis subclass with increased alterations significantly associated to tumor differentiation and survival. TP53 and KRAS mutations occurred in 19% of tumors and 6% of metastases. Pathway analyses revealed association to cancer-associated pathways. Advanced tumor stage, microvascular/perineural invasion, and microscopic positive resection margin (R1) were significantly correlated to metastases, while N1-status, R1-resection, and poor tumor differentiation were significantly correlated to survival. ACGH identified clear differences between N0 (no LNM) and N1 tumors, while N1 tumors and matched LNM displayed high clonality with exclusive gains in the metastases. A novel subclass with increased CNAs and poor tumor differentiation was significantly correlated to survival.

PMID: 30006612 [PubMed - in process]

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Correcting the F508del-CFTR variant by modulating eukaryotic translation initiation factor 3-mediated translation initiation.

J Biol Chem. 2018 Jul 13;:

Authors: Hutt DM, Loguercio S, Roth DM, Su AI, Balch WE

Abstract
Inherited and somatic rare diseases result from > 200,000 genetic variants leading to loss- or gain-of-toxic function, often caused by protein misfolding. Many of these misfolded variants fail to properly interact with other proteins. Understanding the link between factors mediating the transcription, translation, and protein folding of these disease-associated variants remains a major challenge in cell biology. Herein, we utilized the cystic fibrosis transmembrane conductance regulator (CFTR) protein as a model and performed a proteomics-based high-throughput screen (HTS) to identify pathways and components affecting the folding and function of the most common cystic fibrosis-associated mutation, the F508del variant of CFTR. Using a shortest-path algorithm we developed, we mapped HTS hits to the CFTR interactome to provide functional context to the targets and identified the eukaryotic translation initiation factor 3a (eIF3a) as a central hub for the biogenesis of CFTR. Of note, siRNA-mediated silencing of eIF3a reduced the polysome-to-monosome ratio in F508del-expressing cells, which, in turn, decreased the translation of CFTR variants, leading to increased CFTR stability, trafficking, and function at the cell surface. This finding suggested that eIF3a is involved in mediating the impact of genetic variations in CFTR on the folding of this protein. We posit that the number of ribosomes on a CFTR mRNA transcript is inversely correlated with the stability of the translated polypeptide. Polysome-based translation challenges the capacity of the proteostasis environment to balance message fidelity with protein folding, leading to disease. We suggest that this deficit can be corrected through control of translation initiation.

PMID: 30006345 [PubMed - as supplied by publisher]