Integrating Statistical Machine Learning in a Semantic Sensor Web for Proactive Monitoring and Control.

Sensors (Basel). 2017 Apr 09;17(4):

Authors: Adeleke JA, Moodley D, Rens G, Adewumi AO

Abstract
Proactive monitoring and control of our natural and built environments is important in various application scenarios. Semantic Sensor Web technologies have been well researched and used for environmental monitoring applications to expose sensor data for analysis in order to provide responsive actions in situations of interest. While these applications provide quick response to situations, to minimize their unwanted effects, research efforts are still necessary to provide techniques that can anticipate the future to support proactive control, such that unwanted situations can be averted altogether. This study integrates a statistical machine learning based predictive model in a Semantic Sensor Web using stream reasoning. The approach is evaluated in an indoor air quality monitoring case study. A sliding window approach that employs the Multilayer Perceptron model to predict short term PM 2 . 5 pollution situations is integrated into the proactive monitoring and control framework. Results show that the proposed approach can effectively predict short term PM 2 . 5 pollution situations: precision of up to 0.86 and sensitivity of up to 0.85 is achieved over half hour prediction horizons, making it possible for the system to warn occupants or even to autonomously avert the predicted pollution situations within the context of Semantic Sensor Web.

PMID: 28397776 [PubMed - in process]

Pharmacogenomics-Based Point-of-Care Clinical Decision Support Significantly Alters Drug Prescribing.

Clin Pharmacol Ther. 2017 Apr 11;:

Authors: O'Donnell PH, Wadhwa N, Danahey K, Borden BA, Lee SM, Hall JP, Klammer C, Hussain S, Siegler M, Sorrentino MJ, Davis AM, Sacro YA, Nanda R, Polonsky TS, Koyner JL, Burnet DL, Lipstreuer K, Rubin DT, Mulcahy C, Strek ME, Harper W, Cifu AS, Polite B, Patrick-Miller L, Yeo KJ, Leung EK, Volchenboum SL, Altman RB, Olopade OI, Stadler WM, Meltzer DO, Ratain MJ

Abstract
Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green/genomically favorable, yellow/genomic caution, red/high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint. 2279 outpatient encounters were analyzed. Independent of other potential prescribing mediators, medications with high pharmacogenomic risk were changed significantly more often than prescription drugs lacking pharmacogenomic information (odds ratio [OR]=26.2 [9.0-75.3], p<0.0001). Medications with cautionary pharmacogenomic information were also changed more frequently (OR=2.4 [1.7-3.5], p<0.0001). No pharmacogenomically high-risk medications were prescribed during the entire study when physicians consulted the CDS tool. Pharmacogenomic information improved prescribing in patterns aimed at reducing patient risk, demonstrating that enhanced prescription decision-making is achievable through clinical integration of genomic medicine. This article is protected by copyright. All rights reserved.

PMID: 28398598 [PubMed - as supplied by publisher]

SNP-based HLA allele tagging, imputation and association with antiepileptic drug-induced cutaneous reactions in Hong Kong Han Chinese.

Pharmacogenomics J. 2017 Apr 11;:

Authors: Gui H, Kwok M, Baum L, Sham PC, Kwan P, Cherny SS

Abstract
Human leukocyte antigen (HLA) genes control the regulation of the human immune system and are involved in immune-related diseases. Population surveys on relationships between single nucleotide polymorphisms (SNP) and HLA alleles are essential to conduct genetic association between HLA variants and diseases. Samples were obtained from our in-house database for epilepsy genetics and pharmacogenetics research. Using 184 epilepsy patients with both genome-wide SNP array and HLA-A/B candidate gene sequencing data, we sought tagging SNPs that completely represent sixHLA risk alleles; in addition, a Hong Kong population-specific reference panel was constructed for SNP-based HLA imputation. The performance of our new panel was compared to a recent Han Chinese panel. Finally, genetic associations of HLA variants with mild skin rash were performed on the combined sample of 408 patients. Common SNPs rs2571375 and rs144295468 were found to successfully tag HLA risk alleles A*31:01 and B*13:01, respectively. HLA-B*15:02 can be predicted by rs144012689 with >95% sensitivity and specificity. The imputation reference panel for the Hong Kong population had comparable performance to the Han Chinese panel due to the large sample size for common HLA alleles, though it retained discordance for imputing rare alleles. No significant genetic associations were found between HLA genetic variants and mild skin rash induced by aromatic antiepileptic drugs. This study provides new information on the genetic structure of HLA regions in the Hong Kong population by identifying tagging SNPs and serving as a reference panel. Moreover, our comprehensive genetic analyses revealed no significant association between HLA alleles and mild skin rash in Hong Kong Han Chinese.The Pharmacogenomics Journal advance online publication, 11 April 2017; doi:10.1038/tpj.2017.11.

PMID: 28398356 [PubMed - as supplied by publisher]

Prognostic impact of FOXF1 polymorphisms in gastric cancer patients.

Pharmacogenomics J. 2017 Apr 11;:

Authors: Matsusaka S, Wu AH, Cao S, Hanna DL, Chin K, Yang D, Zhang W, Ning Y, Stintzing S, Sebio A, Sunakawa Y, Stremitzer S, Yamauchi S, Okazaki S, Berger MD, Parekh A, Miyamoto Y, Mizunuma N, Lenz HJ

Abstract
A recent genome-wide association study identified seven single-nucleotide polymorphisms (SNPs) in region 16q24, near the Forkhead box-F1 (FOXF1) gene, which confer susceptibility to esophageal adenocarcinoma. We examined whether these SNPs are associated with clinical outcomes in gastric cancer (GC) patients in Japan and the United States. A total of 362 patients were included in this study: 151 Japanese GC patients treated with first-line S1 plus CDDP (training cohort) and 211 GC patients from Los Angeles County (LAC; validation cohort). Genomic DNA was isolated from whole blood or tumor tissue and analyzed by PCR-based direct DNA sequencing. Cox proportional hazard regression analyses were used to assess relationships between FOXF1 SNPs and progression-free survival (PFS) and overall survival (OS). FOXF1 rs3950627 was significantly associated with survival in both the training and validation cohorts. Japanese patients with the C/C genotype had a longer PFS (median 8.2 vs 5.3 months, hazard ratio (HR) 1.44, P=0.037) and OS (median 16.4 vs 12.2 months, HR 1.44, P=0.043) compared to patients with any A allele. Similarly, LAC patients with the C/C genotype had improved OS (3.9 vs 2.3 years, HR 1.5, P=0.022). Subgroup analyses showed these associations were specific to male patients and primary tumor subsite. Our findings suggest that FOXF1 rs3950627 might be a promising prognostic marker in GC patients.The Pharmacogenomics Journal advance online publication, 11 April 2017; doi:10.1038/tpj.2017.9.

PMID: 28398355 [PubMed - as supplied by publisher]

Global genetic variation of select opiate metabolism genes in self-reported healthy individuals.

Pharmacogenomics J. 2017 Apr 11;:

Authors: Wendt FR, Pathak G, Sajantila A, Chakraborty R, Budowle B

Abstract
CYP2D6 is a key pharmacogene encoding an enzyme impacting poor, intermediate, extensive and ultrarapid phase I metabolism of many marketed drugs. The pharmacogenetics of opiate drug metabolism is particularly interesting due to the relatively high incidence of addiction and overdose. Recently, trans-acting opiate metabolism and analgesic response enzymes (UGT2B7, ABCB1, OPRM1 and COMT) have been incorporated into pharmacogenetic studies to generate more comprehensive metabolic profiles of patients. With use of massively parallel sequencing, it is possible to identify additional polymorphisms that fine tune, or redefine, previous pharmacogenetic findings, which typically rely on targeted approaches. The 1000 Genomes Project data were analyzed to describe population genetic variation and statistics for these five genes in self-reported healthy individuals in five global super- and 26 sub-populations. Findings on the variation of these genes in various populations expand baseline understanding of pharmacogenetically relevant polymorphisms for future studies of affected cohorts.The Pharmacogenomics Journal advance online publication, 11 April 2017; doi:10.1038/tpj.2017.13.

PMID: 28398354 [PubMed - as supplied by publisher]

The CACNA1C risk allele rs1006737 is associated with age-related prefrontal cortical thinning in bipolar I disorder.

Transl Psychiatry. 2017 Apr 11;7(4):e1086

Authors: Soeiro-de-Souza MG, Lafer B, Moreno RA, Nery FG, Chile T, Chaim K, da Costa Leite C, Machado-Vieira R, Otaduy MC, Vallada H

Abstract
Calcium channels control the inflow of calcium ions into cells and are involved in diverse cellular functions. The CACNA1C gene polymorphism rs1006737 A allele has been strongly associated with increased risk for bipolar disorder (BD) and with modulation of brain morphology. The medial prefrontal cortex (mPFC) has been widely associated with mood regulation in BD, but the role of this CACNA1C polymorphism in mPFC morphology and brain aging has yet to be elucidated. One hundred seventeen euthymic BD type I subjects were genotyped for CACNA1C rs1006737 and underwent 3 T three-dimensional structural magnetic resonance imaging scans to determine cortical thickness of mPFC components (superior frontal cortex (sFC), medial orbitofrontal cortex (mOFC), caudal anterior cingulate cortex (cACC) and rostral anterior cingulate cortex (rACC)). Carriers of the CACNA1C allele A exhibited greater left mOFC thickness compared to non-carriers. Moreover, CACNA1C A carriers showed age-related cortical thinning of the left cACC, whereas among A non-carriers there was not an effect of age on left cACC cortical thinning. In the sFC, mOFC and rACC (left or right), a negative correlation was observed between age and cortical thickness, regardless of CACNA1C rs1006737 A status. Further studies investigating the direct link between cortical thickness, calcium channel function, apoptosis mechanism and their underlying relationship with aging-associated cognitive decline in BD are warranted.

PMID: 28398341 [PubMed - in process]

Testing Na(+) in blood.

Clin Kidney J. 2017 Apr;10(2):147-148

Authors: Lava SA, Bianchetti MG, Milani GP

Abstract
Both direct potentiometry and indirect potentiometry are currently used for Na(+) testing in blood. These measurement techniques show good agreement as long as protein and lipid concentrations in blood remain normal. In severely ill patients, indirect potentiometry commonly leads to relevant errors in Na(+) estimation: 25% of specimens show a disagreement between direct and indirect potentiometry, which is ≥4 mmol/L (mostly spuriously elevated Na(+) level due to low circulating albumin concentration). There is a need for increased awareness of the poor performance of indirect potentiometry in some clinical settings.

PMID: 28396732 [PubMed - in process]

What's new about oral treatments in Multiple Sclerosis? Immunogenetics still under question.

Pharmacol Res. 2017 Apr 07;:

Authors: Pistono C, Osera C, Boiocchi C, Mallucci G, Cuccia M, Bergamaschi R, Pascale A

Abstract
Multiple Sclerosis (MS) is a chronic pathology affecting the Central Nervous System characterized by inflammatory processes that lead to demyelination and neurodegeneration. In MS treatment, disease modifying therapies (DMTs) are essential to reduce disease progression by suppressing the inflammatory response responsible for promoting lesion formation. Recently, in addition to the classical injectable DMTs like Interferons and Glatiramer acetate, new orally administered drugs have been approved for MS therapy: dimethyl fumarate, teriflunomide and fingolimod. These drugs act with different mechanisms on the immune system, in order to suppress the harmful inflammatory process. An additional layer of complexity is introduced by the influence of polymorphic gene variants in the Human Leukocyte Antigen region on the risk of developing MS and its progression. To date, pharmacogenomic studies have mainly focused on the patient's response following admission of injectable drugs. Therefore, greater consideration must be made to pharmacogenomics with a view to developing more effective and personalized therapies. This review aims to shed light on the mechanism of action of the new oral drugs dimethyl fumarate, teriflunomide and fingolimod, taking into account both the importance of immunogenetics in drug response and pharmacogenomic studies.

PMID: 28396093 [PubMed - as supplied by publisher]

A multicenter phase II study of personalized FOLFIRI-cetuximab for safe dose intensification.

Semin Oncol. 2017 Feb;44(1):24-33

Authors: Boisdron-Celle M, Metges JP, Capitain O, Adenis A, Raoul JL, Lecomte T, Lam YH, Faroux R, Masliah C, Poirier AL, Berger V, Morel A, Gamelin E

Abstract
We conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-cetuximab regimens to explore individual drug tailoring using pharmacogenetics and pharmacokinetics (PK) monitoring. Patients were stratified by their pharmacogenetic/phenotypic status: the irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter, while the 5-fluorouracil (5-FU) dose was initially adjusted according to dihydropyrimidine dehydrogenase (DPD) activity at initial screening (5-FU(ODPM Tox)) followed by PK-guided dose optimization (5-FU(ODPM Protocol)). An advanced cetuximab PK/pharmacodynamics (PD) study was performed but dosage remained unchanged. Eighty-five patients receiving second-line chemotherapy were enrolled. Mean irinotecan doses at 3 months were 247 ± 50, 210 ± 53 and 140 ± 21 mg/m(2) for those with 6/6 (33), 6/7 (26), and 7/7 (7) TATA repeats in the UGT1A1 promoter region, respectively. The 5-FU dose was initially reduced in four patients with DPD deficiency, but mean 5-FU dose at 3 months was 2,412 ± 364 mg/m(2) (1,615-3,170 mg/m(2)). Grade 4 toxicities were not encountered and grade 4 neutropenia occurred in 6.8%, 5.9%, and 0% of patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes. The objective response rate was 25.8% among the 85 patients, 57.3% in patients with tumors wild type (WT) for KRAS, and 25% in those whose tumor harbored a mutant-KRAS. Secondary resection of hepatic metastases was performed in 31.7% of patients. Median progression-free survival (PFS) for all 85 patients was 181 days and 200, 132, and 121 days for patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes, respectively; these differences were not statistically different. In parallel, a strong relationship was shown between cetuximab AUC and regimen efficacy. We conclude that personalized drug tailoring when administering in FOLFIRI + cetuximab allows for safe and efficient individual dose intensification.

PMID: 28395759 [PubMed - in process]

Mucoactive agents for chronic, non-cystic fibrosis lung disease: A systematic review and meta-analysis.

Respirology. 2017 Apr 11;:

Authors: Tarrant BJ, Le Maitre C, Romero L, Steward R, Button BM, Thompson BR, Holland AE

Abstract
Inhaled mucoactive agents are used in respiratory disease to improve mucus properties and enhance secretion clearance. The effect of mannitol, recombinant human deoxyribonuclease/dornase alfa (rhDNase) and hypertonic saline (HS) or normal saline (NS) are not well described in chronic lung conditions other than cystic fibrosis (CF). The aim of this review was to determine the benefit and safety of inhaled mucoactive agents outside of CF. We searched Medline, Embase, CINAHL and CENTRAL for randomized controlled trials investigating the effects of mucoactive agents on lung function, adverse events (AEs), health-related quality of life (HRQOL), hospitalization, length of stay, exacerbations, sputum clearance and inflammation. There were detrimental effects of rhDNase in bronchiectasis, with average declines of 1.9-4.3% in forced expiratory volume in 1 s (FEV1 ) and 3.7-5.4% in forced vital capacity (FVC) (n = 410, two studies), and increased exacerbation risk (relative risk = 1.35, 95% CI = 1.01-1.79 n = 349, one study). Some participants exhibited a reduction in FEV1 (≥10-15%) with mucoactive agents on screening (mannitol = 158 of 1051 participants, rhDNase = 2 of 30, HS = 3 of 80). Most AEs were mild and transient, including bronchospasm, cough and breathlessness. NS eased symptomatic burden in COPD, while NS and HS improved spirometry, HRQOL and sputum burden in non-CF bronchiectasis. Mannitol improved mucociliary clearance in asthma and bronchiectasis, while the effects of N-acetylcysteine were unclear. In chronic lung diseases outside CF, there are small benefits of mannitol, NS and HS. Adverse effects of rhDNase suggest this should not be administered in non-CF bronchiectasis.

PMID: 28397992 [PubMed - as supplied by publisher]

Rifabutin Is Active Against Mycobacterium abscessus Complex.

Antimicrob Agents Chemother. 2017 Apr 10;:

Authors: Aziz DB, Low JL, Wu ML, Gengenbacher M, Teo JW, Dartois V, Dick T

Abstract
Lung infections with Mycobacterium abscessus are emerging as a global threat to individuals with cystic fibrosis and other patient groups. Recent evidence for human-to-human transmission worsens the situation. M. abscessus is an intrinsically multidrug resistant pathogen showing resistance even against standard anti tuberculosis drugs such as rifampicin. Here, our objective was to identify existing drugs that may be employed for the treatment of M. abscessus lung disease. A collection of more than 2700 approved drugs was screened at a single point concentration against an M. abscessus clinical isolate. Hits were confirmed with fresh solids in dose response experiments. For the most attractive hit, growth inhibition and bactericidal activities against reference strains of the three M. abscessus subspecies and a collection of clinical isolates were determined. Surprisingly, the rifampicin derivative rifabutin had an MIC of 3 ± 2 μM (3 μg/mL) against the screening strain, the reference strains M. abscessus subsp. abscessus ATCC 19977, M. abscessus subsp. bolletii CCUG 50184-T and M. abscesuss subsp. massiliense CCUG 48898-T, as well as a collection of clinical isolates. Furthermore, rifabutin was active against clarithromycin resistant strains. In conclusion, rifabutin - in contrast to rifampicin - is active against the Mycobacterium abscessus complex bacteria in vitro and may be considered for treatment of M. abscessus lung disease.

PMID: 28396540 [PubMed - as supplied by publisher]

Sotos syndrome associated with Hirschsprung's disease: A new case and exome sequencing analysis.

Pediatr Res. 2017 Apr 11;:

Authors: Sio CA, Jung K, Kim JH, Cheong HS, Shin E, Jang H, Yoon M, Jang H, Shin HD

Abstract
BACKGROUND: Sotos syndrome (SoS) is an overgrowth disorder with various congenital anomalies and is usually accompanied by other clinical problems. However, anorectal malformations have not been documented as part of the SoS entity. Our objective is to report on a case of SoS associated with Hirschsprung's disease (HSCR) and subsequent genetic analysis.
METHODS: A 2 year old male with SoS experienced constipation since infancy and ultimately showed an aganglionic segment in the histopathologic examination and was followed by exome sequencing analysis.
RESULTS: In the genetic test for SoS diagnosis, two novel mutations of NDS1, c.2465C>A (p.Ser822Tyr) and c.4347T>A (p.Cys1449*), were observed and verified by re-sequencing in the patient and his parents. In further whole exome sequencing analysis using the patient's blood DNA, which was followed by a comparison analysis with the result of our previously reported genome-wide association study (GWAS) of HSCR, three genes (ZNF827, FGD2, and KCNJ12) with significance for HSCR from our previous GWAS were overlapped among the genes showing variants in the exome sequencing.
CONCLUSION: This is the first reported patient with SoS and HSCR. Further studies are required to determine whether there is a genetic relationship between SoS and HSCR.Pediatric Research accepted article preview online, 11 April 2017. doi:10.1038/pr.2017.106.

PMID: 28399120 [PubMed - as supplied by publisher]

Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development.

Sci Rep. 2017 Apr 11;7:46175

Authors: Ferre-Fernández JJ, Aroca-Aguilar JD, Medina-Trillo C, Bonet-Fernández JM, Méndez-Hernández CD, Morales-Fernández L, Corton M, Cabañero-Valera MJ, Gut M, Tonda R, Ayuso C, Coca-Prados M, García-Feijoo J, Escribano J

Abstract
Congenital glaucoma (CG) is a heterogeneous, inherited and severe optical neuropathy that originates from maldevelopment of the anterior segment of the eye. To identify new disease genes, we performed whole-exome sequencing of 26 unrelated CG patients. In one patient we identified two rare, recessive and hypermorphic coding variants in GPATCH3, a gene of unidentified function, and 5% of a second group of 170 unrelated CG patients carried rare variants in this gene. The recombinant GPATCH3 protein activated in vitro the proximal promoter of CXCR4, a gene involved in embryo neural crest cell migration. The GPATCH3 protein was detected in human tissues relevant to glaucoma (e.g., ciliary body). This gene was expressed in the dermis, skeletal muscles, periocular mesenchymal-like cells and corneal endothelium of early zebrafish embryos. Morpholino-mediated knockdown and transient overexpression of gpatch3 led to varying degrees of goniodysgenesis and ocular and craniofacial abnormalities, recapitulating some of the features of zebrafish embryos deficient in the glaucoma-related genes pitx2 and foxc1. In conclusion, our data suggest the existence of high genetic heterogeneity in CG and provide evidence for the role of GPATCH3 in this disease. We also show that GPATCH3 is a new gene involved in ocular and craniofacial development.

PMID: 28397860 [PubMed - in process]

Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families.

Mol Psychiatry. 2017 Apr 11;:

Authors: Harripaul R, Vasli N, Mikhailov A, Rafiq MA, Mittal K, Windpassinger C, Sheikh TI, Noor A, Mahmood H, Downey S, Johnson M, Vleuten K, Bell L, Ilyas M, Khan FS, Khan V, Moradi M, Ayaz M, Naeem F, Heidari A, Ahmed I, Ghadami S, Agha Z, Zeinali S, Qamar R, Mozhdehipanah H, John P, Mir A, Ansar M, French L, Ayub M, Vincent JB

Abstract
Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.Molecular Psychiatry advance online publication, 11 April 2017; doi:10.1038/mp.2017.60.

PMID: 28397838 [PubMed - as supplied by publisher]

From molecular mechanisms to clinical management of antineoplastic drug-induced cardiovascular toxicity: A translational overview.

Antioxid Redox Signal. 2017 Apr 11;:

Authors: Tocchetti CG, Cadeddu C, Di Lisi D, Femminò S, Madonna R, Mele D, Monte I, Novo G, Penna C, Pepe A, Spallarossa P, Varricchi G, Zito C, Pagliaro P, Mercuro G

Abstract
SIGNIFICANCE: Antineoplastic therapies have improved the prognosis of oncology patients sig-nificantly. However, these treatments can bring to a higher incidence of side effects, including the worrying cardiovascular toxicity (CTX). Recent Advances: Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is therefore cru-cial for effective cardioprotection, without compromising the efficacy of anti-cancer treat-ments.
CRITICAL ISSUES: CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity.
FUTURE DIRECTIONS: Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients at high-risk of de-veloping chemotherapy-related CTX, and may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anti-cancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system.

PMID: 28398124 [PubMed - as supplied by publisher]

Ramucirumab in the treatment of non-small cell lung cancer.

Expert Opin Drug Saf. 2017 Apr 11;:

Authors: Oscar A, Zyanya Lucia ZB, Andres FC, Amir C, Mariana LM

Abstract
INTRODUCTION: Therapeutic options for treating Non-Small Cell Lung Cancer (NSCLC) have recently increased. Ramucirumab (Cyramza), an anti-angionenic agent was approved in 2014 for treatment of several malignancies, including second-line treatment of patients with NSCLC with disease progression on or after platinum-based chemotherapy. Areas covered: We performed a comprehensive search of the literature focused on clinical trials with use of ramucirumab, targeting its evolution in the treatment of NSCLC. This review summarizes the results regarding its safety and efficacy. Expert opinion: Angiogenesis has been widely recognized as a quintessential feature in cancer, intrinsically mediating tumor survival and progression. Ramucirumab, an anti-VEGFR2 agent, combined with docetaxel, was FDA-approved for NSCLC patients. Results from a phase III trial have demonstrated the usefulness of this combination, with benefits in progression free survival and overall survival for NSCLC patients. A greater magnitude of benefit is seen in patients with aggressive tumor behavior. Treatment with ramucirumab is generally tolerable, however, there is potential for severe toxicity. Adverse events reported with this combination include neutropenia, febrile neutropenia and hypertension. Also, there is the intrinsic risk of bleeding resulting from the mechanism of action. As such, adverse events should be identified timely, so drug-related complications can be prevented.

PMID: 28395526 [PubMed - as supplied by publisher]

Drug-Induced Liver Injury.

AACN Adv Crit Care. 2016 Oct;27(4):430-440

Authors: Hamilton LA, Collins-Yoder A, Collins RE

Abstract
Drug-induced liver injury (DILI) can result from both idiosyncratic and intrinsic mechanisms. This article discusses the clinical impact of DILI from a broad range of medications as well as herbal and dietary supplements. Risk factors for idiosyncratic DILI (IDILI) are the result of multiple host, environmental, and compound factors. Some triggers of IDILI often seen in critical care include antibiotics, antiepileptic medications, statins, novel anticoagulants, proton pump inhibitors, inhaled anesthetics, nonsteroidal anti-inflammatory agents, methotrexate, sulfasalazine, and azathioprine. The mechanism of IDILI due to these medications varies, and the resulting damage can be cholestatic, hepatocellular, or mixed. The primary treatment of IDILI is to discontinue the causative agent. DILI due to acetaminophen is intrinsic because the liver damage is predictably aligned with the dose ingested. Acute acetaminophen ingestion can be treated with activated charcoal or N-acetylcysteine. Future areas of research include identification of mitochondrial stress biomarkers and of the patients at highest risk for DILI.

PMID: 27959299 [PubMed - indexed for MEDLINE]

Intravenous Lipid Emulsion for Management of Systemic Toxic Effects of Drugs.

AACN Adv Crit Care. 2016 Oct;27(4):394-404

Authors: O'Connor J, Wilson SS

Abstract
The incidence of toxic effects of drugs leading to emergency department visits has increased in the United States in the past several years. Most of these patients can be adequately managed by supportive care alone. However, pharmacological antidotes may be necessary, particularly in patients with hemodynamic instability. In severe cases refractory to conventional antidote therapy, rescue therapy with intravenous lipid emulsion (ILE) may be necessary. Traditionally, ILE has been used as an antidote of choice in treating toxic effects of local anesthetics. But data continue to emerge on the successful use of ILE to treat overdoses of drugs other than local anesthetics, particularly lipophilic medications. The recommended ILE dose is a 1.5 mL/kg bolus followed by infusion of 15 mL/kg per hour, with repeat dosing permissible for continued hemodynamic instability. Use of ILE should be considered early as a rescue therapy in the settings of lipophilic medication overdoses when cardiovascular compromise or cardiac arrest is present.

PMID: 27959295 [PubMed - indexed for MEDLINE]

Patient information could be misleading.

Nurs Stand. 2016 Jul 06;30(45):17

Authors:

Abstract
Researchers in Germany have called for more careful reporting of side effects in clinical trials after a study revealed no clear links between medicines that are labelled as sleep disturbing and problems sleeping.

PMID: 27380677 [PubMed - indexed for MEDLINE]

Challenges and strategies of medication adherence in Parkinson's disease: A qualitative study.

Geriatr Nurs. 2015 May-Jun;36(3):192-6

Authors: Shin JY, Habermann B, Pretzer-Aboff I

Abstract
Little is known about strategies used by people with Parkinson's disease (PD) to facilitate medication adherence in the U.S. The purpose of this study was to describe challenges in adherence to medication regimens and to identify strategies used to facilitate adherence to medication regimens. A qualitative research design was used to interview sixteen community-dwelling people with PD and five caregivers. Data analysis was performed using content analysis. The majority of the participants (81.3%) reported decreased adherence to medication regimens. Seven themes emerged from the data. The main challenges of medication adherence included medication responses, cost of medications, and forgetfulness. Strategies used to facilitate adherence to medication regimens included seeking knowledge about antiparkinsonian medications, seeking advice from family and friends, use of devices, and use of reminders. These findings may be important in formulating interventions to improve adherence to medication regimens for people living with PD.

PMID: 25728485 [PubMed - indexed for MEDLINE]