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Adverse outcome pathway

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https://www.readbyqxmd.com/read/28434116/activation-of-the-serotonin-pathway-is-associated-with-poor-outcome-in-copd-exacerbation-results-of-a-long-term-cohort-study
#1
Marc A Meier, Manuel Ottiger, Alaadin Vögeli, Christian Steuer, Luca Bernasconi, Robert Thomann, Mirjam Christ-Crain, Christoph Henzen, Claus Hoess, Werner Zimmerli, Andreas Huber, Beat Mueller, Philipp Schuetz
BACKGROUND/INTRODUCTION: Indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine. An increase of its activity is associated with severity in patients with pneumonia. In chronic obstructive pulmonary disease (COPD) patients, an elevation of serotonin has been reported. Experimental models showed that cigarette smoke inhibits monoamine oxidase (MAO) leading to higher levels of serotonin. We investigated the prognostic ability of tryptophan, serotonin, kynurenine, IDO, and tryptophan hydroxylase (TPH) to predict short- and long-term outcomes in patients with a COPD exacerbation...
April 22, 2017: Lung
https://www.readbyqxmd.com/read/28427482/a-genetic-variant-brain-dervied-neurotrophic-factor-bdnf-polymorphism-interacts-with-hostile-parenting-to-predict-error-related-brain-activity-and-thereby-risk-for-internalizing-disorders-in-children
#2
Alexandria Meyer, Greg Hajcak, Elizabeth Hayden, Haroon I Sheikh, Shiva M Singh, Daniel N Klein
The error-related negativity (ERN) is a negative deflection in the event-related potential occurring when individuals make mistakes, and is increased in children with internalizing psychopathology. We recently found that harsh parenting predicts a larger ERN in children, and recent work has suggested that variation in the brain-derived neurotrophic factor (BDNF) gene may moderate the impact of early life adversity. Parents and children completed measures of parenting when children were 3 years old (N = 201); 3 years later, the ERN was measured and diagnostic interviews as well as dimensional symptom measures were completed...
April 21, 2017: Development and Psychopathology
https://www.readbyqxmd.com/read/28427158/the-varied-distribution-and-impact-of-ras-codon-and-other-key-dna-alterations-across-the-translocation-cyclin-d-subgroups-in-multiple-myeloma
#3
Caleb K Stein, Charlotte Pawlyn, Shweta Chavan, Leo Rasche, Niels Weinhold, Adam Corken, Amy Buros, Pieter Sonneveld, Graham H Jackson, Ola Landgren, Tariq Mughal, Jie He, Bart Barlogie, P Leif Bergsagel, Faith E Davies, Brian A Walker, Gareth J Morgan
We examined a set of 805 cases that underwent DNA sequencing using the FoundationOne Heme (F1H) targeted sequencing panel and gene expression profiling. Known and likely variant calls from the mutational data were analyzed for significant associations with gene expression defined translocation cyclin D (TC) molecular subgroups. The spectrum of KRAS, NRAS, and BRAF codon mutations varied across subgroups with NRAS mutations at Q61 codon being common in hyperdiploid (HRD) and t(11;14) myeloma while being rare in MMSET and MAF...
February 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28424891/a-phase-i-dose-escalation-study-of-selumetinib-in-combination-with-erlotinib-or-temsirolimus-in-patients-with-advanced-solid-tumors
#4
Jeffrey R Infante, Roger B Cohen, Kevin B Kim, Howard A Burris, Gregory Curt, Ugochi Emeribe, Delyth Clemett, Helen K Tomkinson, Patricia M LoRusso
Background Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors...
April 19, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28424801/problem-based-review-immune-mediated-complications-of-checkpoint-inhibitors-for-the-acute-physician
#5
Philip Webb, Terry W Rice, Tim Cooksley
Immunotherapy with 'checkpoint-inhibitors' has significantly improved outcomes for patients with a range of malignancies. However, significant immune-mediated toxicities of these therapies are well-described. These immune-mediated toxicities can affect virtually all organ systems and are potentially fatal. The timing of onset of the adverse effects is dependent on the organ system affected and can occur after completion of the treatment. The increasing utilisation of 'checkpoint-inhibitors' means that Acute Physicians are likely to see a number of immune-mediated complications presenting to the AMU...
2017: Acute Medicine
https://www.readbyqxmd.com/read/28423913/application-of-iata-a-case-study-in-evaluating-the-global-and-local-performance-of-a-bayesian-network-model-for-skin-sensitization
#6
J M Fitzpatrick, G Patlewicz
The information characterizing key events in an Adverse Outcome Pathway (AOP) can be generated from in silico, in chemico, in vitro and in vivo approaches. Integration of this information and interpretation for decision making are known as integrated approaches to testing and assessment (IATA). One such IATA was published by Jaworska et al., which describes a Bayesian network model known as ITS-2. The current work evaluated the performance of ITS-2 using a stratified cross-validation approach. We also characterized the impact of replacing the most significant component of the network, output from the expert system TIMES-SS, with structural alert information from the OECD Toolbox and Toxtree...
April 20, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28421173/cerebral-autoregulation-brain-injury-and-the-transitioning-premature-infant
#7
REVIEW
Zachary A Vesoulis, Amit M Mathur
Improvements in clinical management of the preterm infant have reduced the rates of the two most common forms of brain injury, such as severe intraventricular hemorrhage and white matter injury, both of which are contributory factors in the development of cerebral palsy. Nonetheless, they remain a persistent challenge and are associated with a significant increase in the risk of adverse neurodevelopment outcomes. Repeated episodes of ischemia-reperfusion represent a common pathway for both forms of injury, arising from discordance between systemic blood flow and the innate regulation of cerebral blood flow in the germinal matrix and periventricular white matter...
2017: Frontiers in Pediatrics
https://www.readbyqxmd.com/read/28419428/platelets-much-more-than-bricks-in-a-breached-wall
#8
REVIEW
Maria Elisa Mancuso, Elena Santagostino
Platelets have various roles in vascular biology and homeostasis. They are the first actor in primary haemostasis and play important roles in thrombosis pathogenesis, but they are also part of innate immunity, which initiates and accelerate many inflammatory conditions. In some contexts, their immune functions are protective, while in others they contribute to adverse inflammatory outcomes. Platelets express numerous receptors and contain hundreds of secretory molecules that are crucial for platelet functional responses...
April 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28416457/mono-2-ethylhexyl-phthalate-inhibits-human-extravillous-trophoblast-invasion-via-the-ppar%C3%AE-pathway
#9
Fumei Gao, Wenxin Hu, Yu Li, Huan Shen, Jianying Hu
Concerns over the adverse reproductive outcomes in human have been raised, more evidence including the underlying mechanism are required. Since extravillous trophoblast (EVT) invasion is an important physiological step during early development, the effects of mono-2-ethylhexyl phthalate (MEHP), the bioactive metabolite of DEHP, on EVT invasion were investigated using Matrigel-coated transwell chambers and cell line HTR-8/SVneo. In the transwell-based invasive assay, MEHP exposure inhibited EVT invasion as judged by decreased invasion index...
April 14, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28414088/embryonic-vascular-disruption-adverse-outcomes-linking-high-throughput-signaling-signatures-with-functional-consequences
#10
Robert G Ellis-Hutchings, Raja S Settivari, Alene T McCoy, Nicole Kleinstreuer, Jill Franzosa, Thomas B Knudsen, Edward W Carney
Embryonic vascular disruption is an important adverse outcome pathway (AOP) as chemical disruption of cardiovascular development induces broad prenatal defects. High-throughput screening (HTS) assays aid AOP development although linking in vitro data to in vivo apical endpoints remains challenging. This study evaluated two anti-angiogenic agents, 5HPP-33 and TNP-470, across the ToxCastDB HTS assay platform and anchored the results to complex in vitro functional assays: the rat aortic explant assay (AEA), rat whole embryo culture (WEC), and the zebrafish embryotoxicity (ZET) assay...
April 13, 2017: Reproductive Toxicology
https://www.readbyqxmd.com/read/28413140/is-day-of-surgery-associated-with-adverse-clinical-and-economic-outcomes-following-primary-total-knee-arthroplasty
#11
Matthew R Boylan, Dean C Perfetti, Qais Naziri, Aditya V Maheshwari, Carl B Paulino, Michael A Mont
BACKGROUND: As orthopedics transition to value-based purchasing, hospitals and providers are incentivized to identify inefficiencies of care delivery. In our experience, weekends are characterized by decreased staffing of ancillary services to coordinate patient discharges, which can lead to prolonged hospital stays for many of our primary total knee arthroplasty (TKA) admissions. METHODS: We identified 115,053 patients who underwent primary TKA on a weekday between 2009 and 2013 in New York State...
March 22, 2017: Journal of Arthroplasty
https://www.readbyqxmd.com/read/28412943/generic-care-pathway-for-elderly-patients-in-need-of-home-care-services-after-discharge-from-hospital-a-cluster-randomised-controlled-trial
#12
Tove Røsstad, Øyvind Salvesen, Aslak Steinsbekk, Anders Grimsmo, Olav Sletvold, Helge Garåsen
BACKGROUND: Improved discharge arrangements and targeted post-discharge follow-up can reduce the risk of adverse events after hospital discharge for elderly patients. Although more care is to shift from specialist to primary care, there are few studies on post-discharge interventions run by primary care. A generic care pathway, Patient Trajectory for Home-dwelling elders (PaTH) including discharge arrangements and follow-up by primary care, was developed and introduced in Central Norway Region in 2009, applying checklists at defined stages in the patient trajectory...
April 17, 2017: BMC Health Services Research
https://www.readbyqxmd.com/read/28412168/facilitating-translational-nanomedicine-via-predictive-safety-assessment
#13
REVIEW
Vahid Mirshafiee, Wen Jiang, Bingbing Sun, Xiang Wang, Tian Xia
Extensive research on engineered nanomaterials (ENMs) has led to the development of numerous nano-based formulations for theranostic purposes. Although some nano-based drug delivery systems already exist on the market, growing numbers of newly designed ENMs exhibit improved physicochemical properties and are being assessed in preclinical stages. While these ENMs are designed to improve the efficacy of current nano-based therapeutic or imaging systems, it is necessary to thoroughly determine their safety profiles for successful clinical applications...
April 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28411872/induction-therapy-with-the-selective-interleukin-23-inhibitor-risankizumab-in-patients-with-moderate-to-severe-crohn-s-disease-a-randomised-double-blind-placebo-controlled-phase-2-study
#14
Brian G Feagan, William J Sandborn, Geert D'Haens, Julián Panés, Arthur Kaser, Marc Ferrante, Edouard Louis, Denis Franchimont, Olivier Dewit, Ursula Seidler, Kyung-Jo Kim, Markus F Neurath, Stefan Schreiber, Paul Scholl, Chandrasena Pamulapati, Bojan Lalovic, Sudha Visvanathan, Steven J Padula, Ivona Herichova, Adina Soaita, David B Hall, Wulf O Böcher
BACKGROUND: The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohn's disease. We aimed to assess the efficacy and safety of risankizumab (BI 655066, Boehringer Ingelheim, Ingelheim, Germany), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23, in patients with moderately-to-severely active Crohn's disease. METHODS: In this randomised, double-blind, placebo-controlled phase 2 study, we enrolled patients at 36 referral sites in North America, Europe, and southeast Asia...
April 12, 2017: Lancet
https://www.readbyqxmd.com/read/28410647/disease-trajectories-before-esrd-implications-for-clinical-management
#15
REVIEW
Keiichi Sumida, Csaba P Kovesdy
One of the biggest challenges nephrologists face is to predict complex clinical pathways of kidney disease progression that do not follow a steady linear decline. This unpredictability often becomes a barrier to timely shared decision making between patients and physicians and could lead to adverse patient outcomes. By using numerous analytic approaches to characterize the longitudinal changes in kidney function, emerging evidence has disclosed the heterogeneous trajectories of kidney disease progression, particularly in late-stage chronic kidney disease (CKD) nearing end-stage renal disease (ESRD), and showed their independent associations with various clinical outcomes...
March 2017: Seminars in Nephrology
https://www.readbyqxmd.com/read/28407743/new-drugs-new-toxicities-severe-side-effects-of-modern-targeted-and-immunotherapy-of-cancer-and-their-management
#16
REVIEW
Frank Kroschinsky, Friedrich Stölzel, Simone von Bonin, Gernot Beutel, Matthias Kochanek, Michael Kiehl, Peter Schellongowski
Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity...
April 14, 2017: Critical Care: the Official Journal of the Critical Care Forum
https://www.readbyqxmd.com/read/28403850/rationale-and-design-of-a-multicenter-placebo-controlled-double-blind-randomized-trial-to-evaluate-the-effect-of-empagliflozin-on-endothelial-function-the-emblem-trial
#17
RANDOMIZED CONTROLLED TRIAL
Atsushi Tanaka, Michio Shimabukuro, Yosuke Okada, Isao Taguchi, Minako Yamaoka-Tojo, Hirofumi Tomiyama, Hiroki Teragawa, Seigo Sugiyama, Hisako Yoshida, Yasunori Sato, Atsushi Kawaguchi, Yumi Ikehara, Noritaka Machii, Tatsuya Maruhashi, Kosuke R Shima, Toshinari Takamura, Yasushi Matsuzawa, Kazuo Kimura, Masashi Sakuma, Jun-Ichi Oyama, Teruo Inoue, Yukihito Higashi, Shinichiro Ueda, Koichi Node
BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD)...
April 12, 2017: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/28402153/maternal-fetal-transmission-of-zika-virus-routes-and-signals-for-infection
#18
Bin Cao, Michael S Diamond, Indira U Mysorekar
The emerging mosquito-borne virus, Zika virus (ZIKV), has been causally associated with adverse pregnancy and neonatal outcomes, including miscarriage, microcephaly, serious brain abnormalities, and other birth defects indicative of a congenital ZIKV syndrome. In this review, we highlight work from human and animal studies on routes of infection in pregnancy that lead to adverse fetal and neonatal outcomes. A number of innate and adaptive immune mechanisms and signaling molecules that may have key roles in ZIKV infection pathogenesis are discussed along with putative viral entry pathways...
April 12, 2017: Journal of Interferon & Cytokine Research
https://www.readbyqxmd.com/read/28398675/pregnancy-related-listeriosis
#19
REVIEW
Rahat Wadhwa Desai, Mary Alice Smith
About one in seven cases of listeriosis occurs in pregnant women, and, although listeriosis is rare, it is the third leading cause of death from food-borne infections. Pregnancy-related listeriosis increases the risk for fetal and neonatal mortality by approximately 21%. During pregnancy, infections are more likely to occur in the third trimester (66%) than the first trimester (3%). However, fetal and neonatal adverse effects are less common as gestational age increases or with older gestational age at birth...
March 15, 2017: Birth Defects Res
https://www.readbyqxmd.com/read/28397649/support-and-assessment-for-fall-emergency-referrals-safer-2-a-cluster-randomised-trial-and-systematic-review-of-clinical-effectiveness-and-cost-effectiveness-of-new-protocols-for-emergency-ambulance-paramedics-to-assess-older-people-following-a-fall-with-referral
#20
Helen A Snooks, Rebecca Anthony, Robin Chatters, Jeremy Dale, Rachael Fothergill, Sarah Gaze, Mary Halter, Ioan Humphreys, Marina Koniotou, Phillipa Logan, Ronan Lyons, Suzanne Mason, Jon Nicholl, Julie Peconi, Ceri Phillips, Judith Phillips, Alison Porter, A Niroshan Siriwardena, Graham Smith, Alun Toghill, Mushtaq Wani, Alan Watkins, Richard Whitfield, Lynsey Wilson, Ian T Russell
BACKGROUND: Emergency calls are frequently made to ambulance services for older people who have fallen, but ambulance crews often leave patients at the scene without any ongoing care. We evaluated a new clinical protocol which allowed paramedics to assess older people who had fallen and, if appropriate, refer them to community-based falls services. OBJECTIVES: To compare outcomes, processes and costs of care between intervention and control groups; and to understand factors which facilitate or hinder use...
March 2017: Health Technology Assessment: HTA
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