bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advancing Concussion Assessment in Pediatrics (A-CAP): a prospective, concurrent cohort, longitudinal study of mild traumatic brain injury in children: study protocol
Authors: Yeates Keith Owen , Beauchamp Miriam , Craig William , Doan Quynh , Zemek Roger , Bjornson Bruce H , Gravel Jocelyn , Mikrogianakis Angelo , Goodyear Bradley , Abdeen Nishard , Beaulieu Christian , Dehaes Mathieu , Deschenes Sylvain , Harris Ashley , Lebel Catherine , Lamont Ryan , Williamson Tyler , Barlow Karen Maria , Bernier Francois , Brooks Brian L , Emery Carolyn , Freedman Stephen B , Kowalski Kristina , Mrklas Kelly , Tomfohr-Madsen Lianne , Schneider Kathryn J 
Published: July 2017

IntroductionPaediatric mild traumatic brain injury (mTBI) is a public health burden. Clinicians urgently need evidence-based guidance to manage mTBI, but gold standards for diagnosing and predicting the outcomes of mTBI are lacking. The objective of the Advancing Concussion Assessment in Pediatrics (A-CAP) study is to assess a broad pool of neurobiological and psychosocial markers to examine associations with postinjury outcomes in a large sample of children with either mTBI or orthopaedic injury (OI), with the goal of improving the diagnosis and prognostication of outcomes of paediatric mTBI.Methods and analysisA-CAP is a prospective, longitudinal cohort study of children aged 8.00–16.99 years with either mTBI or OI, recruited during acute emergency department (ED) visits at five sites from the Pediatric Emergency Research Canada network. Injury information is collected in the ED; follow-up assessments at 10 days and 3 and 6 months postinjury measure a variety of neurobiological and psychosocial markers, covariates/confounders and outcomes. Weekly postconcussive symptom ratings are obtained electronically. Recruitment began in September 2016 and will occur for approximately 24 months. Analyses will test the major hypotheses that neurobiological and psychosocial markers can: (1) differentiate mTBI from OI and (2) predict outcomes of mTBI. Models initially will focus within domains (eg, genes, imaging biomarkers, psychosocial markers), followed by multivariable modelling across domains. The planned sample size (700 mTBI, 300 OI) provides adequate statistical power and allows for internal cross-validation of some analyses.Ethics and disseminationThe ethics boards at all participating institutions have approved the study and all participants and their parents will provide informed consent or assent. Dissemination will follow an integrated knowledge translation plan, with study findings presented at scientific conferences and in multiple manuscripts in peer-reviewed journals.
PIRATE project: point-of-care, informatics-based randomised controlled trial for decreasing overuse of antibiotic therapy in Gram-negative bacteraemia
Authors: Huttner Angela , Albrich Werner C , Bochud Pierre-Yves , Gayet-Ageron Angèle , Rossel Anne , Dach Elodie von , Harbarth Stephan , Kaiser Laurent 
Published: July 2017

IntroductionAntibiotic overuse drives antibiotic resistance. The optimal duration of antibiotic therapy for Gram-negative bacteraemia (GNB), a common community and hospital-associated infection, remains unknown and unstudied via randomised controlled trials (RCTs).Methods and analysisThis investigator-initiated, multicentre, non-inferiority, informatics-based point-of-care RCT will randomly assign adult hospitalised patients receiving microbiologically efficacious antibiotic(s) for GNB to (1) 14 days of antibiotic therapy, (2) 7 days of therapy or (3) an individualised duration determined by clinical response and 75% reduction in peak C reactive protein (CRP) values. The randomisation will occur in equal proportions (1:1:1) on day 5 (±1) of efficacious antibiotic therapy as determined by antibiogram; patients, their physicians and study investigators will be blind to treatment duration allocation until the day of antibiotic discontinuation. Immunosuppressed patients and those with GNB due to complicated infections (endocarditis, osteomyelitis, etc) and/or non-fermenting bacilli (Acinetobacterspp,Burkholderiaspp,Pseudomonasspp)Brucellaspp,Fusobacteriumspp or polymicrobial growth with Gram-positive organisms will be ineligible. The primary outcome is incidence of clinical failure at day 30; secondary outcomes include clinical failure, all-cause mortality and incidence ofClostridiumdifficileinfection in the 90-day study period. An interim safety analysis will be performed after the first 150 patients have been followed for ≤30 days. Given a chosen margin of 10%, the required sample size to determine non-inferiority is roughly 500 patients. Analyses will be performed on both intention-to-treat and per-protocol populations.Ethics and disseminationEthics approval was obtained from the cantonal ethics committees of all three participating sites. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.Trial registration numberThis trial is registered atwww.clinicaltrials.gov(NCT03101072; pre-results).
Onyx embolization prior to stereotactic radiosurgery for brain arteriovenous malformations: a single-center treatment algorithm
Authors: Nerva John D , Barber Jason , Levitt Michael R , Rockhill Jason K , Hallam Danial K , Ghodke Basavaraj V , Sekhar Laligam N , Kim Louis J 
Published: July 2017

BackgroundEmbolization before stereotactic radiosurgery (SRS) for brain arteriovenous malformations (BAVMs) is controversial.ObjectiveTo compare clinical and radiographic outcomes in patients undergoing pre-SRS embolization with ethylene copolymer (Onyx) with outcomes in patients undergoing SRS alone.MethodsSeventy consecutive patients with BAVMs who underwent SRS were retrospectively reviewed. Univariate and multivariate analyses were performed to assess the factors associated with radiographic obliteration and complication.ResultsForty-one (59%) patients presented without BAVM rupture and 29 (41%) patients presented with rupture. Pre-SRS embolization was used in 20 patients (28.6%; 7 unruptured and 13 ruptured). Twenty-five of 70 (36%) patients sustained a complication from treatment, including 6 (9%) patients with a post-SRS latency period hemorrhage. Ten (14%) patients had persistent neurological deficits after treatment. Functional outcome (as modified Rankin Scale), complication rate, and radiographic obliteration at last follow-up were not significantly different between embolized and non-embolized groups in both unruptured and ruptured BAVMs. For unruptured BAVMs, 3- and 5-year rates of radiographic obliteration were 23% and 73% for non-embolized patients and 20% and 60% for embolized patients, respectively. For ruptured BAVMs, 3- and 5-year rates of radiographic obliteration were 45% and 72% for non-embolized patients and 53% and 82% for embolized patients, respectively.ConclusionPre-SRS embolization with Onyx was not associated with worse clinical or radiographic outcomes than SRS treatment without embolization. Pre-SRS embolization has a low complication rate and can safely be used to target high-risk BAVM features in carefully selected patients destined for SRS.
Smoke-free signage in public parks: impacts on smoking behaviour
Authors: Platter Heather N , Pokorny Steven B 
Published: July 2017

ObjectiveBehavioural interventions, such as smoke-free signage, are used to support air quality in public outdoor spaces that are not protected by a smoke-free policy, such as states with preemptive clause legislation. However, there is little evidence of the effectiveness of these interventions. This paper is an evaluation of whether smoke-free signage posted in public parks altered smoking behaviours of park patrons.MethodsA time-series quasi-experimental design was used. Cigarette butts were collected at the same day and time every week in ten amenities within four parks in 2011. Each park completed a baseline period until a stable trend emerged at six weeks, then received smoke-free signage for the six week intervention period. There were 1684 cigarette butts collected during baseline and 1008 collected during the intervention phase.FindingsWilcoxon signed-rank test demonstrated that smoking at seven out of ten amenities decreased and the overall decrease was significant at p=0.028. Individual parks and amenities grouped by type did not experience a statistically significant change. A neighbourhood median income trend was visually discovered, revealing that as income increased, there was a greater decrease in cigarette butts.ConclusionsThis study provides evidence on the impact of smoke-free signage not supported by local ordinance in public parks using a reproducible measure. States, especially those with a preemptive clause legislation, may benefit from incorporating smoke-free signage in public areas to protect community members from exposure to tobacco smoke, reduce littering, and denormalise smoking.
Gq-activated fibroblasts induce cardiomyocyte action potential prolongation and automaticity in a three-dimensional microtissue environment
Authors: Kofron C. M. , Kim T. Y. , King M. E. , Xie A. , Feng F. , Park E. , Qu Z. , Choi B.-R. , Mende U. 
Published: July 2017

Cardiac fibroblasts (CFs) are known to regulate cardiomyocyte (CM) function in vivo and in two-dimensional in vitro cultures. This study examined the effect of CF activation on the regulation of CM electrical activity in a three-dimensional (3-D) microtissue environment. Using a scaffold-free 3-D platform with interspersed neonatal rat ventricular CMs and CFs, Gq-mediated signaling was selectively enhanced in CFs by Gαqadenoviral infection before coseeding with CMs in nonadhesive hydrogels. After 3 days, the microtissues were analyzed by signaling assay, histological staining, quantitative PCR, Western blots, optical mapping with voltage- or Ca2+-sensitive dyes, and microelectrode recordings of CF resting membrane potential (RMPCF). Enhanced Gqsignaling in CFs increased microtissue size and profibrotic and prohypertrophic markers. Expression of constitutively active Gαqin CFs prolonged CM action potential duration (by 33%) and rise time (by 31%), prolonged Ca2+transient duration (by 98%) and rise time (by 65%), and caused abnormal electrical activity based on depolarization-induced automaticity. Constitutive Gqactivation in CFs also depolarized RMPCFfrom –33 to −20 mV and increased connexin 43 and connexin 45 expression. Computational modeling confers that elevated RMPCFand increased cell-cell coupling between CMs and CFs in a 3-D environment could lead to automaticity. In conclusion, our data demonstrate that CF activation alone is capable of altering action potential and Ca2+transient characteristics of CMs, leading to proarrhythmic electrical activity. Our results also emphasize the importance of a 3-D environment where cell-cell interactions are prevalent, underscoring that CF activation in 3-D tissue plays a significant role in modulating CM electrophysiology and arrhythmias.NEW & NOTEWORTHY In a three-dimensional microtissue model, which lowers baseline activation of cardiac fibroblasts but enables cell-cell, paracrine, and cell-extracellular matrix interactions, we demonstrate that selective cardiac fibroblast activation by enhanced Gqsignaling, a pathophysiological trigger in the diseased heart, modulates cardiomyocyte electrical activity, leading to proarrhythmogenic automaticity.
Vitamin C mitigates oxidative/nitrosative stress and inflammation in doxorubicin-induced cardiomyopathy
Authors: Akolkar Gauri , da Silva Dias Danielle , Ayyappan Prathapan , Bagchi Ashim K. , Jassal Davinder S. , Salemi Vera Maria Cury , Irigoyen Maria Claudia , De Angelis Katia , Singal Pawan K. 
Published: July 2017

Increase in oxidative/nitrosative stress is one of the mechanisms associated with the development of cardiotoxicity due to doxorubicin (Dox), a potent chemotherapy drug. Previously, we reported mitigation of Dox-induced oxidative/nitrosative stress and apoptosis by vitamin C (Vit C) in isolated cardiomyocytes. In the present in vivo study in rats, we investigated the effect of prophylactic treatment with Vit C on Dox-induced apoptosis, inflammation, oxidative/nitrosative stress, cardiac dysfunction, and Vit C transporter proteins. Dox (cumulative dose: 15 mg/kg) in rats reduced systolic and diastolic cardiac function and caused structural damage. These changes were associated with a myocardial increase in reactive oxygen species, reduction in antioxidant enzyme activities, increased expression of apoptotic proteins, and inflammation. Dox also caused an increase in the expression of proapoptotic proteins Bax, Bnip-3, Bak, and caspase-3. An increase in oxidative/nitrosative stress attributable to Dox was indicated by an increase in superoxide, protein carbonyl formation, lipid peroxidation, nitric oxide (NO), NO synthase (NOS) activity, protein nitrosylation, and inducible NOS protein expression. Dox increased the levels of cardiac proinflammatory cytokines TNF-α, IL-1β, and IL-6, whereas the expression of Vit C transporter proteins (sodium-ascorbate cotransporter 2 and glucose transporter 4) was reduced. Prophylactic and concurrent treatment with Vit C prevented all these changes and improved survival in the Vit C + Dox group. Vit C also improved Dox-mediated systolic and diastolic dysfunctions and structural damage. These results suggest a cardioprotective role of Vit C in Dox-induced cardiomyopathy by reducing oxidative/nitrosative stress, inflammation, and apoptosis, as well as improving Vit C transporter proteins. NEW & NOTEWORTHY This in vivo study provides novel data that vitamin C improves cardiac structure and function in doxorubicin-induced cardiomyopathy by reducing oxidative/nitrosative stress, apoptosis, and inflammation along with upregulation of cardiac vitamin C transporter proteins. The latter may have a crucial role in improving antioxidant status in this cardiomyopathy.
Circulating acylcarnitine profile in human heart failure: a surrogate of fatty acid metabolic dysregulation in mitochondria and beyond
Authors: Ruiz Matthieu , Labarthe François , Fortier Annik , Bouchard Bertrand , Thompson Legault Julie , Bolduc Virginie , Rigal Odile , Chen Jane , Ducharme Anique , Crawford Peter A. , Tardif Jean-Claude , Des Rosiers Christine 
Published: July 2017

Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 ± 6.9%) and mostly of ischemic etiology with ≥2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22–79% higher circulating ACs, irrespective of chain length ( P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial β-oxidation, and were significantly associated with levels of NH2-terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF. NEW & NOTEWORTHY Mass spectrometry-based profiling of circulating energy metabolites, including acylcarnitines, in two cohorts of heart failure versus control subjects revealed multiple alterations in fatty acid metabolism in peroxisomes in addition to mitochondria, thereby highlighting a novel mechanism contributing to global lipid perturbations in heart failure. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acylcarnitines-in-human-heart-failure/ .
Tobacco Product Use Patterns, and Nicotine and Tobacco-Specific Nitrosamine Exposure: NHANES 1999–2012
Authors: Choi Kelvin , Sabado Melanie , El-Toukhy Sherine , Vogtmann Emily , Freedman Neal D. , Hatsukami Dorothy 
Published: July 2017

Abstract
Background: Few studies have examined differences in product consumption patterns and nicotine and tobacco-specific nitrosamines (TSNA) exposure between single versus dual- and poly-tobacco users. We applied the Tobacco Product Use Patterns (T-PUPs) model to fill this gap in the literature.
Methods: Data from adults (age ≥18 years) who used any tobacco products during the 5 days prior to participating in the 1999–2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Participants were classified into seven T-PUPs: (1) cigarettes only, (2) noncigarette combustibles only, (3) noncombustibles only, (4) dual noncigarette combustibles and noncombustibles, (5) dual cigarettes and noncombustibles, (6) dual cigarettes and noncigarette combustibles, and (7) poly-tobacco use. Weighted regression models were used to compare product consumption, serum cotinine, and urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (i.e., NNAL) levels between single-, dual-, and poly-tobacco T-PUPs.
Results: Dual- and poly-tobacco T-PUPs were associated with lower product consumption compared with single-product T-PUPs only in some cases (e.g., dual cigarette and noncombustible users smoked cigarettes on 0.6 fewer days in the past 5 days compared with cigarette-only users; P &lt; 0.05). Dual- and poly-tobacco T-PUPs had either nondistinguishable or higher levels of serum cotinine and urinary total NNAL than corresponding single-product T-PUPs.
Conclusions: Product consumption, and nicotine and TSNAs exposure of dual- and poly-tobacco product category users somewhat differ from those of single-product category users as defined by the T-TUPs model.
Impact: Higher levels of cotinine and NNAL among dual- and poly-tobacco T-TUPs users compared with the single-product T-TUPs users may indicate health concerns. Cancer Epidemiol Biomarkers Prev; 26(10); 1525–30. ©2017 AACR.
Opportunities and Challenges for Environmental Exposure Assessment in Population-Based Studies
Authors: Patel Chirag J. , Kerr Jacqueline , Thomas Duncan C. , Mukherjee Bhramar , Ritz Beate , Chatterjee Nilanjan , Jankowska Marta , Madan Juliette , Karagas Margaret R. , McAllister Kimberly A. , Mechanic Leah E. , Fallin M. Daniele , Ladd-Acosta Christine , Blair Ian A. , Teitelbaum Susan L. , Amos Christopher I. 
Published: July 2017

Abstract
A growing number and increasing diversity of factors are available for epidemiological studies. These measures provide new avenues for discovery and prevention, yet they also raise many challenges for adoption in epidemiological investigations. Here, we evaluate 1) designs to investigate diseases that consider heterogeneous and multidimensional indicators of exposure and behavior, 2) the implementation of numerous methods to capture indicators of exposure, and 3) the analytical methods required for discovery and validation. We find that case-control studies have provided insights into genetic susceptibility but are insufficient for characterizing complex effects of environmental factors on disease development. Prospective and two-phase designs are required but must balance extended data collection with follow-up of study participants. We discuss innovations in assessments including the microbiome; mass spectrometry and metabolomics; behavioral assessment; dietary, physical activity, and occupational exposure assessment; air pollution monitoring; and global positioning and individual sensors. We claim the the availability of extensive correlated data raises new challenges in disentangling specific exposures that influence cancer risk from among extensive and often correlated exposures. In conclusion, new high-dimensional exposure assessments offer many new opportunities for environmental assessment in cancer development. Cancer Epidemiol Biomarkers Prev; 26(9); 1370–80. ©2017 AACR.
Tuberin Regulates Prostaglandin Receptor–Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells
Authors: Li Chenggang , Liu Xiaolei , Liu Yang , Zhang Erik , Medepalli Kantha , Masuda Kouhei , Li Na , Wikenheiser-Brokamp Kathryn A. , Osterburg Andrew , Borchers Michael T. , Kopras Elizabeth J. , Plas David R. , Sun Julia , Franz David N. , Capal Jamie K. , Mays Maxwell , Sun Yang , Kwiatkowski David J. , Alayev Anya , Holz Marina K. , Krueger Darcy A. , Siroky Brian J. , Yu Jane J. 
Published: July 2017

Abstract
Tuberous sclerosis complex (TSC) is a tumor-suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC is associated with mutations in TSC1 or TSC2, resulting in hyperactivation of mTOR complex 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume and stabilize lung function in TSC patients; however, mTOR inhibitors are cytostatic not cytocidal, and long-term benefits and toxicities are uncertain. Previously, we identified rapamycin-insensitive upregulation of cyclooxygenase 2 (PTGS2/COX2) and prostaglandin E2 (PGE2) production in TSC2-deficient cells and postulated that the action of excess PGE2 and its cognate receptors (EP) contributes to cell survival. In this study, we identify upregulation of EP3 (PTGER3) expression in TSC2-deficient cells, TSC renal angiomyolipomas, lymphangioleiomyomatosis lung nodules, and epileptic brain tubers. TSC2 negatively regulated EP3 expression via Rheb in a rapamycin-insensitive manner. The EP3 antagonist, L-798106, selectively suppressed the viability of TSC2-deficient cells in vitro and decreased the lung colonization of TSC2-deficient cells. Collectively, these data reveal a novel function of TSC2 and Rheb in the regulation of EP3 expression and cell viability.
Implications: Therapeutic targeting of an aberrant PGE2-EP3 signaling axis may have therapeutic benefit for TSC patients and for other mTOR-hyperactive neoplasms. Mol Cancer Res; 15(10); 1318–30. ©2017 AACR.