bluuebunny/crossref_metadata_2025_split huggingface dataset:
EVALUATION OF A PEDIATRIC LIQUID FORMULATION TO IMPROVE 6-MERCAPTOPURINE THERAPY IN CHILDREN
Authors: de Beaumanis Tiphanie Adam , Hjalgrim Lisa Lynqsie , Nersting Jacob , Breitkreutz Jörg , Bertrand Yves , Stanulla Martin , Leverger Guy , Baruchel André , Schmiegelow Kjeld , Jacqz-Aigrain Evelyne 
Published: December 2015

Background6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluation was performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization.MethodsThe pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50 mg fixed dose of Loulla compared to 50 mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9 hours were obtained each day at to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0–9 and AUC0–∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination.ResultsThe preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred.ConclusionPharmacokinetic, palatability and safety data support the use of Loulla in children.
SAFETY OF LAMOTRIGINE IN PAEDIATRICS: A SYSTEMIC REVIEW
Authors: Egunsola Oluwaseun , Choonara Imti , Sammons Helen 
Published: December 2015

BackgroundLamotrigine has been increasingly used for the treatment of paediatric epilepsy. It is the most commonly prescribed new generation antiepileptic drug in the UK.ObjectivesTo identify adverse drug reactions associated with lamotrigine in children, compare the safety profile with other antiepileptic drugs and identify all clinical studies and case reports involving lamotrigine safety in children.MethodsDatabases EMBASE (1974-November 2013), Medline (1946-November 2013), PubMed and the Cochrane library for randomised controlled trials were searched for original research or reports in which paediatric patients received at least a single dose of lamotrigine for the treatment of epilepsy, with safety as an outcome measure.ResultsA total of 76 articles involving 2,184 paediatric patients were identified. There were 1,952 adverse events (AEs) reported. Fifty two of these AEs were from 49 case reports. Rash was most commonly reported, with a risk of 8.96 per 100 patients. Other common AEs included headache, fever, somnolence, vomiting, seizure aggravation, dizziness, cough, aggression, ataxia and insomnia. There were significantly higher risks of dizziness [RR 4.57, 95% CI: 1.88–11.12, p<0.001], abdominal pain [RR: 2.53, 95% CI: 1.12–5.70, p=0.03] and nausea [RR: 5.94, 95% CI: 1.59–22.13, p=0.008] with lamotrigine than placebo. When compared with valproic acid, the risk of somnolence and vomiting was significantly lower for lamotrigine [RR: 0.35, 95% CI: 0.13–0.89, p=0.04] and [RR: 0.20, 95% CI: 0.04–0.89, p=0.03]. Discontinuation due to an adverse drug reaction was recorded in 72 children (3.2% of all treated patients). Rash was the most common reason, with 58% of treatment discontinuation attributed to different forms of rash.ConclusionRash is the most common adverse reaction of lamotrigine, seen in around 9% of patients, and it is the most common reason for treatment discontinuation.
QUALITY ASSESSMENT OF ANTIBIOTIC PRESCRIPTIONS IN PAEDIATRIC PRIMARY CARE SETTINGS IN SERBIA, USING EUROPEAN QUALITY INDICATORS
Authors: Božić Bojana , Bajčetić Milica 
Published: December 2015

ObjectiveThe aim of the study was to compare the quality of antibiotic use among children in primary care settings for acute upper respiratory tract infections, acute tonsillitis and acute otitis media (AOM) with the internationally developed disease-specific antibiotic prescribing quality indicators (APQI) and with National Guidelines.MethodsPrescriptions of systemic antibiotics to the paediatric population (<18 years) with three conditions for the period between 2011 and 2013, at the primary level of health care were analysed by using the National Health Insurance Fund's outpatient reimbursement database.ResultsDuring the followed up period acute upper respiratory infections, 42%, acute tonsillitis, 25%, and AOM/myringitis, 2%, represented more than 69% of the all indications for prescribing antibiotics. The percentage of patients prescribed an antibiotic for acute upper respiratory tract infections, acute tonsillitis and acute otitis media (AOM) was above the proposed range (≤20), 87%–96%. The percentage of patients prescribed a recommended antibiotic was below the proposed range (≥80%), 1%–17%, while the adherence rate to National Guidelines was low, 19%–28%. The percentage of patients prescribed quinolones was above the proposed range for AOM (≤5%), 7%. There were no significant differences in indicators value at the regional level in Serbia.ConclusionBased on results for disease-specific quality indicators for the most common children diseases and low adherence rates with our National guidelines we can conclude that antibiotic use is inappropriate in Serbia.
Cenozoic structural evolution of the Andaman Sea: evolution from an extensional to a sheared margin
Authors: Morley C. K. 
Published: December 2015

Abstract
The Andaman Sea is proposed to have developed from a margin where Palaeogene back-arc collapse closed a mid-Cretaceous back-arc oceanic basin, and resulted in the collision between island arc crust to the west and the western margin of Sundaland. Subsequent east–west to WNW–ESE extension during the Late Eocene–Oligocene resulted in highly extended continental crust underlying the Alcock and Sewell rises, and the East Andaman Basin, and moderately extended crust in the Megui–North Sumatra Basin. As India coupled with western Myanmar, the margin became dominated by dextral strike-slip and NNW–SSE transtensional deformation during the Miocene. The narrow belt of NNW–SSE-directed extension is proposed to have focused on the region where ductile middle crust remained following Late Eocene–Oligocene extension, whereas strike-slip faults are located in the regions of necking where ductile middle crust was considerably thinned by Late Eocene–Oligocene extension. The last phase of NNW–SSE-extension switched between probable Late Miocene–Early Pliocene seafloor spreading, and extension (by dyke intrusion and faulting) in the Alcock and Sewell rises, and then recently back to the spreading centre.
Development history of the southern terminus of the Central Atlantic; Guyana–Suriname case study
Authors: Nemčok M. , Rybár S. , Odegard M. , Dickson W. , Pelech O. , Ledvényiová L. , Matejová M. , Molčan M. , Hermeston S. , Jones D. , Cuervo E. , Cheng R. , Forero G. 
Published: December 2015

Abstract
The study focuses on the offshore Guyana–Suriname–French Guiana region. It draws from seismic, well, gravimetric and magnetic data. They indicate that the continental break-up along the western margin of the Demerara Plateau took place during the Callovian–Oxfordian, associated with the Central Atlantic opening, and accommodated by normal faults. The continental break-up in the SE offshore Guyana accommodated by strike-slip faults was coeval. The continental break-up along the NE and eastern margins of the Demerara Plateau took place during the late Aptian–Albian, associated with the opening of the Equatorial Atlantic, and accommodated by dextral strike-slip and normal faults, respectively.
Different spreading vectors of the Central and Equatorial Atlantic required development of the Accommodation Block during the late Aptian/Albian–Paleocene in their contact region, and in the region between the Central Atlantic and its southernmost portion represented by the Offshore Guyana Block, which were separated from each other by the opening Equatorial Atlantic. Its role was to accommodate for about 20° mismatch between the Central and Equatorial Atlantic spreading vectors, which has decreased from the late Aptian/Albian to Paleocene down to 0°.
Differential movements between the Central and Equatorial Atlantic oceans were also accommodated by strike-slip faults of the Guyana continental margin, some active until the Paleocene.

Supplementary material:

Extended methods and discussion chapters are available at
http://www.geolsoc.org.uk/SUP18875
Transpressional structures and hydrocarbon potential along the Romanche Fracture Zone: a review
Authors: Davison Ian , Faull Theodore , Greenhalgh Jenny , O Beirne Eoin , Steel Ian 
Published: December 2015

Abstract
The Romanche Fracture Zone was originally a corridor of Aptian-age dextral transtensional rifting along the Equatorial Atlantic margins. Late Albian plate tectonic compression occurred due to a change in plate vectors, when the African and South American continents were still in contact across a 500 km-long section of the Romanche Fracture Zone. This dextral compression produced reactivation of the rift faults to produce asymmetric landward-vergent anticlines and thrusts that trend ENE to NE. Fold-axial planes dip seaward, parallel to the rift faults. Minor asymmetric anticlines were developed on the long seaward-dipping fold limbs and these have subvertical axial planes. The asymmetry of the minor folds is due to the southward stratal dip having been oblique to the horizontal maximum principal stress during the Albian inversion. The folds on the African margin were subsequently tightened by compression in Santonian and Oligo-Miocene times. Aptian-age ENE strike-slip faults were reactivated during the compression phases to produce broad positive flower structures up to 30 km wide that formed topographical ridges along the original strike-slip faults. The intervening and broader flat-bottomed synclines do not appear to be associated with rift faults.
The folding and thrust faulting created seabed relief of 1–2 km at the end of the Albian; evidenced by the amount of subsequent erosion that removed the better-quality reservoirs in the upper Albian sequence from the major fold crests. Consequently, there has been a significant number of failed oil exploration wells drilled along the fold crests. The fold ridges would have diverted turbidite channels in the onlapping Cenomanian–Campanian sequence and these will be preferentially located on the landward side of the anticlinal crests. Late Cretaceous stratigraphic and structural traps located between the major anticlines have not yet been explored for hydrocarbons along the Romanche Fracture Zone margins.
The role of break-up localization in microcontinent separation along a strike-slip margin: the East India–Elan Bank case study
Authors: Sinha Sudipta Tapan , Nemčok Michal , Choudhuri Mainak , Sinha Neeraj , Rao D. Pundarika 
Published: December 2015

Abstract
The Elan Bank microcontinent was separated from East India during the Early Cretaceous break-up. The crustal architecture and rifting geometry of East India and the Elan Bank margins document that the early break-up between India and Antarctica was initiated in the eastern portions of the Cauvery and Krishna–Godavari rift zones, and in the southern portion of Elan Bank. However, the westwards break-up propagation along the Krishna–Godavari Rift Zone continued even after the break-up in the overstepping portion of the Cauvery Rift Zone. Eventually, the western propagating end of the Krishna–Godavari Rift Zone became hard-linked with the failed western portion of the Cauvery Rift Zone by the dextral Coromandel transfer fault zone. Consequently, the break-up location between India and Antarctica shifted from its initial to its final location along the northern portion of the Elan Bank formed by the western Krishna–Godavari Rift Zone. The competition between the two rift zones to capture continental break-up and asymmetric ridge propagation resulted in a ridge jump and the Elan Bank microcontinent release.

Supplementary material:

Supplementary figures are available at
http://www.geolsoc.org.uk/SUP18864
Lower-crust ductility patterns associated with transform margins
Authors: Henk A. , Nemčok M. 
Published: December 2015

Abstract

A three-dimensional (3D) thermal–kinematic modelling approach based on finite-element techniques is used to study lower-crustal viscosity at transform margins during the continent–ocean transform development stage and after the ridge has passed by. Nine modelling scenarios combining different equilibrium surface heat flows and lower-crustal rheologies are studied. Modelling results indicate that substantial parts of the lower crust at transform margins have the potential to flow at geologically appreciable strain rates, which can lead to uplift/subsidence, as well as lateral variations, in upper- and lower-crustal thicknesses and Moho depth. These low-viscosity zones (i.e. parts of the lower crust with effective viscosities of less than 10
18
Pa s) make up distinct ductility distributions that vary in space and time during margin evolution. Three basic ductility patterns and related thermal processes can be identified: reduced lower-crustal viscosities originating at the continental rift and the continent–ocean boundary (COB), respectively; reduced lower-crustal viscosities along the transform caused by the migrating ridge; and the background distribution of lower-crustal ductility resulting from the equilibrium temperature field. Superposition of all three ductility patterns and the complex interaction of the underlying perturbations of the temperature field result in distinct differences in the potential of lower-crustal flow both in space (parallel and perpendicular to the transform) and with time. Thus, modelling results provide templates for understanding lower-crustal flow at transform margins in general and await further studies comparing model predictions with actual field observations.
A Federated Network for Translational Cancer Research Using Clinical Data and Biospecimens
Authors: Jacobson Rebecca S. , Becich Michael J. , Bollag Roni J. , Chavan Girish , Corrigan Julia , Dhir Rajiv , Feldman Michael D. , Gaudioso Carmelo , Legowski Elizabeth , Maihle Nita J. , Mitchell Kevin , Murphy Monica , Sakthivel Mayurapriyan , Tseytlin Eugene , Weaver JoEllen 
Published: December 2015

Abstract
Advances in cancer research and personalized medicine will require significant new bridging infrastructures, including more robust biorepositories that link human tissue to clinical phenotypes and outcomes. In order to meet that challenge, four cancer centers formed the Text Information Extraction System (TIES) Cancer Research Network, a federated network that facilitates data and biospecimen sharing among member institutions. Member sites can access pathology data that are de-identified and processed with the TIES natural language processing system, which creates a repository of rich phenotype data linked to clinical biospecimens. TIES incorporates multiple security and privacy best practices that, combined with legal agreements, network policies, and procedures, enable regulatory compliance. The TIES Cancer Research Network now provides integrated access to investigators at all member institutions, where multiple investigator-driven pilot projects are underway. Examples of federated search across the network illustrate the potential impact on translational research, particularly for studies involving rare cancers, rare phenotypes, and specific biologic behaviors. The network satisfies several key desiderata including local control of data and credentialing, inclusion of rich phenotype information, and applicability to diverse research objectives. The TIES Cancer Research Network presents a model for a national data and biospecimen network. Cancer Res; 75(24); 5194–201. ©2015 AACR.
ALCHEMIST Trials: A Golden Opportunity to Transform Outcomes in Early-Stage Non–Small Cell Lung Cancer
Authors: Govindan Ramaswamy , Mandrekar Sumithra J. , Gerber David E. , Oxnard Geoffrey R. , Dahlberg Suzanne E. , Chaft Jamie , Malik Shakun , Mooney Margaret , Abrams Jeffrey S. , Jänne Pasi A. , Gandara David R. , Ramalingam Suresh S. , Vokes Everett E. 
Published: December 2015

Abstract
The treatment of patients with metastatic non–small cell lung cancer (NSCLC) is slowly evolving from empirical cytotoxic chemotherapy to personalized treatment based on specific molecular alterations. Despite this 10-year evolution, targeted therapies have not been studied adequately in patients with resected NSCLC who have clearly defined actionable mutations. The advent of next-generation sequencing has now made it possible to characterize genomic alterations in unprecedented detail. The efforts begun by The Cancer Genome Atlas project to understand the complexities of the genomic landscape of lung cancer will be supplemented further by studying a large number of tumor specimens. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is an NCI-sponsored national clinical trials network (NCTN) initiative to address the needs to refine therapy for early-stage NSCLC. This program will screen several thousand patients with operable lung adenocarcinoma to determine whether their tumors contain specific molecular alterations [epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase rearrangement (ALK)], making them eligible for treatment trials that target these alterations. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively, after completion of their standard adjuvant therapy. ALCHEMIST will also contain a large discovery component that will provide an opportunity to incorporate genomic studies to fully understand the clonal architecture, clonal evolution, and mechanisms of resistance to therapy. In this review, we describe the concept, rationale, and outline of ALCHEMIST and the plan for genomic studies in patients with lung adenocarcinoma. Clin Cancer Res; 21(24); 5439–44. ©2015 AACR.
Prospective Validation of Pooled Prognostic Factors in Women with Advanced Cervical Cancer Treated with Chemotherapy with/without Bevacizumab: NRG Oncology/GOG Study
Authors: Tewari Krishnansu S. , Sill Michael W. , Monk Bradley J. , Penson Richard T. , Long Harry J. , Poveda Andrés , Landrum Lisa M. , Leitao Mario M. , Brown Jubilee , Reid Thomas J.A. , Michael Helen E. , Moore David H. 
Published: December 2015

AbstractPurpose: In the randomized phase III trial, Gynecologic Oncology Group (GOG) protocol 240, the incorporation of bevacizumab with chemotherapy significantly increased overall survival (OS) in women with advanced cervical cancer. A major objective of GOG-240 was to prospectively analyze previously identified pooled clinical prognostic factors known as the Moore criteria.Experimental Design: Potential negative factors included black race, performance status 1, pelvic disease, prior cisplatin, and progression-free interval &lt;365 days. Risk categories included low-risk (0–1 factor), mid-risk (2–3 factors), and high-risk (4–5 factors). Each test of association was conducted at the 5% level of significance. Logistic regression and survival analysis was used to determine whether factors were prognostic or could be used to guide therapy.Results: For the entire population (n = 452), high-risk patients had significantly worse OS (P &lt; 0.0001). The HRs of death for treating with topotecan in low-risk, mid-risk, and high-risk subsets are 1.18 [95% confidence interval (CI), 0.63–2.24], 1.11 (95% CI, 0.82–1.5), and 0.84 (95% CI, 0.50–1.42), respectively. The HRs of death for treating with bevacizumab in low-risk, mid-risk, and high-risk subsets are 0.96 (95% CI, 0.51–1.83; P = 0.9087), 0.673 (95% CI, 0.5–0.91; P = 0.0094), and 0.536 (95% CI, 0.32–0.905; P = 0.0196), respectively.Conclusions: This is the first prospectively validated scoring system in cervical cancer. The Moore criteria have real-world clinical applicability. Toxicity concerns may justify omission of bevacizumab in some low-risk patients where survival benefit is small. The benefit to receiving bevacizumab appears to be greatest in the moderate- and high-risk subgroups (5.8-month increase in median OS). Clin Cancer Res; 21(24); 5480–7. ©2015 AACR.
Heterogeneity of Programmed Cell Death Ligand 1 Expression in Multifocal Lung Cancer
Authors: Mansfield Aaron S. , Murphy Stephen J. , Peikert Tobias , Yi Eunhee S. , Vasmatzis George , Wigle Dennis A. , Aubry Marie Christine 
Published: December 2015

Abstract
Purpose: The expression of programmed cell death ligand 1 (PD-L1) provides limited predictive value in identifying patients most likely to respond to immunotherapy. As the heterogeneity of PD-L1 expression may lead to sampling error and the misclassification of PD-L1 status, we assessed the distribution of PD-L1 expression in paired, resected multifocal lung cancers.
Experimental Design: PD-L1 was assessed by IHC. Paired lesions were defined as independent primaries or related lesions using mate pair next-generation sequencing. Agreement statistics were used for analysis.
Results: Sixty-seven multifocal lung cancers from 32 patients were sequenced and stained for PD-L1. There was agreement of PD-L1 expression by the tumor cells in paired lesions of 20 patients and disagreement of PD-L1 expression by the tumor cells in paired lesions of 12 patients (κ = 0.01). Sequencing identified that 23 patients had independent primary lung cancers and that 9 patients had related cancers. In paired lesions of patients with independent cancers, there was agreement of PD-L1 expression by the tumor cells in 12 patients and disagreement in 11 patients (κ = 0.31). In paired lesions of patients with related lung cancers, there was agreement of PD-L1 expression by the tumor cells in 8 patients and disagreement in 1 patient (κ = 0.73).
Conclusions: The expression of PD-L1 is heterogeneous among paired independent lung cancers, but there are high levels of agreement in intrapulmonary metastasis. Clin Cancer Res; 22(9); 2177–82. ©2015 AACR.