bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combining brief contact interventions (BCI) into a decision-making algorithm to reduce suicide reattempt: the VigilanS study protocol
Authors: Duhem Stéphane , Berrouiguet Sofian , Debien Christophe , Ducrocq François , Demarty Anne Laure , Messiah Antoine , Courtet Philippe , Jehel Louis , Thomas Pierre , Deplanque Dominique , Danel Thierry , Walter Michel , Notredame Charles-Edouard , Vaiva Guillaume 
Published: October 2018

IntroductionThe early postattempt period is considered to be one of the most at-risk time windows for suicide reattempt or completion. Among the postcrisis prevention programmes developed to compensate for this risk, brief contact interventions (BCIs) have been proven to be efficient but not equally for each subpopulation of attempters. VigilanS is a region-wide programme that relies on an algorithmic system to tailor surveillance and BCI provisions to individuals discharged from the hospital after a suicide attempt.AimVigilanS’ main objective is to reduce suicide and suicide reattempt rates both at the individual level (patients included in VigilanS) and at the populational level (inhabitants of the Nord–Pas-de-Calais region).Methods and analysisAt discharge, every attempter coming from a participating centre is given a crisis card with an emergency number to contact in case of distress. Patients are then systematically recontacted 6 months later. An additional 10-day call is also given if the index suicide attempt is not the first one. Depending on the clinical evaluation during the phone call, thecall teammay carry out proportionated crisis interventions. Personalised postcards are sent whenever patients are unreachable by phone or in distress. On the populational level, mean suicide and suicide attempt rates in Nord–Pas-de-Calais will be compared before and after the implementation of the programme. Here/there cross-sectional comparisons with a control region will test the spatial specificity of the observed fluctuations, while time-series analyses will be performed to corroborate the temporal plausibility of imputing these fluctuations to the implementation of the programme. On the individual level, patients entered in VigilanS will be prospectively compared with a matched control cohort by means of survival analyses (survival curve comparisons and Cox models).DiscussionVigilanS interventional components fall under the ordinary law care regime, and the individuals’ general rights as patients apply with no addendums or restrictions for their participation in the programme. The research section received authorisation from the Ethical Committee of Lille Nord-Ouest under the caption ‘Study aimed at evaluating routine care’ and is registered in ‘Clinical Trials’. The French Ministry of Health plans to extend the experimentation to other regions and probe the relevance of this type of ‘bottom–up’ territorial prevention policy at the national level.Trial registration numberNCT03134885.
Protocol for evaluating and implementing a pragmatic value-based healthcare management model for patients with inflammatory arthritis: a Danish population-based regional cohort and qualitative implementation study
Authors: Jørgensen Tanja Schjødt , Lykkegaard Jens Jørgen , Hansen Annette , Schrøder Heidi Morsø , Stampe Betina , Sweeney Anne-Marie Tetsche , Appel Esbensen Bente , Bech Bianca , Christensen Katja , Friis-Mikkelsen Ellen , Røgind Henrik , Lundbak Tine , Taylor Peter C , Petersson Ingemar F , Wæhrens Eva Ejlersen , Kjellberg Jakob , Gudbergsen Henrik , Kristensen Lars Erik 
Published: October 2018

IntroductionThe provision of healthcare for patients with inflammatory arthritis occurs in the context of somewhat conflicting targets, values and drivers. Therefore, there is a need for introducing ‘value-based healthcare’ defined as the value of patient relevant health outcomes in relation to costs. This term is a central part of tomorrow’s healthcare sector, especially for rheumatic diseases, yet the transition is a huge challenge, as it will impact the development, delivery and assessment of healthcare.AimsThe aim of this study is to compare medical and patient evaluated impact of the traditional settlement and financing production (DAGS) controlled healthcare setting with a value-based and patient-centred adjunctive to standard care.Methods and analysisPatients with inflammatory arthritis receiving treatment in routine care at the outpatient clinics in the Capital Region of Denmark will prospectively and consecutively be enrolled in a Non-Intervention-Study framework providing a pragmatic value-based management model. A Danish reference cohort, used for comparison will be collected as part of routine clinical care. The enrolment period will be from 1 June 2018 until 31December 2023. Baseline and follow-up visits will be according to routine clinical care. Registry data will be obtained directly from patients and include personal, clinical and outcomes information. The study results will be reported in accordance with the STROBE statement.Ethics and disseminationThe study has been notified to the Danish Data Protection Agency and granted authorisation for the period June 2018 to January 2025 (pending). Informed consent will be obtained from all patients before enrolment in the study. The study is approved by the ethics committee, Capital Region of Denmark (H-18013158). Results of the study will be disseminated through publication in international peer-reviewed journals.
Neurite density is reduced in the presymptomatic phase ofC9orf72disease
Authors: Wen Junhao , Zhang Hui , Alexander Daniel C , Durrleman Stanley , Routier Alexandre , Rinaldi Daisy , Houot Marion , Couratier Philippe , Hannequin Didier , Pasquier Florence , Zhang Jiaying , Colliot Olivier , Le Ber Isabelle , Bertrand Anne 
Published: October 2018

ObjectiveTo assess the added value of neurite orientation dispersion and density imaging (NODDI) compared with conventional diffusion tensor imaging (DTI) and anatomical MRI to detect changes in presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation.MethodsThe PREV-DEMALS (Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis) study is a prospective, multicentre, observational study of first-degree relatives of individuals carrying theC9orf72mutation. Sixty-seven participants (38 presymptomaticC9orf72mutation carriers (C9+) and 29 non-carriers (C9−)) were included in the present cross-sectional study. Each participant underwent one single-shell, multishell diffusion MRI and three-dimensional T1-weighted MRI. Volumetric measures, DTI and NODDI metrics were calculated within regions of interest. Differences in white matter integrity, grey matter volume and free water fraction betweenC9+andC9−individuals were assessed using linear mixed-effects models.ResultsCompared withC9−,C9+demonstrated white matter abnormalities in 10 tracts with neurite density index and only 5 tracts with DTI metrics. Effect size was significantly higher for the neurite density index than for DTI metrics in two tracts. No tract had a significantly higher effect size for DTI than for NODDI. For grey matter cortical analysis, free water fraction was increased in 13 regions inC9+, whereas 11 regions displayed volumetric atrophy.ConclusionsNODDI provides higher sensitivity and greater tissue specificity compared with conventional DTI for identifying white matter abnormalities in the presymptomaticC9orf72carriers. Our results encourage the use of neurite density as a biomarker of the preclinical phase.Trial registration numberNCT02590276.
MadMax: surviving out-of-gas conditions in Ethereum smart contracts
Authors: Grech Neville , Kong Michael , Jurisevic Anton , Brent Lexi , Scholz Bernhard , Smaragdakis Yannis 
Published: October 2018

Ethereum is a distributed blockchain platform, serving as an ecosystem for smart contracts: full-fledged inter-communicating programs that capture the transaction logic of an account. Unlike programs in mainstream languages, a gas limit restricts the execution of an Ethereum smart contract: execution proceeds as long as gas is available. Thus, gas is a valuable resource that can be manipulated by an attacker to provoke unwanted behavior in a victim's smart contract (e.g., wasting or blocking funds of said victim). Gas-focused vulnerabilities exploit undesired behavior when a contract (directly or through other interacting contracts) runs out of gas. Such vulnerabilities are among the hardest for programmers to protect against, as out-of-gas behavior may be uncommon in non-attack scenarios and reasoning about it is far from trivial.
In this paper, we classify and identify gas-focused vulnerabilities, and present MadMax: a static program analysis technique to automatically detect gas-focused vulnerabilities with very high confidence. Our approach combines a control-flow-analysis-based decompiler and declarative program-structure queries. The combined analysis captures high-level domain-specific concepts (such as "dynamic data structure storage" and "safely resumable loops") and achieves high precision and scalability. MadMax analyzes the entirety of smart contracts in the Ethereum blockchain in just 10 hours (with decompilation timeouts in 8% of the cases) and flags contracts with a (highly volatile) monetary value of over $2.8B as vulnerable. Manual inspection of a sample of flagged contracts shows that 81% of the sampled warnings do indeed lead to vulnerabilities, which we report on in our experiment.
ShareJIT: JIT code cache sharing across processes and its practical implementation
Authors: Xu Xiaoran , Cooper Keith , Brock Jacob , Zhang Yan , Ye Handong 
Published: October 2018

Just-in-time (JIT) compilation coupled with code caching are widely used to improve performance in dynamic programming language implementations. These code caches, along with the associated profiling data for the hot code, however, consume significant amounts of memory. Furthermore, they incur extra JIT compilation time for their creation. On Android, the current standard JIT compiler and its code caches are not shared among processes—that is, the runtime system maintains a private code cache, and its associated data, for each runtime process. However, applications running on the same platform tend to share multiple libraries in common. Sharing cached code across multiple applications and multiple processes can lead to a reduction in memory use. It can directly reduce compile time. It can also reduce the cumulative amount of time spent interpreting code. All three of these effects can improve actual runtime performance.
In this paper, we describe ShareJIT, a global code cache for JITs that can share code across multiple applications and multiple processes. We implemented ShareJIT in the context of the Android Runtime (ART), a widely used, state-of-the-art system. To increase sharing, our implementation constrains the amount of context that the JIT compiler can use to optimize the code. This exposes a fundamental tradeoff: increased specialization to a single process’ context decreases the extent to which the compiled code can be shared. In ShareJIT, we limit some optimization to increase shareability. To evaluate the ShareJIT, we tested 8 popular Android apps in a total of 30 experiments. ShareJIT improved overall performance by 9% on average, while decreasing memory consumption by 16% on average and JIT compilation time by 37% on average.
Precision-guided context sensitivity for pointer analysis
Authors: Li Yue , Tan Tian , Møller Anders , Smaragdakis Yannis 
Published: October 2018

Context sensitivity is an essential technique for ensuring high precision in Java pointer analyses. It has been observed that applying context sensitivity partially, only on a select subset of the methods, can improve the balance between analysis precision and speed. However, existing techniques are based on heuristics that do not provide much insight into what characterizes this method subset. In this work, we present a more principled approach for identifying precision-critical methods, based on general patterns of value flows that explain where most of the imprecision arises in context-insensitive pointer analysis. Accordingly, we provide an efficient algorithm to recognize these flow patterns in a given program and exploit them to yield good tradeoffs between analysis precision and speed.
Our experimental results on standard benchmark and real-world programs show that a pointer analysis that applies context sensitivity partially, only on the identified precision-critical methods, preserves effectively all (98.8%) of the precision of a highly-precise conventional context-sensitive pointer analysis (2-object-sensitive with a context-sensitive heap), with a substantial speedup (on average 3.4X, and up to 9.2X).
Development of human electrophysiological brain networks
Authors: Briley Paul M. , Liddle Elizabeth B. , Groom Madeleine J. , Smith Helen J. F. , Morris Peter G. , Colclough Giles L. , Brookes Matthew J. , Liddle Peter F. 
Published: October 2018

Functional activity in the human brain is intrinsically organized into independently active, connected brain regions. These networks include sensorimotor systems, as well as higher-order cognitive networks such as the default mode network (DMN), which dominates activity when the brain is at rest, and the frontoparietal (FPN) and salience (SN) networks, which are often engaged during demanding tasks. Evidence from functional magnetic resonance imaging (fMRI) suggests that although sensory systems are mature by the end of childhood, the integrity of the FPN and SN develops throughout adolescence. There has been little work to corroborate these findings with electrophysiology. Using magnetoencephalography (MEG) recordings of 48 participants (aged 9–25 yr) at rest, we find that beta-band functional connectivity within the FPN, SN, and DMN continues to increase through adolescence, whereas connectivity in the visual system is mature by late childhood. In contrast to fMRI results, but replicating the MEG findings of Schäfer et al. (Schäfer CB, Morgan BR, Ye AX, Taylor MJ, Doesburg SM. Hum Brain Mapp 35: 5249–5261, 2014), we also see that connectivity between networks increases rather than decreases with age. This suggests that the development of coordinated beta-band oscillations within and between higher-order cognitive networks through adolescence might contribute to the developing abilities of adolescents to focus their attention and coordinate diverse aspects of mental activity. NEW & NOTEWORTHY Using magnetoencephalography to assess beta frequency oscillations, we show that functional connectivity within higher-order cognitive networks increases from childhood, reaching adult values by age 20 yr. In contrast, connectivity within a primary sensory (visual) network reaches adult values by age 14 yr. In contrast to functional MRI findings, connectivity between cognitive networks matures at a rate similar to within-network connectivity, suggesting that coordination of beta oscillations both within and between networks is associated with maturation of cognitive skills.
Choline and NMDG directly reduce outward currents: reduced outward current when these substances replace Na+is alone not evidence of Na+-activated K+currents
Authors: Thuma Jeffrey B. , Hooper Scott L. 
Published: October 2018

Choline chloride is often, and N-methyl-d-glucamine (NMDG) sometimes, used to replace sodium chloride in studies of sodium-activated potassium channels. Given the high concentrations used in sodium replacement protocols, it is essential to test that it is not the replacement substances themselves, as opposed to the lack of sodium, that cause any observed effects. We therefore compared, in lobster stomatogastric neurons and leech Retzius cells, the effects of applying salines in which choline chloride replaced sodium chloride, and in which choline hydroxide or sucrose was added to normal saline. We also tested, in stomatogastric neurons, the effect of adding NMDG to normal saline. These protocols allowed us to measure the direct effects (i.e., effects not due to changes in sodium concentration or saline osmolarity or ionic strength) of choline on stomatogastric and leech currents, and of NMDG on stomatogastric currents. Choline directly reduced transient and sustained depolarization-activated outward currents in both species, and NMDG directly reduced transient depolarization-activated outward currents in stomatogastric neurons. Experiments with lower choline concentrations showed that adding as little as 150 mM (stomatogastric) or 5 mM (leech) choline reduced at least some depolarization-activated outward currents. Reductions in outward current with choline chloride or NMDG replacement alone are thus not evidence of sodium-activated potassium currents.NEW & NOTEWORTHY We show that choline or N-methyl-d-glucamine (NMDG) directly (i.e., not due to changes in extracellular sodium) decrease outward currents. Prior work studying sodium-activated potassium channels in which sodium was replaced with choline or NMDG without an addition control may therefore be artifactual.
The NCI Transcriptional Pharmacodynamics Workbench: A Tool to Examine Dynamic Expression Profiling of Therapeutic Response in the NCI-60 Cell Line Panel
Authors: Monks Anne , Zhao Yingdong , Hose Curtis , Hamed Hossein , Krushkal Julia , Fang Jianwen , Sonkin Dmitriy , Palmisano Alida , Polley Eric C. , Fogli Laura K. , Konaté Mariam M. , Miller Sarah B. , Simpson Melanie A. , Voth Andrea Regier , Li Ming-Chung , Harris Erik , Wu Xiaolin , Connelly John W. , Rapisarda Annamaria , Teicher Beverly A. , Simon Richard , Doroshow James H. 
Published: October 2018

AbstractThe intracellular effects and overall efficacies of anticancer therapies can vary significantly by tumor type. To identify patterns of drug-induced gene modulation that occur in different cancer cell types, we measured gene-expression changes across the NCI-60 cell line panel after exposure to 15 anticancer agents. The results were integrated into a combined database and set of interactive analysis tools, designated the NCI Transcriptional Pharmacodynamics Workbench (NCI TPW), that allows exploration of gene-expression modulation by molecular pathway, drug target, and association with drug sensitivity. We identified common transcriptional responses across agents and cell types and uncovered gene-expression changes associated with drug sensitivity. We also demonstrated the value of this tool for investigating clinically relevant molecular hypotheses and identifying candidate biomarkers of drug activity. The NCI TPW, publicly available at https://tpwb.nci.nih.gov, provides a comprehensive resource to facilitate understanding of tumor cell characteristics that define sensitivity to commonly used anticancer drugs.Significance:The NCI Transcriptional Pharmacodynamics Workbench represents the most extensive compilation to date of directly measured longitudinal transcriptional responses to anticancer agents across a thoroughly characterized ensemble of cancer cell lines.
PTPN11 Plays Oncogenic Roles and Is a Therapeutic Target for BRAF Wild-Type Melanomas
Authors: Hill Kristen S. , Roberts Evan R. , Wang Xue , Marin Ellen , Park Taeeun D. , Son Sorany , Ren Yuan , Fang Bin , Yoder Sean , Kim Sungjune , Wan Lixin , Sarnaik Amod A. , Koomen John M. , Messina Jane L. , Teer Jamie K. , Kim Youngchul , Wu Jie , Chalfant Charles E. , Kim Minjung 
Published: October 2018

Abstract

Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten- and Cdkn2a-null mice, tet-inducible and melanocyte-specific PTPN11E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence, and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRASQ61K-mutant melanoma. Using a quantitative tyrosine phosphoproteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3β signaling pathways.

Implications:
This study identifies PTPN11 as an oncogenic driver and a novel and actionable therapeutic target for BRAF wild-type melanoma.
Frequent ESR1 and CDK Pathway Copy-Number Alterations in Metastatic Breast Cancer
Authors: Basudan Ahmed , Priedigkeit Nolan , Hartmaier Ryan J. , Sokol Ethan S. , Bahreini Amir , Watters Rebecca J. , Boisen Michelle M. , Bhargava Rohit , Weiss Kurt R. , Karsten Maria M. , Denkert Carsten , Blohmer Jens-Uwe , Leone Jose P. , Hamilton Ronald L. , Brufsky Adam M. , Elishaev Esther , Lucas Peter C. , Lee Adrian V. , Oesterreich Steffi 
Published: October 2018

Abstract

DNA sequencing has identified a limited number of driver mutations in metastatic breast cancer beyond single base-pair mutations in the estrogen receptor (ESR1). However, our previous studies and others have observed that structural variants, such as ESR1 fusions, may also play a role. Therefore, we expanded upon these observations by performing a comprehensive and highly sensitive characterization of copy-number (CN) alterations in a large clinical cohort of metastatic specimens. NanoString DNA hybridization was utilized to measure CN gains, amplifications, and deletions of 67 genes in 108 breast cancer metastases, and in 26 cases, the patient-matched primary tumor. For ESR1, a copyshift algorithm was applied to identify CN imbalances at exon-specific resolution and queried large data sets (&gt;15,000 tumors) that had previously undergone next-generation sequencing (NGS). Interestingly, a subset of ER+ tumors showed increased ESR1 CN (11/82, 13%); three had CN amplifications (4%) and eight had gains (10%). Increased ESR1 CN was enriched in metastatic specimens versus primary tumors, and this was orthogonally confirmed in a large NGS data set. ESR1-amplified tumors showed a site-specific enrichment for bone metastases and worse outcomes than nonamplified tumors. No ESR1 CN amplifications and only one gain was identified in ER− tumors. ESR1 copyshift was present in 5 of the 11 ESR1-amplified tumors. Other frequent amplifications included ERBB2, GRB7, and cell-cycle pathway members CCND1 and CDK4/6, which showed mutually exclusivity with deletions of CDKN2A, CDKN2B, and CDKN1B.

Implications:
Copy-number alterations of ESR1 and key CDK pathway genes are frequent in metastatic breast cancers, and their clinical relevance should be tested further.