bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toll-Like Receptor 7 Mediates Early Innate Immune Responses to Malaria
Authors: Baccarella Alyssa , Fontana Mary F. , Chen Eunice C. , Kim Charles C. 
Published: September 2013

ABSTRACTInnate immune recognition of malaria parasites is the critical first step in the development of the host response. At present, Toll-like receptor 9 (TLR9) is thought to play a central role in sensing malaria infection. However, we and others have observed thatTlr9−/−mice, in contrast to mice deficient in the downstream adaptor, Myeloid differentiation primary response gene 88 (MYD88), exhibit few deficiencies in immune function during early infection with the malaria parasitePlasmodium chabaudi, implying that another MYD88-dependent receptor also contributes to the antimalarial response. Here we use candidate-based screening to identify TLR7 as a key sensor of earlyP. chabaudiinfection. We show that TLR7 mediates a rapid systemic response to infection through induction of cytokines such as type I interferons (IFN-I), interleukin 12, and gamma interferon. TLR7 is also required for induction of IFN-I by other species and strains ofPlasmodium, including an etiological agent of human disease,P. falciparum, suggesting that malaria parasites harbor a common pathogen-associated molecular pattern (PAMP) recognized by TLR7. In contrast to the nonredundant requirement for TLR7 in early immune activation, sensing through both TLR7 and TLR9 was required for proinflammatory cytokine production and immune cell activation during the peak of parasitemia. Our findings indicate that TLR7 plays a central role in early immune activation during malaria infection, whereas TLR7 and TLR9 contribute combinatorially to immune responses as infection progresses.
Knowledge about sports-related concussion: is the message getting through to coaches and trainers?
Authors: White Peta E , Newton Joshua D , Makdissi Michael , Sullivan S John , Davis Gavin , McCrory Paul , Donaldson Alex , Ewing Michael T , Finch Caroline F 
Published: September 2013

AimThe need for accurate diagnosis and appropriate return-to-play decisions following a concussion in sports has prompted the dissemination of guidelines to assist managing this condition. This study aimed to assess whether key messages within these guidelines are reflected in the knowledge of coaches and sports trainers involved in community sport.MethodsAn online knowledge survey was widely promoted across Australia in May–August 2012 targeting community Australian Football (AF) and Rugby League (RL) coaches and sports trainers. 260 AF coaches, 161 AF sports trainers, 267 RL coaches and 228 RL sports trainers completed the survey. Knowledge scores were constructed from Likert scales and compared across football codes and respondent groups.ResultsGeneral concussion knowledge did not differ across codes but sports trainers had higher levels than did coaches. There were no significant differences in either concussion symptoms or concussion management knowledge across codes or team roles. Over 90% of respondents correctly identified five of the eight key signs or symptoms of concussion. Fewer than 50% recognised the increased risk of another concussion following an initial concussion. Most incorrectly believed or were uncertain that scans typically show damage to the brain after a concussion occurs. Fewer than 25% recognised, and >40% were uncertain that younger players typically take longer to recover from concussion than adults.ConclusionsThe key messages from published concussion management guidelines have not reached community sports coaches and sports trainers. This needs to be redressed to maximise the safety of all of those involved in community sport.
Do general practitioners follow treatment recommendations from guidelines in their decisions on heart failure management? A cross-sectional study
Authors: Swennen Maartje H J , Rutten Frans H , Kalkman Cor J , van der Graaf Yolanda , Sachs Alfred P E , van der Heijden Geert J M G 
Published: September 2013

ObjectiveTo investigate whether general practitioners (GPs) follow treatment recommendations from clinical practice guidelines in their decisions on the management of heart failure patients, and assess whether doctors’ characteristics are related to their decisions.DesignCross-sectional vignette study.SettingContinuing Medical Education meeting.Participants451 Dutch GPs.Main outcome measuresAnswers to four multiple-choice treatment decisions in clinical vignettes of a patient with heart failure and a reduced ejection fraction. With univariable and multivariable regression analyses, respondent characteristics were related to optimal treatment decisions.ResultsOf the 451 GPs, none took four optimal decisions: 7% considered stopping statin treatment, 36% initiated β-blocker treatment at a low-dose and 4% doubled the β-blocker in the up-titration phase. Finally, for our vignette patient now also suffering from chronic obstructive pulmonary disease, 45% of the GPs continued β-blocker therapy even when they considered prescribing a long-acting β2-agonist. While the relation between respondent characteristics and each decision was very different, none was independently associated with all four decisions. Giving priority to evidence-based medicine was independently related to stopping statin treatment and doubling the β-blocker in the up-titration phase.ConclusionsGPs seem not to follow treatment recommendations from clinical practice guidelines in their decisions on the management of heart failure patients. The recommendations from guidelines may appear counterintuitive when statin treatment needs to be stopped when a patient feels comfortable, or when a β-blocker should be up-titrated in patients who experience more symptoms. Giving priority to evidence-based medicine is possibly positively related to difficult treatment decisions.
CTrigger
Authors: Park Soyeon , Lu Shan , Zhou Yuanyuan 
Published: September 2013

Multicore hardware is making concurrent programs pervasive. Unfortunately, concurrent programs are prone to bugs. Among different types of concurrency bugs, atomicity violation bugs are common and important. Existing techniques to detect atomicity violation bugs suffer from one limitation: requiring bugs to manifest during monitored runs, which is an open problem in concurrent program testing.
This paper makes two contributions. First, it studies the interleaving characteristics of the common practice in concurrent program testing (i.e., running a program over and over) to understand why atomicity violation bugs are hard to expose. Second, it proposes CTrigger to effectively and efficiently expose atomicity violation bugs in large programs. CTrigger focuses on a special type of interleavings (i.e., unserializable interleavings) that are inherently correlated to atomicity violation bugs, and uses trace analysis to systematically identify (likely) feasible unserializable interleavings with low occurrence-probability. CTrigger then uses minimum execution perturbation to exercise low-probability interleavings and expose difficult-to-catch atomicity violation.
We evaluate CTrigger with real-world atomicity violation bugs from four sever/desktop applications (Apache, MySQL, Mozilla, and PBZIP2) and three SPLASH2 applications on 8-core machines. CTrigger efficiently exposes the tested bugs within 1--235 seconds, two to four orders of magnitude faster than stress testing. Without CTrigger, some of these bugs do not manifest even after 7 full days of stress testing. In addition, without deterministic replay support, once a bug is exposed, CTrigger can help programmers reliably reproduce it for diagnosis. Our tested bugs are reproduced by CTrigger mostly within 5 seconds, 300 to over 60000 times faster than stress testing.
Kendo
Authors: Olszewski Marek , Ansel Jason , Amarasinghe Saman 
Published: September 2013

Although chip-multiprocessors have become the industry standard, developing parallel applications that target them remains a daunting task. Non-determinism, inherent in threaded applications, causes significant challenges for parallel programmers by hindering their ability to create parallel applications with repeatable results. As a consequence, parallel applications are significantly harder to debug, test, and maintain than sequential programs.
This paper introduces Kendo: a new software-only system that provides deterministic multithreading of parallel applications. Kendo enforces a deterministic interleaving of lock acquisitions and specially declared non-protected reads through a novel dynamically load-balanced deterministic scheduling algorithm. The algorithm tracks the progress of each thread using performance counters to construct a deterministic logical time that is used to compute an interleaving of shared data accesses that is both deterministic and provides good load balancing. Kendo can run on today's commodity hardware while incurring only a modest performance cost. Experimental results on the SPLASH-2 applications yield a geometric mean overhead of only 16% when running on 4 processors. This low overhead makes it possible to benefit from Kendo even after an application is deployed. Programmers can start using Kendo today to program parallel applications that are easier to develop, debug, and test.
Per-thread cycle accounting in SMT processors
Authors: Eyerman Stijn , Eeckhout Lieven 
Published: September 2013

This paper proposes a cycle accounting architecture for Simultaneous Multithreading (SMT) processors that estimates the execution times for each of the threads had they been executed alone, while they are running simultaneously on the SMT processor. This is done by accounting each cycle to either a base, miss event or waiting cycle component during multi-threaded execution. Single-threaded alone execution time is then estimated as the sum of the base and miss event components; the waiting cycle component represents the lost cycle count due to SMT execution. The cycle accounting architecture incurs reasonable hardware cost (around 1KB of storage) and estimates single-threaded performance with average prediction errors around 7.2% for two-program workloads and 11.7% for four-program workloads.
The cycle accounting architecture has several important applications to system software and its interaction with SMT hardware. For one, the estimated single-thread alone execution time provides an accurate picture to system software of the actually consumed processor cycles per thread. The alone execution time instead of the total execution time (timeslice) may make system software scheduling policies more effective. Second, a new class of thread-progress aware SMT fetch policies based on per-thread progress indicators enable system software level priorities to be enforced at the hardware level.
Efficient online validation with delta execution
Authors: Tucek Joseph , Xiong Weiwei , Zhou Yuanyuan 
Published: September 2013

Software systems are constantly changing. Patches to fix bugs and patches to add features are all too common. Every change risks breaking a previously working system. Hence administrators loathe change, and are willing to delay even critical security patches until after fully validating their correctness. Compared to off-line validation, on-line validation has clear advantages since it tests against real life workloads. Yet unfortunately it imposes restrictive overheads as it requires running the old and new versions side-by-side. Moreover, due to spurious differences (e.g. event timing, random number generation, and thread interleavings), it is difficult to compare the two for validation.
To allow more effective on-line patch validation, we propose a new mechanism, called delta execution, that is based on the observation that most patches are small. Delta execution merges the two side-by-side executions for most of the time and splits only when necessary, such as when they access different data or execute different code. This allows us to perform on-line validation not only with lower overhead but also with greatly reduced spurious differences, allowing us to effectively validate changes.
We first validate the feasibility of our idea by studying the characteristics of 240 patches from 4 server programs; our examination shows that 77% of the changes should not be expected to cause large changes and are thereby feasible for Delta execution. We then implemented Delta execution using dynamic instrumentation. Using real world patches from 7 server applications and 3 other programs, we compared our implementation of Delta execution against a traditional side-by-side on-line validation. Delta execution outperformed traditional validation by up to 128%; further, for 3 of the changes, spurious differences caused the traditional validation to fail completely while Delta execution succeeded. This demonstrates that Delta execution can allow administrators to use on-line validation to confidently ensure the correctness of the changes they apply.
Leak pruning
Authors: Bond Michael D. , McKinley Kathryn S. 
Published: September 2013

Managed languages improve programmer productivity with type safety and garbage collection, which eliminate memory errors such as dangling pointers, double frees, and buffer overflows. However, because garbage collection uses reachability to over-approximate live objects, programs may still leak memory if programmers forget to eliminate the last reference to an object that will not be used again. Leaks slow programs by increasing collector workload and frequency. Growing leaks eventually crash programs.
This paper introduces leak pruning, which keeps programs running by predicting and reclaiming leaked objects at run time. It predicts dead objects and reclaims them based on observing data structure usage patterns. Leak pruning preserves semantics because it waits for heap exhaustion before reclaiming objects and poisons references to objects it reclaims. If the program later tries to access a poisoned reference, the virtual machine (VM) throws an error. We show leak pruning has low overhead in a Java VM and evaluate it on 10 leaking programs. Leak pruning does not help two programs, executes five substantial programs 1.6-81X longer, and executes three programs, including a leak in Eclipse, for at least 24 hours. In the worst case, leak pruning defers fatal errors. In the best case, it keeps leaky programs running with preserved semantics and consistent throughput.
TwinDrivers
Authors: Menon Aravind , Schubert Simon , Zwaenepoel Willy 
Published: September 2013

In a virtualized environment, device drivers are often run inside a virtual machine (VM) rather than in the hypervisor, for reasons of safety and reduction in software engineering effort. Unfortunately, this approach results in poor performance for I/O-intensive devices such as network cards. The alternative approach of running device drivers directly in the hypervisor yields better performance, but results in the loss of safety guarantees for the hypervisor and incurs additional software engineering costs.
In this paper we present TwinDrivers, a framework which allows us to semi-automatically create safe and efficient hypervisor drivers from guest OS drivers. The hypervisor driver runs directly in the hypervisor, but its data resides completely in the driver VM address space. A Software Virtual Memory mechanism allows the driver to access its VM data efficiently from the hypervisor running in any guest context, and also protects the hypervisor from invalid memory accesses from the driver. An upcall mechanism allows the hypervisor to largely reuse the driver support infrastructure present in the VM. The TwinDriver system thus combines most of the performance benefits of hypervisor-based driver approaches with the safety and software engineering benefits of VM-based driver approaches.
Using the TwinDrivers hypervisor driver, we are able to improve the guest domain networking throughput in Xen by a factor of 2.4 for transmit workloads, and 2.1 for receive workloads, both in CPU-scaled units, and achieve close to 64-67 of native Linux throughput.
Peptide Vaccination in Montanide Adjuvant Induces and GM-CSF Increases CXCR3 and Cutaneous Lymphocyte Antigen Expression by Tumor Antigen–Specific CD8 T Cells
Authors: Clancy-Thompson Eleanor , King Laura K. , Nunnley Lenora D. , Mullins Irene M. , Slingluff Craig L. , Mullins David W. 
Published: September 2013

AbstractT-cell infiltration of melanoma is associated with enhanced clinical efficacy and is a desirable endpoint of immunotherapeutic vaccination. Infiltration is regulated, in part, by chemokine receptors and selectin ligands on the surface of tumor-specific lymphocytes. Therefore, we investigated the expression of two homing molecules, CXC chemokine receptor 3 (CXCR3) and cutaneous lymphocyte antigen (CLA), on vaccine-induced CD8 T cells, in the context of a clinical trial of a melanoma-specific peptide vaccine. Both CXCR3 and CLA have been associated with T-cell infiltration of melanoma. We show that a single subcutaneous/intradermal administration of peptide vaccine in Montanide adjuvant induces tumor-specific CD8 T cells that are predominantly positive for CXCR3, with a subpopulation of CXCR3+CLA+ cells. Addition of granulocyte macrophage colony—stimulating factor (GM-CSF) significantly enhances CXCR3 expression and increases the proportion of CLA-expressing cells. Concurrent with CXCR3 and CLA expression, vaccine-induced CD8 cells express high levels of T-bet, IFN-γ, and interleukin-12 receptor (IL-12Rβ1). Collectively, these studies show that peptide vaccination in adjuvant induces CD8 T cells with a phenotype that may support infiltration of melanoma. Cancer Immunol Res; 1(5); 332–9. ©2013 AACR.
Effect of Montanide and Poly-ICLC Adjuvant on Human Self/Tumor Antigen-Specific CD4+ T Cells in Phase I Overlapping Long Peptide Vaccine Trial
Authors: Tsuji Takemasa , Sabbatini Paul , Jungbluth Achim A. , Ritter Erika , Pan Linda , Ritter Gerd , Ferran Luis , Spriggs David , Salazar Andres M. , Gnjatic Sacha 
Published: September 2013

AbstractVaccination of patients with ovarian cancer with overlapping long peptides (OLP) from cancer-testis antigen NY-ESO-1 and poly-ICLC in Montanide-ISA-51 (Montanide) was found to consistently induce integrated immune responses (antibody, CD4+, and CD8+ T cells). Using detailed methods, we investigated the respective effects of poly-ICLC and Montanide adjuvant on pre- and postvaccine NY-ESO-1–specific CD4+ T cells, because of their central function for induction and maintenance of both antibody and CD8+ T cells. Polyclonal NY-ESO-1–specific CD4+ T-cell lines were generated from 12 patients using CD154-based selection of precursors before and after vaccination with (i) OLP alone, (ii) OLP in Montanide, or (iii) OLP and poly-ICLC in Montanide. Kinetics, quantification, fine specificity, avidity, and cytokine-producing pattern were analyzed in depth and compared between vaccine cohorts. Vaccination with OLP alone did not elicit CD4+ T-cell responses; it suppressed high-avidity CD4+ T-cell precursors that recognized naturally processed NY-ESO-1 protein before vaccination. Emulsification of OLP in Montanide was required for the expansion of high-avidity NY-ESO-1–specific CD4+ T-cell precursors. Poly-ICLC significantly enhanced CD4+ Th1 responses while suppressing the induction of interleukin (IL)-4–producing Th2 and IL-9–producing Th9 cells. In summary, Montanide and poly-ICLC had distinct and cooperative effects for the induction of NY-ESO-1–specific Th1 cells and integrated immune responses by OLP vaccination. These results support the use of admixing poly-ICLC in Montanide adjuvant to rapidly induce antitumor type I immune responses by OLP from self/tumor antigens in human cancer vaccines. Cancer Immunol Res; 1(5); 340–50. ©2013 AACR.
Establishing the Relationship Between Clinical Outcome and Extent of Osseous Bridging Between Computed Tomography Assessment in Isolated Hindfoot and Ankle Fusions
Authors: Glazebrook Mark , Beasley William , Daniels Timothy , Evangelista Peter T. , Donahue Rafe , Younger Alastair , Pinzur Michael S. , Baumhauer Judith F. , DiGiovanni Christopher W. 
Published: September 2013

Background: Determining the success of joint fusion operations is often a diagnostic dilemma, and many factors may be considered. Most would agree that the broad categories of clinical success and radiographic success are likely most useful to determine the overall success of a joint fusion operation. Very little evidence exists to assist the surgeon in determining what constitutes a successful radiographic fusion. The aim of this study was to determine the extent of osseous bridging as measured by computed tomography (CT) that was associated with a good clinical outcome as measured by the 12-Item Short Form (SF-12), Foot Function Index (FFI), and American Orthopaedic Foot & Ankle Society (AOFAS) clinical outcomes questionnaires at 24 weeks. Methods: Patients who had isolated joint fusions were evaluated (n = 275) to determine the correlation of extent of osseous bridging with clinical outcome. The extent of osseous bridging across the joint in question was categorized as absent (0%-24%), minimal (25%-49%) moderate (50%-74%), or complete (75%-100%). Clinical outcome scores included the SF-12, FFI, and AOFAS outcomes score. Results: Patients evaluated to have at least minimal osseous bridging at fusion sites (25%-49%) on CT reported a clinically important improvement in SF-12, FFI, and AOFAS, whereas those with “absent” osseous bridging (0%-24%) did not report a clinically important improvement in outcome scores. Conclusion: This study suggests that osseous bridging of greater than 25% to 49% at the fusion site measured by CT may be necessary to consider a hindfoot or ankle fusion clinically successful. Level of Evidence: Level IV, case series.