bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of rheumatoid arthritis in patients with hepatitis C virus infection receiving interferon-based therapy: a retrospective cohort study using the Taiwanese national claims database
Authors: Tung Chien-Hsueh , Lai Ning-Sheng , Li Chung-Yi , Tsai Shiang-Jiun , Chen Yen-Chun , Chen Yi-Chun
Published: July 2018

Objectives

To illuminate the association between interferon-based therapy (IBT) and the risk of rheumatoid arthritis (RA) in patients infected with hepatitis C virus (HCV).

Design, setting, participants and interventions

This retrospective cohort study used Taiwan’s Longitudinal Health Insurance Database 2005 that included 18 971 patients with HCV infection between 1 January 1997 and 31 December 2012. We identified 1966 patients with HCV infection who received IBT (treated cohort) and used 1:4 propensity score-matching to select 7864 counterpart controls who did not receive IBT (untreated cohort).

Outcome measures

All study participants were followed until the end of 2012 to calculate the incidence rate and risk of incident RA.

Results

During the study period, 305 RA events (3.1%) occurred. The incidence rate of RA was significantly lower in the treated cohort than the untreated cohort (4.0 compared with 5.5 per 1000 person-years, p<0.018), and the adjusted HR remained significant at 0.63 (95% CI 0.43 to 0.94, p=0.023) in a Cox proportional hazards regression model. Multivariate stratified analyses revealed that the attenuation in RA risk was greater in men (0.35; 0.15 to 0.81, p=0.014) and men<60 years (0.29; 0.09 to 0.93, p=0.036).

Conclusions

This study demonstrates that IBT may reduce the risk of RA and contributes to growing evidence that HCV infection may lead to development of RA.
Comprehensive investigation of congenital anomalies in cerebral palsy: protocol for a European-Australian population-based data linkage study (The Comprehensive CA-CP Study)
Authors: Goldsmith Shona , Garcia Jalon Guiomar , Badawi Nadia , Blair Eve , Garne Ester , Gibson Catherine , McIntyre Sarah , Scott Heather , Smithers-Sheedy Hayley , Andersen Guro L
Published: July 2018

Introduction

Cerebral palsy (CP), an umbrella term for non-progressive conditions of cerebral origin resulting in motor impairments, is collectively the most common cause of physical disability in childhood. Cerebral and/or non-cerebral congenital anomalies are present in 15%–40% of children with CP. In order to identify effective prevention strategies for this substantial proportion of CP, a comprehensive understanding of the epidemiology of these congenital anomalies is required. International collaboration is needed, as previous attempts have fallen short due to a lack of power, since the anomalies are individually rare and CP comprises many clinical descriptions. The aim of this study is to generate new knowledge about the aetiologies of CP through a focused investigation into the role of congenital anomalies.

Methods and analysis

This collaborative, population-based data linkage study includes nine geographic regions (six in Europe, three in Australia) served by both congenital anomaly and CP registers. Register data for children with CP (both with and without congenital anomalies) and children with specific congenital anomalies (without CP) born between 1991 and 2009 will be linked and de-identified within each region. The resulting linked data sets will be quality assured, recoded, harmonised and then pooled into one data set. Analysis of the combined data set will include: frequencies/proportions of congenital anomalies and outcomes (type of CP, severity, impairments); descriptive analyses comparing timing of congenital anomaly development and brain injury/abnormality responsible for CP; ORs to calculate the odds of CP following a specific congenital anomaly; and identification of anomalies on causal pathways to CP.

Ethics and dissemination

Ethics approval for this collaborative study, The Comprehensive CA-CP Study, has been obtained from the Cerebral Palsy Alliance Human Research Ethics Committee (EC00402). Study findings will be disseminated at conferences and published in peer-reviewed journals, and recommendations will be made regarding the collection and classification of congenital anomaly data by CP registers.
Begin risk assessment for falls in women at 45, not 65
Authors: Harmon Katherine J , Hakenewerth Anne M , Waller Anna E , Ising Amy , Tintinalli Judith E
Published: July 2018

The clinical and epidemiological literature provides guidelines for fall prevention starting at age 65; however, the focus on age ≥65 is not evidence based. Therefore, this study examined state-wide North Carolina emergency department visit data to examine the characteristics of falls across the age spectrum, identify the age at which the incidence of fall-related emergency department visits started to increase and determine whether these trends were similar for men and women. We determined that incidence rates of fall-related emergency department visits began to increase in early middle age, particularly for women. Since fall risk assessment and prevention activities should be initiated prior to an injurious fall, we recommend beginning these activities before age 65.
Dog bite injuries in the USA: prevalence, correlates and recent trends
Authors: Holzer Katherine J , Vaughn Michael G , Murugan Vithya
Published: July 2018

Dog bite-related injuries are associated with high medical costs. The aim of this study was to estimate the prevalence, correlates and recent trends in dog bite injuries among male and female individuals presenting to US emergency departments. The prevalence of dog bites was calculated for years 2010–2014 using the Nationwide Emergency Department Sample. Sex-stratified multivariate logistic regression analyses were conducted with ‘dog bite’ as the dependent variable and patient and hospital characteristics as independent variables. Overall, the prevalence of dog bite injuries decreased from 2010 to 2014. The prevalence is highest in this sample among male youth. Male individuals diagnosed with an externalising behaviour disorder were more likely to present with a dog bite (OR=1.21, 95% CI 1.27 to 1.30). While the prevalence of dog bites has decreased in recent years, this costly and largely preventable injury remains a concern, especially among youth.
Curative cerebrovascular reconstruction with the Pipeline embolization device: the emergence of definitive endovascular therapy for intracranial aneurysms
Authors: Fiorella D , Lylyk P , Szikora I , Kelly M E , Albuquerque F C , McDougall C G , Nelson P K
Published: July 2018

Endovascular, endosaccular, coil embolization has emerged as an established therapy for both ruptured and unruptured cerebral aneurysms. However, many aneurysms are not cured using conventional endovascular techniques. Coil embolization often results in incomplete aneurysm occlusion or recanalization in the ensuing months after treatment. The Pipeline embolization device (PED; Chestnut Medical) represents a new generation endoluminal implant which is designed to treat aneurysms by reconstructing the diseased parent artery. Immediately after implantation, the PED functions to divert flow from the aneurysm, creating an environment conducive to thrombosis. With time, the PED is incorporated into the vessel wall as neointimal–endothelial overgrowth occurs along the construct. Ultimately, this process results in the durable complete exclusion of the aneurysm from the cerebrovasculature and a definitive endoluminal reconstruction of the diseased parent artery.
The POST trial: initial post-market experience of the Penumbra system: revascularization of large vessel occlusion in acute ischemic stroke in the United States and Europe
Authors: Tarr Robert , Hsu Dan , Kulcsar Zsolt , Bonvin Christophe , Rufenacht Daniel , Alfke Karsten , Stingele Robert , Jansen Olav , Frei Donald , Bellon Richard , Madison Michael , Struffert Tobias , Dorfler Arnd , Grunwald Iris Q , Reith Wolfgang , Haass Anton
Published: July 2018

Background and purpose

The purpose of this study was to assess the initial post-market experience of the device and how it is compared with the Penumbra Pivotal trial used to support the 510k application.

Methods

A retrospective case review of 157 consecutive patients treated with the Penumbra system at seven international centers was performed. Primary endpoints were revascularization of the target vessel (TIMI score of 2 or 3), good functional outcome as defined by a modified Rankin scale (mRS) score of ≤2 and incidence of procedural serious adverse events. Results were compared with those of the Penumbra pivotal trial.

Results

A total of 157 vessels were treated. Mean baseline values at enrollment were: age 65 years, NIHSS score 16. After use of the Penumbra system, 87% of the treated vessels were revascularized to TIMI 2 (54%) or 3 (33%) as compared with 82% reported in the Pivotal trial. Nine procedural serious adverse events were reported in 157 patients (5.7%). All-cause mortality was 20% (32/157), and 41% had a mRS of ≤2 at 90-day follow-up as compared with only 25% in the Pivotal trial. Patients who were successfully revascularized by the Penumbra system had significantly better outcomes than those who were not.

Conclusion

Initial post-market experience of the Penumbra system revealed that the revascularization rate and safety profile of the device are comparable to those reported in the Pivotal trial. However, the proportion of patients who had good functional outcome was higher than expected.
ADAPT FAST study: a direct aspiration first pass technique for acute stroke thrombectomy
Authors: Turk Aquilla S , Frei Don , Fiorella David , Mocco J , Baxter Blaise , Siddiqui Adnan , Spiotta Alex , Mokin Maxim , Dewan Michael , Quarfordt Steve , Battenhouse Holly , Turner Raymond , Chaudry Imran
Published: July 2018

Background

The development of new revascularization devices has improved recanalization rates and time, but not clinical outcomes. We report a prospectively collected clinical experience with a new technique utilizing a direct aspiration first pass technique with large bore aspiration catheter as the primary method for vessel recanalization.

Methods

98 prospectively identified acute ischemic stroke patients with 100 occluded large cerebral vessels at six institutions were included in the study. The ADAPT technique was utilized in all patients. Procedural and clinical data were captured for analysis.

Results

The aspiration component of the ADAPT technique alone was successful in achieving Thrombolysis in Cerebral Infarction (TICI) 2b or 3 revascularization in 78% of cases. The additional use of stent retrievers improved the TICI 2b/3 revascularization rate to 95%. The average time from groin puncture to at least TICI 2b recanalization was 37 min. A 5MAX demonstrated similar success to a 5MAX ACE in achieving TICI 2b/3 revascularization alone (75% vs 82%, p=0.43). Patients presented with an admitting median National Institutes of Health Stroke Scale (NIHSS) score of 17.0 (12.0–21.0) and improved to a median NIHSS score at discharge of 7.3 (1.0–11.0). Ninety day functional outcomes were 40% (modified Rankin Scale (mRS) 0–2) and 20% (mRS 6). There were two procedural complications and no symptomatic intracerebral hemorrhages.

Discussion

The ADAPT technique is a fast, safe, simple, and effective method that has facilitated our approach to acute ischemic stroke thrombectomy by utilizing the latest generation of large bore aspiration catheters to achieve previously unparalleled angiographic outcomes.
Risk factors for incident heart failure with preserved or reduced ejection fraction, and valvular heart failure, in a community-based cohort
Authors: Gong Fei Fei , Jelinek Michael V , Castro Julian M , Coller Jennifer M , McGrady Michele , Boffa Umberto , Shiel Louise , Liew Danny , Wolfe Rory , Stewart Simon , Owen Alice J , Krum Henry , Reid Christopher M , Prior David L , Campbell Duncan J
Published: July 2018

Background

The lack of effective therapies for heart failure with preserved ejection fraction (HFpEF) reflects an incomplete understanding of its pathogenesis.

Design

We analysed baseline risk factors for incident HFpEF, heart failure with reduced ejection fraction (HFrEF) and valvular heart failure (VHF) in a community-based cohort.

Methods

We recruited 2101 men and 1746 women ≥60 years of age with hypertension, diabetes, ischaemic heart disease (IHD), abnormal heart rhythm, cerebrovascular disease or renal impairment. Exclusion criteria were known heart failure, left ventricular ejection fraction <50% or valve abnormality >mild in severity. Median follow-up was 5.6 (IQR 4.6–6.3) years.

Results

Median time to heart failure diagnosis in 162 participants was 4.5 (IQR 2.7–5.4) years, 73 with HFpEF, 53 with HFrEF and 36 with VHF. Baseline age and amino-terminal pro-B-type natriuretic peptide levels were associated with HFpEF, HFrEF and VHF. Pulse pressure, IHD, waist circumference, obstructive sleep apnoea and pacemaker were associated with HFpEF and HFrEF; atrial fibrillation (AF) and warfarin therapy were associated with HFpEF and VHF and peripheral vascular disease and low platelet count were associated with HFrEF and VHF. Additional risk factors for HFpEF were body mass index (BMI), hypertension, diabetes, renal dysfunction, low haemoglobin, white cell count and β-blocker, statin, loop diuretic, non-steroidal anti-inflammatory and clopidogrel therapies, for HFrEF were male gender and cigarette smoking and for VHF were low diastolic blood pressure and alcohol intake. BMI, diabetes, low haemoglobin, white cell count and warfarin therapy were more strongly associated with HFpEF than HFrEF, whereas male gender and low platelet count were more strongly associated with HFrEF than HFpEF.

Conclusions

Our data suggest a major role for BMI, hypertension, diabetes, renal dysfunction, and inflammation in HFpEF pathogenesis; strategies directed to prevention of these risk factors may prevent a sizeable proportion of HFpEF in the community.

Trial registration number

NCT00400257,NCT00604006andNCT01581827.
A molecular dynamics study: Structures and thermal stability of PdmPt(13−m)Ag42 ternary nanoalloys
Authors: Garip Ali Kemal
Published: July 2018

Structural optimization of ternary PdmPt[Formula: see text]Ag[Formula: see text] nanoalloys was performed using the basin-hopping algorithm, and the Gupta many-body potential was adopted to model interatomic interaction. The optimization results show that all compositions have a structure based on icosahedron with a core–shell segregation. While the Ag atoms prefer to segregate to the surface, Pd and Pt atoms were located at the core of the cluster due to the higher surface and cohesive energy. The single platinum atom with the highest cohesive energy in Pd[Formula: see text]Pt1Ag[Formula: see text] nanoalloy was located at the center of the cluster. Also in all other compositions except Pd[Formula: see text]Ag[Formula: see text], Pd atoms occupy the second shell position of the icosahedron structure. We used classical molecular dynamics (MD) simulations in canonical ensemble conditions (NVT) to investigate the melting temperatures of ternary PdmPt[Formula: see text]Ag[Formula: see text] nanoalloys with the interatomic interactions modeled by the same potential with optimizations. The icosahedral structures were taken as the initial configurations for MD simulations. We obtained caloric curves and Lindemann indexes to investigate the melting transitions. The simulation results showed that varying the composition gives rise to a fluctuation in melting temperatures. The highest melting temperature belongs to the Pd9Pt4Ag[Formula: see text] nanoalloy cluster within the other compositions. However, the relative stability investigation indicates the Pd8Pt5Ag[Formula: see text] nanoalloy cluster as the most stable composition. The Lindemann indexes obtained for the second and third shell of icosahedral structures show that the melting takes place as a whole without any surface premelting.
Experimental Verification of Pseudo-Differential Electronically Controllable Multifunction Filter Using Modified Current Differencing/Summing Units
Authors: Jerabek Jan , Dvorak Jan , Sotner Roman , Herencsar Norbert , Koton Jaroslav
Published: July 2018

This paper presents the synthesis and analysis of reconfigurable frequency filter with differential input and differential output terminals and its experimental verification. The inner structure of the filter has single-ended form, i.e., filter behaves as the so-called pseudo-differential circuit. Filtering function can be electronically reconfigured between low-pass (LP) and band-pass (BP) responses. Active elements of the filter are differential voltage buffer (DVB) as an input stage and modified current differencing unit (MCDU) together with modified current summing unit (MCSU) as the inner and also output stage. Each of the important parameters of the filter (angular pole frequency, quality factor and pass-band gain) is electronically controllable by parameters of these active elements used. Some of the parameters of the filter are controlled by two independent parameters, i.e., are dual-controlled, which enables the extended electronic controllability. The proposed topology operates in the voltage mode and both input nodes have high input impedance. Expected behavior of the filter is analyzed and verified by PSpice simulations using CMOS models of above-mentioned active elements. Moreover, features of the filter in both configurations were successfully verified also by experimental measurements using behavioral models of active elements.
Does a Standalone, “Cold” (Low-Thermal-Noise), Linear Resistor Exist Without Cooling?
Authors: Song Jiaao , Kish Laszlo B.
Published: July 2018

Classical ways of cooling require some of these elements: phase transition, compressor, nonlinearity, valve and/or switch. A recent example is the 2018 patent of Linear Technology Corporation; they utilize the shot noise of a diode to produce a standalone nonlinear resistor that has [Formula: see text]/2 noise temperature (about 150[Formula: see text]K). While such “resistor” can cool its environment when it is AC coupled to a resistor, the thermal cooling effect is only academically interesting. The importance of the invention is of another nature: In low-noise electronics, it is essential to have resistors with low-noise temperature to improve the signal-to-noise ratio. A natural question is raised: can we use a linear system with feedback to cool and, most importantly, to show reduced noise temperature? Exploring this problem, we were able to produce standalone linear resistors showing strongly reduced thermal noise. Our must successful test shows [Formula: see text]/100 (about 3[Formula: see text]K) noise temperature, as if the resistor would have been immersed in liquid helium. We also found that there is an old solution offering similar results utilizing the virtual ground of an inverting amplifier at negative feedback. There, the “cold” resistor is generated at the input of an amplifier. On the other hand, our system generates the “cold” resistance at the output, which can have practical advantages.
Fekete–Szegö inequalities for some subclasses of bi-univalent functions through quasi-subordination
Authors: Bharavi Sharma R. , Rajya Laxmi K.
Published: July 2018

In this paper, we have investigated Fekete–Szegö problems and coefficient estimates for some subclasses of bi-univalent functions defined in terms of quasi-subordination. These inequalities result in the bounds of the third coefficient in Maclaurin’s series expansion in the unit disc.
Opportunistic Spectrum Allocation for Interference Mitigation Amongst Coexisting Wireless Body Area Networks
Authors: Movassaghi Samaneh , Smith David B. , Abolhasan Mehran , Jamalipour Abbas
Published: July 2018

Wireless Body Area Networks (WBANs) are seen as the enabling technology for developing new generations of medical applications, such as remote health monitoring. As such it is expected that WBANs will predominantly transport mission-critical and delay sensitive data. A key strategy towards building a reliable WBAN is to ensure such networks are highly immune to interference. To achieve this, new and intelligent wireless spectrum allocation strategies are required not only to avoid interference, but also to make best-use of the limited available spectrum. This article presents a new spectrum allocation scheme referred to as Smart Channel Assignment (SCA), which maximizes the resource usage and transmission speed by deploying a partially-orthogonal channel assignment scheme between coexisting WBANs as well as offering a convenient tradeoff among spectral reuse efficiency, transmission rate, and outage. Detailed analytical studies verify that the proposed SCA strategy is robust to variations in channel conditions, increase in sensor node-density within each WBAN, and an increase in number of coexisting WBANs.
Novel Character Identification Utilizing Semantic Relation with Animate Nouns in Korean
Authors: Park Taekeun , Kim Seung-Hoon
Published: July 2018

For identifying speakers of quoted speech or extracting social networks from literature, it is indispensable to extract character names and nominals. However, detecting proper nouns in the novels translated into or written in Korean is harder than in English because Korean does not have a capitalization feature. In addition, it is almost impossible for any proper noun dictionary to include all kinds of character names that have been created or will be created by authors. Fortunately, a previous study shows that utilizing postpositions for animate nouns is a simple and effective tool for character identification in Korean novels without a proper noun dictionary and a training corpus. In this article, we propose a character identification method utilizing the semantic relation with known animate nouns. For 80 novels in Korean, the proposed method increases the micro- and macro-average recall by 13.68% and 11.86%, respectively, while decreasing the micro-average precision by 0.28% and increasing the macro-average precision by 0.07% compared to the previous study. If we focus on characters that are responsible for more than 1% of the character name mentions in each novel, the micro- and macro-average F-measure of the proposed method are 96.98% and 97.32%, respectively.
Comparison of Methods to Annotate Named Entity Corpora
Authors: Komiya Kanako , Suzuki Masaya , Iwakura Tomoya , Sasaki Minoru , Shinnou Hiroyuki
Published: July 2018

The authors compared two methods for annotating a corpus for the named entity (NE) recognition task using non-expert annotators: (i) revising the results of an existing NE recognizer and (ii) manually annotating the NEs completely. The annotation time, degree of agreement, and performance were evaluated based on the gold standard. Because there were two annotators for one text for each method, two performances were evaluated: the average performance of both annotators and the performance when at least one annotator is correct. The experiments reveal that semi-automatic annotation is faster, achieves better agreement, and performs better on average. However, they also indicate that sometimes, fully manual annotation should be used for some texts whose document types are substantially different from the training data document types. In addition, the machine learning experiments using semi-automatic and fully manually annotated corpora as training data indicate that the F-measures could be better for some texts when manual instead of semi-automatic annotation was used. Finally, experiments using the annotated corpora for training as additional corpora show that (i) the NE recognition performance does not always correspond to the performance of the NE tag annotation and (ii) the system trained with the manually annotated corpus outperforms the system trained with the semi-automatically annotated corpus with respect to newswires, even though the existing NE recognizer was mainly trained with newswires.
Liveness-based garbage collection for lazy languages
Authors: Kumar K. Prasanna , Sanyal Amitabha , Karkare Amey
Published: July 2018

We consider the problem of reducing the memory required to run lazy first-order functional programs. Our approach is to analyze programs for liveness of heap-allocated data. The result of the analysis is used to preserve only live data—a subset of reachable data—during garbage collection. The result is an increase in the garbage reclaimed and a reduction in the peak memory requirement of programs. Whereas this technique has already been shown to yield benefits for eager first-order languages, the lack of a statically determinable execution order and the presence of closures pose new challenges for lazy languages. These require changes both in the liveness analysis itself and in the design of the garbage collector. To show the effectiveness of our method, we implemented a copying collector that uses the results of the liveness analysis to preserve live objects, both evaluated and closures. Our experiments confirm that for programs running with a liveness-based garbage collector, there is a significant decrease in peak memory requirements. In addition, a sizable reduction in the number of collections ensures that in spite of using a more complex garbage collector, the execution times of programs running with liveness and reachability-based collectors remain comparable.
Prescient memory: exposing weak memory model behavior by looking into the future
Authors: Cao Man , Roemer Jake , Sengupta Aritra , Bond Michael D.
Published: July 2018

Shared-memory parallel programs are hard to get right. A major challenge is that language and hardware memory models allow unexpected, erroneous behaviors for executions containing data races. Researchers have introduced dynamic analyses that expose weak memory model behaviors, but these approaches cannot expose behaviors due to loading a "future value" -- a value written by a program store that executes after the program load that uses the value. This paper presents prescient memory (PM), a novel dynamic analysis that exposes behaviors due to future values. PM speculatively returns a future value at a program load, and tries to validate the speculative value at a later store. To enable PM to expose behaviors due to future values in real application executions, we introduce a novel approach that increases the chances of using and successfully validating future values, by profiling and predicting future values and guiding execution. Experiments show that our approach is able to uncover a few previously unknown behaviors due to future values in benchmarked versions of real applications. Overall, PM overcomes a key limitation of existing approaches, broadening the scope of program behaviors that dynamic analyses can expose.
Understanding and improving JVM GC work stealing at the data center scale
Authors: Hassanein Wessam
Published: July 2018

Garbage collection (GC) is a critical part of performance in managed run-time systems such as the OpenJDK Java Virtual Machine (JVM). With a large number of latency sensitive applications written in Java the performance of the JVM is essential. Java application servers run in data centers on a large number of multi-core servers, thus load balancing in multi-threaded GC phases is critical. Dynamic load balancing in the JVM GC is achieved through work stealing, a well known and effective method to balance tasks across threads. This paper analyzes the JVM work stealing behaviour, and introduces a novel work stealing technique that improves performance, GC CPU utilization, scalability, and reduces the cost of jobs running on Google’s data-centers. We analyze both the DaCapo benchmark suite as well as Google’s data-center jobs. Our results show that the Gmail front-end server shows a 15-20% GC CPU reduction, and a 5% CPU performance improvement. Our analysis of a sample of ~59K jobs shows that GC CPU utilization improves by 38% geomean, 12% weighted geomean. GC pause time improves by 16% geomean, 20% weighted geomean. Full GC pause time improves by 34% geomean, 12% weighted geomean.
Rethinking a heap hierarchy as a cache hierarchy: a higher-order theory of memory demand (HOTM)
Authors: Li Pengcheng , Luo Hao , Ding Chen
Published: July 2018

Modern memory allocators divide the available memory between different threads and object size classes. They use many parameters that are related and mutually affecting. Existing solutions are based on heuristics which cannot serve all applications equally well. This paper presents a theory of memory demand. The theory enables the global optimization of heap parameters for an application. The paper evaluates the theory and the optimization using multi-threaded micro-benchmarks as well as real applications including Apache, Ghostscript interpreter, and a database benchmarking tool and shows that the global optimization theoretically outperforms three typical heuristics by 15% to 113%.
FitSpec: refining property sets for functional testing
Authors: Braquehais Rudy , Runciman Colin
Published: July 2018

This paper presents FitSpec, a tool providing automated assistance in the task of refining sets of test properties for Haskell functions. FitSpec tests mutant variations of functions under test against a given property set, recording any surviving mutants that pass all tests. The number of surviving mutants and any smallest survivor are presented to the user. A surviving mutant indicates incompleteness of the property set, prompting the user to amend a property or to add a new one, making the property set stronger. Based on the same test results, FitSpec also provides conjectures in the form of equivalences and implications between property subsets. These conjectures help the user to identify minimal core subsets of properties and so to reduce the cost of future property-based testing.
How to twist pointers without breaking them
Authors: Chauhan Satvik , Kurur Piyush P. , Yorgey Brent A.
Published: July 2018

Using the theory of monoids and monoid actions, we give a unified framework that handles three common pointer manipulation tasks, namely, data serialisation, deserialisation, and memory allocation. Our main theoretical contribution is the formulation of the notion of a
twisted functor
, a generalisation of the semi-direct product construction for monoids. We show that semi-direct products and twisted functors are particularly well suited as an abstraction for many pointer manipulation tasks.

We describe the implementation of these abstractions in the context of a cryptographic library for Haskell. Twisted functors allow us to abstract all pointer arithmetic and size calculations into a few lines of code, significantly reducing the opportunities for buffer overflows.
Experience report: developing high performance HTTP/2 server in Haskell
Authors: Yamamoto Kazuhiko
Published: July 2018

While the speed of the Internet has been increasing, HTTP/1.1 has been plagued by head-of-line blocking, low concurrency and redundant headers. To solve these problems, HTTP/2 was standardized. This paper summarizes our experience implementing HTTP/2 in Haskell. We found several techniques to improve the performance of the header compression and identified a suitable data structure for HTTP/2 priority. Also, we showed that Haskell lightweight threads are useful for HTTP/2 where the common tactics of one lightweight thread per connection cannot be used. The HTTP/2 implementation of Warp, the popular HTTP server library in Haskell, ultimately provides better throughput than its HTTP/1.1 counterpart.
Autobahn: using genetic algorithms to infer strictness annotations
Authors: Wang Yisu Remy , Nunez Diogenes , Fisher Kathleen
Published: July 2018

Although laziness enables beautiful code, it comes with non-trivial performance costs. The ghc compiler for Haskell has optimizations to reduce those costs, but the optimizations are not sufficient. As a result, Haskell also provides a variety of strictness annotations so that users can indicate program points where an expression should be evaluated eagerly. Skillful use of those annotations is a black art, known only to expert Haskell programmers. In this paper, we introduce AUTOBAHN, a tool that uses genetic algorithms to automatically infer strictness annotations that improve program performance on representative inputs. Users examine the suggested annotations for soundness and can instruct AUTOBAHN to automatically produce modified sources. Experiments on 60 programs from the NoFib benchmark suite show that AUTOBAHN can infer annotation sets that improve runtime performance by a geometric mean of 8.5%. Case studies show AUTOBAHN can reduce the live size of a GC simulator by 99% and infer application-specific annotations for Aeson library code. A 10-fold cross-validation study shows the AUTOBAHN -optimized GC simulator generally outperforms a version optimized by an expert.
Lazy graph processing in Haskell
Authors: Dexter Philip , Liu Yu David , Chiu Kenneth
Published: July 2018

This paper presents a Haskell library for graph processing: DeltaGraph. One unique feature of this system is that intentions to perform graph updates can be memoized
in-graph
in a decentralized fashion, and the propagation of these intentions within the graph can be decoupled from the realization of the updates. As a result, DeltaGraph can respond to updates in constant time and work elegantly with parallelism support. We build a Twitter-like application on top of DeltaGraph to demonstrate its effectiveness and explore parallelism and opportunistic computing optimizations.
QuickFuzz: an automatic random fuzzer for common file formats
Authors: Grieco Gustavo , Ceresa Martín , Buiras Pablo
Published: July 2018

Fuzzing is a technique that involves testing programs using invalid or erroneous inputs. Most fuzzers require a set of valid inputs as a starting point, in which mutations are then introduced. QuickFuzz is a fuzzer that leverages QuickCheck-style random test-case generationto automatically test programs that manipulate common file formats by fuzzing. We rely on existing Haskell implementations of file-format-handling libraries found on Hackage, the community-driven Haskell code repository. We have tried QuickFuzz in the wild and found that the approach is effective in discovering vulnerabilities in real-world implementations of browsers, image processing utilities and file compressors among others. In addition, we introduce a mechanism to automatically derive random generators for the types representing these formats. QuickFuzz handles most well-known image and media formats, and can be used to test programs and libraries written in any language.
Causal commutative arrows revisited
Authors: Yallop Jeremy , Liu Hai
Published: July 2018

Causal commutative arrows (CCA) extend arrows with additional constructs and laws that make them suitable for modelling domains such as functional reactive programming, differential equations and synchronous dataflow.

Earlier work has revealed that a syntactic transformation of CCA computations into normal form can result in significant performance improvements, sometimes increasing the speed of programs by orders of magnitude.

In this work we reformulate the normalization as a type class instance and derive optimized observation functions via a specialization to stream transformers to demonstrate that the same dramatic improvements can be achieved without leaving the language.
Detrended fluctuation analysis in a simple spreadsheet as a tool for teaching fractal physiology
Authors: Arsac Laurent M. , Deschodt-Arsac Véronique
Published: July 2018

Fractal physiology demonstrated growing interest over the last decades among physiologists, neuroscientists, and clinicians. Many physiological systems coordinate themselves for reducing variability and maintain a steady state. When recorded over time, the output signal exhibits small fluctuations around a stable value. It is becoming increasingly clear that these fluctuations, in most free-running healthy systems, are not simply due to uncorrelated random errors and possess interesting properties, one of which is the property of fractal dynamics. Fractal dynamics model temporal processes in which similar patterns occur across multiple timescales of measurement. Smaller copies of a pattern are nested within larger copies of the pattern, a property termed scale invariance. It is an intriguing process that may deserve attention for implementing curricular development for students to reconsider homeostasis. Teaching fractal dynamics needs to make calculating resources available for students. The present paper offers a calculating resource that uses a basic formula and is executable in a simple spreadsheet. The spreadsheet allows computing detrended fluctuation analysis (DFA), the most frequently used method in the literature to quantify the fractal-scaling index of a physiological time series. DFA has been nicely described by the group at Harvard that designed it; the authors made the C language source available. Going further, it is suggested here that a guide to build DFA step by step in a spreadsheet has many advantages for teaching fractal physiology and beyond: 1) it promotes the DIY (do-it-yourself) in students and highlights scaling concepts; and 2) it makes DFA available for people not familiarized with executing code in C language.
CDKN2AGermline Rare Coding Variants and Risk of Pancreatic Cancer in Minority Populations
Authors: McWilliams Robert R. , Wieben Eric D. , Chaffee Kari G. , Antwi Samuel O. , Raskin Leon , Olopade Olufunmilayo I. , Li Donghui , Highsmith W. Edward , Colon-Otero Gerardo , Khanna Lauren G. , Permuth Jennifer B. , Olson Janet E. , Frucht Harold , Genkinger Jeanine , Zheng Wei , Blot William J. , Wu Lang , Almada Luciana L. , Fernandez-Zapico Martin E. , Sicotte Hugues , Pedersen Katrina S. , Petersen Gloria M.
Published: July 2018

Background: Pathogenic germline mutations in the CDKN2A tumor suppressor gene are rare and associated with highly penetrant familial melanoma and pancreatic cancer in non-Hispanic whites (NHW). To date, the prevalence and impact of CDKN2A rare coding variants (RCV) in racial minority groups remain poorly characterized. We examined the role of CDKN2A RCVs on the risk of pancreatic cancer among minority subjects.

Methods: We sequenced CDKN2A in 220 African American (AA) pancreatic cancer cases, 900 noncancer AA controls, and 183 Nigerian controls. RCV frequencies were determined for each group and compared with that of 1,537 NHW patients with pancreatic cancer. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for both a case–case comparison of RCV frequencies in AAs versus NHWs, and case–control comparison between AA cases versus noncancer AA controls plus Nigerian controls. Smaller sets of Hispanic and Native American cases and controls also were sequenced.

Results: One novel missense RCV and one novel frameshift RCV were found among AA patients: 400G>A and 258_278del. RCV carrier status was associated with increased risk of pancreatic cancer among AA cases (11/220; OR, 3.3; 95% CI, 1.5–7.1; P = 0.004) compared with AA and Nigerian controls (17/1,083). Further, AA cases had higher frequency of RCVs: 5.0% (OR, 13.4; 95% CI, 4.9–36.7; P < 0.001) compared with NHW cases (0.4%).

Conclusions: CDKN2A RCVs are more common in AA than in NHW patients with pancreatic cancer and associated with moderately increased pancreatic cancer risk among AAs.

Impact: RCVs in CDKN2A are frequent in AAs and are associated with risk for pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 27(11); 1364–70. ©2018 AACR.
Dietary Fat Intake after Colon Cancer Diagnosis in Relation to Cancer Recurrence and Survival: CALGB 89803 (Alliance)
Authors: Van Blarigan Erin L. , Ou Fang-Shu , Niedzwiecki Donna , Zhang Sui , Fuchs Charles S. , Saltz Leonard , Mayer Robert J. , Venook Alan , Ogino Shuji , Song Mingyang , Benson Al , Hantel Alexander , Atkins James N. , Giovannucci Edward L. , Meyerhardt Jeffrey A.
Published: July 2018

Background: Higher intake of long-chain ω-3 polyunsaturated fatty acids and nuts, rich plant sources of unsaturated fats, after colon cancer diagnosis are associated with improved survival. It is not known whether the amount or the distribution of other types of fat is associated with survival after colon cancer.

Methods: We prospectively examined postdiagnostic total, animal, and vegetable fats, as well as the saturated, monounsaturated, polyunsaturated, and trans fat in relation to disease-free survival among 1,011 patients with stage III colon cancer. Patients were enrolled between 1999 and 2001 at the onset of adjuvant chemotherapy and followed for recurrence or death through 2009.

Results: During median follow-up of 7 years, we observed 305 deaths and 81 recurrences (total events: 386). Neither total nor any specific type of dietary fat examined was statistically significantly associated with risk of cancer recurrence or death from any cause (disease-free survival) after stage III colon cancer.

Conclusions: The amount and type (animal, vegetable, saturated, monounsaturated, polyunsaturated, and trans) of dietary fat consumed after colon cancer does not appear to be substantially associated with risk of recurrence or survival.

Impact: Neither total nor major types (animal, vegetable, saturated, monounsaturated, polyunsaturated, and trans) of dietary fat consumed after colon cancer was associated with cancer recurrence or survival. Cancer Epidemiol Biomarkers Prev; 27(10); 1227–30. ©2018 AACR.
SK3 Gene Polymorphism Is Associated with Taxane Neurotoxicity and Cell Calcium Homeostasis
Authors: Rua Carina , Guéguinou Maxime , Soubai Imane , Viel Erika , Potier-Cartereau Marie , Chantome Aurélie , Barbe Catherine , Bougnoux Philippe , Barin-Le Guellec Chantal , Vandier Christophe
Published: July 2018

Purpose: Taxane-induced peripheral neuropathy is a common side effect induced by anticancer agents, and no drug capable of preventing its occurrence or ameliorating its long-term course has been identified. The physiology of taxane neuropathy is not clear, and diverse mechanisms have been suggested, with ion channels regulating Ca2+ homeostasis appearing good candidates. The calcium-activated potassium channel SK3 is encoded by the KCNN3 gene, which is characterized by a length polymorphism due to variable number of CAG repeats.

Experimental Design: To study the influence of the polymorphism of CAG motif repeat of KCNN3 on the development of taxane-induced neuropathy, we evaluated 176 patients treated with taxanes for breast cancer. In parallel, we measured Ca2+ entry using Fura2-AM dye in HEK cells expressing short versus long CAG alleles of KCNN3.

Results: In the current study, we report that in the presence of docetaxel, Ca2+ entry was significantly increased in cells expressing short versus long CAG alleles of SK3 and that a SK3-lipid blocker inhibits this effect. We found that patients carrying a short KCNN3 allele exhibited significantly increased incidence of taxane neuropathy compared with those carrying longer alleles.

Conclusions: The clinical implication of these findings is that KCNN3 polymorphism may increase patient susceptibility to taxane neurotoxicity and that the use of SK3 blockers during taxanes’ administration may represent an interesting approach for the prevention of this neurotoxicity. Clin Cancer Res; 24(21); 5313–20. ©2018 AACR.
Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss
Authors: de Bono Johann S. , De Giorgi Ugo , Rodrigues Daniel Nava , Massard Christophe , Bracarda Sergio , Font Albert , Arranz Arija Jose Angel , Shih Kent C. , Radavoi George Daniel , Xu Na , Chan Wai Y. , Ma Han , Gendreau Steven , Riisnaes Ruth , Patel Premal H. , Maslyar Daniel J. , Jinga Viorel
Published: July 2018

Purpose:

PI3K–Akt–mTOR and androgen receptor (AR) signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating with poor prognosis. We therefore conducted a phase Ib/II study of the combination of ipatasertib, an Akt inhibitor, with the CYP17 inhibitor abiraterone in patients with mCRPC.

Patients and Methods: Patients were randomized 1:1:1 to ipatasertib 400 mg, ipatasertib 200 mg, or placebo, with abiraterone 1,000 mg orally. Coprimary efficacy endpoints were radiographic progression-free survival (rPFS) in the intent-to-treat population and in patients with PTEN-loss tumors.

Results:

rPFS was prolonged in the ipatasertib cohort versus placebo, with similar trends in overall survival and time-to-PSA progression. A larger rPFS prolongation for the combination was demonstrated in PTEN-loss tumors versus those without. The combination was well tolerated, with no treatment-related deaths.

Conclusions:

In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors.

See related commentary by Zhang et al., p. 901
Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma
Authors: Ishida Chiaki T. , Zhang Yiru , Bianchetti Elena , Shu Chang , Nguyen Trang T.T. , Kleiner Giulio , Sanchez-Quintero Maria J. , Quinzii Catarina M. , Westhoff Mike-Andrew , Karpel-Massler Georg , Prabhu Varun V. , Allen Joshua E. , Siegelin Markus D.
Published: July 2018

Purpose: The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma (GBM).

Experimental Design: Gene set enrichment, LC/MS, and extracellular flux analyses were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency.

Results: Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures in vitro and in multiple xenograft models in vivo. ONC212 displayed the highest potency. High levels of c-myc predict susceptibility to growth inhibition and apoptosis induction by imipridones and increased host survival in orthotopic patient-derived xenografts. As early as 1 hour, imipridones elicit on-target inhibition, followed by dephosphorylation of GSK3β at serine 9. GSK3β promotes phosphorylation of c-myc at threonine 58 and enhances its proteasomal degradation. Moreover, inhibition of c-myc by BRD4 antagonists sensitizes for imipridone-induced apoptosis in stem-like GBM cells in vitro and in vivo. Imipridones affect energy metabolism by suppressing both glycolysis and oxidative phosphorylation, which is accompanied by a compensatory activation of the serine-one carbon-glycine (SOG) pathway, involving the transcription factor ATF4. Interference with the SOG pathway through novel inhibitors of PHGDH results in synergistic cell death induction in vitro and in vivo.

Conclusions: These results suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridones lead to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies. Clin Cancer Res; 24(21); 5392–406. ©2018 AACR.