bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of targeted next-generation sequencing forRASmutation detection in FFPE colorectal cancer tissues: comparison with Sanger sequencing and ARMS-Scorpion real-time PCR
Authors: Gao Jie , Wu Huanwen , Wang Li , Zhang Hui , Duan Huanli , Lu Junliang , Liang Zhiyong
Published: January 2016

Objective

To validate the targeted next-generation sequencing (NGS) platform-Ion Torrent PGM forKRASexon 2 and expandedRASmutations detection in formalin-fixed paraffin-embedded (FFPE) colorectal cancer (CRC) specimens, with comparison of Sanger sequencing and ARMS-Scorpion real-time PCR.

Setting

Beijing, China.

Participants

51 archived FFPE CRC samples (36 men, 15 women) were retrospectively randomly selected and then checked by an experienced pathologist for sequencing based on histological confirmation of CRC and availability of sufficient tissue.

Methods

RAS mutations were detected in the 51 FFPE CRC samples by PGM analysis, Sanger sequencing and the TherascreenKRASassay, respectively. Agreement among the 3 methods was assessed. Assay sensitivity was further determined by sequencing serially diluted DNA from FFPE cell lines with known mutation statuses.

Results

13 of 51 (25.5%) cases had a mutation inKRASexon 2, as determined by PGM analysis. PGM analysis showed 100% (51/51) concordance with Sanger sequencing (κ=1.000, 95% CI 1 to 1) and 98.04% (50/51) agreement with the Therascreen assay (κ=0.947, 95% CI 0.844 to 1) for detectingKRASexon 2 mutations, respectively. The only discrepant case harboured aKRASexon 2 mutation (c.37G>T) that was not covered by the Therascreen kit. The dilution series experiment results showed that PGM was able to detectKRASmutations at a frequency of as low as 1%. Importantly,RASmutations other thanKRASexon 2 mutations were also detected in 10 samples by PGM. Furthermore, mutations in other CRC-related genes could be simultaneously detected in a single test by PGM.

Conclusions

The targeted NGS platform is specific and sensitive forKRASexon 2 mutation detection and is appropriate for use in routine clinical testing. Moreover, it is sample saving and cost-efficient and time-efficient, and has great potential for clinical application to expand testing to include mutations inRASand other CRC-related genes.
Competing priorities in treatment decision-making: a US national survey of individuals with depression and clinicians who treat depression
Authors: Barr Paul J , Forcino Rachel C , Mishra Manish , Blitzer Rachel , Elwyn Glyn
Published: January 2016

Objective

To identify information priorities for consumers and clinicians making depression treatment decisions and assess shared decision-making (SDM) in routine depression care.

Design

20 questions related to common features of depression treatments were provided. Participants were initially asked to select which features were important, and in a second stage they were asked to rank their top 5 ‘important features’ in order of importance. Clinicians were asked to provide rankings according to both consumer and clinician perspectives. Consumers completed CollaboRATE, a measure of SDM. Multiple logistic regression analysis identified consumer characteristics associated with CollaboRATE scores.

Setting

Online cross-sectional surveys fielded in September to December 2014.

Participants

We administered surveys to convenience samples of US adults with depression and clinicians who treat depression. Consumer sampling was targeted to reflect age, gender and educational attainment of adults with depression in the USA.

Primary outcome measures

Information priority rankings; CollaboRATE, a 3-item consumer-reported measure of SDM.

Results

972 consumers and 244 clinicians completed the surveys. The highest ranked question for both consumers and clinicians was ‘Will the treatment work?’ Clinicians were aware of consumers’ priorities, yet did not always prioritise that information themselves, particularly insurance coverage and cost of treatment. Only 18% of consumers reported high levels of SDM. Working with a psychiatrist (OR 1.87; 95% CI 1.07 to 3.26) and female gender (OR 2.04; 95% CI 1.25 to 3.34) were associated with top CollaboRATE scores.

Conclusions

While clinicians know what information is important to consumers making depression treatment decisions, they do not always address these concerns. This mismatch, coupled with low SDM, adversely affects the quality of depression care. Development of a decision support intervention based on our findings can improve levels of SDM and provide clinicians and consumers with a tool to address the existing misalignment in information priorities.
Lessons learnt from the Bristol Girls Dance Project cluster RCT: implications for designing and implementing after-school physical activity interventions
Authors: Edwards Mark J , May Thomas , Kesten Joanna M , Banfield Kate , Bird Emma L , Powell Jane E , Sebire Simon J , Jago Russell
Published: January 2016

Objective

To consider implementation issues associated with the delivery of Bristol Girls Dance Project (BGDP) and to identify improvements that may aid the design of after-school physical activity (PA) interventions.

Design

Two-armed cluster randomised control trial. The BGDP was a 20-week school-based intervention, consisting of two 75 min after-school dance sessions per week, which aimed to support Year 7 girls to be more physically active.

Setting

18 secondary schools (nine intervention, nine control) in the Greater Bristol area (as an indication of deprivation, children eligible for the pupil premium in participant schools ranged from 6.9 to 53.3%).

Participants

571 Year 7 girls. This article reports on qualitative data collected from 59 girls in the intervention arm of the trial, 10 dance instructors and 9 school contacts involved in the delivering of the BGDP.

Methods

Data were obtained from nine focus groups with girls (one per intervention school), and interviews with dance instructors and school contacts. Focus groups sought views of girls’ motivation to participate, teaching styles and experiences of the intervention. Interviews explored views on implementation and dissemination. Framework analysis was used to analyse data.

Results

Qualitative data elicited three themes associated with the delivery of BGDP that affected implementation: project design, session content and project organisation. ‘Project design’ found issues associated with recruitment, timetabling and session quantity to influence the effectiveness of BGDP. ‘Session content’ found that dance instructors delivered a range of content and that girls enjoyed a variety of dance. Themes within ‘project organisation’ suggested an ‘open enrolment’ policy and greater parental involvement may facilitate better attendance.

Conclusions

After-school PA interventions have potential for increasing PA levels among adolescent girls. There is a need to consider the context in which interventions are delivered and implement them in ways that are appropriate to the needs of participants.

Trial registration number

ISRCTN52882523.
A qualitative assessment of the impact of a uterine balloon tamponade package on decisions regarding the role of emergency hysterectomy in women with uncontrolled postpartum haemorrhage in Kenya and Senegal
Authors: Pendleton Anna Alaska , Natarajan Abirami , Ahn Roy , Nelson Brett D , Eckardt Melody J , Burke Thomas F
Published: January 2016

Objectives

To assess the impact of a every second matters for mothers and babies uterine balloon tamponade package (ESM-UBT) on provider decisions regarding emergency hysterectomy in cases of uncontrolled postpartum haemorrhage (PPH).

Design

Qualitative assessment and analysis of a subgroup extracted from a larger database that contains all UBT device uses among ESM-UBT trained health providers.

Setting

Health facilities in Kenya and Senegal with ESM-UBT training and capable of performing emergency hysterectomies.

Participants

All medical doctors who had placed a UBT for uncontrolled PPH subsequent to implementation of ESM-UBT at their facility, and who also had the capabilities of performing emergency hysterectomies.

Primary outcome measures

The impact of ESM-UBT on decisions regarding emergency hysterectomy in cases of uncontrolled PPH.

Results

30 of the 31 medical doctors (97%) who fulfilled the inclusion criteria were independently interviewed. Collectively the interviewed medical doctors had placed over 80 UBT devices for uncontrolled PPH since ESM-UBT implementation. All 30 responded that UBT devices immediately controlled haemorrhage and prevented women from being taken to emergency hysterectomy. All 30 would continue to use UBT devices in future cases of uncontrolled PPH.

Conclusions

These preliminary data suggest that following ESM-UBT implementation, emergency hysterectomy for uncontrolled PPH may be averted by use of uterine balloon tamponade.
Adolescent girls and young adult women's perceptions of superslims cigarette packaging: a qualitative study
Authors: Ford Allison , Moodie Crawford , Purves Richard , MacKintosh Anne Marie
Published: January 2016

Objectives

To explore perceptions of superslims packaging, including compact ‘lipstick’ packs, in line with 3 potential impacts identified within the impact assessment of the European Union (EU) Tobacco Products Directive: appeal, harm perceptions and the seriousness of warning of health risks.

Design

Qualitative focus group study.

Setting

Informal community venues in Scotland, UK.

Participants

75 female non-smokers and occasional smokers (age range 12–24).

Results

Compact ‘lipstick’-type superslims packs were perceived most positively and rated as most appealing. They were also viewed as less harmful than more standard sized cigarette packs because of their smaller size and likeness to cosmetics. Additionally, ‘lipstick’ packs were rated as less serious in terms of warning about the health risks associated with smoking, either because the small font size of the warnings was difficult to read or because the small pack size prevented the text on the warnings from being displayed properly. Bright pack colours and floral designs were also thought to detract from the health warning.

Conclusions

As superslims packs were found to increase appeal, mislead with respect to level of harm, and undermine the on-pack health warnings, this provides support for the decision to ban ‘lipstick’-style cigarette packs in the EU and has implications for policy elsewhere.
Safety performance testing of climbing helmet-mounted cameras
Authors: Martin Philip S , StClair Vincent J , Willis Claire , Rickman Alastair C , Hynd David
Published: January 2016

Background

No research establishing the effects of climbing helmet-mounted cameras on head injury biomechanics.

Objective

Establish the potential effects of climbing helmet-mounted cameras on the injury risks associated with falling object strikes and falls onto flat and angled surfaces.

Methods

Three experimental studies were developed via the adaptation of European helmet testing standards and regulations. Study 1 performed falling striker tests to the helmet, Study 2 performed linear headform drop tests onto a flat anvil and Study 3 performed oblique headform drop tests onto an anvil angled 15° from vertical. Three helmet categories (hard-shell, foam and hybrid) were impacted at three locations (vertex, front and side), using five camera mounting combinations and three control helmets. Data was collected for the forces, linear accelerations, rotational velocities and rotational accelerations experienced by the headform.

Results

All helmet and camera combinations investigated by this project complied with current legislative performance criteria, while no combination exceeded published injury thresholds. No increase in head injury risk was observed for the forces transferred to the head during falling object strikes or with the linear accelerations experienced during falls onto flat and angled surfaces. Finally, although greater rotational head velocities and accelerations were observed with falls onto flat and angled surfaces, no injury threshold was exceeded by any investigated helmet and camera combination.

Conclusions

All helmet and camera combinations investigated by this project complied with current legislative performance criteria, while no combination exceeded published injury thresholds. Further research may be required to establish the effects of additional impact mechanism, helmet or camera mounting configurations.
The impact of evidence: evolving therapy for acute ischemic stroke in a large healthcare system
Authors: Mascitelli Justin R , Wilson Natalie , Shoirah Hazem , De Leacy Reade A , Furtado Sunil V , Paramasivam Srinivasan , Oermann Eric K , Mack William J , Tuhrim Stanley , Dangayach Neha S , Meyer Stephan A , Bederson Joshua B , Mocco J , Fifi Johanna T
Published: January 2016

Background

With a recent surge of clinical trials, the treatment of ischemic stroke has undergone dramatic changes.

Objective

To evaluate the impact of evidence and a revamped stroke protocol on a large healthcare system.

Methods

A retrospective review of 69 patients with ischemic stroke treated with intra-arterial therapy was carried out. Cohort 1 included patients treated before implementation of a new stroke protocol, and cohort 2 after implementation. Angiographic outcome was graded using the Thrombolysis in Cerebral Infarction (TICI) score. Clinical outcomes were assessed using the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS).

Results

Primary outcomes comparing cohorts demonstrated decreased arrival-to-puncture time (cohort 2: 104 vs cohort 1: 181 min, p<0.001), similar TICI 2b/3 rates (86.5% vs 81.3%, p=0.5530), and similar percentage of patients with discharge mRS 0–2 (18.9% vs 21.9%, p=0.7740). Notable secondary outcomes for cohort 2 included decreased puncture-to-first pass time (34 vs 53 min, p <0.001), increased TICI 3 rates (37.8% vs 18.8%, p=0.0290), a trend toward greater improvements in NIHSS on postoperative day 1 (6.8 vs 2.6, p=0.0980) and discharge (9.5 vs 6.7, p=0.1130), and a trend toward increased percentage of patients discharged with mRS 0–3 (48.6% vs 34.4%, p=0.3280 NS). There were similar rates of symptomatic intracerebral hemorrhage (10.8% vs 9.4%, p=0.9570) and death (10.8% vs 15.6%, p=0.5530).

Conclusions

An interdisciplinary and rapid response to the emergence of strong clinical evidence can result in dramatic changes in a large healthcare system.
Prevalence of dural venous sinus stenosis and hypoplasia in a generalized population
Authors: Durst Christopher R , Ornan David A , Reardon Michael A , Mehndiratta Prachi , Mukherjee Sugoto , Starke Robert M , Wintermark Max , Evans Avery , Jensen Mary E , Crowley R Webster , Gaughen John , Liu Kenneth C
Published: January 2016

Background and purpose

While recent literature has described the prevalence of transverse sinus stenosis in patients with idiopathic intracranial hypertension, tinnitus, and refractory headaches, it is unclear what the prevalence is in the general population. This study evaluates the prevalence of venous sinus stenosis and hypoplasia in the general patient population.

Materials and methods

355 of 600 consecutive patients who underwent CT angiography of the head met the inclusion criteria. The diameters of the dural venous sinuses were recorded. Each study was evaluated by a neuroradiologist for the presence of stenoses. Univariate and multivariate statistical analyses were performed by a statistician.

Results

The prevalence of unilateral transverse sinus stenosis or hypoplasia in a sample of patients representing the general population was 33%, the prevalence of bilateral transverse sinus stenosis was 5%, and the prevalence of unilateral stenosis with contralateral hypoplasia was 1%. A multivariate analysis identified arachnoid granulations as a predictor of stenosis (p<0.001). Gender trended toward significance (p=0.094). Race was not a significant predictor of stenosis (p=0.745).

Conclusions

The prevalence of bilateral transverse sinus stenosis in the general population is not trivial. These data may be used as a reference for understanding the mechanistic role of stenoses in idiopathic intracranial hypertension, tinnitus, and refractory headaches.
Suppression of arthritis-induced bone erosion by a CRAC channel antagonist
Authors: Blair Harry C , Soboloff Jonathan , Robinson Lisa J , Tourkova Irina L , Larrouture Quitterie C , Witt Michelle R , Holaskova Ida , Schafer Rosana , Elliott Meenal , Hirsch Raphael , Barnett John B
Published: January 2016

Objective

We have shown in vitro and in vivo that osteoclast maturation requires calcium-release activated calcium (CRAC) channels. In inflammatory arthritis, osteoclasts mediate severe and debilitating bone erosion. In the current study, we assess the value of CRAC channels as a therapeutic target to suppress bone erosion in acute inflammatory arthritis.

Methods

Collagen-induced arthritis (CIA) was induced in mice. The CRAC channel inhibitor 3,4-dichloropropionaniline (DCPA) and a placebo was administered 1 day prior to collagen II booster to induce arthritis. Effects on swelling, inflammatory cell invasion in joints, serum cytokines and bone erosion were measured.

Results

Assays, by blinded observers, of arthritis severity showed that DCPA, 21 mg/kg/day, suppressed arthritis development over 3 weeks. Bone and cartilage damage in sections of animal feet was reduced approximately 50%; overall swelling of joints was reduced by a similar amount. Effects on bone density by µCT showed clear separation in DCPA-treated CIA animals from CIA without treatment, while differences between controls without CIA and CIA treated with DCPA differed by small amounts and in most cases were not statistically different. Response was not related to anticollagen titres. There were no adverse effects in the treated group on animal weight or activity, consistent with low toxicity. The effect was maximal 12–17 days after collagen booster, during the rapid appearance of arthritis in untreated CIA. At 20 days after treatment (day 40), differences in arthritis score were reduced and tumour necrosis factor α, interleukin (IL)-1, or IL-6 in the serum of the animals were similar in treated and untreated animals.

Conclusions

DCPA, a novel inhibitor of CRAC channels, suppresses bone erosion associated with acute arthritis in mice and might represent a new treatment modality for acute arthrits.
Relationships between maximal strength, muscle size, and myosin heavy chain isoform composition and postactivation potentiation
Authors: Seitz Laurent B. , Trajano Gabriel S. , Haff G. Gregory , Dumke Charles C.L.S. , Tufano James J. , Blazevich Anthony J.
Published: January 2016

The purpose of this study was to examine the relationships between maximal voluntary postactivation potentiation (PAP) and maximal knee extensor torque, quadriceps cross-sectional area (CSA) and volume, and type II myosin heavy chain (MHC) isoform percentage in human skeletal muscle. Thirteen resistance-trained men completed a test protocol consisting of 2 isokinetic knee extensions at 180°·s–1performed before and 1, 4, 7, and 10 min after the completion of 4 maximal knee extensions at 60°·s–1(i.e., a conditioning activity (CA)). Magnetic resonance imaging and muscle microbiopsy procedures were completed on separate days to assess quadriceps CSA and volume and MHC isoform content. Maximal voluntary PAP response was assessed as the ratio of the highest knee extensor torques measured before and after the CA. There were large to very large correlations between maximal voluntary PAP response and maximal knee extensor torque (r = 0.62) and quadriceps CSA (r = 0.68) and volume (r = 0.63). Nonetheless, these correlations were not statistically significant after adjusting for the influence of type II MHC percentage using partial correlation analysis. By contrast, the strongest correlation was observed for type II MHC percentage (r = 0.77), and this correlation remained significant after adjusting for the other variables. Maximal voluntary PAP response is strongly correlated with maximal knee extensor torque and quadriceps CSA and volume, but is mostly clearly associated with the type II myosin isoform percentage in human skeletal muscle.
Acute administration of high doses of taurine does not substantially improve high-intensity running performance and the effect on maximal accumulated oxygen deficit is unclear
Authors: Milioni Fabio , Malta Elvis de Souza , Rocha Leandro George Spinola do Amaral , Mesquita Camila Angélica Asahi , de Freitas Ellen Cristini , Zagatto Alessandro Moura
Published: January 2016

The aim of the present study was to investigate the effects of acute administration of taurine overload on time to exhaustion (TTE) of high-intensity running performance and alternative maximal accumulated oxygen deficit (MAODALT). The study design was a randomized, placebo-controlled, crossover design. Seventeen healthy male volunteers (age: 25 ± 6 years; maximal oxygen uptake: 50.5 ± 7.6 mL·kg−1·min−1) performed an incremental treadmill-running test until voluntary exhaustion to determine maximal oxygen uptake and exercise intensity at maximal oxygen uptake. Subsequently, participants completed randomly 2 bouts of supramaximal treadmill-running at 110% exercise intensity at maximal oxygen uptake until exhaustion (placebo (6 g dextrose) or taurine (6 g) supplementation), separated by 1 week. MAODALT was determined using a single supramaximal effort by summating the contribution of the phosphagen and glycolytic pathways. When comparing the results of the supramaximal trials (i.e., placebo and taurine conditions) no differences were observed for high-intensity running TTE (237.70 ± 66.00 and 277.30 ± 40.64 s; p = 0.44) and MAODALT (55.77 ± 8.22 and 55.06 ± 7.89 mL·kg−1; p = 0.61), which seem to indicate trivial and unclear differences using the magnitude-based inferences approach, respectively. In conclusion, acute 6 g taurine supplementation before exercise did not substantially improve high-intensity running performance and showed an unclear effect on MAODALT.
Speech Act Identification Using Semantic Dependency Graphs with Probabilistic Context-Free Grammars
Authors: Yeh Jui-Feng
Published: January 2016

We propose an approach for identifying the speech acts of speakers’ utterances in conversational spoken dialogue that involves using semantic dependency graphs with probabilistic context-free grammars (PCFGs). The semantic dependency graph based on the HowNet knowledge base is adopted to model the relationships between words in an utterance parsed by PCFG. Dependency relationships between words within the utterance are extracted by decomposing the semantic dependency graph according to predefined events. The corresponding values of semantic slots are subsequently extracted from the speaker's utterances according to the corresponding identified speech act. The experimental results obtained when using the proposed approach indicated that the accuracy rates of speech act detection and task completion were 95.6% and 77.4% for human-generated transcription (REF) and speech-to-text recognition output (STT), respectively, and the average numbers of turns of each dialogue were 8.3 and 11.8 for REF and STT, respectively. Compared with Bayes classifier, partial pattern tree, and Bayesian-network-based approaches, we obtained 14.1%, 9.2%, and 3% improvements in the accuracy of speech act identification, respectively.
The Hoare Logic of Deterministic and Nondeterministic Monadic Recursion Schemes
Authors: Mamouras Konstantinos
Published: January 2016

The equational theory of deterministic monadic recursion schemes is known to be decidable by the result of Sénizergues on the decidability of the problem of DPDA equivalence. In order to capture some properties of the domain of computation, we augment equations with certain hypotheses. This preserves the decidability of the theory, which we call
simple implicational theory
. The asymptotically fastest algorithm known for deciding the equational theory, and also for deciding the simple implicational theory, has a running time that is nonelementary. We therefore consider a restriction of the properties about schemes to check: instead of arbitrary equations
f
≡
g
between schemes, we focus on propositional Hoare assertions {
p
}
f
{
q
}, where
f
is a scheme and
p
,
q
are tests. Such Hoare assertions have a straightforward encoding as equations. For this subclass of program properties, we can also handle nondeterminism at the syntactic and/or at the semantic level, without increasing the complexity of the theories. We investigate the
Hoare theory
of monadic recursion schemes, that is, the set of valid implications whose conclusions are Hoare assertions and whose premises are of a certain simple form. We present a sound and complete Hoare-style calculus for this theory. We also show that the Hoare theory can be decided in exponential time, and that it is complete for this class.
Mechanics of Hydraulic Fractures
Authors: Detournay Emmanuel
Published: January 2016

Hydraulic fractures represent a particular class of tensile fractures that propagate in solid media under pre-existing compressive stresses as a result of internal pressurization by an injected viscous fluid. The main application of engineered hydraulic fractures is the stimulation of oil and gas wells to increase production. Several physical processes affect the propagation of these fractures, including the flow of viscous fluid, creation of solid surfaces, and leak-off of fracturing fluid. The interplay and the competition between these processes lead to multiple length scales and timescales in the system, which reveal the shifting influence of the far-field stress, viscous dissipation, fracture energy, and leak-off as the fracture propagates.
Motion and Deformation of Elastic Capsules and Vesicles in Flow
Authors: Barthès-Biesel Dominique
Published: January 2016

This article reviews the mechanical behavior of a capsule under the influence of viscous deforming forces due to a flowing fluid. It focuses on artificial capsules and vesicles with an internal liquid core enclosed by a very thin membrane with different constitutive laws. The recent modeling strategies are outlined together with their respective advantages and limitations. I then consider the motion and deformation of a single, initially spherical capsule freely suspended in a simple shear or plane hyperbolic flow and discuss the effect of the membrane constitutive law, initial prestress, membrane buckling, and bulk or membrane viscosity. Finally, I consider the flow of spherical capsules in small pores and show how numerical models can be used to evaluate the mechanical properties of the membrane.
A Normal Mode Perspective of Intrinsic Ocean-Climate Variability
Authors: Dijkstra Henk
Published: January 2016

Observations of the sea surface temperature field over more than a century indicate that there is pronounced variability in the climate system. Understanding the mechanisms of this variability is crucial to determine the role of variations in ocean heat content in past and future climate changes. When a steady background state in an ocean-climate model is slightly perturbed, the long-time response is determined by the spatial patterns of the normal modes. Here, the type and patterns of normal modes for a range of different equilibrium states in a hierarchy of ocean-climate models are reviewed. The rather elegant organization of these normal modes is demonstrated, and prototype physical mechanisms explaining patterns of sea surface temperature variability based on these normal modes are provided.
Seismic Sounding of Convection in the Sun
Authors: Hanasoge Shravan , Gizon Laurent , Sreenivasan Katepalli R.
Published: January 2016

Thermal convection is the dominant mechanism of energy transport in the outer envelope of the Sun (one-third by radius). It drives global fluid circulations and magnetic fields observed on the solar surface. Vigorous surface convection excites a broadband spectrum of acoustic waves that propagate within the interior and set up modal resonances. These acoustic waves, also called seismic waves in this context, are observed at the surface of the Sun by space- and ground-based telescopes. Seismic sounding, the study of these seismic waves to infer the internal properties of the Sun, constitutes helioseismology. Here we review our knowledge of solar convection, especially that obtained through seismic inference. Several characteristics of solar convection, such as differential rotation, anisotropic Reynolds stresses, the influence of rotation on convection, and supergranulation, are considered. On larger scales, several inferences suggest that convective velocities are substantially smaller than those predicted by theory and simulations. This discrepancy challenges the models of internal differential rotation that rely on convective stresses as a driving mechanism and provide an important benchmark for numerical simulations.
Quadrant Analysis in Turbulence Research: History and Evolution
Authors: Wallace James M.
Published: January 2016

Quadrant analysis is a simple, but quite useful, turbulence data-processing technique that has been widely used, principally in the investigation of turbulent shear flows. This article traces the origins of the technique and reviews how it has been applied during the more than 40 years since it was conceived. Applications are highlighted that have expanded the technique beyond its original formulation.
Dynamics and Instabilities of Vortex Pairs
Authors: Leweke Thomas , Le Dizès Stéphane , Williamson Charles H.K.
Published: January 2016

This article reviews the characteristics and behavior of counter-rotating and corotating vortex pairs, which are seemingly simple flow configurations yet immensely rich in phenomena. Since the reviews in this journal by Widnall (1975) and Spalart (1998) , who studied the fundamental structure and dynamics of vortices and airplane trailing vortices, respectively, there have been many analytical, computational, and experimental studies of vortex pair flows. We discuss two-dimensional dynamics, including the merging of same-sign vortices and the interaction with the mutually induced strain, as well as three-dimensional displacement and core instabilities resulting from this interaction. Flows subject to combined instabilities are also considered, in particular the impingement of opposite-sign vortices on a ground plane. We emphasize the physical mechanisms responsible for the flow phenomena and clearly present the key results that are useful to the reader for predicting the dynamics and instabilities of parallel vortices.
Bacterial Hydrodynamics
Authors: Lauga Eric
Published: January 2016

Bacteria predate plants and animals by billions of years. Today, they are the world's smallest cells, yet they represent the bulk of the world's biomass and the main reservoir of nutrients for higher organisms. Most bacteria can move on their own, and the majority of motile bacteria are able to swim in viscous fluids using slender helical appendages called flagella. Low–Reynolds number hydrodynamics is at the heart of the ability of flagella to generate propulsion at the micrometer scale. In fact, fluid dynamic forces impact many aspects of bacteriology, ranging from the ability of cells to reorient and search their surroundings to their interactions within mechanically and chemically complex environments. Using hydrodynamics as an organizing framework, I review the biomechanics of bacterial motility and look ahead to future challenges.
Nitrogen and Oxygen Isotopic Studies of the Marine Nitrogen Cycle
Authors: Casciotti Karen L.
Published: January 2016

The marine nitrogen cycle is a complex web of microbially mediated reactions that control the inventory, distribution, and speciation of nitrogen in the marine environment. Because nitrogen is a major nutrient that is required by all life, its availability can control biological productivity and ecosystem structure in both surface and deep-ocean communities. Stable isotopes of nitrogen and oxygen in nitrate and nitrite have provided new insights into the rates and distributions of marine nitrogen cycle processes, especially when analyzed in combination with numerical simulations of ocean circulation and biogeochemistry. This review highlights the insights gained from dual-isotope studies applied at regional to global scales and their incorporation into oceanic biogeochemical models. These studies represent significant new advances in the use of isotopic measurements to understand the modern nitrogen cycle, with implications for the study of past ocean productivity, oxygenation, and nutrient status.
Cross-Shelf Exchange
Authors: Brink K.H.
Published: January 2016

Cross-shelf exchange dominates the pathways and rates by which nutrients, biota, and materials on the continental shelf are delivered and removed. This follows because cross-shelf gradients of most properties are usually far greater than those in the alongshore direction. The resulting transports are limited by Earth's rotation, which inhibits flow from crossing isobaths. Thus, cross-shelf flows are generally weak compared with alongshore flows, and this leads to interesting observational issues. Cross-shelf flows are enabled by turbulent mixing processes, nonlinear processes (such as momentum advection), and time dependence. Thus, there is a wide range of possible effects that can allow these critical transports, and different natural settings are often governed by different combinations of processes. This review discusses examples of representative transport mechanisms and explores possible observational and theoretical paths to future progress.
Sex differences in clinical characteristics and long-term outcome in acute decompensated heart failure patients with preserved and reduced ejection fraction
Authors: Nakada Yasuki , Kawakami Rika , Nakano Tomoya , Takitsume Akihiro , Nakagawa Hitoshi , Ueda Tomoya , Nishida Taku , Onoue Kenji , Soeda Tsunenari , Okayama Satoshi , Takeda Yukiji , Watanabe Makoto , Kawata Hiroyuki , Okura Hiroyuki , Saito Yoshihiko
Published: January 2016

In patients with acute decompensated heart failure (ADHF), sex differences considering clinical and pathophysiologic features are not fully understood. We investigated sex differences in left ventricular (LV) ejection fraction (LVEF), plasma B-type natriuretic peptide (BNP) levels, and prognostic factors in patients with ADHF in Japan. We studied 748 consecutive ADHF patients of 821 patients registered in the ADHF registry between January 2007 and December 2014. Patients were divided into four groups based on sex and LVEF [reduced (ejection fraction, or EF, <50%, heart failure with reduced EF, or HFrEF) or preserved (EF ≥50%, heart failure with preserved LVEF, or HFpEF)]. The primary endpoint was the combination of cardiovascular death and heart failure (HF) admission. The present study consisted of 311 female patients (50% HFrEF, 50% HFpEF) and 437 male patients (63% HFrEF, 37% HFpEF). There was significant difference between sexes in the LVEF distribution profile. The ratio of HFpEF patients was significantly higher in female patients than in male patients ( P = 0.0004). Although there were no significant sex differences in median plasma BNP levels, the prognostic value of BNP levels was different between sexes. Kaplan-Meier analysis revealed that the high BNP group had worse prognosis than the low BNP group in male but not in female patients. In multivariate analysis, log transformed BNP at discharge predicted cardiovascular events in male but not in female HF patients (female, hazard ratio: 1.169; 95% confidence interval: 0.981–1.399; P = 0.0806; male, hazard ratio: 1.289; 95% confidence interval: 1.120–1.481; P = 0.0004). In patients with ADHF, the distribution of LV function and the prognostic significance of plasma BNP levels for long-term outcome were different between the sexes.
Consequences of intravascular lymphatic valve properties: a study of contraction timing in a multi-lymphangion model
Authors: Bertram Christopher D. , Macaskill Charlie , Davis Michael J. , Moore James E.
Published: January 2016

The observed properties of valves in collecting lymphatic vessels include transmural pressure-dependent bias to the open state and hysteresis. The bias may reduce resistance to flow when the vessel is functioning as a conduit. However, lymphatic pumping implies a streamwise increase in mean pressure across each valve, suggesting that the bias is then potentially unhelpful. Lymph pumping by a model of several collecting lymphatic vessel segments (lymphangions) in series, which incorporated these properties, was investigated under conditions of adverse pressure difference while varying the refractory period between active muscular contractions and the inter-lymphangion contraction delay. It was found that many combinations of the timing parameters and the adverse pressure difference led to one or more intermediate valves remaining open instead of switching between open and closed states during repetitive contraction cycles. Cyclic valve switching was reliably indicated if the mean pressure in a lymphangion over a cycle was higher than that in the lymphangion upstream, but either lack of or very brief valve closure could cause mean pressure to be lower downstream. Widely separated combinations of refractory period and delay time were found to produce the greatest flow-rate for a given pressure difference. The efficiency of pumping was always maximized by a long refractory period and lymphangion contraction starting when the contraction of the lymphangion immediately upstream was peaking. By means of an ex vivo experiment, it was verified that intermediate valves in a chain of pumping lymphangions can remain open, while the lymphangions on either side of the open valve continue to execute contractions.
Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury
Authors: House Stacey L. , Castro Angela M. , Lupu Traian S. , Weinheimer Carla , Smith Craig , Kovacs Attila , Ornitz David M.
Published: January 2016

Fibroblast growth factor (FGF) signaling is cardioprotective in various models of myocardial infarction. FGF receptors (FGFRs) are expressed in multiple cell types in the adult heart, but the cell type-specific FGFR signaling that mediates different cardioprotective endpoints is not known. To determine the requirement for FGFR signaling in endothelium in cardiac ischemia-reperfusion injury, we conditionally inactivated the Fgfr1 and Fgfr2 genes in endothelial cells with Tie2-Cre ( Tie2-Cre, Fgfr1f/f, Fgfr2f/fDCKO mice). Tie2-Cre, Fgfr1f/f, Fgfr2f/fDCKO mice had normal baseline cardiac morphometry, function, and vessel density. When subjected to closed-chest, regional cardiac ischemia-reperfusion injury, Tie2-Cre, Fgfr1f/f, Fgfr2f/fDCKO mice showed a significantly increased hypokinetic area at 7 days, but not 1 day, after reperfusion. Tie2-Cre, Fgfr1f/f, Fgfr2f/fDCKO mice also showed significantly worsened cardiac function compared with controls at 7 days but not 1 day after reperfusion. Pathophysiological analysis showed significantly decreased vessel density, increased endothelial cell apoptosis, and worsened tissue hypoxia in the peri-infarct area at 7 days following reperfusion. Notably, Tie2-Cre, Fgfr1f/f, Fgfr2f/fDCKO mice showed no impairment in the cardiac hypertrophic response. These data demonstrate an essential role for FGFR1 and FGFR2 in endothelial cells for cardiac functional recovery and vascular remodeling following in vivo cardiac ischemia-reperfusion injury, without affecting the cardiac hypertrophic response. This study suggests the potential for therapeutic benefit from activation of endothelial FGFR pathways following ischemic injury to the heart.
Targeting host calpain proteases decreases influenza A virus infection
Authors: Blanc Fany , Furio Laetitia , Moisy Dorothée , Yen Hui-Ling , Chignard Michel , Letavernier Emmanuel , Naffakh Nadia , Mok Chris Ka Pun , Si-Tahar Mustapha
Published: January 2016

Influenza A viruses (IAV) trigger contagious acute respiratory diseases. A better understanding of the molecular mechanisms of IAV pathogenesis and host immune responses is required for the development of more efficient treatments of severe influenza. Calpains are intracellular proteases that participate in diverse cellular responses, including inflammation. Here, we used in vitro and in vivo approaches to investigate the role of calpain signaling in IAV pathogenesis. Calpain expression and activity were found altered in IAV-infected bronchial epithelial cells. With the use of small-interfering RNA (siRNA) gene silencing, specific synthetic inhibitors of calpains, and mice overexpressing calpastatin, we found that calpain inhibition dampens IAV replication and IAV-triggered secretion of proinflammatory mediators and leukocyte infiltration. Remarkably, calpain inhibition has a protective impact in IAV infection, since it significantly reduced mortality of mice challenged not only by seasonal H3N2- but also by hypervirulent H5N1 IAV strains. Hence, our study suggests that calpains are promising therapeutic targets for treating IAV acute pneumonia.
miR-185 mediates lung epithelial cell death after oxidative stress
Authors: Zhang Duo , Lee Heedoo , Cao Yong , Dela Cruz Charles S. , Jin Yang
Published: January 2016

Lung epithelial cell death is a prominent feature involved in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Hyperoxia-induced ALI is an established animal model mimicking human ARDS. Small noncoding RNAs such as microRNAs (miRNAs) have potent physiological and pathological functions involving multiple disease processes. Emerging interests focus on the potential of miRNAs to serve as novel therapeutic targets and diagnostic biomarkers. We found that hyperoxia highly induces miR-185 and its precursor in human lung epithelial cells in a time-dependent manner, and this observation is confirmed using mouse primary lung epithelial cells. The hyperoxia-induced miR-185 is mediated by reactive oxygen species. Furthermore, histone deacetylase 4 (HDAC4) locates in the promoter region of miR-185. We found that hyperoxia suppresses HDAC4 specifically in a time-dependent manner and subsequently affects histone deacetylation, resulting in an elevated miR-185 transcription. Using MC1586, an inhibitor of class IIa HDACs, we showed that inhibition of class IIa HDACs upregulates the expression of miR-185, mimicking the effects of hyperoxia. Functionally, miR-185 promotes hyperoxia-induced lung epithelial cell death through inducing DNA damage. We confirmed functional roles of miR-185 using both the loss- and gain-of-function approaches. Moreover, multiple 14-3-3δ pathway proteins are highly attenuated by miR-185 in the presence of hyperoxia. Taken together, hyperoxia-induced miR-185 in lung epithelial cells contributes to oxidative stress-associated epithelial cell death through enhanced DNA damage and modulation of 14-3-3δ pathways.
Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression
Authors: Galam Lakshmi , Rajan Ashna , Failla Athena , Soundararajan Ramani , Lockey Richard F. , Kolliputi Narasaiah
Published: January 2016

Increasing evidence shows that hyperoxia is a serious complication of oxygen therapy in acutely ill patients that causes excessive production of free radicals leading to hyperoxia-induced acute lung injury (HALI). Our previous studies have shown that P2X7 receptor activation is required for inflammasome activation during HALI. However, the role of P2X7 in HALI is unclear. The main aim of this study was to determine the effect of P2X7 receptor gene deletion on HALI. Wild-type (WT) and P2X7 knockout (P2X7 KO) mice were exposed to 100% O2for 72 h. P2X7 KO mice treated with hyperoxia had enhanced survival in 100% O2compared with the WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1β, TNF-α, monocyte chemoattractant protein-1, and IL-6 levels were attenuated in P2X7 KO mice. P2X7 deletion decreased lung edema and alveolar protein content, which are associated with enhanced alveolar fluid clearance. In addition, activation of the inflammasome was suppressed in P2X7-deficient alveolar macrophages and was associated with suppression of IL-1β release. Furthermore, P2X7-deficient alveolar macrophage in type II alveolar epithelial cells (AECs) coculture model abolished protein permeability across mouse type II AEC monolayers. Deletion of P2X7 does not lead to a decrease in epithelial sodium channel expression in cocultures of alveolar macrophages and type II AECs. Taken together, these findings show that deletion of P2X7 is a protective factor and therapeutic target for the amelioration of hyperoxia-induced lung injury.
Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686)
Authors: Karlovich Chris , Goldman Jonathan W. , Sun Jong-Mu , Mann Elaina , Sequist Lecia V. , Konopa Krzysztof , Wen Wei , Angenendt Philipp , Horn Leora , Spigel David , Soria Jean-Charles , Solomon Benjamin , Camidge D. Ross , Gadgeel Shirish , Paweletz Cloud , Wu Lin , Chien Sean , O'Donnell Patrick , Matheny Shannon , Despain Darrin , Rolfe Lindsey , Raponi Mitch , Allen Andrew R. , Park Keunchil , Wakelee Heather
Published: January 2016

Purpose: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors.

Experimental Design: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing.

Results: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 – 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 – 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response.

Conclusions: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386–95. ©2016 AACR.