bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction: The Modern-Day Sport-Science and Sports-Medicine “Quest for the Holy Grail”
Authors: McCall Alan , Fanchini Maurizio , Coutts Aaron J.
Published: May 2017

In high-performance sport, science and medicine practitioners employ a variety of physical and psychological tests, training and match monitoring, and injury-screening tools for a variety of reasons, mainly to predict performance, identify talented individuals, and flag when an injury will occur. The ability to “predict” outcomes such as performance, talent, or injury is arguably sport science and medicine’s modern-day equivalent of the “Quest for the Holy Grail.” The purpose of this invited commentary is to highlight the common misinterpretation of studies investigating association to those actually analyzing prediction and to provide practitioners with simple recommendations to quickly distinguish between methods pertaining to association and those of prediction.
Novel Sampling Method for Assessing Human-Pathogen Interactions in the Natural Environment Using Boot Socks and Citizen Scientists, with Application to Campylobacter Seasonality
Authors: Jones Natalia R. , Millman Caroline , van der Es Mike , Hukelova Miroslava , Forbes Ken J. , Glover Catherine , Haldenby Sam , Hunter Paul R. , Jackson Kathryn , O'Brien Sarah J. , Rigby Dan , Strachan Norval J. C. , Williams Nicola , Lake Iain R. ,   for the ENIGMA Consortium
Published: May 2017

This paper introduces a novel method for sampling pathogens in natural environments. It uses fabric boot socks worn over walkers' shoes to allow the collection of composite samples over large areas. Wide-area sampling is better suited to studies focusing on human exposure to pathogens (e.g., recreational walking). This sampling method is implemented using a citizen science approach: groups of three walkers wearing boot socks undertook one of six routes, 40 times over 16 months in the North West (NW) and East Anglian (EA) regions of England. To validate this methodology, we report the successful implementation of this citizen science approach, the observation that
Campylobacter
bacteria were detected on 47% of boot socks, and the observation that multiple boot socks from individual walks produced consistent results. The findings indicate higher
Campylobacter
levels in the livestock-dominated NW than in EA (55.8% versus 38.6%). Seasonal differences in the presence of
Campylobacter
bacteria were found between the regions, with indications of winter peaks in both regions but a spring peak in the NW. The presence of
Campylobacter
bacteria on boot socks was negatively associated with ambient temperature (
P
= 0.011) and positively associated with precipitation (
P
< 0.001), results consistent with our understanding of
Campylobacter
survival and the probability of material adhering to boot socks.
Campylobacter jejuni
was the predominant species found;
Campylobacter coli
was largely restricted to the livestock-dominated NW. Source attribution analysis indicated that the potential source of
C. jejuni
was predominantly sheep in the NW and wild birds in EA but did not differ between peak and nonpeak periods of human incidence.

IMPORTANCE
There is debate in the literature on the pathways through which pathogens are transferred from the environment to humans. We report on the success of a novel method for sampling human-pathogen interactions using boot socks and citizen science techniques, which enable us to sample human-pathogen interactions that may occur through visits to natural environments. This contrasts with traditional environmental sampling, which is based on spot sampling techniques and does not sample human-pathogen interactions. Our methods are of practical value to scientists trying to understand the transmission of pathogens from the environment to people. Our findings provide insight into the risk of
Campylobacter
exposure from recreational visits and an understanding of seasonal differences in risk and the factors behind these patterns. We highlight the
Campylobacter
species predominantly encountered and the potential sources of
C. jejuni
.
Digitally Barcoding
Mycobacterium tuberculosis
Reveals
In Vivo
Infection Dynamics in the Macaque Model of Tuberculosis
Authors: Martin Constance J. , Cadena Anthony M. , Leung Vivian W. , Lin Philana Ling , Maiello Pauline , Hicks Nathan , Chase Michael R. , Flynn JoAnne L. , Fortune Sarah M.
Published: May 2017

Infection with
Mycobacterium tuberculosis
causes a spectrum of outcomes; the majority of individuals contain but do not eliminate the infection, while a small subset present with primary active tuberculosis (TB) disease. This variability in infection outcomes is recapitulated at the granuloma level within each host, such that some sites of infection can be fully cleared while others progress. Understanding the spectrum of TB outcomes requires new tools to deconstruct the mechanisms underlying differences in granuloma fate. Here, we use novel genome-encoded barcodes to uniquely tag individual
M. tuberculosis
bacilli, enabling us to quantitatively track the trajectory of each infecting bacterium in a macaque model of TB. We also introduce a robust bioinformatics pipeline capable of identifying and counting barcode sequences within complex mixtures and at various read depths. By coupling this tagging strategy with serial positron emission tomography coregistered with computed tomography (PET/CT) imaging of lung pathology in macaques, we define a lesional map of
M. tuberculosis
infection dynamics. We find that there is no significant infection bottleneck, but there are significant constraints on productive bacterial trafficking out of primary granulomas. Our findings validate our barcoding approach and demonstrate its utility in probing lesion-specific biology and dissemination. This novel technology has the potential to greatly enhance our understanding of local dynamics in tuberculosis.

IMPORTANCE
Classically,
M. tuberculosis
infection was thought to result in either latent infection or active disease. More recently, the field has recognized that there is a spectrum of
M. tuberculosis
infection clinical outcomes. Within a single host, this spectrum is recapitulated at the granuloma level, where there can simultaneously be lesional sterilization and poorly contained disease. To better understand the lesional biology of TB infection, we digitally barcoded
M. tuberculosis
to quantitatively track the fate of each infecting bacterium. By combining this technology with serial PET-CT imaging, we can dynamically track both bacterial populations and granuloma trajectories. We demonstrate that there is little constraint on the bacterial population at the time of infection. However, the granuloma imposes a strong bottleneck on dissemination, and the subset of granulomas at risk of dissemination can be distinguished by physical features.
Microbiota-Derived Short-Chain Fatty Acids Modulate Expression of
Campylobacter jejuni
Determinants Required for Commensalism and Virulence
Authors: Luethy Paul M. , Huynh Steven , Ribardo Deborah A. , Winter Sebastian E. , Parker Craig T. , Hendrixson David R.
Published: May 2017

Campylobacter jejuni
promotes commensalism in the intestinal tracts of avian hosts and diarrheal disease in humans, yet components of intestinal environments recognized as spatial cues specific for different intestinal regions by the bacterium to initiate interactions in either host are mostly unknown. By analyzing a
C. jejuni
acetogenesis mutant defective in converting acetyl coenzyme A (Ac-CoA) to acetate and commensal colonization of young chicks, we discovered evidence for
in vivo
microbiota-derived short-chain fatty acids (SCFAs) and organic acids as cues recognized by
C. jejuni
that modulate expression of determinants required for commensalism. We identified a set of
C. jejuni
genes encoding catabolic enzymes and transport systems for amino acids required for
in vivo
growth whose expression was modulated by SCFAs. Transcription of these genes was reduced in the acetogenesis mutant but was restored upon supplementation with physiological concentrations of the SCFAs acetate and butyrate present in the lower intestinal tracts of avian and human hosts. Conversely, the organic acid lactate, which is abundant in the upper intestinal tract where
C. jejuni
colonizes less efficiently, reduced expression of these genes. We propose that microbiota-generated SCFAs and lactate are cues for
C. jejuni
to discriminate between different intestinal regions. Spatial gradients of these metabolites likely allow
C. jejuni
to locate preferred niches in the lower intestinal tract and induce expression of factors required for intestinal growth and commensal colonization. Our findings provide insights into the types of cues
C. jejuni
monitors in the avian host for commensalism and likely in humans to promote diarrheal disease.

IMPORTANCE
Campylobacter jejuni
is a commensal of the intestinal tracts of avian species and other animals and a leading cause of diarrheal disease in humans. The types of cues sensed by
C. jejuni
to influence responses to promote commensalism or infection are largely lacking. By analyzing a
C. jejuni
acetogenesis mutant, we discovered a set of genes whose expression is modulated by lactate and short-chain fatty acids produced by the microbiota in the intestinal tract. These genes include those encoding catabolic enzymes and transport systems for amino acids that are required by
C. jejuni
for
in vivo
growth and intestinal colonization. We propose that gradients of these microbiota-generated metabolites are cues for spatial discrimination between areas of the intestines so that the bacterium can locate niches in the lower intestinal tract for optimal growth for commensalism in avian species and possibly infection of human hosts leading to diarrheal disease.
Different Roles of Mitochondrial Calcium Uniporter Complex Subunits in Growth and Infectivity of
Trypanosoma cruzi
Authors: Chiurillo Miguel A. , Lander Noelia , Bertolini Mayara S. , Storey Melissa , Vercesi Anibal E. , Docampo Roberto
Published: May 2017

Trypanosoma cruzi
is the agent of Chagas disease, and the finding that this parasite possesses a mitochondrial calcium uniporter (TcMCU) with characteristics similar to that of mammalian mitochondria was fundamental for the discovery of the molecular nature of MCU in eukaryotes. We report here that ablation of
TcMCU
, or its paralog
TcMCUb
, by clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 led to a marked decrease in mitochondrial Ca
2+
uptake without affecting the membrane potential of these cells, whereas overexpression of each gene caused a significant increase in the ability of mitochondria to accumulate Ca
2+
. While
TcMCU-
knockout (KO) epimastigotes were viable and able to differentiate into trypomastigotes, infect host cells, and replicate normally, ablation of
TcMCUb
resulted in epimastigotes having an important growth defect, lower rates of respiration and metacyclogenesis, more pronounced autophagy changes under starvation, and significantly reduced infectivity. Overexpression of
TcMCUb
, in contrast to what was proposed for its mammalian ortholog, did not result in a dominant negative effect on TcMCU.

IMPORTANCE
The finding of a mitochondrial calcium uniporter (MCU) in
Trypanosoma cruzi
was essential for the discovery of the molecular nature of this transporter in mammals. In this work, we used the CRISPR/Cas9 technique that we recently developed for
T. cruzi
to knock out two components of the uniporter: MCU, the pore subunit, and MCUb, which was proposed as a negative regulator of MCU in human cells. In contrast to what occurs in human cells, MCU is not essential, while MCUb is essential for growth, differentiation, and infectivity; has a bioenergetic role; and does not act as a dominant negative subunit of MCU.
Fault core process and clay content derived from XRF analysis: Salina Creek Fault, Utah
Authors: Brown Alton A. , Davies Russell K. , Treverton Anne Covault
Published: May 2017

The distribution of fault rocks interpreted across a modelled fault in oil or gas reservoirs is most often described by its clay content derived from standard industry algorithms such as shale gouge ratio and clay smear factor. These distributions are below the mapping resolution in seismic data, and the actual processes and mechanisms for the fault-rock development are not well understood. A well-exposed and well-preserved low-throw fault in an old railroad tunnel near Salina, Utah provides the access and scale to interpret fault-rock distributions, measure their clay contents and describe the fault-rock development. A significant number of fault-rock elemental compositions were measured quickly on the outcrop surface using a hand-held X-ray fluorescence (XRF) elemental analyser with a novel surface preparation and analysis strategy. The elemental data were converted to clay contents using a small set of samples where elemental composition was calibrated to X-ray diffraction mineralogy. The mineralogy data provide a basis for evaluating the degree of mixing of protolith beds during fault-rock development in the fault core. The fault core is not randomly mixed fragments derived from the protolith (gouge or breccia), but rather discrete, thin layers parallel to the fault surface, many of which can be traced back to a source sandstone or mudstone bed. The mineralogical composition of some fault-rock layers are unchanged from their protolith source bed, but other layers are mechanical mixtures of several source beds. The shale gouge ratio algorithm under-represents the average measured fault-rock clay content. The clay smear algorithm more accurately describes the clay content distribution, but underestimates the clay content heterogeneity along the smear length. A key uncertainty for predicting fault sealing remains prediction of the lengths and continuity of smears.
An Approach for Resiliency Quantification of Large Scale Systems
Authors: Longo Francesco , Ghosh Rahul , Naik Vijay K. , Rindos Andrew J. , Trivedi Kishor S.
Published: May 2017

We quantify the resiliency of large scale systems upon changes encountered beyond the normal system behavior. Formal definitions for resiliency and change are provided together with general steps for resiliency quantification and a set of resiliency metrics that can be used to quantify the effects of changes. A formalization of the approach is also shown in the form of a set of four algorithms that can be applied when large scale systems are modeled through stochastic analytic state space models (monolithic models or interacting sub-models). In particular, in the case of interacting submodels, since resiliency quantification involves understanding the transient behavior of the system, fixed-point variables evolve with time leading to non-homogenous Markov chains. At the best of our knowledge, this is the first paper facing this problem in a general way. The proposed approach is applied to an Infrastructure-as-a-Service (IaaS) Cloud use case. Specifically, we assess the impact of changes in demand and available capacity on the Cloud resiliency and we show that the approach proposed in this paper can scale for a real sized Cloud without significantly compromising the accuracy.
A Markov Reward based Resource-Latency Aware Heuristic for the Virtual Network Embedding Problem
Authors: Bianchi Francesco , Lo Presti Francesco
Published: May 2017

An ever increasing use of virtualization in various emerging scenarios, e.g.: Cloud Computing, Software Defined Networks, Data Streaming Processing, asks Infrastructure Providers (InPs) to optimize the allocation of the virtual network requests (VNRs) into a substrate network while satisfying QoS requirements. In this work, we propose MCRM, a two-stage virtual network embedding (VNE) algorithm with delay and placement constraints. Our solution revolves around a novel notion of similarity between virtual and physical nodes. To this end, taking advantage of Markov Reward theory, we define a set of metrics for each physical and virtual node which captures the amount of resources in a node neighborhood as well as the degree of proximity among nodes. By defining a notion of similarity between nodes we then simply map virtual nodes to the most similar physical node in the substrate network. We have thoroughly evaluated our algorithm through simulation. Our experiments show that MCRM achieves good performance results in terms of blocking probability and revenues for the InP, as well as a high and uniform utilization of resources, while satisfying the delay and placement requirements.
Quantitative Trade Models: Developments and Challenges
Authors: Kehoe Timothy J. , Pujolàs Pau S. , Rossbach Jack
Published: May 2017

Applied general equilibrium (AGE) models, which feature multiple countries, multiple industries, and input–output linkages across industries, have been the dominant tool for evaluating the impact of trade reforms since the 1980s. We review how these models are used to perform policy analysis and document their shortcomings in predicting the industry-level effects of past trade reforms. We argue that, to improve their performance, AGE models need to incorporate product-level data on bilateral trade relations by industry and better model how trade reforms lower bilateral trade costs. We use the least-traded-products methodology of Kehoe et al. (2015) to provide guidance on how improvements can be made. We provide further suggestions on how AGE models can incorporate recent advances in quantitative trade theory to improve their predictive ability and better quantify the gains from trade liberalization.
The Evidential Basis of Decision Making in Plant Disease Management
Authors: Hughes Gareth
Published: May 2017

The evidential basis for disease management decision making is provided by data relating to risk factors. The decision process involves an assessment of the evidence leading to taking (or refraining from) action on the basis of a prediction. The primary objective of the decision process is to identify—at the time the decision is made—the control action that provides the best predicted end-of-season outcome, calculated in terms of revenue or another appropriate metric. Data relating to disease risk factors may take a variety of forms (e.g., continuous, discrete, categorical) on measurement scales in a variety of units. Log10-likelihood ratios provide a principled basis for the accumulation of evidence based on such data and allow predictions to be made via Bayesian updating of prior probabilities.
Immune-Related Gene Expression Profiling After PD-1 Blockade in Non–Small Cell Lung Carcinoma, Head and Neck Squamous Cell Carcinoma, and Melanoma
Authors: Prat Aleix , Navarro Alejandro , Paré Laia , Reguart Noemí , Galván Patricia , Pascual Tomás , Martínez Alex , Nuciforo Paolo , Comerma Laura , Alos Llucia , Pardo Nuria , Cedrés Susana , Fan Cheng , Parker Joel S. , Gaba Lydia , Victoria Iván , Viñolas Nuria , Vivancos Ana , Arance Ana , Felip Enriqueta
Published: May 2017

Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD <3%). Overall, our results support the hypothesis that identification of a preexisting and stable adaptive immune response as defined by mRNA expression pattern is reproducible and sufficient to predict clinical outcome, regardless of the type of cancer or the PD1 therapeutic antibody administered to patients. Cancer Res; 77(13); 3540–50. ©2017 AACR.
Noninvasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer
Authors: Sharma Sai Kiran , Pourat Jacob , Abdel-Atti Dalya , Carlin Sean D. , Piersigilli Alessandra , Bankovich Alexander J. , Gardner Eric E. , Hamdy Omar , Isse Kumiko , Bheddah Sheila , Sandoval Joseph , Cunanan Kristen M. , Johansen Eric B. , Allaj Viola , Sisodiya Vikram , Liu David , Zeglis Brian M. , Rudin Charles M. , Dylla Scott J. , Poirier John T. , Lewis Jason S.
Published: May 2017

The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T; SC16LD6.5) is a first-in-class DLL3-targeted antibody–drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, although orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed 89Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a noninvasive interrogation of the in vivo status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with 89Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient–derived xenograft models. Cancer Res; 77(14); 3931–41. ©2017 AACR.
The Longitudinal Transcriptional Response to Neoadjuvant Chemotherapy with and without Bevacizumab in Breast Cancer
Authors: Silwal-Pandit Laxmi , Nord Silje , von der Lippe Gythfeldt Hedda , Møller Elen K. , Fleischer Thomas , Rødland Einar , Krohn Marit , Borgen Elin , Garred Øystein , Olsen Tone , Vu Phuong , Skjerven Helle , Fangberget Anne , Holmen Marit M. , Schlitchting Ellen , Wille Elisabeth , Nordberg Stokke Mette , Moen Vollan Hans Kristian , Kristensen Vessela , Langerød Anita , Lundgren Steinar , Wist Erik , Naume Bjørn , Lingjærde Ole Christian , Børresen-Dale Anne-Lise , Engebraaten Olav
Published: May 2017

Purpose: Chemotherapy-induced alterations to gene expression are due to transcriptional reprogramming of tumor cells or subclonal adaptations to treatment. The effect on whole-transcriptome mRNA expression was investigated in a randomized phase II clinical trial to assess the effect of neoadjuvant chemotherapy with the addition of bevacizumab.

Experimental Design: Tumor biopsies and whole-transcriptome mRNA profiles were obtained at three fixed time points with 66 patients in each arm. Altogether, 358 specimens from 132 patients were available, representing the transcriptional state before treatment start, at 12 weeks and after treatment (25 weeks). Pathologic complete response (pCR) in breast and axillary nodes was the primary endpoint.

Results: pCR was observed in 15 patients (23%) receiving bevacizumab and chemotherapy and 8 patients (12%) receiving only chemotherapy. In the estrogen receptor–positive patients, 11 of 54 (20%) treated with bevacizumab and chemotherapy achieved pCR, while only 3 of 57 (5%) treated with chemotherapy reached pCR. In patients with estrogen receptor–positive tumors treated with combination therapy, an elevated immune activity was associated with good response. Proliferation was reduced after treatment in both treatment arms and most pronounced in the combination therapy arm, where the reduction in proliferation accelerated during treatment. Transcriptional alterations during therapy were subtype specific, and the effect of adding bevacizumab was most evident for luminal-B tumors.

Conclusions: Clinical response and gene expression response differed between patients receiving combination therapy and chemotherapy alone. The results may guide identification of patients likely to benefit from antiangiogenic therapy. Clin Cancer Res; 23(16); 4662–70. ©2017 AACR.
Atheroma Susceptible to Thrombosis Exhibit Impaired Endothelial Permeability In Vivo as Assessed by Nanoparticle-Based Fluorescence Molecular Imaging
Authors: Stein-Merlob Ashley F. , Hara Tetsuya , McCarthy Jason R. , Mauskapf Adam , Hamilton James A. , Ntziachristos Vasilis , Libby Peter , Jaffer Farouc A.
Published: May 2017

Background—

The role of local alterations in endothelial functional integrity in atherosclerosis remains incompletely understood. This study used nanoparticle-enhanced optical molecular imaging to probe in vivo mechanisms involving impaired endothelial barrier function in experimental atherothrombosis.

Methods and Results—

Atherosclerosis was induced in rabbits (n=31) using aortic balloon injury and high-cholesterol diet. Rabbits received ultrasmall superparamagnetic iron oxide nanoparticles (CLIO) derivatized with a near-infrared fluorophore (CyAm7) 24 hours before near-infrared fluorescence imaging. Rabbits were then either euthanized (n=9) or underwent a pharmacological triggering protocol to induce thrombosis (n=22). CLIO-CyAm7 nanoparticles accumulated in areas of atheroma (
P
<0.05 versus reference areas). On near-infrared fluorescence microscopy, CLIO-CyAm7 primarily deposited in the superficial intima within plaque macrophages, endothelial cells, and smooth muscle cells. Nanoparticle-positive areas further exhibited impaired endothelial barrier function as illuminated by Evans blue leakage. Deeper nanoparticle deposition occurred in areas of plaque neovascularization. In rabbits subject to pharmacological triggering, plaques that thrombosed exhibited significantly higher CLIO-CyAm7 accumulation compared with nonthrombosed plaques (
P
<0.05). In thrombosed plaques, nanoparticles accumulated preferentially at the plaque-thrombus interface. Intravascular 2-dimensional near-infrared fluorescence imaging detected nanoparticles in human coronary artery–sized atheroma in vivo (
P
<0.05 versus reference segments).

Conclusions—

Plaques that exhibit impaired in vivo endothelial permeability in cell-rich areas are susceptible to subsequent thrombosis. Molecular imaging of nanoparticle deposition may help to identify biologically high-risk atheroma.
Impact of Coronary Calcification on Clinical Management in Patients With Acute Chest Pain
Authors: Bittner Daniel O. , Mayrhofer Thomas , Bamberg Fabian , Hallett Travis R. , Janjua Sumbal , Addison Daniel , Nagurney John T. , Udelson James E. , Lu Michael T. , Truong Quynh A. , Woodard Pamela K. , Hollander Judd E. , Miller Chadwick , Chang Anna Marie , Singh Harjit , Litt Harold , Hoffmann Udo , Ferencik Maros
Published: May 2017

Background—

Coronary artery calcification (CAC) may impair diagnostic assessment of coronary computed tomography angiography (CTA). We determined whether CAC affects efficiency of coronary CTA in patients with suspected acute coronary syndrome (ACS).

Methods and Results—

This is a pooled analysis of ACRIN-PA (American College of Radiology Imaging Network–Pennsylvania) 4005 and the ROMICAT-II trial (Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography) comparing an initial coronary CTA strategy to standard of care in acute chest pain patients. In the CTA arms, we investigated appropriateness of downstream testing, cost, and diagnostic yield to identify patients with obstructive coronary artery disease on subsequent invasive coronary angiography across CAC score strata (Agatston score: 0, >0–10, >10–100, >100–400, >400). Out of 1234 patients (mean age 51±8.8 years), 80 (6.5%) had obstructive coronary artery disease (≥70% stenosis) and 68 (5.5%) had ACS. Prevalence of obstructive coronary artery disease (1%–64%), ACS (1%–44%), downstream testing (4%–72%), and total (2337–8484 US$) and diagnostic cost (2310–6678 US$) increased across CAC strata (
P
<0.001). As the increase in testing and cost were lower than the increase of ACS rate in patients with CAC>400, cost to diagnose one ACS was lowest in this group (19 283 US$ versus 464 399 US$) as compared with patients without CAC. The diagnostic yield of invasive coronary angiography was highest in patients with CAC>400 (87% versus 38%).

Conclusions—

Downstream testing, total, and diagnostic cost increased with increasing CAC, but were found to be appropriate because obstructive coronary artery disease and ACS were more prevalent in patients with high CAC. In patients with acute chest pain undergoing coronary CTA, cost-efficient testing and excellent diagnostic yield can be achieved even with high CAC burden.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT01084239 and NCT00933400.
Intravascular Ultrasound Guidance Is Associated With Better Outcome in Patients Undergoing Unprotected Left Main Coronary Artery Stenting Compared With Angiography Guidance Alone
Authors: Andell Pontus , Karlsson Sofia , Mohammad Moman A. , Götberg Matthias , James Stefan , Jensen Jens , Fröbert Ole , Angerås Oskar , Nilsson Johan , Omerovic Elmir , Lagerqvist Bo , Persson Jonas , Koul Sasha , Erlinge David
Published: May 2017

Background—

Small observational studies have indicated better outcome with intravascular ultrasound (IVUS) guidance when performing unprotected left main coronary artery (LMCA) percutaneous coronary intervention (PCI), but the overall picture remains inconclusive and warrants further investigation. We studied the impact of IVUS guidance on outcome in patients undergoing unprotected LMCA PCI in a Swedish nationwide observational study.

Methods and Results—

Patients who underwent unprotected LMCA PCI between 2005 and 2014 because of stable coronary artery disease or acute coronary syndrome were included from the nationwide SCAAR (Swedish Coronary Angiography and Angioplasty Registry). Of 2468 patients, IVUS guidance was used in 621 (25.2%). The IVUS group was younger (median age, 70 versus 75 years) and had fewer comorbidities but more complex lesions. IVUS was associated with larger stent diameters (median, 4 mm versus 3.5 mm). After adjusting for potential confounders, IVUS was associated with significantly lower occurrence of the primary composite end point of all-cause mortality, restenosis, or definite stent thrombosis (hazard ratio, 0.65; 95% confidence interval, 0.50–0.84) and all-cause mortality alone (hazard ratio, 0.62; 95% confidence interval, 0.47–0.82). In 340 propensity score–matched pairs, IVUS was also associated with significantly lower occurrence of the primary end point (hazard ratio, 0.54; 95% confidence interval, 0.37–0.80).

Conclusions—

IVUS was associated with an independent and significant outcome benefit when performing unprotected LMCA PCI. Potential mediators of this benefit include larger and more appropriately sized stents, perhaps translating into lower risk of subsequent stent thrombosis. Although residual confounding cannot be ruled out, our findings indicate a possible hazard when performing unprotected LMCA PCI without IVUS guidance.
EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis
Authors: Finney Alexandra C. , Funk Steven D. , Green Jonette M. , Yurdagul Arif , Rana Mohammad Atif , Pistorius Rebecca , Henry Miriam , Yurochko Andrew , Pattillo Christopher B. , Traylor James G. , Chen Jin , Woolard Matthew D. , Kevil Christopher G. , Orr A. Wayne
Published: May 2017

Background:

Atherosclerotic plaque formation results from chronic inflammation and fibroproliferative remodeling in the vascular wall. We previously demonstrated that both human and mouse atherosclerotic plaques show elevated expression of EphA2, a guidance molecule involved in cell-cell interactions and tumorigenesis.

Methods:

Here, we assessed the role of EphA2 in atherosclerosis by deleting EphA2 in a mouse model of atherosclerosis (Apoe
−
/−
) and by assessing EphA2 function in multiple vascular cell culture models. After 8 to 16 weeks on a Western diet, male and female mice were assessed for atherosclerotic burden in the large vessels, and plasma lipid levels were analyzed.

Results:

Despite enhanced weight gain and plasma lipid levels compared with Apoe
−/−
controls, EphA2
−/−
Apoe
−/−
knockout mice show diminished atherosclerotic plaque formation, characterized by reduced proinflammatory gene expression and plaque macrophage content. Although plaque macrophages express EphA2, EphA2 deletion does not affect macrophage phenotype, inflammatory responses, and lipid uptake, and bone marrow chimeras suggest that hematopoietic EphA2 deletion does not affect plaque formation. In contrast, endothelial EphA2 knockdown significantly reduces monocyte firm adhesion under flow. In addition, EphA2
−/−
Apoe
−/−
mice show reduced progression to advanced atherosclerotic plaques with diminished smooth muscle and collagen content. Consistent with this phenotype, EphA2 shows enhanced expression after smooth muscle transition to a synthetic phenotype, and EphA2 depletion reduces smooth muscle proliferation, mitogenic signaling, and extracellular matrix deposition both in atherosclerotic plaques and in vascular smooth muscle cells in culture.

Conclusions:

Together, these data identify a novel role for EphA2 in atherosclerosis, regulating both plaque inflammation and progression to advanced atherosclerotic lesions. Cell culture studies suggest that endothelial EphA2 contributes to atherosclerotic inflammation by promoting monocyte firm adhesion, whereas smooth muscle EphA2 expression may regulate the progression to advanced atherosclerosis by regulating smooth muscle proliferation and extracellular matrix deposition.
Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation
Authors: Sharma Rishi , Oni Olurinde A. , Gupta Kamal , Sharma Mukut , Sharma Ram , Singh Vikas , Parashara Deepak , Kamalakar Surineni , Dawn Buddhadeb , Chen Guoqing , Ambrose John A. , Barua Rajat S.
Published: May 2017

Background

Atrial fibrillation (
AF
) is the most common cardiac dysrhythmia associated with significant morbidity and mortality. Several small studies have reported that low serum total testosterone (
TT
) levels were associated with a higher incidence of
AF
. In contrast, it is also reported that anabolic steroid use is associated with an increase in the risk of
AF
. To date, no study has explored the effect of testosterone normalization on new incidence of
AF
after testosterone replacement therapy (
TRT
) in patients with low testosterone.

Methods and Results

Using data from the Veterans Administrations Corporate Data Warehouse, we identified a national cohort of 76 639 veterans with low
TT
levels and divided them into 3 groups. Group 1 had
TRT
resulting in normalization of
TT
levels (normalized
TRT
), group 2 had
TRT
without normalization of
TT
levels (nonnormalized
TRT
), and group 3 did not receive
TRT
(no
TRT
). Propensity score–weighted stabilized inverse probability of treatment weighting Cox proportional hazard methods were used for analysis of the data from these groups to determine the association between post‐
TRT
levels of
TT
and the incidence of
AF
. Group 1 (40 856 patients, median age 66 years) had significantly lower risk of
AF
than group 2 (23 939 patients, median age 65 years; hazard ratio 0.90, 95%
CI
0.81–0.99,
P
=0.0255) and group 3 (11 853 patients, median age 67 years; hazard ratio 0.79, 95%
CI
0.70–0.89,
P
=0.0001). There was no statistical difference between groups 2 and 3 (hazard ratio 0.89, 95%
CI
0.78– 1.0009,
P
=0.0675) in incidence of
AF
.

Conclusions

These novel results suggest that normalization of
TT
levels after
TRT
is associated with a significant decrease in the incidence of
AF
.
Neurocognitive Performance After Cerebral Revascularization in Adult Moyamoya Disease
Authors: Zeifert Penelope D. , Karzmark Peter , Bell-Stephens Teresa E. , Steinberg Gary K. , Dorfman Leslie J.
Published: May 2017

Background and Purpose—

Cerebral revascularization using EC-IC bypass is widely used to treat moyamoya disease, but the effects of surgery on cognition are unknown. We compared performance on formal neurocognitive testing in adults with moyamoya disease before and after undergoing direct EC-IC bypass.

Methods—

We performed a structured battery of 13 neurocognitive tests on 84 adults with moyamoya disease before and 6 months after EC-IC bypass. The results were analyzed using reliable change indices for each test, to minimize test–retest variability and practice effects.

Results—

Twelve patients (14%) showed significant decline postoperatively, 9 patients (11%) improved, and 63 patients (75%) were unchanged. Similar results were obtained when the analysis was confined to those who underwent unilateral (33) or bilateral (51) revascularization.

Conclusions—

The majority of patients showed neither significant decline nor improvement in neurocognitive performance after EC-IC bypass surgery. Uncomplicated EC-IC bypass seems not to be a risk factor for cognitive decline in this patient population.
White Matter Imaging Correlates of Early Cognitive Impairment Detected by the Montreal Cognitive Assessment After Transient Ischemic Attack and Minor Stroke
Authors: Zamboni Giovanna , Griffanti Ludovica , Jenkinson Mark , Mazzucco Sara , Li Linxin , Küker Wilhelm , Pendlebury Sarah T. , Rothwell Peter M.
Published: May 2017

Background and Purpose—

Among screening tools for cognitive impairment in large cohorts, the Montreal Cognitive Assessment (MoCA) seems to be more sensitive to early cognitive impairment than the Mini-Mental State Examination (MMSE), particularly after transient ischemic attack or minor stroke. We reasoned that if MoCA-detected early cognitive impairment is pathologically significant, then it should be specifically associated with the presence of white matter hyperintensities (WMHs) and reduced fractional anisotropy (FA) on magnetic resonance imaging.

Methods—

Consecutive eligible patients with transient ischemic attack or minor stroke (Oxford Vascular Study) underwent magnetic resonance imaging and cognitive assessment. We correlated MoCA and MMSE scores with WMH and FA, then specifically studied patients with low MoCA and normal MMSE.

Results—

Among 400 patients, MoCA and MMSE scores were significantly correlated (all
P
<0.001) with WMH volumes (
r
MoCA
=−0.336;
r
MMSE
=−0.297) and FA (
r
MoCA
=0.409;
r
MMSE
=0.369) and—on voxel-wise analyses—with WMH in frontal white matter and reduced FA in almost all white matter tracts. However, only the MoCA was independently correlated with WMH volumes (
r
=−0.183;
P
<0.001), average FA values (
r
=0.218;
P
<0.001), and voxel-wise reduced FA in anterior tracts after controlling for the MMSE. In addition, patients with low MoCA but normal MMSE (n=57) had higher WMH volumes (
t
=3.1;
P
=0.002), lower average FA (
t
=−4.0;
P
<0.001), and lower voxel-wise FA in almost all white matter tracts than those with normal MoCA and MMSE (n=238).

Conclusions—

In patients with transient ischemic attack or minor stroke, early cognitive impairment detected with the MoCA but not with the MMSE was independently associated with white matter damage on magnetic resonance imaging, particularly reduced FA.
XBP1 (X-Box–Binding Protein-1)–Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G
Authors: Jiang Meng , Yu Shu , Yu Zhui , Sheng Huaxin , Li Ying , Liu Shuai , Warner David S. , Paschen Wulf , Yang Wei
Published: May 2017

Background and Purpose—

Impaired protein homeostasis induced by endoplasmic reticulum dysfunction is a key feature of a variety of age-related brain diseases including stroke. To restore endoplasmic reticulum function impaired by stress, the unfolded protein response is activated. A key unfolded protein response prosurvival pathway is controlled by the endoplasmic reticulum stress sensor (inositol-requiring enzyme-1), XBP1 (downstream X-box–binding protein-1), and O-GlcNAc (O-linked β-N-acetylglucosamine) modification of proteins (O-GlcNAcylation). Stroke impairs endoplasmic reticulum function, which activates unfolded protein response. The rationale of this study was to explore the potentials of the IRE1/XBP1/O-GlcNAc axis as a target for neuroprotection in ischemic stroke.

Methods—

Mice with
Xbp1
loss and gain of function in neurons were generated. Stroke was induced by transient or permanent occlusion of the middle cerebral artery in young and aged mice. Thiamet-G was used to increase O-GlcNAcylation.

Results—

Deletion of
Xbp1
worsened outcome after transient and permanent middle cerebral artery occlusion. After stroke, O-GlcNAcylation was activated in neurons of the stroke penumbra in young mice, which was largely Xbp1 dependent. This activation of O-GlcNAcylation was impaired in aged mice. Pharmacological increase of O-GlcNAcylation before or after stroke improved outcome in both young and aged mice.

Conclusions—

Our study indicates a critical role for the IRE1/XBP1 unfolded protein response branch in stroke outcome. O-GlcNAcylation is a prosurvival pathway that is activated in the stroke penumbra in young mice but impaired in aged mice. Boosting prosurvival pathways to counterbalance the age-related decline in the brain’s self-healing capacity could be a promising strategy to improve ischemic stroke outcome in aged brains.
On Estimating the Fiscal Benefits of Early Intervention
Authors: Feinstein Leon , Chowdry Haroon , Asmussen Kirsten
Published: May 2017

In this paper we explain some of the difficulties of providing forecasts of the financial benefits of early intervention programmes, focussing on those delivered during the early childhood period. We highlight the diversity of early intervention, and the complexity and multiplicity of outcomes. We summarise recent work at the Early Intervention Foundation to assess the evidence on the impacts of early intervention, recognising the diversity of approaches to delivery and the importance of innovation and local practice as well as of rigorous approaches to evaluating causal effects. We also describe new ways of assessing accurately the local fiscal costs of late intervention and consider the implications of this for addressing the well-established barriers to investment in prevention. Our analysis brings to the fore gaps in the evidence from which even the most rigorous ‘gold-standard’ research is not immune. These limitations prevent the production of an accurate and realistic cost-benefit ratio or net present value for the majority of programmes as delivered in practice. We suggest some paths towards a firmer foundation of evidence and a better alignment of evidence and policy.
Are Some Attitudes More Self-Defining Than Others? Assessing Self-Related Attitude Functions and Their Consequences
Authors: Zunick Peter V. , Teeny Jacob D. , Fazio Russell H.
Published: May 2017

Attitudes serve multiple functions, some related to the self-concept. We call attitudes that help people define who they are “self-defining.” Across four studies, we tested a brief self-report measure of the extent to which an attitude is self-defining. Studies 1 and 2 showed that self-defining attitudes tend to be extreme, positive, and unambivalent. Studies 3 and 4 produced two main findings. First, self-definition was related to, but not redundant with, a number of other characteristics of the attitude (e.g., attitude certainty). Second, self-definition predicted participants’ intentions to spontaneously advocate and, in Study 4, their reactions to an opportunity to advocate behaviorally (i.e., writing about their attitude in an optional response box) following a self-threat. Overall, the results highlight the utility of this approach and, more broadly, demonstrate the value of considering the role of the self in attitudinal processes, and vice versa.
Optimisation of chemical oxygen demand removal from landfill leachate by sonocatalytic degradation in the presence of cupric oxide nanoparticles
Authors: Amirian Paria , Bazrafshan Edris , Payandeh Abolfazl
Published: May 2017

Leachate is the liquid formed when waste breaks down in the landfill and water filters through that waste. This liquid is very toxic and can pollute the land, ground water, and water resources. In most countries, it is mandatory for landfills to be protected against leachate. In addition to all other harms to the environment, disposal of raw landfill leachate can be a major source of hazard to closed water bodies. Hence, treatment of landfill leachate is considered an essential step prior to its discharge from source. This article describes the sonocatalytic degradation of chemical oxygen demand in landfill leachate using cupric oxide nanoparticles as sonocatalyst (cupric oxide/ultrasonic) and aims to establish this method as an effective alternative to currently used approaches. An ideal experimental design was carried out based on a central composite design with response surface methodology. The response surface methodology was used to evaluate the effect of process variables including pH values (3, 7, 11), cupric oxide nanoparticles dose (0.02, 0.035, 0.05 g), reaction time (10, 35, 60 minutes), ultrasonic frequency (35, 37, 130 KHz), and their interaction towards the attainment of their optimum conditions. The derived second-order model, including both significant linear and quadratic terms, seemed to be adequate in predicting responses (R2 = 0.9684 and prediction R2 = 0.9581). The optimum conditions for the maximum chemical oxygen demand sonocatalytic degradation of 85.82% were found to be pH 6.9, cupric oxide nanoparticles dosage of 0.05 gr L−1, and the ultrasonic frequency of 130 kHz at a contact time of 10 min.
Analysis of design and performance of tram-train profiles for dual-operation running
Authors: Crosbee D , Allen PD , Carroll R
Published: May 2017

This article explores the design of a new wheel profile which can be used in a tram-train vehicle. A tram-train is a dual-mode vehicle that operates on two very different railway infrastructures: as a tram on light rail infrastructure and as a conventional train on heavy rail infrastructure. The challenges of wheel–rail interface have been highlighted and discussed, and the analysis and design process required to develop an optimised wheel profile for dual-operation running have been presented. One of the key issues in developing a dual-operation wheel profile was managing the contact conditions within the wheel–rail interface. The interface is critical not only to the safe running of the vehicle but also to maximise asset life and to minimise wheel–rail damage. A combination of vehicle dynamic simulations and bespoke software was used to allow the development of a new wheel profile for tram-train operations.