bluuebunny/crossref_metadata_2025_split huggingface dataset:
FRCS first pass variance: deanery and specialty contrariety
Authors: Brown Chris , Abdelrahman Tarig , Pollitt John , Holt Mark , Lewis Wyn G 
Published: August 2017

AbstractBackgroundFRCS exit examination success may be interpreted as a surrogate marker for UK Deanery-related training quality. The aim of this study was to evaluate relative FRCS examination pass rates related to Deanery and Surgical Specialty.MethodsJoint Committee on Surgical Training-published examination first attempt pass rates were scrutinised for type I higher surgical trainees and outcomes compared related to Deanery and Surgical Specialty.ResultsOf 9363 FRCS first attempts, 3974 were successful (42.4%). Median and mean pass rates related to Deanery were 42.1% and 30.7%, respectively, and ranged from 26.7% to 45.6%. Median (range) pass rates by specialty were urology 76.3% (60%–100%), trauma and orthopaedic surgery 74.7% (58.2%–100%), general surgery 70.0% (63.1%–86%), ENT 62.5% (50%–100%), cardiothoracic surgery 50.0% (25%–100%), oral and maxillofacial surgery 50% (40.0%–100%), neurosurgery 50% (22.7%–100%), plastic surgery 47.6% (30.0%–100%) and paediatric surgery 25% (16.7%–100%). Significant variance was observed across all specialties and deaneries (p=0.001).ConclusionAs much as threefold variance exists related to FRCS examination first attempt success, trainees should be aware of this spectrum when preferencing deaneries during national selection.
Characterization of decision commitment rule alterations during an auditory change detection task
Authors: Johnson Bridgette , Verma Rebeka , Sun Manying , Hanks Timothy D. 
Published: August 2017

A critical component of decision making is determining when to commit to a choice. This involves stopping rules that specify the requirements for decision commitment. Flexibility of decision stopping rules provides an important means of control over decision-making processes. In many situations, these stopping rules establish a balance between premature decisions and late decisions. In this study we use a novel change detection paradigm to examine how subjects control this balance when invoking different decision stopping rules. The task design allows us to estimate the temporal weighting of sensory information for the decisions, and we find that different stopping rules did not result in systematic differences in that weighting. We also find bidirectional post-error alterations of decision strategy that depend on the type of error and effectively reduce the probability of making consecutive mistakes of the same type. This is a generalization to change detection tasks of the widespread observation of unidirectional post-error slowing in forced-choice tasks. On the basis of these results, we suggest change detection tasks as a promising paradigm to study the neural mechanisms that support flexible control of decision rules. NEW & NOTEWORTHY Flexible decision stopping rules confer control over decision processes. Using an auditory change detection task, we found that alterations of decision stopping rules did not result in systematic changes in the temporal weighting of sensory information. We also found that post-error alterations of decision stopping rules depended on the type of mistake subjects make. These results provide guidance for understanding the neural mechanisms that control decision stopping rules, one of the critical components of decision making and behavioral flexibility.
Object comparison in the lateral intraparietal area
Authors: Ong Wei Song , Mirpour Koorosh , Bisley James W. 
Published: August 2017

We can search for and locate specific objects in our environment by looking for objects with similar features. Object recognition involves stimulus similarity responses in ventral visual areas and task-related responses in prefrontal cortex. We tested whether neurons in the lateral intraparietal area (LIP) of posterior parietal cortex could form an intermediary representation, collating information from object-specific similarity map representations to allow general decisions about whether a stimulus matches the object being looked for. We hypothesized that responses to stimuli would correlate with how similar they are to a sample stimulus. When animals compared two peripheral stimuli to a sample at their fovea, the response to the matching stimulus was similar, independent of the sample identity, but the response to the nonmatch depended on how similar it was to the sample: the more similar, the greater the response to the nonmatch stimulus. These results could not be explained by task difficulty or confidence. We propose that LIP uses its known mechanistic properties to integrate incoming visual information, including that from the ventral stream about object identity, to create a dynamic representation that is concise, low dimensional, and task relevant and that signifies the choice priorities in mental matching behavior. NEW & NOTEWORTHY Studies in object recognition have focused on the ventral stream, in which neurons respond as a function of how similar a stimulus is to their preferred stimulus, and on prefrontal cortex, where neurons indicate which stimulus is being looked for. We found that parietal area LIP uses its known mechanistic properties to form an intermediary representation in this process. This creates a perceptual similarity map that can be used to guide decisions in prefrontal areas.
ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage
Authors: Perkhofer Lukas , Schmitt Anna , Romero Carrasco Maria Carolina , Ihle Michaela , Hampp Stephanie , Ruess Dietrich Alexander , Hessmann Elisabeth , Russell Ronan , Lechel André , Azoitei Ninel , Lin Qiong , Liebau Stefan , Hohwieler Meike , Bohnenberger Hanibal , Lesina Marina , Algül Hana , Gieldon Laura , Schröck Evelin , Gaedcke Jochen , Wagner Martin , Wiesmüller Lisa , Sipos Bence , Seufferlein Thomas , Reinhardt Hans Christian , Frappart Pierre-Olivier , Kleger Alexander 
Published: August 2017

Abstract
Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial–mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. Cancer Res; 77(20); 5576–90. ©2017 AACR.
GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity
Authors: Cichocki Frank , Valamehr Bahram , Bjordahl Ryan , Zhang Bin , Rezner Betsy , Rogers Paul , Gaidarova Svetlana , Moreno Stacey , Tuininga Katie , Dougherty Phillip , McCullar Valarie , Howard Peter , Sarhan Dhifaf , Taras Emily , Schlums Heinrich , Abbot Stewart , Shoemaker Daniel , Bryceson Yenan T. , Blazar Bruce R. , Wolchko Scott , Cooley Sarah , Miller Jeffrey S. 
Published: August 2017

AbstractMaturation of human natural killer (NK) cells as defined by accumulation of cell-surface expression of CD57 is associated with increased cytotoxic character and TNF and IFNγ production upon target-cell recognition. Notably, multiple studies point to a unique role for CD57+ NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacologic inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL15 greatly enhances CD57 upregulation and late-stage maturation. GSK3 inhibition elevated the expression of several transcription factors associated with late-stage NK-cell maturation including T-BET, ZEB2, and BLIMP-1 without affecting viability or proliferation. When exposed to human cancer cells, NK cell expanded ex vivo in the presence of a GSK3 inhibitor exhibited significantly higher production of TNF and IFNγ, elevated natural cytotoxicity, and increased antibody-dependent cellular cytotoxicity. In an established mouse xenograft model of ovarian cancer, adoptive transfer of NK cells conditioned in the same way also displayed more robust and durable tumor control. Our findings show how GSK3 kinase inhibition can greatly enhance the mature character of NK cells most desired for effective cancer immunotherapy. Cancer Res; 77(20); 5664–75. ©2017 AACR.
Cyclophilin A Maintains Glioma-Initiating Cell Stemness by Regulating Wnt/β-Catenin Signaling
Authors: Wang Guangzhi , Shen Jia , Sun Jiahang , Jiang Zhenfeng , Fan Jiabing , Wang Hongjun , Yu Shan , Long Yu , Liu Yi , Bao Hongbo , Zhang Kelvin Xi , Han Ke , Zhu Minwei , Zheng Yongri , Lin Zhiguo , Jiang Chuanlu , Guo Mian 
Published: August 2017

AbstractPurpose: Glioma-initiating cells (GIC) are glioma stem–like cells that contribute to glioblastoma (GBM) development, recurrence, and resistance to chemotherapy and radiotherapy. They have recently become the focus of novel treatment strategies. Cyclophilin A (CypA) is a cytosolic protein that belongs to the peptidyl–prolyl isomerase (PPIase) family and the major intracellular target of the immunosuppressive drug cyclosporin A (CsA). In this study, we investigate the functions of CypA and its mechanism of action in GICs' development.Experimental Design: We analyzed differences in CypA expression between primary tumors and neurospheres from the GDS database, both before and after GIC differentiation. A series of experiments was conducted to investigate the role of CypA in GIC stemness, self-renewal, proliferation, radiotherapy resistance, and mechanism. We then designed glutathione S-transferase (GST) pulldown and coimmunoprecipitation assays to detect signaling activity.Results: In this study, we demonstrated that CypA promotes GIC stemness, self-renewal, proliferation, and radiotherapy resistance. Mechanistically, we found that CypA binds β-catenin and is recruited to Wnt target gene promoters. By increasing the interaction between β-catenin and TCF4, CypA enhances transcriptional activity.Conclusions: Our results demonstrate that CypA enhances GIC stemness, self-renewal, and radioresistance through Wnt/β-catenin signaling. Due to its promotive effects on GICs, CypA is a potential target for future glioma therapy. Clin Cancer Res; 23(21); 6640–9. ©2017 AACR.
Prospective Validation of Molecular Prognostic Markers in Cutaneous Melanoma: A Correlative Analysis of E1690
Authors: Kashani-Sabet Mohammed , Nosrati Mehdi , Miller James R. , Sagebiel Richard W. , Leong Stanley P.L. , Lesniak Andrew , Tong Schuyler , Lee Sandra J. , Kirkwood John M. 
Published: August 2017

Abstract
Purpose: To validate the prognostic impact of combined expression levels of three markers (SPP1, RGS1, and NCOA3) in melanoma specimens from patients enrolled in the E1690 clinical trial of high-dose or low-dose IFNα-2b versus observation.
Experimental Design: Tissue was available from 248 patients. Marker expression was determined by digital imaging of immunohistochemically stained slides. The prognostic impact of each marker was first assessed by recording its expression value relative to the median. A multimarker index was then developed to combine marker expression levels by counting for each patient the number of markers with high expression. The impact of the multimarker index on relapse-free survival (RFS) and overall survival (OS) was assessed using Kaplan–Meier analysis, and both univariate and multivariate Cox regression analyses.
Results: By Kaplan–Meier analysis, high multimarker expression scores were significantly predictive of RFS (P &lt; 0.001) and OS (P &lt; 0.001). Stepwise multivariate Cox regression analysis with backward elimination that included routine clinical and histologic prognostic factors revealed high multimarker expression scores and tumor thickness as the only factors significantly and independently predicting RFS and OS. Stepwise multivariate Cox regression analyses that also included treatment type and number of positive lymph nodes generated identical results for both RFS and OS. In the molecularly defined low-risk subgroup, patients treated with high-dose IFN had a significantly improved RFS compared with patients in the other two subgroups (P &lt; 0.05).
Conclusions: These results validate the independent impact of combined expression levels of SPP1, RGS1, and NCOA3 on survival of melanoma in a prospectively collected cohort. Clin Cancer Res; 23(22); 6888–92. ©2017 AACR.
First-in-Man Analysis of the Relationship Between Electrical Rotors From Noninvasive Panoramic Mapping and Atrial Fibrosis From Magnetic Resonance Imaging in Patients With Persistent Atrial Fibrillation
Authors: Sohns Christian , Lemes Christine , Metzner Andreas , Fink Thomas , Chmelevsky Mikhail , Maurer Tilman , Budanova Margarita , Solntsev Vladislav , Schulze Walther H.W. , Staab Wieland , Mathew Shibu , Heeger Christian , Reißmann Bruno , Kholmovski Eugene , Kivelitz Dietmar , Ouyang Feifan , Kuck Karl-Heinz 
Published: August 2017

Background—
Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging can be used to evaluate characteristics of atrial fibrosis. The novel noninvasive epicardial and endocardial electrophysiology system (NEEES) allows for the identification of sources with rotor activity. This study describes a new technique to examine the relationship between rotors and LGE signal intensity in patients with persistent atrial fibrillation (PERS) scheduled for ablation.

Methods and Results—
Ten consecutive patients underwent pulmonary vein isolation for persistent atrial fibrillation. LGE CMR of both atria was performed, and NEEES-based analysis was conducted to identify rotors. For each mapping point, the intracardiac locations were transferred onto an individual CMR-derived 3-dimensional shell. This allowed the LGE signal intensity to be projected onto the anatomy from the NEEES analysis. NEEES analysis identified a total number of 410 electric rotors, 47.8% were located in the left atrium and 52.2% in the right atrium. Magnetic resonance imaging analysis was performed from 10 right atria and 10 left atria data sets, including 86 axial LGE CMR planes per atrium. The mean LGE burden for left atrium and right atrium was 23.9±1.6% and 15.9±1.8%, respectively. Statistical analysis demonstrated a lack of regional association between the extent of LGE signal intensity and the presence of rotors.

Conclusions—
This is the first study demonstrating that the presence of rotors based on NEEES analysis is not directly associated with the extent and anatomic location of LGE signal intensity from CMR. Further studies evaluating the relationship between rotors and fibrosis in patients with persistent atrial fibrillation are mandatory and may inform strategies to improve ablation outcome.
Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing
Authors: Burns Charlotte , Bagnall Richard D. , Lam Lien , Semsarian Christopher , Ingles Jodie 
Published: August 2017

Background—
Multiple likely pathogenic/pathogenic (LP/P; ≥2) variants in patients with hypertrophic cardiomyopathy were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in patients with hypertrophic cardiomyopathy in the setting of comprehensive and targeted panels.

Methods and Results—

Of 758 hypertrophic cardiomyopathy probands, we included 382 with ≥45 cardiomyopathy genes screened. There were 224 (59%) with ≥1 rare variant (allele frequency ≤0.02%). Variants were analyzed using varying sized gene panels to represent comprehensive or targeted testing. Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance, and 66 (17%) had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) variants of uncertain significance, and 14 (4%) had multiple rare variants. No proband had 2 LP/P variants. Including affected family members (total n=412), cluster-adjusted analyses identified a phenotype effect, with younger age (odds ratio, 0.95; 95% confidence interval, 0.92–0.98;
P
=0.004) and family history of sudden cardiac death (odds ratio, 3.5; 95% confidence interval, 1.3–9.9;
P
=0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel but not larger panels. Those with multiple variants had worse event-free survival from all-cause death, cardiac transplantation, and cardiac arrest (log-rank
P
=0.008).

Conclusions—
No proband had multiple LP/P variants in contrast to previous reports. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in hypertrophic cardiomyopathy.
Prognostic Value of Fractional Flow Reserve Measured Immediately After Drug-Eluting Stent Implantation
Authors: Piroth Zsolt , Toth Gabor G. , Tonino Pim A.L. , Barbato Emanuele , Aghlmandi Soheila , Curzen Nick , Rioufol Gilles , Pijls Nico H.J. , Fearon William F. , Jüni Peter , De Bruyne Bernard 
Published: August 2017

Background—
The predictive value of fractional flow reserve (FFR) measured immediately after percutaneous coronary intervention (PCI) with drug-eluting stent placement has not been prospectively investigated. We investigated the potential of post-PCI FFR measurements to predict clinical outcome in patients from FAME 1 and 2 trials (Fractional Flow Reserve or Angiography for Multivessel Evaluation).

Methods and Results—

All patients of FAME 1 and FAME 2 who had post-PCI FFR measurement were included. The primary outcome was vessel-oriented composite end point at 2 years, defined as vessel-related cardiovascular death, vessel-related spontaneous myocardial infarction, and ischemia-driven target vessel revascularization. Eight hundred thirty-eight vessels in 639 patients were analyzed. Baseline FFR values did not differ between vessels with versus without vessel-oriented composite end point (0.66±0.11 versus 0.63±0.14, respectively;
P
=0.207). Post-PCI FFR was significantly lower in vessels with vessel-oriented composite end point (0.88±0.06 versus 0.90±0.06, respectively;
P
=0.019). Comparing the 2-year outcome of lower and upper tertiles of post-PCI FFR significant difference was found favoring upper tertile in terms of overall vessel-oriented composite end point (9.2% versus 3.8%, respectively; hazard ratio, 1.46; 95% confidence interval, 1.02–2.08;
P
=0.037) and target vessel revascularization (7.0% versus 2.4%, respectively; hazard ratio, 1.59; 95% confidence interval, 1.03–2.46;
P
=0.037). When adjusted to sex, hypertension, diabetes mellitus, target vessel, serial stenosis, and baseline percentage diameter stenosis, a strong trend was preserved in terms of target vessel revascularization (harzard ratio, 1.55; 95% confidence interval, 0.97–2.46;
P
=0.066), favoring the upper tertile. Post-PCI FFR of 0.92 was found to have the highest diagnostic accuracy; however, the positive likelihood ratio remained low (<1.4).

Conclusions—
A higher post-PCI FFR value is associated with a better vessel-related outcome. However, its predictive value is too low to advocate its use as a surrogate clinical end point.
Explaining Global Norms: The Case of Negotiations on Restraining Conventional Arms
Authors: Garcia Denise 
Published: August 2017

AbstractInternational norms are central to world politics and they set boundaries for what is deemed commonly accepted behavior. The literature has not effectively explained the rise of new norms through negotiation and how actors from the Global South have played active roles, especially in the complex areas of developing security norms. This article argues that norm-making is not a unidirectional movement or phenomenon, but rather a highly circuitous process. The circuitous norm building model accounts for an increasing connectedness among domestic and regional/international levels in norm building in Global South and North countries.
A 1D Theoretical Analysis of Northerly Low-Level Jets over the Great Plains
Authors: Gebauer Joshua G. , Fedorovich Evgeni , Shapiro Alan 
Published: August 2017

Abstract
The forcing of northerly low-level jets over the eastward-sloped terrain of the U.S. Great Plains was studied using a one-dimensional (1D) nonstationary analytical model based on the Boussinesq-approximated equations of motion and thermal energy. For northerly low-level jets, the forcing from diurnal changes in surface heating of the sloped terrain (Holton mechanism) is out of phase with the nocturnal inertial oscillation resulting from the cessation of turbulent mixing at sunset (Blackadar mechanism), which results in weaker northerly nocturnal low-level jets when compared to southerly nocturnal low-levels jets with the same-magnitude background pressure gradient forcing. Because of the Blackadar and Holton mechanisms acting out of phase, nocturnal northerly low-level jets cannot solely explain the northerly low-level jet maximum over the Great Plains found in climatological studies. It is shown that negative buoyancy values over the eastward-sloped terrain enhance the low-level northerly geostrophic wind, which can cause low-level jetlike wind profiles that do not necessarily depend on the diurnal cycle. However, nocturnal northerly low-level jets primarily caused by an inertial oscillation still occur when daytime mixing is strong and buoyancy is small at sunset. These conditions are possible when strong capping inversions are present in the daytime convective boundary layer. The occurrence of both types of northerly low-level jets, those caused by negative buoyancy values over the sloped terrain and those driven by an inertial oscillation, better explains the findings of previous low-level jet climatologies.
A Grid-Refinement-Based Approach for Modeling the Convective Boundary Layer in the Gray Zone: A Pilot Study
Authors: Zhou Bowen , Xue Ming , Zhu Kefeng 
Published: August 2017

Abstract
The model gray zone refers to the range of grid spacings comparable to the dominant length scale of the flow. In the gray zone, the flow is partially resolved and partially subgrid scale (SGS). Neither ensemble-averaging-based parameterizations nor turbulence closures are appropriate for parameterizing the effects of SGS motions on the resolved flow. The gray zone of the convective boundary layer (CBL) is in the range of CBL depth, typically O(1) km. A new approach that seeks explicit resolution of the unstable surface layer through a nest layer of fine grid spacing is proposed to improve CBL parameterization in the gray zone. To provide the theoretical basis for the approach, a linear analytic model is presented, and one-way nested simulations are performed to investigate the dynamical coupling between the surface layer and the mixed layer. The analytic model shows that at the onset of thermal instability, the vertical and horizontal structures of the mixed layer are set by surface-layer forcings. The nested 3D simulations extend the findings from the analytic model and further reveal potential improvements in high-order statistics and resolved convective structures both including and extending above the nest region compared to the stand-alone gray-zone simulations. This study suggests that when the most energetic scales of CBL convection are resolved in the surface layer, the overall simulation of the CBL improves at gray-zone resolutions.