bluuebunny/crossref_metadata_2025 huggingface dataset:
Static stages for heterogeneous programming
Authors: Sampson Adrian , McKinley Kathryn S. , Mytkowicz Todd
Published: October 2017

Heterogeneous hardware is central to modern advances in performance and efficiency. Mainstream programming models for heterogeneous architectures, however, sacrifice safety and expressiveness in favor of low-level control over performance details. The interfaces between hardware units consist of verbose, unsafe APIs; hardware-specific languages make it difficult to move code between units; and brittle preprocessor macros complicate the task of specializing general code for efficient accelerated execution. We propose a unified low-level programming model for heterogeneous systems that offers control over performance, safe communication constructs, cross-device code portability, and hygienic metaprogramming for specialization. The language extends constructs from multi-stage programming to separate code for different hardware units, to communicate between them, and to express compile-time code optimization. We introduce static staging, a different take on multi-stage programming that lets the compiler generate all code and communication constructs ahead of time.

To demonstrate our approach, we use static staging to implement BraidGL, a real-time graphics programming language for CPU-GPU systems. Current real-time graphics software in OpenGL uses stringly-typed APIs for communication and unsafe preprocessing to generate specialized GPU code variants. In BraidGL, programmers instead write hybrid CPU-GPU software in a unified language. The compiler statically generates target-specific code and guarantees safe communication between the CPU and the graphics pipeline stages. Example scenes demonstrate the language's productivity advantages: BraidGL eliminates the safety and expressiveness pitfalls of OpenGL and makes common specialization techniques easy to apply. The case study demonstrates how static staging can express core placement and specialization in general heterogeneous programming.
Robust and compositional verification of object capability patterns
Authors: Swasey David , Garg Deepak , Dreyer Derek
Published: October 2017

In scenarios such as web programming, where code is linked together from multiple sources,
object capability patterns
(OCPs) provide an essential safeguard, enabling programmers to protect the private state of their objects from corruption by unknown and untrusted code. However, the benefits of OCPs in terms of program verification have never been properly formalized. In this paper, building on the recently developed Iris framework for concurrent separation logic, we develop OCPL, the first program logic for compositionally specifying and verifying OCPs in a language with closures, mutable state, and concurrency. The key idea of OCPL is to account for the interface between verified and untrusted code by adopting a well-known idea from the literature on security protocol verification, namely
robust safety
. Programs that export only properly wrapped values to their environment can be proven robustly safe, meaning that their untrusted environment cannot violate their internal invariants. We use OCPL to give the first general, compositional, and machine-checked specs for several commonly-used OCPs—including the
dynamic sealing
,
membrane
, and
caretaker
patterns—which we then use to verify robust safety for representative client code. All our results are fully mechanized in the Coq proof assistant.
Reliable and automatic composition of language extensions to C: the ableC extensible language framework
Authors: Kaminski Ted , Kramer Lucas , Carlson Travis , Van Wyk Eric
Published: October 2017

This paper describes an extensible language framework, ableC, that allows programmers to import new, domain-specific, independently-developed language features into their programming language, in this case C. Most importantly, this framework ensures that the language extensions will automatically compose to form a working translator that does not terminate abnormally. This is possible due to two modular analyses that extension developers can apply to their language extension to check its composability. Specifically, these ensure that the composed concrete syntax specification is non-ambiguous and the composed attribute grammar specifying the semantics is well-defined. This assurance and the expressiveness of the supported extensions is a distinguishing characteristic of the approach.

The paper describes a number of techniques for specifying a host language, in this case C at the C11 standard, to make it more amenable to language extension. These include techniques that make additional extensions pass these modular analyses, refactorings of the host language to support a wider range of extensions, and the addition of semantic extension points to support, for example, operator overloading and non-local code transformations.
Deadlock avoidance in parallel programs with futures: why parallel tasks should not wait for strangers
Authors: Cogumbreiro Tiago , Surendran Rishi , Martins Francisco , Sarkar Vivek , Vasconcelos Vasco T. , Grossman Max
Published: October 2017

Futures are an elegant approach to expressing parallelism in functional programs. However, combining futures with imperative programming (as in C++ or in Java) can lead to pernicious bugs in the form of data races and deadlocks, as a consequence of uncontrolled data flow through mutable shared memory.

In this paper we introduce the Known Joins (KJ) property for parallel programs with futures, and relate it to the Deadlock Freedom (DF) and the Data-Race Freedom (DRF) properties. Our paper offers two key theoretical results: 1) DRF implies KJ, and 2) KJ implies DF. These results show that data-race freedom is sufficient to guarantee deadlock freedom in programs with futures that only manipulate unsynchronized shared variables. To the best of our knowledge, these are the first theoretical results to establish sufficient conditions for deadlock freedom in imperative parallel programs with futures, and to characterize the subset of data races that can trigger deadlocks (those that violate the KJ property).

From result 2), we developed a tool that avoids deadlocks in linear time and space when KJ holds, i.e., when there are no data races among references to futures. When KJ fails, the tool reports the data race and optionally falls back to a standard deadlock avoidance algorithm by cycle detection. Our tool verified a dataset of ∼2,300 student’s homework solutions and found one deadlocked program. The performance results obtained from our tool are very encouraging: a maximum slowdown of 1.06× on a 16-core machine, always outperforming deadlock avoidance via cycle-detection. Proofs of the two main results were formalized using the Coq proof assistant.
The Sociology of Constitutions
Authors: Thornhill Chris
Published: October 2017

This article sets out an account of the historical development and the contemporary elaboration of sociological approaches to constitutional law. It argues that recent years have seen a broad sociological turn in constitutional theory, such that sociological constitutionalism now forms a distinct field of legal research. This is due to the general increase in the importance of constitutionalism in different national societies across the globe. This is also due to the emergence of new patterns of constitutional formation, both within and beyond national societies, resulting from the interaction between national and domestic constitutional law. The article separates different constitutional-sociological approaches into two categories: those with a primarily national, and those with a primarily transnational focus. Overall, however, it claims that sociological constitutionalism is driven primarily by engagement with transnational law, and the main insights in this field relate, in different ways, to global processes of transnational norm formation.
50 Years of “Obedience to Authority”: From Blind Conformity to Engaged Followership
Authors: Haslam S. Alexander , Reicher Stephen D.
Published: October 2017

Despite being conducted half a century ago, Stanley Milgram's studies of obedience to authority remain the most well-known, most controversial, and most important in social psychology. Yet in recent years, increased scrutiny has served to question the integrity of Milgram's research reports, the validity of his explanation of the phenomena he reported, and the broader relevance of his research to processes of collective harm-doing. We review these debates and argue that the main problem with received understandings of Milgram's work arises from seeing it as an exploration of obedience. Instead, we argue that it is better understood as providing insight into processes of engaged followership, in which people are prepared to harm others because they identify with their leaders' cause and believe their actions to be virtuous. We review evidence that supports this analysis and shows that it explains the behavior not only of Milgram's participants but also of his research assistants and of the textbook writers and teachers who continue to reproduce misleading accounts of his work.
Live cell imaging of cytosolic NADH/NAD+ratio in hepatocytes and liver slices
Authors: Masia Ricard , McCarty William J. , Lahmann Carolina , Luther Jay , Chung Raymond T. , Yarmush Martin L. , Yellen Gary
Published: October 2017

Fatty liver disease (FLD), the most common chronic liver disease in the United States, may be caused by alcohol or the metabolic syndrome. Alcohol is oxidized in the cytosol of hepatocytes by alcohol dehydrogenase (ADH), which generates NADH and increases cytosolic NADH/NAD+ratio. The increased ratio may be important for development of FLD, but our ability to examine this question is hindered by methodological limitations. To address this, we used the genetically encoded fluorescent sensor Peredox to obtain dynamic, real-time measurements of cytosolic NADH/NAD+ratio in living hepatocytes. Peredox was expressed in dissociated rat hepatocytes and HepG2 cells by transfection, and in mouse liver slices by tail-vein injection of adeno-associated virus (AAV)-encoded sensor. Under control conditions, hepatocytes and liver slices exhibit a relatively low (oxidized) cytosolic NADH/NAD+ratio as reported by Peredox. The ratio responds rapidly and reversibly to substrates of lactate dehydrogenase (LDH) and sorbitol dehydrogenase (SDH). Ethanol causes a robust dose-dependent increase in cytosolic NADH/NAD+ratio, and this increase is mitigated by the presence of NAD+-generating substrates of LDH or SDH. In contrast to hepatocytes and slices, HepG2 cells exhibit a relatively high (reduced) ratio and show minimal responses to substrates of ADH and SDH. In slices, we show that comparable results are obtained with epifluorescence imaging and two-photon fluorescence lifetime imaging (2p-FLIM). Live cell imaging with Peredox is a promising new approach to investigate cytosolic NADH/NAD+ratio in hepatocytes. Imaging in liver slices is particularly attractive because it allows preservation of liver microanatomy and metabolic zonation of hepatocytes.

NEW & NOTEWORTHY We describe and validate a new approach for measuring free cytosolic NADH/NAD+ratio in hepatocytes and liver slices: live cell imaging with the fluorescent biosensor Peredox. This approach yields dynamic, real-time measurements of the ratio in living, functioning liver cells, overcoming many limitations of previous methods for measuring this important redox parameter. The feasibility of using Peredox in liver slices is particularly attractive because slices allow preservation of hepatic microanatomy and metabolic zonation of hepatocytes.
Apelin-13 inhibits gastric motility through vagal cholinergic pathway in rats
Authors: Bülbül Mehmet , Sinen Osman , Gök Melahat , Travagli R. Alberto
Published: October 2017

The expression of apelin and its receptors (APJ) in central autonomic networks suggests that apelin may regulate gastrointestinal motor functions. In rodents, central administration of apelin-13 has been shown to inhibit gastric emptying; however, the mechanisms involved remain to be determined. Using male adult Sprague-Dawley rats, the aims of the present study were 1) to determine the expression of APJ receptor in the dorsal vagal complex (DVC), 2) to assess the effects of central application of apelin-13 into the DVC on gastric tone and motility, and 3) to investigate the neuronal pathways responsible for apelin-induced alterations. APJ receptor immunoreactivity was detected in gastric-projecting and choline acetyltransferase-positive neurons of the DVC. Microinjection of apelin-13 into the DVC significantly decreased gastric tone and motility in both corpus and antrum. The apelin-induced reduction in gastric tone and motility was prevented by surgical vagotomy or fourth ventricular application of the APJ receptor antagonist, [Ala13]apelin-13 (F13A). Systemic administration of the muscarinic receptor antagonist atropine, but not the nitric oxide synthase inhibitor nitro-l-arginine methyl ester (l-NAME), abolished the apelin-induced inhibitory responses. The present results indicate a central modulatory role of apelin in the vagal neurocircuitry that controls gastric motor functions via withdrawal of the tonically active cholinergic pathway.

NEW & NOTEWORTHY This is the first study investigating the effects induced by brain stem application of apelin-13 while monitoring gastric tone and motility in rats. We have found that gastric-projecting neurons of the dorsal vagal complex express apelin receptors (APJ), which mediate the inhibitory actions of apelin-13. The inhibitory effects of apelin were abolished by systemic preadministration of atropine, but not nitro-l-arginine methyl ester (l-NAME). Apelin seems to modulate gastric motility via withdrawal of the tonically active vagal cholinergic pathway.
Estrogen replacement attenuates stress-induced pressor responses through vasorelaxation via β2-adrenoceptors in peripheral arteries of ovariectomized rats
Authors: Tazumi Shoko , Omoto Sayo , Nagatomo Yu , Kawahara Mariko , Yokota-Nakagi Naoko , Kawakami Mizuho , Takamata Akira , Morimoto Keiko
Published: October 2017

We examined whether chronic estrogen replacement has an inhibitory effect on stress-induced pressor responses via activation of β2-adrenoceptor (AR) in peripheral arteries of ovariectomized rats. Female Wistar rats aged 9 wk were ovariectomized. After 4 wk, pellets containing either 17β-estradiol (E2) or placebo (Pla) were subcutaneously implanted into the rats. After 4 wk of treatment, rats underwent cage-switch stress, and, in a separate experiment, a subset received an infusion of isoproterenol (ISO) with or without pretreatment with the β1-AR blocker atenolol or the β2-AR blocker butoxamine. In addition, the isolated mesenteric artery was used to assess the concentration-related relaxing responses to ISO and the β1- or β2-AR mRNA level. The cage-switch stress-induced pressor response was significantly attenuated in the E2-treated group compared with the Pla-treated group. Pretreatment with atenolol reduced blood pressure responses in both groups. However, butoxamine enhanced the pressor response only in the E2-treated group, resulting in no difference between the two groups. In addition, the intravenous ISO-induced depressor response was significantly enhanced in the E2-treated group compared with the Pla-treated group. Furthermore, the difference in the depressor response was abolished by pretreatment with butoxamine but not by atenolol. In the isolated mesenteric artery, butoxamine caused a rightward shift in ISO-induced concentration-related relaxation in the E2-treated group. The β2-AR mRNA level in the mesenteric artery was higher in the E2-treated group than in the Pla-treated group. These results suggest that estrogen replacement attenuated the stress-induced pressor response probably by suppressing vasoconstriction via activation of β2-ARs in peripheral arteries of ovariectomized rats.

NEW & NOTEWORTHY In this study, we show, for the first time, that estrogen replacement has an inhibitory effect on the psychological stress-induced pressor response through vasorelaxation via β2-adrenoceptors, probably due to overexpression of β2-adrenoceptor mRNA, in peripheral arteries of ovariectomized rats.
Effects of age and exercise training on coronary microvascular smooth muscle phenotype and function
Authors: Muller-Delp Judy M. , Hotta Kazuki , Chen Bei , Behnke Bradley J. , Maraj Joshua J. , Delp Michael D. , Lucero Tiffani R. , Bramy Jeremy A. , Alarcon David B. , Morgan Hannah E. , Cowan Morgan R. , Haynes Anthony D.
Published: October 2017

Coronary microvascular function and blood flow responses during acute exercise are impaired in the aged heart but can be restored by exercise training. Coronary microvascular resistance is directly dependent on vascular smooth muscle function in coronary resistance arterioles; therefore, we hypothesized that age impairs contractile function and alters the phenotype of vascular smooth muscle in coronary arterioles. We further hypothesized that exercise training restores contractile function and reverses age-induced phenotypic alterations of arteriolar smooth muscle. Young and old Fischer 344 rats underwent 10 wk of treadmill exercise training or remained sedentary. At the end of training or cage confinement, contractile responses, vascular smooth muscle proliferation, and expression of contractile proteins were assessed in isolated coronary arterioles. Both receptor- and non-receptor-mediated contractile function were impaired in coronary arterioles from aged rats. Vascular smooth muscle shifted from a differentiated, contractile phenotype to a secretory phenotype with associated proliferation of smooth muscle in the arteriolar wall. Expression of smooth muscle myosin heavy chain 1 (SM1) was decreased in arterioles from aged rats, whereas expression of phospho-histone H3 and of the synthetic protein ribosomal protein S6 (rpS6) were increased. Exercise training improved contractile responses, reduced smooth muscle proliferation and expression of rpS6, and increased expression of SM1 in arterioles from old rats. Thus age-induced contractile dysfunction of coronary arterioles and emergence of a secretory smooth muscle phenotype may contribute to impaired coronary blood flow responses, but arteriolar contractile responsiveness and a younger smooth muscle phenotype can be restored with late-life exercise training.

NEW & NOTEWORTHY Aging impairs contractile function of coronary arterioles and induces a shift of the vascular smooth muscle toward a proliferative, noncontractile phenotype. Late-life exercise training reverses contractile dysfunction of coronary arterioles and restores a young phenotype to the vascular smooth muscle.
Intrinsic aerobic capacity governs the associations between gut microbiota composition and fat metabolism age-dependently in rat siblings
Authors: Pekkala Satu , Lensu Sanna , Nokia Miriam , Vanhatalo Sanja , Koch Lauren G. , Britton Steven L. , Kainulainen Heikki
Published: October 2017

Host genetic factors affecting the gut microbiome play an important role in obesity, yet limited attention has been paid on the host genetic factors linked to physical fitness in modifying the microbiome. This study determined whether sibling-matched pairs of rats selectively bred for high (HCR) and low (LCR) aerobic capacity differ in their microbiome age-dependently and which taxa associate with differential in metabolism. Several taxa in young adult rats (hereafter young) linked to inherited aerobic capacity, while in older adult (hereafter old) rats most of the differences between the lines associated with body weight. Despite the absence of weight differential between LCR and HCR when young, the LCR microbiome contained more Actinobacteria, Veillonellaceae, Coriobacteriaceae, Phascolarctobacterium, and Ruminococcus; taxa previously linked to obesity. This raises the question whether the microbiome contributes to the later development of obesity in LCR. Age-related differences were detected in almost all taxa in both rat lines. The young HCR measured higher for serum glycerol and free fatty-acids and lower for cholesterol, HDL, LDL, and triglycerides than LCR. The old HCR differed from the old LCR by lower LDL. Several metabolites, including LDL, are associated age and genetic background-dependently with the microbiome, which might explain the metabolic differences between the lines. While old lines did not differ in visceral adipose tissue gene expression, the young HCR expressed more inflammatory genes than LCR, and several taxa including Proteobacteria associated with these genes. In conclusion, intrinsic aerobic capacity governs the microbiome, which may influence body weight, metabolism, and gene expression.
CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors
Authors: Min Irene M. , Shevlin Enda , Vedvyas Yogindra , Zaman Marjan , Wyrwas Brian , Scognamiglio Theresa , Moore Maureen D. , Wang Weibin , Park Susan , Park Spencer , Panjwani Suraj , Gray Katherine D. , Tassler Andrew B. , Zarnegar Rasa , Fahey Thomas J. , Jin Moonsoo M.
Published: October 2017

Purpose: Poorly differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet lethal malignancies with limited treatment options. Many malignant tumors, including papillary thyroid cancer (PTC) and ATC, are associated with increased expression of ICAM-1, providing a rationale for utilizing ICAM-1–targeting agents for the treatment of aggressive cancer. We developed a third-generation chimeric antigen receptor (CAR) targeting ICAM-1 to leverage adoptive T-cell therapy as a new treatment modality.

Experimental Design: ICAM-1 CAR T cells were applied to multiple malignant and nonmalignant target cells to investigate specific target cell death and “off-tumor” toxicity in vitro. In vivo therapeutic efficacy of ICAM-1 CAR T cells was examined in ATC mouse models established from a cell line and patient-derived tumors that rapidly develop systemic metastases.

Results: ICAM-1 CAR T cells demonstrated robust and specific killing of PTC and ATC cell lines in vitro. Interestingly, although certain ATC cell lines showed heterogeneous levels of ICAM-1 expression, addition of cytotoxic CAR T cells induced increased ICAM-1 expression such that all cell lines became targetable. In mice with systemic ATC, a single administration of ICAM-1 CAR T cells mediated profound tumor killing that resulted in long-term remission and significantly improved survival. Patient-derived ATC cells overexpressed ICAM-1 and were largely eliminated by autologous ICAM-1 CAR T cells in vitro and in animal models.

Conclusions: Our findings are the first demonstration of CAR T therapy against both a metastatic, thyroid cancer cell line and advanced ATC patient-derived tumors that exhibit dramatic therapeutic efficacy and survival benefit in animal studies. Clin Cancer Res; 23(24); 7569–83. ©2017 AACR.
Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab
Authors: Krejcik Jakub , Frerichs Kris A. , Nijhof Inger S. , van Kessel Berris , van Velzen Jeroen F. , Bloem Andries C. , Broekmans Marloes E.C. , Zweegman Sonja , van Meerloo Johan , Musters René J.P. , Poddighe Pino J. , Groen Richard W.J. , Chiu Christopher , Plesner Torben , Lokhorst Henk M. , Sasser A. Kate , Mutis Tuna , van de Donk Niels W.C.J.
Published: October 2017

Purpose: Daratumumab treatment results in a marked reduction of CD38 expression on multiple myeloma cells. The aim of this study was to investigate the clinical implications and the underlying mechanisms of daratumumab-mediated CD38 reduction.

Experimental Design: We evaluated the effect of daratumumab alone or in combination with lenalidomide-dexamethasone, on CD38 levels of multiple myeloma cells and nontumor immune cells in the GEN501 study (daratumumab monotherapy) and the GEN503 study (daratumumab combined with lenalidomide-dexamethasone). In vitro assays were also performed.

Results: In both trials, daratumumab reduced CD38 expression on multiple myeloma cells within hours after starting the first infusion, regardless of depth and duration of the response. In addition, CD38 expression on nontumor immune cells, including natural killer cells, T cells, B cells, and monocytes, was also reduced irrespective of alterations in their absolute numbers during therapy. In-depth analyses revealed that CD38 levels of multiple myeloma cells were only reduced in the presence of complement or effector cells, suggesting that the rapid elimination of CD38high multiple myeloma cells can contribute to CD38 reduction. In addition, we discovered that daratumumab–CD38 complexes and accompanying cell membrane were actively transferred from multiple myeloma cells to monocytes and granulocytes. This process of trogocytosis was also associated with reduced surface levels of some other membrane proteins, including CD49d, CD56, and CD138.

Conclusions: Daratumumab rapidly reduced CD38 expression levels, at least in part, through trogocytosis. Importantly, all these effects also occurred in patients with deep and durable responses, thus excluding CD38 reduction alone as a mechanism of daratumumab resistance.

The trials were registered at www.clinicaltrials.gov as NCT00574288 (GEN501) and NCT1615029 (GEN503). Clin Cancer Res; 23(24); 7498–511. ©2017 AACR.
On OX40 and PD-1 Combination: Why Should OX40 Be First in Sequence?
Authors: Colombo Mario P.
Published: October 2017

The larger fraction of patients treated with immune checkpoint inhibitors remain nonresponding eventually. Combination of checkpoint inhibitor and costimulatory antibodies is thought additive, but for such effect, they may require to be given in the right sequence. Clin Cancer Res; 23(20); 5999–6001. ©2017 AACR.

See related article by Messenheimer et al., p. 6165
Diffuse Dermal Angiomatosis of the Breast: A Distinct Entity in the Spectrum of Cutaneous Reactive Angiomatoses – Clinicopathologic Study of Two Cases and Comprehensive Review of the Literature
Authors: Galambos Jörg , Meuli-Simmen Claudia , Schmid Regula , Steinmann Lisa S. , Kempf Werner
Published: October 2017

Diffuse dermal angiomatosis (DDA) is a rare reactive angioproliferation in the skin and considered to be a subtype in the group of cutaneous reactive angiomatoses. DDA is clinically characterized by livedoid patches and plaques with tender ulceration. Its histologic features are a reactive diffuse proliferation of bland endothelial cells and pericytes within the dermis, forming small capillary vessels. Previously described cases of DDA most commonly involved the limbs and were associated with a wide spectrum of predisposing comorbidities, especially advanced atherosclerotic vascular disease and arteriovenous fistula. However, several cases of DDA of the breast (DDAB) have been reported in recent years. In this study we present 2 additional patients with DDAB and review all 36 cases of DDAB published in the literature. We describe the clinical and histopathologic characteristics, hypothesized pathogenetic mechanisms, and predisposing conditions of this rare skin disorder and discuss treatment options. The breast is a more commonly involved site of DDA than previously believed. DDAB typically occurs in middle-aged women and is associated with macromastia, overweight or obesity, and probably smoking. Predisposing comorbid conditions differ from those of DDA involving other parts of the body, making DDAB a unique clinicopathologic entity in the spectrum of cutaneous reactive angiomatoses. Currently there is no consensus on the best therapeutic approach. Isotretinoin and other medical therapies have been used with limited success. Breast reduction surgery appears to be a viable treatment option for DDAB in women with macromastia and might provide definitive healing.
Association Between QT-Interval Components and Sudden Cardiac Death
Authors: O’Neal Wesley T. , Singleton Matthew J. , Roberts Jason D. , Tereshchenko Larisa G. , Sotoodehnia Nona , Chen Lin Y. , Marcus Gregory M. , Soliman Elsayed Z.
Published: October 2017

Background:

Several reports have demonstrated that prolongation of the QT interval is associated with sudden cardiac death (SCD). However, it is unknown whether any of the components within the QT interval are responsible for its association with SCD.

Methods and Results:

We examined the association of the individual QT-interval components (R-wave onset to R-peak, R-peak to R-wave end, ST-segment, T-wave onset to T-peak, and T-peak to T-wave end) with SCD in 12 241 participants (54±5.7 years; 26% black; 55% women) from the ARIC study (Atherosclerosis Risk in Communities). The QT interval and its components were measured at baseline (1987–1989) from 12-lead ECGs. SCD cases were adjudicated by a group of physicians through December 31, 2012. During a median follow-up of 23.6 years, a total of 346 cases of SCD were identified. Although prolongation of the QT interval was associated with a 49% increased risk of SCD (hazard ratio, 1.49; 95% confidence interval, 1.01–2.18), only the T-wave onset to T-peak component (per 1-SD increase: hazard ratio, 1.19; 95% confidence interval, 1.06–1.34) was associated with SCD and not any of the other components in separate models. When all of the QT-interval components were included in the same model, T-wave onset to T-peak remained the strongest predictor of SCD (per 1-SD increase: hazard ratio, 1.21; 95% confidence interval, 1.06–1.37).

Conclusions:

The risk of SCD with the QT interval is driven by prolongation of the T-wave onset to T-peak component. This suggests that shifting the focus from the overall QT interval to its individual components will refine SCD prediction in the community.
Transcriptome and Functional Profile of Cardiac Myocytes Is Influenced by Biological Sex
Authors: Trexler Christa L. , Odell Aaron T. , Jeong Mark Y. , Dowell Robin D. , Leinwand Leslie A.
Published: October 2017

Background—

Although cardiovascular disease is the primary killer of women in the United States, women and female animals have traditionally been omitted from research studies. In reports that do include both sexes, significant sexual dimorphisms have been demonstrated in development, presentation, and outcome of cardiovascular disease. However, there is little understanding of the mechanisms underlying these observations. A more thorough understanding of sex-specific cardiovascular differences both at baseline and in disease is required to effectively consider and treat all patients with cardiovascular disease.

Methods and Results—

We analyzed contractility in the whole rat heart, adult rat ventricular myocytes (ARVMs), and myofibrils from both sexes of rats and observed functional sex differences at all levels. Hearts and ARVMs from female rats displayed greater fractional shortening than males, and female ARVMs and myofibrils took longer to relax. To define factors underlying these functional differences, we performed an RNA sequencing experiment on ARVMs from male and female rats and identified ≈600 genes were expressed in a sexually dimorphic manner. Further analysis revealed sex-specific enrichment of signaling pathways and key regulators. At the protein level, female ARVMs exhibited higher protein kinase A activity, consistent with pathway enrichment identified through RNA sequencing. In addition, activating the protein kinase A pathway diminished the contractile sexual dimorphisms previously observed.

Conclusions—

These data support the notion that sex-specific gene expression differences at baseline influence cardiac function, particularly through the protein kinase A pathway, and could potentially be responsible for differences in cardiovascular disease presentation and outcomes.
Late Onset Postcapillary Pulmonary Hypertension in Patients With Transposition of the Great Arteries and Mustard or Senning Baffles
Authors: Chaix Marie‐A. , Dore Annie , Mercier Lise‐Andrée , Mongeon François‐Pierre , Marcotte François , Ibrahim Réda , Asgar Anita W. , Shohoudi Azadeh , Labombarda Fabien , Mondésert Blandine , Poirier Nancy , Khairy Paul
Published: October 2017

Background

There is a paucity of data regarding late‐onset pulmonary hypertension (
PH
) in patients with transposition of the great arteries and atrial switch surgery.

Methods and Results

A retrospective cohort study was conducted on 140 adults with transposition of the great arteries and atrial switch surgery, age 37.3±7.8, 37.1% female, in order to assess the prevalence and characteristics of late‐onset
PH
and explore associated factors. Patients were followed for a median of 32.3 years after atrial switch surgery and 10.0 years after their first referral visit.
PH
was detected in 18 of 33 (54.5%) patients who had invasive hemodynamic studies. Average age at diagnosis of
PH
was 33.9±8.1 years.
PH
was postcapillary in all, with a mean pulmonary artery pressure of 36±12 mm Hg and mean pulmonary capillary wedge pressure of 28±8 mm Hg.
PH
was diagnosed in 13 of 17 (76.5%) patients who had cardiac catheterization for heart failure or decreased exercise tolerance. In multivariable analyses, systemic hypertension (odds ratio 9.4, 95% confidence interval 2.2‐39.4,
P
=0.002) and heart failure or New York Heart Association class
III
or
IV
symptoms (odds ratio 49.8, 95% confidence interval 8.6‐289.0,
P
<0.001) were independently associated with
PH
. Patients with
PH
were more likely to develop cardiovascular comorbidities including atrial (
P
=0.001) and ventricular (
P
=0.008) arrhythmias, require hospitalizations for heart failure (
P
<0.001), and undergo tricuspid valve surgery (
P
<0.001). Mortality was significantly higher in patients with
PH
(hazard ratio 9.4, 95% confidence interval 2.1‐43.0],
P
<0.001).

Conclusions

Late‐onset postcapillary
PH
is highly prevalent in adults with transposition of the great arteries and atrial switch surgery and is associated with an adverse prognosis.
Clinical Prediction Model for Time in Therapeutic Range While on Warfarin in Newly Diagnosed Atrial Fibrillation
Authors: Williams Brent A. , Evans Michael A. , Honushefsky Ashley M. , Berger Peter B.
Published: October 2017

Background

Though warfarin has historically been the primary oral anticoagulant for stroke prevention in newly diagnosed atrial fibrillation (
AF
), several new direct oral anticoagulants may be preferred when anticoagulation control with warfarin is expected to be poor. This study developed a prediction model for time in therapeutic range (
TTR
) among newly diagnosed
AF
patients on newly initiated warfarin as a tool to assist decision making between warfarin and direct oral anticoagulants.

Methods and Results

This electronic medical record–based, retrospective study included newly diagnosed, nonvalvular
AF
patients with no recent warfarin exposure receiving primary care services through a large healthcare system in rural Pennsylvania.
TTR
was estimated as the percentage of time international normalized ratio measurements were between 2.0 and 3.0 during the first year following warfarin initiation. Candidate predictors of
TTR
were chosen from data elements collected during usual clinical care. A
TTR
prediction model was developed and temporally validated and its predictive performance was compared with the
SAM
e‐
TT
2
R
2
score (sex, age, medical history, treatment, tobacco, race) using
R
2
and c‐statistics. A total of 7877 newly diagnosed
AF
patients met study inclusion criteria. Median (interquartile range)
TTR
within the first year of starting warfarin was 51% (32, 67). Of 85 candidate predictors evaluated, 15 were included in the final validated model with an
R
2
of 15.4%. The proposed model showed better predictive performance than the
SAM
e‐
TT
2
R
2
score (
R
2
=3.0%).

Conclusions

The proposed prediction model may assist decision making on the proper mode of oral anticoagulant among newly diagnosed
AF
patients. However, predicting
TTR
on warfarin remains challenging.
Fludrocortisone Is Associated With a Higher Risk of All‐Cause Hospitalizations Compared With Midodrine in Patients With Orthostatic Hypotension
Authors: Grijalva Carlos G. , Biaggioni Italo , Griffin Marie R. , Shibao Cyndya A.
Published: October 2017

Background

Orthostatic hypotension causes ≈80 000 hospitalizations per year in the United States. Treatments for orthostatic hypotension include fludrocortisone, a mineralocorticoid analog that promotes sodium reabsorption; and midodrine, an α‐1 adrenergic agonist that is a direct vasoconstrictor. Although both medications are used to treat orthostatic hypotension, few studies have compared their relative safety.

Methods and Results

We compared incidence rates of hospitalizations for all causes, and for congestive heart failure between users of fludrocortisone and users of midodrine in a retrospective cohort study of Tennessee Medicaid adult enrollees (1995–2009). Adjusted incidence rate ratios were calculated using negative binomial regression models. Subgroup analyses based on history of congestive heart failure were conducted. We studied 1324 patients initiating fludrocortisone and 797 patients initiating midodrine. Compared with fludrocortisone users, midodrine users had higher prevalence of cardiovascular conditions. Incidence rates of all‐cause hospitalizations for fludrocortisone and midodrine users were 1489 and 1330 per 1000 person‐years, respectively (adjusted incidence‐rate ratio 1.20, 95% confidence interval, 1.02–1.40). The respective rates of heart failure–related hospitalization were 76 and 84 per 1000 person‐years (adjusted incidence‐rate ratio: 1.33, 95% confidence interval, 0.79–2.56). Among patients with a history of congestive heart failure, the rates of all‐cause hospitalization for fludrocortisone and midodrine were 2448 and 1820 per 1000 person‐years (adjusted incidence‐rate ratio: 1.42, 95% confidence interval, 1.07–1.90), and the respective rates of heart failure exacerbation–related hospitalizations were 297 and 263 per 1000 person‐years (adjusted incidence‐rate ratio: 1.48, 95% confidence interval, 0.69–3.16).

Conclusions

Compared with users of midodrine, users of fludrocortisone had higher rates of all‐cause hospitalizations, especially among patients with congestive heart failure.
An Indo-European Origin of Kartvelian Names for Two Maloid Fruits
Authors: Fenwick Rhona S. H.
Published: October 2017

The four living Kartvelian languages preserve a rich, largely inherited suite of terms for cultivated fruit trees. But many identifiable Indo-European loans are present even at the level of Kartvelian unity, which leads one to wonder to what extent intercultural exchanges may be responsible for this rich Kartvelian fruit-tree terminology. Here, I propose an etymological connection between Proto-Kartvelian names for the medlar and the domestic pear and suggest that both arise from a borrowing of Late PIE *(s)h2éml- “apple, tree fruit”. I close by discussing this etymology’s implications for the chronology of IE-Kartvelian contact and for the phonetics of the PIE laryngeal *h2.
The Zhoujiatai Occult Manuscripts (周家臺的數術簡)
Authors: Harper (夏德安) Donald
Published: October 2017

Bamboo-slip manuscripts from Zhoujiatai tomb 30, Hubei (burial dated ca. 209 b.c.e.), provide important evidence of ancient Chinese occult manuscripts belonging to a man of modest status. One manuscript, identified as a rishu “day book” by the modern editors of the Zhoujiatai manuscripts, treats of hemerology and astrology and is the focus of this study. The bamboo slips of a calendar for years corresponding to 211–210 b.c.e. can be associated with the rishu and may have formed one manuscript unit. The contents of the rishu include two large-size diagrams related to hemerological and astro-calendrical systems. The first diagram involves calculations based on the position of the handle of the Dipper constellation and the second diagram is notable for reference to one of the years (211 b.c.e.) of the associated calendar. A third diagram, for which the title rong liri “rong calendar day [divination]” is written on the manuscript, has a slightly different form in a second occurrence on the manuscript. Both forms of the diagram show thirty lines arranged in a vertical column, corresponding to the thirty days of the ideal month, with some lines enclosed in boxes. Days of the month are counted in the sequence of lines on the diagram in order to determine the lucky and unlucky aspects of a given day. A related hemerological system is attested in a manuscript from Mawangdui tomb 3, Hunan (burial dated 168 b.c.e.), and in medieval occult manuscripts from Dunhuang.

湖北省周家臺30號墓簡(約公元前209年)提供了關於古代中國一名低級官吏所擁有的數術簡的寶貴資料。本文主要研究其中由整理者认定为《日書》的簡文及其涉及的擇日、星象等內容。同墓出土的暦譜(公元前211–210年)與《日書》相關,可能本來屬於同一卷簡冊。《日書》包括兩幅大圖,一個與擇日有關,一個與星象曆法體系有關。第一圖講基於北斗七星斗柄指向的算法,第二圖因爲涉及到暦譜記載公元前211年的內容而受到矚目。另外第三幅圖簡文記述其名曰“戎磿日”,存在兩個稍微不同的版本。兩個版本的圖都是由縱向排列的三十條橫綫構成,代表一个月的理想天数三十,並和周圍的綫條組成方框。按照圖中橫綫的順序判斷每個月中相應的那一天是否吉利。與此相關的擇日法也在湖南馬王堆3號墓(約公元前168年)與中古時期敦煌的數術文獻中出現。
Turbulent Heat Fluxes during an Extreme Lake-Effect Snow Event
Authors: Fujisaki-Manome Ayumi , Fitzpatrick Lindsay E. , Gronewold Andrew D. , Anderson Eric J. , Lofgren Brent M. , Spence Christopher , Chen Jiquan , Shao Changliang , Wright David M. , Xiao Chuliang
Published: October 2017

Proper modeling of the turbulent heat fluxes over lakes is critical for accurate predictions of lake-effect snowfall (LES). However, model evaluation of such a process has not been possible because of the lack of direct flux measurements over lakes. The authors conducted the first-ever comparison of the turbulent latent and sensible heat fluxes between state-of-the-art numerical models and direct flux measurements over Lake Erie, focusing on a record LES event in southwest New York in November 2014. The model suite consisted of numerical models that were operationally and experimentally used to provide nowcasts and forecasts of weather and lake conditions. The models captured the rise of the observed turbulent heat fluxes, while the peak values varied significantly. This variation resulted in an increased spread of simulated lake temperature and cumulative evaporation as the representation of the model uncertainty. The water budget analysis of the atmospheric model results showed that the majority of the moisture during this event came from lake evaporation rather than a larger synoptic system. The unstructured-grid Finite-Volume Community Ocean Model (FVCOM) simulations, especially those using the Coupled Ocean–Atmosphere Response Experiment (COARE)-Met Flux algorithm, presented better agreement with the observed fluxes likely due to the model’s capability in representing the detailed spatial patterns of the turbulent heat fluxes and the COARE algorithm’s more realistic treatment of the surface boundary layer than those in the other models.
Flash Flooding in Arid/Semiarid Regions: Dissecting the Hydrometeorology and Hydrology of the 19 August 2014 Storm and Flood Hydroclimatology in Arizona
Authors: Yang Long , Smith James , Baeck Mary Lynn , Morin Efrat , Goodrich David C.
Published: October 2017

The hydroclimatology, hydrometeorology, and hydrology of flash floods in the arid/semiarid southwestern United States are examined through empirical analyses of long-term, high-resolution rainfall and stream gauging observations, together with hydrological modeling analyses of the 19 August 2014 storm based on the Kinematic Runoff and Erosion Model (KINEROS2). The analyses presented here are centered on identifying the structure and evolution of flood-producing storms, as well as the interactions of space–time rainfall variability and basin characteristics in determining the upper-tail properties of rainfall and flood magnitudes over this region. This study focuses on four watersheds in Maricopa County, Arizona, with contrasting geomorphological properties. Flash floods over central Arizona are concentrated in both time and space, reflecting controls of the North American monsoon and complex terrain. Thunderstorm systems during the North American monsoon, as represented by the 19 August 2014 storm, are the dominant flood agents that determine the upper tail of flood frequency over central Arizona and that also shape the envelope curve of floods for watersheds smaller than 250 km2. Flood response for the 19 August 2014 storm is associated with storm elements of comparable spatial extent to the drainage area and slow movement for the three compact, headwater watersheds. Flood response for the elongated and relatively flat Skunk Creek highlights the importance of the spatial distribution of rainfall for transmission losses in arid/semiarid watersheds.
Nonlinear Least Squares En4DVar to 4DEnVar Methods for Data Assimilation: Formulation, Analysis, and Preliminary Evaluation
Authors: Tian Xiangjun , Zhang Hongqin , Feng Xiaobing , Xie Yuanfu
Published: October 2017

The En4DVar method is designed to combine the flow-dependent statistical covariance information of EnKF into the traditional 4DVar method. However, the En4DVar method is still hampered by its strong dependence on the adjoint model of the underlying forecast model and by its complexity, maintenance requirements, and the high cost of computer implementation and simulation. The primary goal of this paper is to propose an alternative approach to overcome the main difficulty of the En4DVar method caused by the use of adjoint models. The proposed approach, the nonlinear least squares En4DVar (NLS-En4DVar) method, begins with rewriting the standard En4DVar formulation into a nonlinear least squares problem, which is followed by solving the resulting NLS problem by a Gauss–Newton iterative method. To reduce the computational and implementation complexity of the proposed NLS-En4DVar method, a few variants of the new method are proposed; these modifications make the model cheaper and easier to use than the full NLS-En4DVar method at the expense of reduced accuracy. Furthermore, an improved iterative method based on the comprehensive analysis on the above NLSi-En4DVar family of methods is also proposed. These proposed NLSi-En4DVar methods provide more flexible choices of the computational capabilities for the broader and more realistic data assimilation problems arising from various applications. The pros and cons of the proposed NLSi-En4DVar family of methods are further examined in the paper and their relationships and performance are also evaluated by several sets of numerical experiments based on the Lorenz-96 model and the Advanced Research WRF (ARW) Model, respectively.
Qatar and Rising China
Authors: Saidy Brahim
Published: October 2017

This article explores the Qatari perception of the partnership with China on the basis of three factors: globalisation, the absence of a legacy of colonialism and the principles of non-intervention and respect for state sovereignty professed in China’s foreign policy. China’s perception of its relations with Qatar is embedded within its understanding of the regional order in the Middle East and reflects its assessment of the geopolitical factors that are transforming Gulf countries. It emerges from this analysis that the diplomatic and economic aspects of Qatar–China relations are substantial and well institutionalised. However, military cooperation is still underdeveloped despite the increase of military-to-military contacts.
Unique Tailoring of Th17 at the Gingival Oral Mucosal Barrier
Authors: Konkel J.E. , Moutsopoulos N.M.
Published: October 2017

Our recent work highlights unique requirements for the induction of Th17 cells at the oral/gingival mucosal barrier. Unlike other barrier sites, such as the skin and gastrointestinal tract, we found that Th17 cells can develop at the gingiva independently of commensal microbiota colonization. Instead, we identified that damage, which occurs physiologically due to mastication, promotes induction of Th17 cells and tones homeostatic immunity at the gingiva.