bluuebunny/crossref_metadata_2025 huggingface dataset:
Individualized Pazopanib Dosing: A Prospective Feasibility Study in Cancer Patients
Authors: Verheijen Remy B. , Bins Sander , Mathijssen Ron H.J. , Lolkema Martijn P. , van Doorn Leni , Schellens Jan H.M. , Beijnen Jos H. , Langenberg Marlies H.G. , Huitema Alwin D.R. , Steeghs Neeltje
Published: July 2016

Purpose: Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median progression-free survival and tumor shrinkage appear in patients with higher plasma trough levels (Cmin). Therefore, patients with low Cmin might benefit from pharmacokinetically guided individualized dosing.

Experimental Design: We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cmin was measured weekly by LC-MS/MS. At weeks 3, 5, and 7, the pazopanib dose was increased if the measured Cmin was <20 mg/L and toxicity was <grade 3.

Results: In total, 17 patients had at least one Cmin <20 mg/L at weeks 3, 5, and 7. Of these, 10 were successfully treated with a pharmacokinetically guided dose escalation, leading to daily dosages ranging from 1,000 to 1,800 mg. Cmin in these patients increased significantly from 13.2 (38.0%) mg/L [mean (CV%)] to 22.9 mg/L (44.9%). Thirteen patients had all Cmin levels ≥20.0 mg/L. Of these, 9 patients with a high Cmin of 51.3 mg/L (45.1%) experienced ≥grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients, Cmin remained above the threshold at 28.2 mg/L (25.3%).

Conclusions: A pharmacokinetically guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1,800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes, such as progression-free survival. Clin Cancer Res; 22(23); 5738–46. ©2016 AACR.

See related commentary by Ornstein and Rini, p. 5626
Ubiquitin Ligase, Fbw7, Targets CDX2 for Degradation via Two Phosphodegron Motifs in a GSK3β-Dependent Manner
Authors: Kumar Yogesh , Shukla Nidhi , Thacker Gatha , Kapoor Isha , Lochab Savita , Bhatt Madan Lal Brahma , Chattopadhyay Naibedya , Sanyal Sabyasachi , Trivedi Arun Kumar
Published: July 2016

Drosophila caudal–related homeobox transcription factor 2 (CDX2) drives differentiation of the intestinal epithelium. Loss of CDX2 expression has been reported in several colorectal cancers and cancer cell lines with a potential inverse correlation between CDX2 levels and tumor stage. Ubiquitination of CDX2 leading to its downregulation has been implicated in several studies; however, the E3 ubiquitin ligases involved in CDX2 ubiquitination have largely remained unknown. Here, it is mechanistically determined that the E3 ubiquitin ligase Fbw7 promotes CDX2 ubiquitination and degradation through two phosphodegron motifs present within CDX2 in a GSK3β-dependent manner leading to its reduced expression and function in colon cancer cells. Fbw7, through its WD domain, interacted with CDX2 both in a heterologous HEK293T cell system and in colon cancer cells. GSK3β was also present in the same complex as determined by coimmunoprecipitation. Furthermore, overexpression of both Fbw7 or GSK3β down regulated endogenous CDX2 expression and function; however, both failed to inhibit endogenous CDX2 when either of them were depleted in colon cancer cells. Fbw7-mediated inhibition of CDX2 expression also led to reduced CDX2 transactivation and growth arrest of colon cancer cells. Both GSK3β and Fbw7 degraded mutant-CDX2 having either of the Cdc4-phosphodegron (CPD) motifs disrupted (CDX2-S60A or CDX-S281A), but were unable to degrade mutant-CDX2 having both CPDs disrupted (CDX2-S60,64,281A).

Implications: Taken together, these findings demonstrate that Fbw7 negatively regulates CDX2 expression in a GSK3β-dependent manner through two CPDs present in CDX2. Mol Cancer Res; 14(11); 1097–109. ©2016 AACR.
Serum Alkaline Phosphatase Levels are Not Associated with Increased Death Risk in Prevalent Hemodialysis Patients: 5-Year Experience in a Single Hemodialysis Center
Authors: Zhu Jin-Gang , Cheng Ben-Chung , Lee Wen-Chin , Li Lung-Chih , Lee Chih-Hsiung , Long Gang , Chen Jin-Bor
Published: July 2016

Background/Aims: Although high serum alkaline phosphatase (ALP) levels were reported as predictive factors for death risk in dialysis patients on the basis of large databank analyses, the real scenario in a single hemodialysis (HD) center is unknown. Methods: In this study, a 5-year cohort of 1126 prevalent HD patients in the largest HD center in Taiwan was studied. The associations of ALP levels expressed as baseline, time-average, and time-dependent with all-cause mortality and cardiovascular mortality were evaluated by using adjusted Cox regression models. Results: At baseline, levels of serum parathyroid hormone, calcium, and liver enzymes are increased in parallel with ALP quartiles. The hazard ratio (HR) for all-cause mortality was significantly increased in time-average and time-dependent ALP quartile in the unadjusted Cox analysis. The significance disappeared when multivariate adjusted Cox analysis was used. Similarly, HR was not significantly increased for cardiovascular mortality with ALP quartile expressed as baseline, time-average, and time-dependent in three models of Cox analyses. Conclusion: Our study demonstrated that serum ALP levels were not associated with increased death risk in prevalent HD patients over a 5-year interval.
Postoperative Delirium in Patients after Pancreaticoduodenectomy
Authors: Ito Yasuhiro , Abe Yuta , Handa Kan , Shibutani Shintaro , Egawa Tomohisa , Nagashima Atsushi , Kitago Minoru , Itano Osamu , Kitagawa Yuko
Published: July 2016

Background/Aims: Postoperative delirium (POD) is one of the most common complications after various types of surgery. The aim of this study was to investigate the incidence and risk factors for delirium after pancreaticoduodenectomy (PD). Methods: This was a retrospective study of 146 consecutive patients who underwent PD between April 2007 and June 2015 at Saiseikai Yokohamashi Tobu Hospital. Results: Twenty-nine patients (19.9%) were diagnosed with delirium. Patients who were >70 years were divided into a delirium group (n = 24) and a non-delirium group (n = 41). Multivariate analysis showed that only the Charlson Age Comorbidity Index (CACI) (OR 1.8; 95% CI 1.067-3.036; p = 0.028) was an independent risk factor of delirium for patients >70 years. The receiver operating characteristic curve revealed an optimal cutoff value of 4.5 for the CACI score in all patients (sensitivity 62.1%; specificity 82.9%; area under the curve 0.782). The higher CACI score (≥5) is significantly different from the lower CACI score (p < 0.0001) with respect to POD occurrence. Conclusions: The CACI, especially in elderly patients, was associated with the incidence of POD. Therefore, utilizing this validated and practical tool preoperatively might be useful for POD.
The Need for a Rational Approach to Vasoconstrictive Syndromes: Transcranial Doppler and Calcium Channel Blockade in Reversible Cerebral Vasoconstriction Syndrome
Authors: Marsh Elisabeth B. , Ziai Wendy C. , Llinas Rafael H.
Published: July 2016

Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) typically affects young patients and left untreated can result in hemorrhage or ischemic stroke. Though the disorder has been well characterized in the literature, the most appropriate way to diagnose, treat, and evaluate therapeutic response remains unclear. In previous studies, transcranial Doppler ultrasound (TCD) has shown elevated velocities indicative of vasospasm. This imaging modality is noninvasive and inexpensive; an attractive option for diagnosis and therapeutic monitoring if it is sensitive enough to detect changes in the acute setting given that RCVS often affects the distal vessels early in the course of disease. There is also limited data that calcium channel blockade may be effective in treating vasospasm secondary to RCVS, though the agent of choice, formulation, and dose are unclear. Methods: We report a small cohort of seven patients presenting with thunderclap headache whose vascular imaging was consistent with RCVS. All were treated with calcium channel blockade and monitored with TCD performed every 1–2 days. Results: On presentation, TCD correlated with standard neuroimaging findings of vasospasm (on MR, CT, and conventional angiography). TCD was also able to detect improvement in velocities in the acute setting that correlated well with initiation of calcium channel blockade. Long-acting verapamil appeared to have the greatest effect on velocities compared to nimodipine and shorter-acting calcium channel blockers. Conclusion: Though small, our cohort demonstrates potential utility of TCD to monitor RCVS, and relative superiority of extended-release verapamil over other calcium channel blockers, illustrating the need for larger randomized trials.
Hypoxic Proliferation of Osteosarcoma Cells Depends on Arginase II
Authors: Setty Bhuvana A. , Jin Yi , Houghton Peter J. , Yeager Nicholas D. , Gross Thomas G. , Nelin Leif D.
Published: July 2016

Background/Aims: Despite significant advancements in the diagnosis and treatment of osteosarcoma, the overall survival has remained relatively unchanged for over two decades. Hypoxic conditions have been demonstrated in solid tumors and are associated with increased cell proliferation and angiogenesis. L-arginine metabolism by arginase produces L-ornithine, the precursor for polyamine and proline synthesis required for cellular proliferation. We hypothesized that hypoxia would increase cellular proliferation via arginase induction in human osteosarcoma cell lines. Methods: We utilized a variety of approaches to examine the role of arginase II in hypoxic (1% O2, 5% CO2) cellular proliferation. Results: Arginase II mRNA and protein levels were significantly increased in osteosarcoma cells exposed to hypoxia for 48 hours. There were twice as many viable cells following 48 hours of hypoxia than following 48 hours of normoxia (21% O2, 5% CO2). The addition of difluoromethylornithine (DFMO), a putative arginase inhibitor, prevented hypoxia-induced proliferation. Transfection of small interfering RNAs (siRNA) targeting arginase II resulted in knockdown of arginase II protein levels and prevented hypoxia-induced cellular proliferation. Conclusions: These data support our hypothesis that hypoxia increases proliferation of osteosarcoma cells in an arginase II-dependent manner. We speculate that arginase II may represent a therapeutic target in osteosarcoma.
Bazex Syndrome with Hypoalbuminemia and Severe Ascites
Authors: Matsui Hidetoshi , Iwae Shigemichi , Hirayama Yuji , Yonezawa Koichiro , Shigeji Jun
Published: July 2016

Bazex syndrome is a rare paraneoplastic dermatosis. The underlying malignancy frequently is squamous cell carcinoma of the upper aerodigestive tract or cervical lymph nodes from an unknown primary site. We report a 63-year-old man with squamous cell carcinoma of cervical lymph nodes from an unknown primary site. He developed a mass on the right side of his neck, cutaneous lesions diagnosed as Bazex syndrome, hypoalbuminemia, and severe ascites. Right neck dissection was performed. After neck dissection, not only the cutaneous lesions, but also the severe hypoalbuminemia and severe ascites were improved. Bazex syndrome may be associated with hypoalbuminemia and ascites.
A política no pódio: episódios de tensões e conflitos nos Jogos Olímpicos da Era Moderna
Authors: Campos Flavio de
Published: July 2016

Em tempos de protestos e conflitos em praças esportivas brasileiras, este artigo tem como objetivo retomar alguns episódios marcantes de tensões e enfrentamentos ideológicos ocorridos durante a história dos Jogos Olímpicos de Verão da Era Moderna. Pretende-se questionar a perspectiva, contida nos discursos oficiais do Comitê Olímpico Internacional, entre os organizadores dos mais diversos países e de setores expressivos da imprensa, de que a política e os esportes devem estar apartados em nome do espírito olímpico. A referência a tais episódios demonstra como as situações históricas revelam a recorrência das práticas e confrontos políticos mais ou menos explícitos.
Agenda 20+20 e o fim de um ciclo para o Movimento Olímpico Internacional
Authors: Rubio Katia
Published: July 2016

Passado mais de um século desde o início dos Jogos Olímpicos da Era Moderna, o Movimento Olímpico busca uma mudança de trajetória na busca do espírito olímpico perdido. Depois de sofrer profundas transformações que puseram em risco o chamado “espírito olímpico”, colaborando para isso a ascensão do profissionalismo e dos interesses comerciais que rondam o maior espetáculo do planeta, o atual presidente do Comitê Olímpico Internacional (COI) faz um chamamento à comunidade olímpica internacional propondo diálogo, inclusão e transformações em uma das instituições mais fechadas do planeta. O objetivo deste texto é discutir o reposicionamento do Movimento Olímpico e as recomendações estratégicas do COI denominados Agenda 20 + 20, no que diz respeito ao futuro do Movimento Olímpico e dos Jogos Olímpicos.
As estratégias de João Havelange para enfraquecer o futebol olímpico
Authors: Giglio Sérgio Settani
Published: July 2016

A proposta deste artigo é apresentar as estratégias de João Havelange quando assumiu a presidência da Fifa (1974). Uma de suas estratégias foi enfraquecer o futebol olímpico com a criação de uma Copa do Mundo Júnior (1977) e produzir a ideia para os jovens atletas de que a Copa do Mundo era a principal competição. Em 1992, como último ato de restrições, a Fifa implementou o limite de idade para participação no futebol olímpico. As estratégias de Havelange na presidência da Fifa representam a atualização dos conflitos entre o COI e a Fifa em relação ao controle das regras referentes ao futebol. E, portanto, fornece um caminho para compreender como ações políticas separaram essas duas competições, produzindo discursos diferentes em torno delas.
O doping e os Jogos Olímpicos: diferentes dimensões do fenômeno
Authors: Almeida Marco Bettine de , Gutierrez Diego Monteiro , Gutierrez Gustavo Luis
Published: July 2016

Este artigo apresenta uma rápida história do doping nos Jogos Olímpicos, a sua evolução nas provas e o desenvolvimento das formas de controle. Ilustra alguns dados quantitativos sobre substâncias mais comuns e casos denunciados para, no fim, desenvolver uma reflexão sobre as consequências da repercussão do doping na sociedade de uma forma geral.
A contribuição dos Jogos Paralímpicos para a promoção da inclusão social: o discurso midiático como um obstáculo
Authors: Marques Renato Francisco Rodrigues
Published: July 2016

A inclusão social de pessoas com deficiência é um processo que perpassa tanto pelo empoderamento quanto por transformações da sociedade, de modo a proporcionar oportunidades de participação social plena. Sua efetividade está intimamente atrelada à transformação de paradigmas, estereótipos e preconceitos. Isso é possível por meio da educação formal, da mídia e de fenômenos socioculturais capazes de contribuir para modificar ou reforçar valores morais, como o esporte. O objetivo geral deste ensaio é propor uma reflexão a respeito da maneira como atletas paralímpicos são retratados pela mídia durante os Jogos Paralímpicos e o produto dessa forma de interação com os espectadores. Conclui-se que os atletas querem ser reconhecidos como pessoas produtivas e eficientes assim como qualquer outro cidadão.
E-Selectin Inhibition Mitigates Splenic HSC Activation and Myelopoiesis in Hypercholesterolemic Mice With Myocardial Infarction
Authors: Dutta Partha , Hoyer Friedrich Felix , Sun Yuan , Iwamoto Yoshiko , Tricot Benoit , Weissleder Ralph , Magnani John L. , Swirski Filip K. , Nahrendorf Matthias
Published: July 2016

Objective—

Atherosclerosis is a chronic disease characterized by lipid accumulation in the arterial wall. After myocardial infarction (MI), atherosclerotic plaques are infiltrated by inflammatory myeloid cells that aggravate the disease and increase the risk of secondary myocardial ischemia. Splenic myelopoiesis provides a steady flow of myeloid cells to inflamed atherosclerotic lesions after MI. Therefore, targeting myeloid cell production in the spleen could ameliorate increased atherosclerotic plaque inflammation after MI.

Approach and Results—

Here we show that MI increases splenic myelopoiesis by driving hematopoietic stem and progenitor cells into the cell cycle. In an atherosclerotic mouse model, E-selectin inhibition decreased hematopoietic stem and progenitor cell proliferation in the spleen after MI. This led to reduced extramedullary myelopoiesis and decreased myeloid cell accumulation in atherosclerotic lesions. Finally, we observed stable atherosclerotic plaque features, including smaller plaque size, reduced necrotic core area, and thicker fibrous cap after E-selectin inhibition.

Conclusions—

Inhibiting E-selectin attenuated inflammation in atherosclerotic plaques, likely by reducing leukocyte recruitment into plaques and by mitigating hematopoietic stem and progenitor cell activation in the spleen of mice with MI.
Hypercholesterolemia Induced by a PCSK9 Gain-of-Function Mutation Augments Angiotensin II–Induced Abdominal Aortic Aneurysms in C57BL/6 Mice—Brief Report
Authors: Lu Hong , Howatt Deborah A. , Balakrishnan Anju , Graham Mark J. , Mullick Adam E. , Daugherty Alan
Published: July 2016

Objective—

Gain-of-function mutations of PCSK9 (proprotein convertase subtilisin/kexin type 9) lead to hypercholesterolemia. This study was to determine whether infection of normocholesterolemic mice with an adeno-associated viral (AAV) vector expressing a gain-of-function mutation of mouse PCSK9 increased angiotensin II (AngII)–induced abdominal aortic aneurysms.

Approach and Results—

In an initial study, male C57BL/6 mice were injected intraperitoneally with either an empty vector or PCSK9 gain-of-function mutation (D377Y). AAV at 3 doses and fed a saturated fat-enriched diet for 6 weeks. Two weeks after AAV injection, mice were infused with AngII for 4 weeks. Plasma PCSK9 concentrations were increased dose dependently in mice injected with AAV containing PCSK9D377Y mutation and positively associated with elevations of plasma cholesterol concentrations. Infection with intermediate and high doses of PCSK9D377Y.AAV led to equivalent increases of maximal width of abdominal aortas in C57BL/6 mice infused with AngII. Therefore, the intermediate dose was used in subsequent experiments. We then determined effects of PCSK9D377Y.AAV infection on 5 normolipidemic mouse strains, demonstrating that C57BL/6 mice were the most susceptible to this AAV infection. PCSK9D377Y.AAV infected male C57BL/6 mice were also compared with age-matched male low-density lipoprotein receptor
−/−
mice. Although plasma cholesterol concentrations were lower in mice infected with PCSK9D377Y.AAV, these mice had equivalent abdominal aortic aneurysmal formation, compared to low-density lipoprotein receptor
−/−
mice. In a separate study, reduced plasma PCSK9 concentrations by PCSK9 antisense oligonucleotides in male low-density lipoprotein receptor
−/−
mice did not influence AngII-induced abdominal aortic aneurysms.

Conclusion—

AAV-mediated infection with a mouse PCSK9 gain-of-function mutation is a rapid, easy, and efficient approach for inducing hypercholesterolemia and promoting abdominal aortic aneurysms in C57BL/6 mice infused with AngII.
Fibroblast Growth Factor 12 Is a Novel Regulator of Vascular Smooth Muscle Cell Plasticity and Fate
Authors: Song Sun-Hwa , Kim Kyungjong , Jo Eun-Kyung , Kim Young-Wook , Kwon Jin-Sook , Bae Sun Sik , Sung Jong-Hyuk , Park Sang Gyu , Kim Jee Taek , Suh Wonhee
Published: July 2016

Objective—

Vascular smooth muscle cells (VSMCs) modulate their phenotype between synthetic and contractile states in response to environmental changes; this modulation plays a crucial role in the pathogenesis of restenosis and atherosclerosis. Here, we identified fibroblast growth factor 12 (FGF12) as a novel key regulator of the VSMC phenotype switch.

Approach and Results—

Using murine models and human specimens, we found that FGF12 was highly expressed in contractile VSMCs of normal vessel walls but was downregulated in synthetic VSMCs from injured and atherosclerotic vessels. In human VSMCs, FGF12 expression was inhibited at the transcriptional level by platelet-derived growth factor-BB. Gain- and loss-of-function experiments showed that FGF12 was both necessary and sufficient for inducing and maintaining the quiescent and contractile phenotypes of VSMCs. FGF12 inhibited cell proliferation through the p53 pathway and upregulated the key factors involved in VSMC lineage differentiation, such as myocardin and serum response factor. Such FGF12-induced phenotypic change was mediated by the p38 MAPK (mitogen-activated protein kinase) pathway. Moreover, FGF12 promoted the differentiation of mouse embryonic stem cells and the transdifferentiation of human dermal fibroblasts into SMC-like cells. Furthermore, adenoviral infection of FGF12 substantially decreased neointima hyperplasia in a rat carotid artery injury model.

Conclusions—

In general, FGF family members induce a synthetic VSMC phenotype. Interestingly, the present study showed the unanticipated finding that FGF12 belonging to FGF family, strongly induced the quiescent and contractile VSMC phenotypes and directly promoted VSMC lineage differentiation. These novel findings suggested that FGF12 could be a new therapeutic target for treating restenosis and atherosclerosis.
12(S)-HETrE, a 12-Lipoxygenase Oxylipin of Dihomo-γ-Linolenic Acid, Inhibits Thrombosis via Gα
s
Signaling in Platelets
Authors: Yeung Jennifer , Tourdot Benjamin E. , Adili Reheman , Green Abigail R. , Freedman Cody J. , Fernandez-Perez Pilar , Yu Johnny , Holman Theodore R. , Holinstat Michael
Published: July 2016

Objective—

Dietary supplementation with polyunsaturated fatty acids has been widely used for primary and secondary prevention of cardiovascular disease in individuals at risk; however, the cardioprotective benefits of polyunsaturated fatty acids remain controversial because of lack of mechanistic and in vivo evidence. We present direct evidence that an omega-6 polyunsaturated fatty acid, dihomo-γ-linolenic acid (DGLA), exhibits in vivo cardioprotection through 12-lipoxygenase (12-LOX) oxidation of DGLA to its reduced oxidized lipid form, 12(S)-hydroxy-8Z,10E,14Z-eicosatrienoic acid (12(S)-HETrE), inhibiting platelet activation and thrombosis.

Approach and Results—

DGLA inhibited ex vivo platelet aggregation and Rap1 activation in wild-type mice, but not in mice lacking 12-LOX expression (12-LOX
−/−
). Similarly, wild-type mice treated with DGLA were able to reduce thrombus growth (platelet and fibrin accumulation) after laser-induced injury of the arteriole of the cremaster muscle, but not 12-LOX
−/−
mice, supporting a 12-LOX requirement for mediating the inhibitory effects of DGLA on platelet-mediated thrombus formation. Platelet activation and thrombus formation were also suppressed when directly treated with 12(S)-HETrE. Importantly, 2 hemostatic models, tail bleeding and arteriole rupture of the cremaster muscle, showed no alteration in hemostasis after 12(S)-HETrE treatment. Finally, the mechanism for 12(S)-HETrE protection was shown to be mediated via a Gα
s
-linked G-protein–coupled receptor pathway in human platelets.

Conclusions—

This study provides the direct evidence that an omega-6 polyunsaturated fatty acid, DGLA, inhibits injury-induced thrombosis through its 12-LOX oxylipin, 12(S)-HETrE, which strongly supports the potential cardioprotective benefits of DGLA supplementation through its regulation of platelet function. Furthermore, this is the first evidence of a 12-LOX oxylipin regulating platelet function in a Gs α subunit–linked G-protein–coupled receptor–dependent manner.
Geographic and Temporal Variation in Cardiac Implanted Electric Devices to Treat Heart Failure
Authors: Hatfield Laura A. , Kramer Daniel B. , Volya Rita , Reynolds Matthew R. , Normand Sharon‐Lise T.
Published: July 2016

Background

Cardiac implantable electric devices are commonly used to treat heart failure. Little is known about temporal and geographic variation in use of cardiac resynchronization therapy (
CRT
) devices in usual care settings.

Methods and Results

We identified new
CRT
with pacemaker (
CRT
‐P) or defibrillator generators (
CRT
‐D) implanted between 2008 and 2013 in the United States from a commercial claims database. For each implant, we characterized prior medication use, comorbidities, and geography. Among 17 780 patients with
CRT
devices (median age 69, 31% women),
CRT
‐Ps were a small and increasing share of
CRT
devices, growing from 12% to 20% in this study period. Compared to
CRT
‐D recipients,
CRT
‐P recipients were older (median age 76 versus 67), and more likely to be female (40% versus 30%). Pre‐implant use of β‐blockers and angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers was low in both
CRT
‐D (46%) and
CRT
‐P (31%) patients. The fraction of
CRT
‐P devices among all new implants varied widely across states. Compared to the increasing national trend, the share of
CRT
‐P implants was relatively increasing in Kansas and relatively decreasing in Minnesota and Oregon.

Conclusions

In this large, contemporary heart failure population,
CRT
‐D use dwarfed
CRT
‐P, though the latter nearly doubled over 6 years. Practice patterns vary substantially across states and over time. Medical therapy appears suboptimal in real‐world practice.
Association of Age at Menopause With Incident Heart Failure: A Prospective Cohort Study and Meta‐Analysis
Authors: Appiah Duke , Schreiner Pamela J. , Demerath Ellen W. , Loehr Laura R. , Chang Patricia P. , Folsom Aaron R.
Published: July 2016

Background

Early age (<45 years) at menopause has been postulated to be associated with increased cardiovascular disease risk; however, evidence of its relation with heart failure (
HF
) incidence is limited. We examined whether age at menopause is associated inversely with
HF
incidence in the Atherosclerosis Risk In Communities (
ARIC
) study and summarized all existing data in a meta‐analysis.

Methods and Results

In
ARIC
, data were obtained from 5629 postmenopausal women (mean age 56 years, 26% with bilateral oophorectomy) without
HF
. During a median follow‐up of 21.4 years, 965 incident
HF
events occurred. In a Cox regression model adjusted for reproductive health and
HF
risk factors, the hazard ratios for incident
HF
across categories of age at menopause (<45, 45–49, 50–54, and ≥55 years) were 1.32, 1.17, 1.00 (referent), and 1.12, respectively. Compared with women with later onset of menopause (aged ≥45 years), those with early menopause had elevated
HF
risk (hazard ratio 1.20, 95%
CI
1.01–1.43). For the meta‐analysis, we searched Medline and Embase for articles published through December 2015 that prospectively evaluated age at menopause and
HF
risk. Summarized estimates from the 3 included studies (3568 events) showed higher
HF
risk among women with early menopause compared with those with later menopause (hazard ratio 1.33, 95%
CI
1.15–1.53).

Conclusions

These results provided evidence that early age at menopause is associated with a modestly greater risk of
HF
. Identification of women with early menopause offers a window of opportunity to implement interventions that will improve overall cardiovascular health during the postmenopausal years.
Association of Major Depressive Episodes With Stroke Risk in a Prospective Study of 0.5 Million Chinese Adults
Authors: Sun Jie , Ma Hongxia , Yu Canqing , Lv Jun , Guo Yu , Bian Zheng , Yang Ling , Chen Yiping , Shen Hongbing , Chen Zhengming , Hu Zhibin , Li Liming
Published: July 2016

Background and Purpose—

Although the relationship between depression and stroke risk has been investigated, findings in previous reports were conflicting. The aim of this study was to prospectively examine the effect of major depressive episodes (MDE) on stroke incidence and further assess the potential dose–response relationship between number of depression symptoms and subsequent stroke risk in Chinese population.

Methods—

A total of 199 294 men and 288 083 women aged 30 to 79 years without a history of stroke, heart disease, and cancer in the China Kadoorie Biobank cohort were followed from 2004 to 2013. A World Health Organization Composite International Diagnostic Interview-Short Form was used to access MDE according to Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Stroke events were ascertained through death certificates, medical records, and health insurance data.

Results—

Past year MDE was marginally associated with a 15% increased risk of stroke (adjusted hazard ratio, 1.15; 95% confidence interval, 0.99–1.33) in the fully adjusted model, and the association was steeper and statistically significant in individuals aged <50 years, smokers, drinkers, those with higher education degree, body mass index <24.0 kg/m
2
, and no history of diabetes mellitus. Moreover, there was a positive dose–response relationship between the number of depression symptoms and increased stroke risk (
P
trend
=0.011). In addition, smoking status significantly interacted with MDE on stroke onset (
P
for multiplicative interaction=0.025).

Conclusions—

Findings from this large prospective study suggest that the presence of MDE is a risk factor for stroke, especially in smokers.
Cyclic Incrementality in Competitive Coevolution: Evolvability through Pseudo-Baldwinian Switching-Genes
Authors: Janssen Rick , Nolfi Stefano , Haselager Pim , Sprinkhuizen-Kuyper Ida
Published: July 2016

Coevolving systems are notoriously difficult to understand. This is largely due to the Red Queen effect that dictates heterospecific fitness interdependence. In simulation studies of coevolving systems, master tournaments are often used to obtain more informed fitness measures by testing evolved individuals against past and future opponents. However, such tournaments still contain certain ambiguities. We introduce the use of a phenotypic cluster analysis to examine the distribution of opponent categories throughout an evolutionary sequence. This analysis, adopted from widespread usage in the bioinformatics community, can be applied to master tournament data. This allows us to construct behavior-based category trees, obtaining a hierarchical classification of phenotypes that are suspected to interleave during cyclic evolution. We use the cluster data to establish the existence of switching-genes that control opponent specialization, suggesting the retention of dormant genetic adaptations, that is, genetic memory. Our overarching goal is to reiterate how computer simulations may have importance to the broader understanding of evolutionary dynamics in general. We emphasize a further shift from a component-driven to an interaction-driven perspective in understanding coevolving systems. As yet, it is unclear how the sudden development of switching-genes relates to the gradual emergence of genetic adaptability. Likely, context genes gradually provide the appropriate genetic environment wherein the switching-gene effect can be exploited.
Open-Ended Evolution: Perspectives from the OEE Workshop in York
Authors: Taylor Tim , Bedau Mark , Channon Alastair , Ackley David , Banzhaf Wolfgang , Beslon Guillaume , Dolson Emily , Froese Tom , Hickinbotham Simon , Ikegami Takashi , McMullin Barry , Packard Norman , Rasmussen Steen , Virgo Nathaniel , Agmon Eran , Clark Edward , McGregor Simon , Ofria Charles , Ropella Glen , Spector Lee , Stanley Kenneth O. , Stanton Adam , Timperley Christopher , Vostinar Anya , Wiser Michael
Published: July 2016

We describe the content and outcomes of the First Workshop on Open-Ended Evolution: Recent Progress and Future Milestones (OEE1), held during the ECAL 2015 conference at the University of York, UK, in July 2015. We briefly summarize the content of the workshop's talks, and identify the main themes that emerged from the open discussions. Two important conclusions from the discussions are: (1) the idea of pluralism about OEE—it seems clear that there is more than one interesting and important kind of OEE; and (2) the importance of distinguishing observable behavioral hallmarks of systems undergoing OEE from hypothesized underlying mechanisms that explain why a system exhibits those hallmarks. We summarize the different hallmarks and mechanisms discussed during the workshop, and list the specific systems that were highlighted with respect to particular hallmarks and mechanisms. We conclude by identifying some of the most important open research questions about OEE that are apparent in light of the discussions. The York workshop provides a foundation for a follow-up OEE2 workshop taking place at the ALIFE XV conference in Cancún, Mexico, in July 2016. Additional materials from the York workshop, including talk abstracts, presentation slides, and videos of each talk, are available at http://alife.org/ws/oee1 .
A Semiotic Approach to Entomophagy
Authors: Ali Ashleigh Elizabeth
Published: July 2016

While there has been a growing interest in entomophagy in theus, the idea of eating insects is still taboo among the majority of Americans. Many studies have successfully established that, even after being informed about the numerous benefits of entomophagy, most people in the Western world continue to shun the idea of eating insects for a variety of reasons. However, few studies have considered the role that sociolinguistic meanings embedded within semiotic systems play in influencing Western perceptions of insects as foodstuffs. This study elaborates on the means through which the practice of entomophagy can be made more appealing to Americans. Drawing on information acquired through the analysis of a completed survey study that explores food neophobia as it relates to entomophagy, I use anthropological methods to semiotically approach food and insects in order to better understand how these signs shape American perceptions of the consumption of insects. The survey results work to demonstrate that positive applications of language, when paired with food localization techniques, can weaken food neophobia in American consumers who are averse to entomophagy.
The Discovery of Altÿnkazgan
Authors: Astafiev Andrey E. , Bogdanov Evgeniï S.
Published: July 2016

This article is devoted to the recently discovered site from the Hunnic period within the territory of the Mangÿshlak Peninsula (Kazakhstan). Inside a stone enclosure the silver facing of a saddle was found bearing depictions of animals and birds. The article provides a cultural interpretation of the site and a stylistic and semantic analysis of the depictions on the facings.
Cystoderma carpaticum (Basidiomycota, Agaricales), a rare fungus newly recorded from Croatia
Authors: SAAR IRJA , MEŠIĆ ARMIN , TKALČEC ZDENKO , PEINTNER URSULA , KUŠAN IVANA
Published: July 2016

Cystoderma carpaticum was collected and originally described from the Carpathians in Poland. Later, it was recombined in the genera Lepiota and Echinoderma. Two recent collections from Croatia allowed for reliable phylogenetic and morphological comparative analyses of this rare fungus, including the holotype specimen. Our results confirmed that this taxon is a distinct species, and a member of the genus Cystoderma, not Lepiota nor Echinoderma (= Lepiota sect. Echinatae). C. carpaticum is re-described in detail, and data on its ecology and distribution are newly presented. Additional two studied collections of C. carpaticum (Austria, Czech Republic) were misidentified and they belong to C. subvinaceum. Synonymization of C. carpaticum with Leucopholiota decorosa is rejected.
Descriptions of two new species of Afrotropical Psychodidae (Diptera)
Authors: JEŽEK JAN , OBOŇA JOZEF
Published: July 2016

Two new species of moth flies (Diptera: Psychodidae: Psychodinae) are described and illustrated on the basis of male morphological characters. Neoarisemus nyahururuensis sp. nov. was collected in the vicinity of Thomson's Falls (Nyahururu) in Kenya and Tonnoiriella veronikae sp. nov. in Toamasina province, Madagascar, Analamazaotra 1.4 km SSW Andasibe vill. (Périnet).
Comparison of Global Precipitation Estimates across a Range of Temporal and Spatial Scales
Authors: Gehne Maria , Hamill Thomas M. , Kiladis George N. , Trenberth Kevin E.
Published: July 2016

Characteristics of precipitation estimates for rate and amount from three global high-resolution precipitation products (HRPPs), four global climate data records (CDRs), and four reanalyses are compared. All datasets considered have at least daily temporal resolution. Estimates of global precipitation differ widely from one product to the next, with some differences likely due to differing goals in producing the estimates. HRPPs are intended to produce the best snapshot of the precipitation estimate locally. CDRs of precipitation emphasize homogeneity over instantaneous accuracy. Precipitation estimates from global reanalyses are dynamically consistent with the large-scale circulation but tend to compare poorly to rain gauge estimates since they are forecast by the reanalysis system and precipitation is not assimilated. Regional differences among the estimates in the means and variances are as large as the means and variances, respectively. Even with similar monthly totals, precipitation rates vary significantly among the estimates. Temporal correlations among datasets are large at annual and daily time scales, suggesting that compensating bias errors at annual and random errors at daily time scales dominate the differences. However, the signal-to-noise ratio at intermediate (monthly) time scales can be large enough to result in high correlations overall. It is shown that differences on annual time scales and continental regions are around 0.8 mm day−1, which corresponds to 23 W m−2. These wide variations in the estimates, even for global averages, highlight the need for better constrained precipitation products in the future.
On the Drivers and Predictability of Seasonal-to-Interannual Variations in Regional Sea Level
Authors: Roberts C. D. , Calvert D. , Dunstone N. , Hermanson L. , Palmer M. D. , Smith D.
Published: July 2016

Observations and eddy-permitting ocean model simulations are used to evaluate the drivers of sea level variability associated with 15 modes of climate variability covering the Atlantic, Pacific, Indian, and Southern Oceans. Sea level signals are decomposed into barotropic, steric, and inverted barometer contributions. Forcings are decomposed into surface winds, buoyancy fluxes, and Ekman pumping. Seasonal-to-interannual sea level variability in the low latitudes is governed almost entirely by the thermosteric response to wind forcing associated with tropical modes of climate variability. In the extratropics, changes to dynamic sea level associated with atmospheric modes of variability include a substantial barotropic response to wind forcing, particularly over the continental shelf seas. However, wind-driven steric changes are also important in some locations. On interannual time scales, wind-forced steric changes dominate, although heat and freshwater fluxes are important in the northwest Atlantic, where low-frequency sea level variations are associated with changes in the Atlantic meridional overturning circulation. Using the version 3 of the Met Office Decadal Prediction System (DePreSys3), the predictability of large-scale dynamic sea level anomalies on seasonal-to-interannual time scales is evaluated. For the first year of the hindcast simulations, DePreSys3 exhibits skill exceeding persistence over large regions of the Pacific, Atlantic, and Indian Oceans. Skill is particularly high in the tropical Indo-Pacific because of the accurate initialization and propagation of thermocline depth anomalies associated with baroclinic adjustments to remote wind forcing. Skill in the extratropics is hindered by the limited predictability of wind anomalies associated with modes of atmospheric variability that dominate local and/or barotropic responses.
Superensemble Statistical Forecasting of Monthly Precipitation over the Contiguous United States, with Improvements from Ocean-Area Precipitation Predictors
Authors: Smith Thomas M. , Shen Samuel S. P. , Ferraro Ralph R.
Published: July 2016

Extended precipitation forecasts, with leads of weeks to seasons, are valuable for planning water use and are produced by the U.S. National Weather Service. Forecast skill tends to be low and any skill improvement could be valuable. Here, methods are discussed for improving statistical precipitation forecasting over the contiguous United States. Monthly precipitation is forecast using predictors from the previous month. Testing shows that improvements are obtained from both improved statistical methods and from the use of satellite-based ocean-area precipitation predictors. The statistical superensemble method gives higher skill compared to traditional statistical forecasting. Ensemble statistical forecasting combines individual forecasts. The proposed superensemble is a weighted mean of many forecasts or of forecasts from different prediction systems and uses the forecast reliability estimate to define weights. The method is tested with different predictors to show its skill and how skill can be improved using additional predictors. Cross validation is used to evaluate the skill. Although predictions are strongly influenced by ENSO, in the superensemble other regions contribute more to the forecast skill. The superensemble optimally combines forecasts based on different predictor regions and predictor types. The contribution from multiple predictor regions improves skill and reduces the ENSO spring barrier. Adding satellite-based ocean-area precipitation predictors noticeably increases forecast skill. The resulting skill is comparable to that from dynamic-model forecasts, but the regions with best forecast skill may be different. This paper shows that the statistical superensemble forecasts may be complementary to dynamic forecasts and that combining them may further increase forecast skill.
Modeling the Evolution and Life Cycle of Stable Cold Pools
Authors: Wilson Travis H. , Fovell Robert G.
Published: July 2016

Stable cold pools in California’s Central Valley (CV) are conducive to freezing temperatures, high relative humidity, and, in some cases, fog. In this study it will be shown that the Weather Research and Forecasting (WRF) Model as commonly configured cannot reproduce such conditions because of a persistent warm and dry bias near the surface. It was found that removing horizontal diffusion, which by default operates on model levels and thus up and down the valley’s sides, can reduce but not entirely fix the problem. Other improvements include enhancing the near-surface vertical resolution and the surface–air coupling, as both directly control the surface fluxes, especially evaporation. However, these alterations actually have the largest impact in the forested region surrounding the Central Valley, and influence the nighttime relative humidity in the CV only indirectly via nocturnal drainage flows. While it is not clear how realistic are the increased evaporation in the forest or the drainage flows, how and why these alterations result in significantly improved relative humidity reconstructions within the Central Valley are shown.
‘Twin Deficits’ Hypothesis
Authors: M.R. Anantha Ramu
Published: July 2016

Higher and persistent level of fiscal deficit and current account deficit is the problem of the day for Indian economy. There exists an argument that higher fiscal deficit is the major factor behind worsening balance of payments position. However, there is no identical perception on the relationship between fiscal deficit and current account deficit both theoretically and empirically. Hence this article is a revisit to the existing debate to see whether fiscal deficit and current account deficit can be called as ‘twin deficits’ pertaining mainly to Indian economy. Using long-term annual data for the period 1980–1981 to 2012–2013 on Indian economy and using vector error correction method, this article seeks to prove that there exists long-term positive association between fiscal deficit and current account deficit, and hence can be called as ‘twins’. Using structural VAR method it has been proved here that fiscal deficit is in line with the pattern illustrated in Keynesian absorption theory and Mundell–Fleming model in regard to its impact on current account deficit. This article negates the relevance of Ricardian equivalence theory in Indian context.
The Revised Inventory of the Dimensions of Emerging Adulthood (IDEA-R) and Substance Use Among College Students
Authors: Allem Jon-Patrick , Sussman Steve , Unger Jennifer B.
Published: July 2016

Transition-to-adulthood themes, or thoughts and feelings about emerging adulthood, have been measured by the Inventory of the Dimensions of Emerging Adulthood (IDEA) and found to be associated with substance use among emerging adults. It has been suggested, however, that the IDEA is lengthy and may not include the most unique and theoretically relevant constructs of emerging adulthood. The Revised Inventory of the Dimensions of Emerging Adulthood (IDEA-R) was developed as an alternative instrument, but research has yet to determine the relationship between the IDEA-R and substance use among emerging adults (ages 18–25 years). College students completed surveys indicating their identification with transition-to-adulthood themes and substance use. Logistic regression models examined the associations between transition-to-adulthood themes and marijuana use and binge drinking, respectively. Participants who felt emerging adulthood was a time of identity exploration were less likely to report marijuana use, while feelings of experimentation/possibility were positively associated with marijuana use and binge drinking. The IDEA-R may be useful for identifying correlates of substance use among emerging adults. Future research should evaluate the IDEA-R among representative samples of emerging adults to confirm the findings of this study. Health professionals working in substance use prevention may consider targeting the themes of identity exploration and experimentation/possibility in programs intended for emerging adults.
Using Embedded Sensors in Independent Living to Predict Gait Changes and Falls
Authors: Phillips Lorraine J. , DeRoche Chelsea B. , Rantz Marilyn , Alexander Gregory L. , Skubic Marjorie , Despins Laurel , Abbott Carmen , Harris Bradford H. , Galambos Colleen , Koopman Richelle J.
Published: July 2016

This study explored using Big Data, totaling 66 terabytes over 10 years, captured from sensor systems installed in independent living apartments to predict falls from pre-fall changes in residents’ Kinect-recorded gait parameters. Over a period of 3 to 48 months, we analyzed gait parameters continuously collected for residents who actually fell ( n = 13) and those who did not fall ( n = 10). We analyzed associations between participants’ fall events ( n = 69) and pre-fall changes in in-home gait speed and stride length ( n = 2,070). Preliminary results indicate that a cumulative change in speed over time is associated with the probability of a fall ( p < .0001). The odds of a resident falling within 3 weeks after a cumulative change of 2.54 cm/s is 4.22 times the odds of a resident falling within 3 weeks after no change in in-home gait speed. Results demonstrate using sensors to measure in-home gait parameters associated with the occurrence of future falls.