bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time to add a new priority target for child injury prevention? The case for an excess burden associated with sport and exercise injury: population-based study
Authors: Finch Caroline F , Wong Shee Anna , Clapperton Angela 
Published: July 2014

ObjectiveTo determine the population-level burden of sports injuries compared with that for road traffic injury for children aged <15 years in Victoria, Australia.DesignRetrospective observational study.SettingAnalysis of routinely collected data relating to non-fatal hospital-treated sports injury and road traffic injury cases for children aged <15 years in Victoria, Australia, over 2004–2010, inclusive.Participants75 413 non-fatal hospital-treated sports injury and road traffic injury cases in children aged <15 years. Data included: all Victorian public and private hospital hospitalisations, using the International Statistical Classification of Diseases and Health Related Problems, 10th Revision, Australian Modification (ICD-10-AM) activity codes to identify sports-related cases and ICD-10-AM cause and location codes to identify road traffic injuries; and injury presentations to 38 Victorian public hospital emergency departments, using a combination of activity, cause and location codes.Main outcome measuresTrends in injury frequency and rate were analysed by log-linear Poisson regression and the population-level injury burden was assessed in terms of years lived with disability (YLD), hospital bed-days and direct hospital costs.ResultsOver the 7-year period, the annual frequency of non-fatal hospital-treated sports injury increased significantly by 29% (from N=7405 to N=9923; p<0.001) but the frequency of non-fatal hospital-treated road traffic injury decreased by 26% (from N=1841 to N=1334; p<0.001). Sports injury accounted for a larger population health burden than did road traffic injury on all measures: 3-fold the number of YLDs (7324.8 vs 2453.9); 1.9-fold the number of bed-days (26 233 vs 13 886) and 2.6-fold the direct hospital costs ($A5.9 millions vs $A2.2 millions).ConclusionsThe significant 7-year increase in the frequency of hospital-treated sports injury and the substantially higher injury population-health burden (direct hospital costs, bed-day usage and YLD impacts) for sports injury compared with road traffic injury for children aged <15 years indicates an urgent need to prioritise sports injury prevention in this age group.
Is ioflupane I123 injection diagnostically effective in patients with movement disorders and dementia? Pooled analysis of four clinical trials
Authors: O'Brien John T , Oertel Wolfgang H , McKeith Ian G , Grosset Donald G , Walker Zuzana , Tatsch Klaus , Tolosa Eduardo , Sherwin Paul F , Grachev Igor D 
Published: July 2014

ObjectivesTo pool clinical trials of similar design to assess overall sensitivity and specificity of ioflupane I123 injection (DaTSCAN or ioflupane (123I)) to detect or exclude a striatal dopaminergic deficit disorder (SDDD), such as parkinsonian syndrome and dementia with Lewy bodies.DesignPooled analysis of three phase 3 and one phase 4 clinical trials. These four trials were selected because they were the four studies used for the US new drug application to the Food and Drug Administration (FDA).SettingMulticentre, open-label, non-randomised.ParticipantsPatients with either a movement disorder or dementia, and healthy volunteers.InterventionsIoflupane (123I) was administered.Outcome measuresImages were assessed by panels of 3–5 blinded experts and/or on-site nuclear medicine physicians, classified as normal or abnormal and compared with clinical diagnosis (reference standard) to determine sensitivity and specificity.ResultsPooling the four studies, 928 participants were enrolled, 849 were dosed and 764 completed their study. Across all studies, when images were assessed by on-site readers, ioflupane (123I) diagnostic effectiveness had an overall (95% CI) sensitivity of 91.9% (88.7% to 94.5%) and specificity of 83.6% (78.7% to 87.9%). When reads were conducted blindly by a panel of independent experts, the overall sensitivity was 88.7% (86.8% to 90.4%) and specificity was 91.2% (89.0% to 93.0%).ConclusionsIn this pooled analysis, the visual assessment of ioflupane (123I) images provided high levels of sensitivity and specificity in detecting the presence/absence of an SDDD. Ioflupane (123I) imaging has the potential to improve diagnostic accuracy in patients with signs and symptoms of a movement disorder and/or dementia.Trial registration numberNCT00209456.
Lifetime alcohol use and overall and cause-specific mortality in the European Prospective Investigation into Cancer and nutrition (EPIC) study
Authors: Ferrari Pietro , Licaj Idlir , Muller David C , Kragh Andersen Per , Johansson Mattias , Boeing Heiner , Weiderpass Elisabete , Dossus Laure , Dartois Laureen , Fagherazzi Guy , Bradbury Kathryn E , Khaw Kay-Tee , Wareham Nick , Duell Eric J , Barricarte Aurelio , Molina-Montes Esther , Sanchez Carmen Navarro , Arriola Larraitz , Wallström Peter , Tjønneland Anne , Olsen Anja , Trichopoulou Antonia , Benetou Vasiliki , Trichopoulos Dimitrios , Tumino Rosario , Agnoli Claudia , Sacerdote Carlotta , Palli Domenico , Li Kuanrong , Kaaks Rudolf , Peeters Petra , Beulens Joline WJ , Nunes Luciana , Gunter Marc , Norat Teresa , Overvad Kim , Brennan Paul , Riboli Elio , Romieu Isabelle 
Published: July 2014

ObjectivesTo investigate the role of factors that modulate the association between alcohol and mortality, and to provide estimates of absolute risk of death.DesignThe European Prospective Investigation into Cancer and nutrition (EPIC).Setting23 centres in 10 countries.Participants380 395 men and women, free of cancer, diabetes, heart attack or stroke at enrolment, followed up for 12.6 years on average.Main outcome measures20 453 fatal events, of which 2053 alcohol-related cancers (ARC, including cancers of upper aerodigestive tract, liver, colorectal and female breast), 4187 cardiovascular diseases/coronary heart disease (CVD/CHD), 856 violent deaths and injuries. Lifetime alcohol use was assessed at recruitment.ResultsHRs comparing extreme drinkers (≥30 g/day in women and ≥60 g/day in men) to moderate drinkers (0.1–4.9 g/day) were 1.27 (95% CI 1.13 to 1.43) in women and 1.53 (1.39 to 1.68) in men. Strong associations were observed for ARC mortality, in men particularly, and for violent deaths and injuries, in men only. No associations were observed for CVD/CHD mortality among drinkers, whereby HRs were higher in never compared to moderate drinkers. Overall mortality seemed to be more strongly related to beer than wine use, particularly in men. The 10-year risks of overall death for women aged 60 years, drinking more than 30 g/day was 5% and 7%, for never and current smokers, respectively. Corresponding figures in men consuming more than 60 g/day were 11% and 18%, in never and current smokers, respectively. In competing risks analyses, mortality due to CVD/CHD was more pronounced than ARC in men, while CVD/CHD and ARC mortality were of similar magnitude in women.ConclusionsIn this large European cohort, alcohol use was positively associated with overall mortality, ARC and violent death and injuries, but marginally to CVD/CHD. Absolute risks of death observed in EPIC suggest that alcohol is an important determinant of total mortality.
Pyrvinium Attenuates Hedgehog Signaling Downstream of Smoothened
Authors: Li Bin , Fei Dennis Liang , Flaveny Colin A. , Dahmane Nadia , Baubet Valérie , Wang Zhiqiang , Bai Feng , Pei Xin-Hai , Rodriguez-Blanco Jezabel , Hang Brian , Orton Darren , Han Lu , Wang Baolin , Capobianco Anthony J. , Lee Ethan , Robbins David J. 
Published: July 2014

Abstract
The Hedgehog (HH) signaling pathway represents an important class of emerging developmental signaling pathways that play critical roles in the genesis of a large number of human cancers. The pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), a key signaling effector of the HH pathway that regulates the levels and activity of the Gli family of transcription factors. Although one of these compounds, vismodegib, is now FDA-approved for patients with advanced basal cell carcinoma, acquired mutations in Smo can result in rapid relapse. Furthermore, many cancers also exhibit a Smo-independent activation of Gli proteins, an observation that may underlie the limited efficacy of Smo inhibitors in clinical trials against other types of cancer. Thus, there remains a critical need for HH inhibitors with different mechanisms of action, particularly those that act downstream of Smo. Recently, we identified the FDA-approved anti-pinworm compound pyrvinium as a novel, potent (IC50, 10 nmol/L) casein kinase-1α (CK1α) agonist. We show here that pyrvinium is a potent inhibitor of HH signaling, which acts by reducing the stability of the Gli family of transcription factors. Consistent with CK1α agonists acting on these most distal components of the HH signaling pathway, pyrvinium is able to inhibit the activity of a clinically relevant, vismodegib -resistant Smo mutant, as well as the Gli activity resulting from loss of the negative regulator suppressor of fused. We go on to demonstrate the utility of this small molecule in vivo, against the HH-dependent cancer medulloblastoma, attenuating its growth and reducing the expression of HH biomarkers. Cancer Res; 74(17); 4811–21. ©2014 AACR.
Hsp70–Bag3 Interactions Regulate Cancer-Related Signaling Networks
Authors: Colvin Teresa A. , Gabai Vladimir L. , Gong Jianlin , Calderwood Stuart K. , Li Hu , Gummuluru Suryaram , Matchuk Olga N. , Smirnova Svetlana G. , Orlova Nina V. , Zamulaeva Irina A. , Garcia-Marcos Mikel , Li Xiaokai , Young Z.T. , Rauch Jennifer N. , Gestwicki Jason E. , Takayama Shinichi , Sherman Michael Y. 
Published: July 2014

Abstract
Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70–Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70–Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70–Bag3 complex may offer an appealing anticancer target. Cancer Res; 74(17); 4731–40. ©2014 AACR.
A Bispecific HER2-Targeting FynomAb with Superior Antitumor Activity and Novel Mode of Action
Authors: Brack Simon , Attinger-Toller Isabella , Schade Babette , Mourlane Frédéric , Klupsch Kristina , Woods Richard , Hachemi Helen , von der Bey Ulrike , Koenig-Friedrich Susann , Bertschinger Julian , Grabulovski Dragan 
Published: July 2014

Abstract
Upregulation of HER2 is a hallmark of 20% to 30% of invasive breast cancers, rendering this receptor an attractive target for cancer therapy. Although HER2-targeting agents have provided substantial clinical benefit as cancer therapeutics, there is a need for the development of new agents aiming at circumventing anti-HER2 resistance. On the basis of the approved antibody pertuzumab, we have created a panel of bispecific FynomAbs, which target two epitopes on HER2. FynomAbs are fusion proteins of an antibody and a Fyn SH3–derived binding protein. One bispecific FynomAb, COVA208, was characterized in detail and showed a remarkable ability to induce rapid HER2 internalization and apoptosis in vitro. Moreover, it elicited a strong inhibition of downstream HER2 signaling by reducing HER2, HER3, and EGFR levels in vitro and in vivo. Importantly, COVA208 demonstrated superior activity in four different xenograft models as compared with the approved antibodies trastuzumab and pertuzumab. The bispecific FynomAb COVA208 has the potential to enhance the clinical efficacy and expand the scope of HER2-directed therapies, and delineates a paradigm for designing a new class of antibody-based therapeutics for other receptor targets. Mol Cancer Ther; 13(8); 2030–9. ©2014 AACR.
Decreased Expression of Cystathionine β-Synthase Promotes Glioma Tumorigenesis
Authors: Takano Naoharu , Sarfraz Yasmeen , Gilkes Daniele M. , Chaturvedi Pallavi , Xiang Lisha , Suematsu Makoto , Zagzag David , Semenza Gregg L. 
Published: July 2014

Abstract
Cystathionine β-synthase (CBS) catalyzes metabolic reactions that convert homocysteine to cystathionine. To assess the role of CBS in human glioma, cells were stably transfected with lentiviral vectors encoding shRNA targeting CBS or a nontargeting control shRNA, and subclones were injected into immunodeficient mice. Interestingly, decreased CBS expression did not affect proliferation in vitro but decreased the latency period before rapid tumor xenograft growth after subcutaneous injection and increased tumor incidence and volume following orthotopic implantation into the caudate–putamen. In soft-agar colony formation assays, CBS knockdown subclones displayed increased anchorage-independent growth. Molecular analysis revealed that CBS knockdown subclones expressed higher basal levels of the transcriptional activator hypoxia-inducible factor 2α (HIF2α/EPAS1). HIF2α knockdown counteracted the effect of CBS knockdown on anchorage-independent growth. Bioinformatic analysis of mRNA expression data from human glioma specimens revealed a significant association between low expression of CBS mRNA and high expression of angiopoietin-like 4 (ANGPTL4) and VEGF transcripts, which are HIF2 target gene products that were also increased in CBS knockdown subclones. These results suggest that decreased CBS expression in glioma increases HIF2α protein levels and HIF2 target gene expression, which promotes glioma tumor formation.
Implications: CBS loss-of-function promotes glioma growth. Mol Cancer Res; 12(10); 1398–406. ©2014 AACR.
Intracranial Hemorrhage Mortality in Atrial Fibrillation Patients Treated With Dabigatran or Warfarin
Authors: Alonso Alvaro , Bengtson Lindsay G.S. , MacLehose Richard F. , Lutsey Pamela L. , Chen Lin Y. , Lakshminarayan Kamakshi 
Published: July 2014

Background and Purpose—
In randomized trials, patients with atrial fibrillation (AF) receiving dabigatran, a direct oral anticoagulant, had lower risk of intracranial bleeding (ICB) than those on warfarin. However, concerns exist about potential worse outcomes in dabigatran users if bleeding occurs, given the lack of approved reversal agents. Thus, we examined in-hospital mortality in AF patients with ICB being treated with dabigatran versus warfarin in a real-world population in the United States.

Methods—
We analyzed healthcare utilization claims in the Truven Health Marketscan Research Databases. The study sample included patients with AF admitted to a hospital with a primary diagnosis of ICB. Information on medications, inpatient, and outpatient diagnoses was obtained from available claims. Propensity score–adjusted risk ratios and 95% confidence intervals of in-hospital mortality comparing current users of dabigatran versus warfarin were estimated using relative risk regression.

Results—
Among 2391 AF patients admitted with ICB (2290 on warfarin, 101 on dabigatran), 531 died during their admission. In-hospital mortality was similar in those treated with warfarin (22%) or dabigatran (20%). Compared with warfarin users, the propensity score–adjusted risk ratio (95% confidence interval) of mortality in dabigatran users was 0.93 (0.62–1.37). Associations were similar across different ICB subtypes (intracerebral hemorrhage, subarachnoid hemorrhage, and subdural hematoma).

Conclusions—
In this sample of AF patients with ICB on oral anticoagulants, dabigatran was not associated with higher in-hospital mortality compared with warfarin. Hence, reluctance to use dabigatran because of a lack of approved reversal agents is not supported by our results.
Acoustic structure and variation in mountain and western gorilla close calls: a syntactic approach
Authors: Hedwig Daniela , Hammerschmidt Kurt , Mundry Roger , Robbins Martha M. , Boesch Christophe 
Published: July 2014

Our understanding of the functioning of a species’ vocal repertoire can be greatly improved by investigating acoustic variation and using objective classification schemes based on acoustic structure. Here we used a syntactic approach to investigate the acoustic structure of the gorilla close distance vocalizations (‘close calls’), which remain as yet little understood. We examined 2130 calls of 10 mountain gorillas (Gorilla beringei beringei) from Bwindi Impenetrable National Park, Uganda, and 5 western lowland gorillas (Gorilla gorilla gorilla) from Bai Hokou, Central African Republic. We segmented calls into units using distinct acoustic features and employed model-based cluster analyses to define the repertoire of unit types. We then examined how unit types were combined into calls. Lastly, we compared unit type use between age–sex classes and the two study groups. We found that the gorilla close calls consist of 5 intergraded acoustic unit types which were flexibly but yet non-randomly concatenated into 159 combinations. Our results are in line with previous quantitative acoustic analyses demonstrating a high degree of acoustic variation in a variety of animal vocal repertoires, particularly close distance vocalizations. Our findings add on to (1) the recent argument that the common practice of describing vocal repertoires as either discrete or graded may be of little value as such distinctions may be driven by human perception and non-quantitative descriptions of vocal repertoires, and (2) recent studies indicating that flexibility in close range social calls can come about through combinatorial systems, which previously have been studied primarily in long distance vocalizations. Furthermore, our study highlights differences in the vocal repertoire of western and mountain gorillas, as expected given differences in environment and social behaviour. Our results offer opportunities for further in-depth studies investigating the function of the gorilla close calls, which will contribute to a more comprehensive understanding of ape vocal communication in general.
Sociosexual behaviours in cycling, intact female rats (Rattus norvegicus) housed in a seminatural environment
Authors: Chu Xi , Ågmo Anders 
Published: July 2014

Groups of 3 males and 4 females were housed in a seminatural environment for a period of 8 days. Female sociosexual behaviours were recorded and analysed from the beginning of behavioural oestrus (defined as the first lordosis response observed in the environment) until the end of oestrus (defined to occur at the moment of a lordosis that was not followed by another one within 60 min). The duration of behavioural oestrus varied between 4.05 and 10.87 h, with a mean of 7.41 ± 0.49 h. In order to analyse changes in behaviour during oestrus, the entire period was divided in 5% segments for each female. The frequency and/or duration of some behaviours changed during the period of oestrus, while others remained stable. Most remarkable among the latter are the frequency of lordosis and the lordosis quotient. From the start of oestrus until the end, the females responded with lordosis to every male mount. Rejections were most frequent at the beginning of the period of oestrus. Then there was a decline, and thereafter rejections remained at a low level, even when the end of oestrus was approached. Paracopulatory behaviours reached a maximum towards the end of the first quarter of the oestrus period. There was no evident decline at the end of oestrus. Females having a high frequency of lordosis showed more paracopulatory behaviours and were pursued more by the males than females with low lordosis frequency. When the behaviour of females with a large number of offspring was compared to that of females with a low number of offspring, no difference in sexual behaviours was found. Comparisons between the females’ behaviour in response to preferred (either defined as the male producing the largest number of lordosis responses or as the male that was most sniffed by the female) and non-preferred males revealed a few minor differences. Location of behaviour was also analysed. Comparisons were made between the environment’s open area and burrow and between different sectors in these parts. Some important differences were found. This is the first detailed description of female rat sociosexual behaviour during the entire period of behavioural oestrus in a seminatural environment.
Dissociating Effects of Movement Preparation and Spatial Attention on Visual Processing: Evidence from Event-Related Potentials
Authors: Ley Pia , Röder Brigitte 
Published: July 2014

The present study investigated whether effects of movement preparation and visual spatial attention on visual processing can be dissociated. Movement preparation and visual spatial attention were manipulated orthogonally in a dual-task design. Ten participants covertly prepared unimanual lateral arm movements to one hemifield, while attending to visual stimuli presented either in the same or in the hemifield opposite to the movement goal. Event-related potentials to task-irrelevant visual stimuli were analysed.
Both joint and distinct modulations of visual ERPs by visual spatial attention and movement preparation were observed: The latencies of all analysed peaks (P1, N1, P2) were shorter for matching (in terms of direction of attention and movement) versus non-matching sensory–motor conditions. The P1 amplitude, as well, depended on the sensory–motor matching: The P1 was larger for non-matching compared to matching conditions. By contrast, the N1 amplitude showed additive effects of sensory attention and movement preparation: with attention and movement preparation directed towards the visual stimulus the N1 was largest, with both directed opposite to the stimulus the N1 was smallest. P2 amplitudes, instead, were only modulated by sensory attention.
The present data show that movement preparation and sensory spatial attention are tightly linked and interrelated, showing joint modulations throughout stimulus processing. At the same time, however, our data argue against the idea of identity of the two systems. Instead, sensory spatial attention and movement preparation seem to be processed at least partially independently, though still exerting a combined influence on visual stimulus processing.