bluuebunny/crossref_metadata_2025 huggingface dataset:
Increasing Organ Donor Registration in a Primary Care Clinic
Authors: Natt Navneet , Klar Erin , Cheung Ingrid , Matharu Pavan , Bordman Risa
Published: April 2017

Only 30% of Ontarians are registered organ donors in spite of the vast unmet need for organ donations in Ontario, Canada. The purpose of this quality improvement (QI) initiative was to increase the number of registered organ donors in a primary care practice by providing an educational fact sheet and registration form to patients in the clinic's waiting room. Three Plan-Do-Study-Act (PDSA) cycles were conducted. In the first PDSA cycle, we created an information sheet to explain the need for organ donors and the registration process. Nine patients were surveyed regarding the clarity of the information sheet, which resulted in subsequent modification of the information sheet prior to the second PDSA cycle. For the second cycle, the revised information sheet was attached to a donor registration form and distributed to 30 patients in the primary care practice over a two-week period. 23 forms were returned, in which 4 patients were already registered organ donors and 5 patients completed registration forms. In the third PDSA cycle, a more compelling graphic was used on the pamphlet. Similarly, 30 forms were distributed; 23 forms were returned, with 6 newly completed registration forms. Overall, the project increased the donor registration rate from 10.0% to 28.3%. The process allowed patients to become more knowledgeable about organ donation need and aware of the Trillium Gift of Life website. We believe that providing patients with an information pamphlet and registration form in the clinic waiting room enhanced their awareness of organ donation and facilitated registration without delay. This QI initiative represents an effective and practical study to increase donor knowledge and provide opportunities for interested individuals to become registered organ donors.
Increasing Patient Safety Event Reporting in an Emergency Medicine Residency
Authors: Steen Sven , Jaeger Cassie , Price Lindsay , Griffen David
Published: April 2017

Patient safety event reporting is an important component for fostering a culture of safety. Our tertiary care hospital utilizes a computerized patient safety event reporting system that has been historically underutilized by residents and faculty, despite encouragement of its use. The objective of this quality project was to increase patient safety event reporting within our Emergency Medicine residency program. Knowledge of event reporting was evaluated with a survey. Eighteen residents and five faculty participated in a formal educational session on event reporting followed by feedback every two months on events reported and actions taken. The educational session included description of which events to report and the logistics of accessing the reporting system. Participants received a survey after the educational intervention to assess resident familiarity and comfort with using the system. The total number of events reported was obtained before and after the educational session. After the educational session, residents reported being more confident in knowing what to report as a patient safety event, knowing how to report events, how to access the reporting tool, and how to enter a patient safety event. In the 14 months preceding the educational session, an average of 0.4 events were reported per month from the residency. In the nine months following the educational session, an average of 3.7 events were reported per month by the residency. In addition, the reported events resulted in meaningful actions taken by the hospital to improve patient safety, which were shared with the residents. Improvement efforts including an educational session, feedback to the residency of events reported, and communication of improvements resulting from reported events successfully increased the frequency of safety event reporting in an Emergency Medicine residency.
Care standards for non-alcoholic fatty liver disease in the United Kingdom 2016: a cross-sectional survey
Authors: Sheridan David A , Aithal Guru , Alazawi William , Allison Michael , Anstee Quentin , Cobbold Jeremy , Khan Shahid , Fowell Andrew , McPherson Stuart , Newsome Philip N , Oben Jude , Tomlinson Jeremy , Tsochatzis Emmanouil
Published: April 2017

Objective

Guidelines for the assessment of non-alcoholic fatty liver disease (NAFLD) have been published in 2016 by National Institute for Health and Care Excellence and European Associations for the study of the Liver–European Association for the study of Diabetes–European Association for the study of Obesity. Prior to publication of these guidelines, we performed a cross-sectional survey of gastroenterologists and hepatologists regarding NAFLD diagnosis and management.

Design

An online survey was circulated to members of British Association for the Study of the Liver and British Society of Gastroenterology between February 2016 and May 2016.

Results

175 gastroenterologists/hepatologists responded, 116 completing the survey, representing 84 UK centres. 22% had local NAFLD guidelines. 45% received >300 referrals per year from primary care for investigation of abnormal liver function tests (LFTs). Clinical assessment tended to be performed in secondary rather than primary care including body mass index (82% vs 26%) and non-invasive liver screen (86% vs 32%) and ultrasound (81% vs 37%).Widely used tools for non-invasive fibrosis risk stratification were aspartate transaminase (AST)/alanine transaminase (ALT) ratio (53%), Fibroscan (50%) and NAFLD fibrosis score (41%). 78% considered liver biopsy in selected cases. 50% recommended 10% weight loss target as first-line treatment. Delivery of lifestyle interventions was mostly handed back to primary care (56%). A minority have direct access to community weight management services (22%).Follow-up was favoured by F3/4 fibrosis (72.9%), and high-risk non-invasive fibrosis tests (51%). Discharge was favoured by simple steatosis at biopsy (30%), and low-risk non-invasive scores (25%).

Conclusions

The survey highlights areas for improvement of service provision for NAFLD assessment including improved recognition of non-alcoholic steatohepatitis in people with type 2 diabetes, streamlining abnormal LFT referral pathways, defining non-invasive liver fibrosis assessment tools, use of liver biopsy, managing metabolic syndrome features and improved access to lifestyle interventions.
Monthly Variation in Pediatric Visits for Headache to Us Emergency Departments
Authors: Caperell Kerry , Rominger Anna
Published: April 2017

Headache is a common pediatric symptom often associated with stress and fatigue which may be more common during the school year. The purpose of this study is to determine if visits for headache are more common during the months of the school year. This study is a secondary analysis of the National Hospital Ambulatory Medical Care Survey (NHAMCS) database from 2001 to 2010. Patient visits in those aged 18 years or younger not associated with injury were examined. Only visits with an International Classification of Diseases, ninth revision (ICD-9) code consistent with headache were included. Data were analyzed using cumulative binomial probabilities. This statistic was used to establish the chance of seeing up to the observed number of visits for headache in a given month assuming that all months have an equal number of visits. A total of 660 unweighted visits representing 3.2 million patient encounters met the inclusion and exclusion criteria. Visits for headache were more common during the months of January, September, and October and less common in March, April, July, and November. Subgroup analysis was performed for children aged 13–18 years. In this subgroup, headaches were more common in January, September, and October. They were less common in July and December. Headache is more common during the first 2 months back to school in the fall as well as after the winter break in January. While we are not able to establish causality, we propose that children with headache require additional attention during the school year, particularly in the months following summer and winter breaks.
Use of non-steroidal anti-inflammatory drugs in US adults: changes over time and by demographic
Authors: Davis Jennifer S , Lee Hwa Young , Kim Jihye , Advani Shailesh M , Peng Ho-Lan , Banfield Emilyn , Hawk Ernest T , Chang Shine , Frazier-Wood Alexis C
Published: April 2017

Objective

Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are preventive against cardiovascular disease (CVD) and several cancer types, but long-term use has been associated with significant health risks, resulting in conflicting recommendations on NSAID use for prevention of CVD and cancer. Previous research indicates that aspirin use increases with age and CVD risk factors and that a large percentage of the US population regularly use analgesics, including NSAIDs, but there has not been a recent, in-depth assessment of NSAID use prevalence, changes in use over time or predictors of NSAID use in the USA.

Methods

We used the cross-sectional, National Health And Nutrition Examination Survey (NHANES) from 1988 to 1994 and three continuous cycles (1999–2004) to assess regular NSAID use prevalence, changes over time and predictors of regular NSAID use.

Results

Overall, regular NSAID use increased over time and varied by demographic features. Participants over 60 years of age, women, participants with high body mass index, increased waist circumference or heart disease were significantly more likely to be regular NSAID users. By contrast, non-Hispanic African American and Mexican American participants were significantly less likely to regularly use NSAIDs.

Conclusions

This study uses a nationally representative data set (NHANES) to provide an exploration of regular NSAID use patterns over time, highlighting several demographic, lifestyle and clinical conditions associated with regular NSAID use. Understanding who is likely to regularly use NSAIDs enables more targeted messaging both for increasing the preventive benefits and for limiting the toxicities associated with regular use of NSAIDs.
A literature review of cost-effectiveness of intravenous recombinant tissue plasminogen activator for treating acute ischaemic stroke
Authors: Joo Heesoo , Wang Guijing , George Mary G
Published: April 2017

Background

Intravenous recombinant tissue plasminogen activator (IV rtPA) is recommended treatment for patients with acute ischaemic stroke, but the cost-effectiveness of IV rtPA within different time windows after the onset of acute ischaemic stroke is not well reviewed.

Aims

To conduct a literature review of the cost-effectiveness studies about IV rtPA by treatment times.

Summary of review

A literature search was conducted using MEDLINE, EMBASE, CINAHL and Cochrane Library, with the keywords acute ischemic stroke, tissue plasminogen activator, cost, economic benefit, saving and incremental cost-effectiveness analysis. The review is limited to original research articles published during 1995–2016 in English-language peer-reviewed journals. We found 16 studies meeting our criteria for this review. Nine of them were cost-effectiveness studies of IV rtPA treatment within 0–3 hours after stroke onset, 2 studies within 3–4.5 hours, 3 studies within 0–4.5 hours and 2 studies within 0–6 hours. IV rtPA is a cost-saving or a cost-effectiveness strategy from most of the study results. Only one study showed incremental cost-effectiveness ratio of IV rtPA within 1 year was marginally above US$50 000 per quality-adjusted life year threshold. IV rtPA within 0–3 hours after stroke led to cost savings for lifetime or 30 years and IV rtPA within 3–4.5 hours after stroke increased costs but still was cost-effective.

Conclusions

The literature generally showed that IV rtPA was a dominant or a cost-effective strategy compared with traditional treatment for patients with acute ischaemic stroke without IV rtPA. The findings from the literature lacked generalisability because of limited data and various assumptions.
Myocardial connexin-43 is upregulated in response to acute cardiac injury in rats
Authors: Viczenczova Csilla , Kura Branislav , Chaudagar Kiranj K. , Szeiffova Bacova Barbara , Egan Benova Tamara , Barancik Miroslav , Knezl Vladimir , Ravingerova Tana , Tribulova Narcis , Slezak Jan
Published: April 2017

We aimed to explore whether myocardial intercellular channel protein connexin-43 (Cx43) along with PKCε and MMP-2 might be implicated in responses to acute cardiac injury induced by 2 distinct sublethal interventions in Wistar rats. Animals underwent either single chest irradiation at dose of 25 Gy or subcutaneous injection of isoproterenol (ISO, 120 mg/kg) and were compared with untreated controls. Forty-two days post-interventions, the hearts were excised and left ventricles were used for analysis. The findings showed an increase of total as well as phosphorylated forms of myocardial Cx43 regardless of the type of interventions. Enhanced phosphorylation of Cx43 coincided with increased PKCε expression in both models. Elevation of Cx43 was associated with its enhanced distribution on lateral surfaces of the cardiomyocytes in response to both interventions, while focal areas of fibrosis without Cx43 were found in post-ISO but not post-irradiated rat hearts. In parallel, MMP-2 activity was decreased in the former while increased in the latter. Cardiac function was maintained and the susceptibility of the hearts to ischemia or malignant arrhythmias was not deteriorated 42 days after interventions when compared with controls. Altogether, the findings indicate that myocardial Cx43 is most likely implicated in potentially salutary responses to acute heart injury.
Unravelling an allochthonous, subaqueously deposited volcanic–epiclastic to subaerial andesitic lava assemblage in Hong Kong: age, stratigraphy and provenance studies of the Middle Jurassic Tuen Mun Formation
Authors: Sewell R. J. , So K. W. F. , Tang D. L. K. , Carter A.
Published: April 2017

The Middle Jurassic Tuen Mun Formation, Hong Kong, is a fault-bounded block of rare andesitic and related rocks that preserve a snapshot of the developing SE China continental arc system during the late Mesozoic. The forearc depositional setting is considered to have been dominated by an emergent andesitic volcanic massif, which shows a transition to a fluvial-dominated volcanic plain, and then to an offshore marine environment. The youngest laser ablation inductively coupled plasma mass spectrometry U–Pb detrital zircon ages obtained from the three packages define a coherent group (
n
 = 396; MSWD = 1.8) suggesting a maximum depositional age of 169.5 ± 0.3 Ma. The dominance of large euhedral and concentrically zoned zircons reflects a common volcanic provenance. Hf isotope data (
ε
Hf
(
t
) = 0 to −11) on the youngest representative zircon grains imply derivation of magmas from dominantly recycled crustal sources. The detrital zircon age signatures and Hf isotope data show no indication of magmatic interaction with adjacent late Palaeozoic and Early to Middle Jurassic sedimentary rocks, or Middle Jurassic to Early Cretaceous magmatic rocks of Hong Kong. On the basis of the structural, zircon age and isotope data, the Tuen Mun Formation is interpreted to be an allochthonous block, emplaced in the Hong Kong region during the late Middle Jurassic.

Supplementary material:
A full dataset of U–Pb dating and Hf isotope analysis of detrital zircons, stratigraphic drillhole logs and a description of the terminology used in this paper are available at
https://doi.org/10.6084/m9.figshare.c.3736972
Geologically driven 3D modelling of physical rock properties in support of interpreting the seismic response of the Lalor volcanogenic massive sulphide deposit, Snow Lake, Manitoba, Canada
Authors: Schetselaar Ernst , Bellefleur Gilles , Craven James , Roots Eric , Cheraghi Saeid , Shamsipour Pejman , Caté Antoine , Mercier-Langevin Patrick , El Goumi Najib , Enkin Randolph , Salisbury Matthew
Published: April 2017

3D lithofacies and physical rock property models were generated to interpret 3D seismic data acquired over the Lalor volcanogenic massive sulphide deposit, Manitoba, Canada. The lithofacies model revealed that strong seismic reflectivity is associated with ore–host rock and mafic–felsic lithofacies contacts, including their hydrothermally altered equivalents. Different physical rock property models were subjected to 3D seismic forward modelling using the SOFI3D finite difference code. Seismic synthetics from discrete and interpolated models in which kriging of P-wave velocity and density was conditioned by curvilinear grids conformable to the 3D-modelled geological structure showed a much better match to the seismic data in comparison with those generated by kriging in Cartesian space. Synthetics from these curvilinear grid models corroborate the origin of seismic reflectors, as qualitatively inferred from the lithofacies model. Seismic synthetics generated from physical rock property models in which physical rock properties were augmented by densely sampled secondary variables, such as FeO percentage, enhanced lateral continuity of seismic reflectivity, although these co-kriged petrophysical models were not more accurate than their kriged equivalents. The physical rock property modelling methodology was also useful for testing the utility of passive interferometric seismic surveys, as this highlighted the limitations of the discrete physical rock property model.
Quantitative cardiac phosphoproteomics profiling during ischemia-reperfusion in an immature swine model
Authors: Ledee Dolena , Kang Min A. , Kajimoto Masaki , Purvine Samuel , Brewer Heather , Pasa-Tolic Ljiljana , Portman Michael A.
Published: April 2017

Ischemia-reperfusion (I/R) results in altered metabolic and molecular responses, and phosphorylation is one of the most noted regulatory mechanisms mediating signaling mechanisms during physiological stresses. To expand our knowledge of the potential phosphoproteomic changes in the myocardium during I/R, we used Isobaric Tags for Relative and Absolute Quantitation-based analyses in left ventricular samples obtained from porcine hearts under control or I/R conditions. The data are available via ProteomeXchange with identifier PXD006066. We identified 1,896 phosphopeptides within left ventricular control and I/R porcine samples. Significant differential phosphorylation between control and I/R groups was discovered in 111 phosphopeptides from 86 proteins. Analysis of the phosphopeptides using Motif-x identified five motifs: (..R..S..), (..SP..), (..S.S..), (..S…S..), and (..S.T..). Semiquantitative immunoblots confirmed site location and directional changes in phosphorylation for phospholamban and pyruvate dehydrogenase E1, two proteins known to be altered by I/R and identified by this study. Novel phosphorylation sites associated with I/R were also identified. Functional characterization of the phosphopeptides identified by our methodology could expand our understanding of the signaling mechanisms involved during I/R damage in the heart as well as identify new areas to target therapeutic strategies.

NEW & NOTEWORTHY We used Isobaric Tags for Relative and Absolute Quantitation technology to investigate the phosphoproteomic changes that occur in cardiac tissue under ischemia-reperfusion conditions. The results of this study provide an extensive catalog of phosphoproteins, both predicted and novel, associated with ischemia-reperfusion, thereby identifying new pathways for investigation.
Molecular structure and function of big calcium-activated potassium channels in skeletal muscle: pharmacological perspectives
Authors: Maqoud Fatima , Cetrone Michela , Mele Antonietta , Tricarico Domenico
Published: April 2017

The large-conductance Ca2+-activated K+(BK) channel is broadly expressed in various mammalian cells and tissues such as neurons, skeletal muscles (sarco-BK), and smooth muscles. These channels are activated by changes in membrane electrical potential and by increases in the concentration of intracellular calcium ion (Ca2+). The BK channel is subjected to many mechanisms that add diversity to the BK channel α-subunit gene. These channels are indeed subject to alternative splicing, auxiliary subunits modulation, posttranslational modifications, and protein-protein interactions. BK channels can be modulated by diverse molecules that may induce either an increase or decrease in channel activity. The linkage of these channels to many intracellular metabolites and pathways, as well as their modulation by extracellular natural agents, have been found to be relevant in many physiological processes. BK channel diversity is obtained by means of alternative splicing and modulatory β- and γ-subunits. The association of the α-subunit with β- or with γ-subunits can change the BK channel phenotype, functional diversity, and pharmacological properties in different tissues. In the case of the skeletal muscle BK channel (sarco-BK channel), we established that the main mechanism regulating BK channel diversity is the alternative splicing of the KCNMA1/slo1 gene encoding for the α-subunit generating different splicing isoform in the muscle phenotypes. This finding helps to design molecules selectively targeting the skeletal muscle subtypes. The use of drugs selectively targeting the skeletal muscle BK channels is a promising strategy in the treatment of familial disorders affecting muscular skeletal apparatus including hyperkalemia and hypokalemia periodic paralysis.
Widespread Use of Misidentified Cell Line KB (HeLa): Incorrect Attribution and Its Impact Revealed through Mining the Scientific Literature
Authors: Vaughan Liwen , Glänzel Wolfgang , Korch Christopher , Capes-Davis Amanda
Published: April 2017

Continuous cell lines are widely used, but can result in invalid, irreproducible research data. Cell line misidentification is a common problem that can be detected by authentication testing; however, misidentified cell lines continue to be used in publications. Here we explore the impact of one misidentified cell line, KB (HeLa), on the scientific literature. We identified 574 articles between 2000 and 2014 that provided an incorrect attribution for KB, in accordance with its false identity as oral epidermoid carcinoma, but only 57 articles that provided a correct attribution for KB, as HeLa or cervical adenocarcinoma. Statistical analysis of 57 correct and 171 incorrect articles showed that the number of citations to these articles increased over time. Content analysis of 200 citing articles showed there was a tendency to describe the cell line in accordance with the description in the cited paper. Analysis of journal impact factor showed no significant difference between correct and incorrect groups. Articles using KB or citing that usage were most frequently published in the subject areas of pharmacology, pharmacy, oncology, and medicinal chemistry. These findings are important for science policy and support the need for journals to require authentication testing as a condition of publication. Cancer Res; 77(11); 2784–8. ©2017 AACR.
CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer
Authors: Wang Dingzhi , Sun Haiyan , Wei Jie , Cen Bo , DuBois Raymond N.
Published: April 2017

Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as premetastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to premetastatic niche formation are not fully understood. Here, we demonstrate that colorectal carcinoma cells secrete VEGFA, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in premetastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a premetastatic niche that ultimately promoted liver metastases. Importantly, premetastatic liver-infiltrating MDSCs induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGFA stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSCs to form a premetastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to premetastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSCs are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rationale for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Cancer Res; 77(13); 3655–65. ©2017 AACR.
Rb Loss and KRAS Mutation Are Predictors of the Response to Platinum-Based Chemotherapy in Pancreatic Neuroendocrine Neoplasm with Grade 3: A Japanese Multicenter Pancreatic NEN-G3 Study
Authors: Hijioka Susumu , Hosoda Waki , Matsuo Keitaro , Ueno Makoto , Furukawa Masayuki , Yoshitomi Hideyuki , Kobayashi Noritoshi , Ikeda Masafumi , Ito Tetsuhide , Nakamori Shoji , Ishii Hiroshi , Kodama Yuzo , Morizane Chigusa , Okusaka Takuji , Yanagimoto Hiroaki , Notohara Kenji , Taguchi Hiroki , Kitano Masayuki , Yane Kei , Maguchi Hiroyuki , Tsuchiya Yoshiaki , Komoto Izumi , Tanaka Hiroki , Tsuji Akihito , Hashigo Syunpei , Kawaguchi Yoshiaki , Mine Tetsuya , Kanno Atsushi , Murohisa Go , Miyabe Katsuyuki , Takagi Tadayuki , Matayoshi Nobutaka , Yoshida Tsukasa , Hara Kazuo , Imamura Masayuki , Furuse Junji , Yatabe Yasushi , Mizuno Nobumasa
Published: April 2017

Purpose: Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival.

Experimental Design: A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype [NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3)] were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed.

Results: Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (P < 0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, P = 0.006; mutated KRAS, 77% versus wild type, 23%, P = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (P = 0.035).

Conclusions: NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3. Clin Cancer Res; 23(16); 4625–32. ©2017 AACR.
Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma
Authors: Eskiocak Banu , McMillan Elizabeth A. , Mendiratta Saurabh , Kollipara Rahul K. , Zhang Hailei , Humphries Caroline G. , Wang Changguang , Garcia-Rodriguez Jose , Ding Ming , Zaman Aubhishek , Rosales Tracy I. , Eskiocak Ugur , Smith Michael P. , Sudderth Jessica , Komurov Kakajan , Deberardinis Ralph J. , Wellbrock Claudia , Davies Michael A. , Wargo Jennifer A. , Yu Yonghao , De Brabander Jef K. , Williams Noelle S. , Chin Lynda , Rizos Helen , Long Georgina V. , Kittler Ralf , White Michael A.
Published: April 2017

Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathologic activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathologic ERK1/2 signaling. By integration of multigenome chemical and genetic screens, recurrent architectural variants in melanoma tumor genomes, and patient outcome data, we identified two mechanistic subtypes of BRAFV600 melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKϵ inhibitors. Importantly, subtype membership can be predicted using a robust quantitative five-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors and identify a cohort of TBK1/IKBKϵ inhibitor–sensitive disease among nonresponders to current targeted therapy.

Significance: This study identified two mechanistic subtypes of melanoma: (1) the best responders to clinical BRAF/MEK inhibitors (25%) and (2) nonresponders due to primary resistance mechanisms (9.9%). We identified robust biomarkers that can detect these subtypes in patient samples and predict clinical outcome. TBK1/IKBKϵ inhibitors were selectively toxic to drug-resistant melanoma. Cancer Discov; 7(8); 832–51. ©2017 AACR.

See related commentary by Jenkins and Barbie, p. 799.

This article is highlighted in the In This Issue feature, p. 783
Temporal Trends in Incidence, Prevalence, and Mortality of Atrial Fibrillation in Primary Care
Authors: Lane Deirdre A. , Skjøth Flemming , Lip Gregory Y. H. , Larsen Torben B. , Kotecha Dipak
Published: April 2017

Background

Incidence and prevalence of atrial fibrillation (
AF
) are expected to increase dramatically; however, we currently lack comprehensive data on temporal trends in unselected clinical populations.

Methods and Results

Analysis of the
UK
Clinical Practice Research Datalink (
CPRD
) from 1998 to 2010 of patients with incident
AF
, excluding major valvular disease, linked to hospital admission data and national statistics. Fifty‐seven thousand eight hundred eighteen adults were identified with mean age 74.2 (
SD
, 11.7) years and 48.3% women. Overall age‐adjusted incidence of
AF
per 1000 person years was 1.11 (95%
CI
, 1.09–1.13) in 1998–2001, 1.33 (1.31–1.34) in 2002–2006, and 1.33 (1.31–1.35) in 2007–2010. Ongoing increases in incidence were noted for patients aged ≥75 years, with similar temporal patterns in women and men. Associated comorbidities varied over time, with a constant prevalence of previous stroke, increases in hypertension and diabetes mellitus, and decreases in ischemic heart disease. Among patients aged 55 to 74 years, there was a significant reduction in mortality over time (
P
<0.001), but mortality rates in patients aged ≥75 years remained static at 14% to 15% per year (
P
=0.84). Projections of
AF
prevalence demonstrated a constant yearly rise, increasing from 700 000 patients in 2010 to between 1.3 and 1.8 million patients with
AF
in the United Kingdom by 2060.

Conclusions

In a large general practice population, incident
AF
increased and then plateaued overall, with a continued increase in patients aged ≥75 years. The large projected increase in
AF
prevalence associated with temporal changes in
AF
‐related comorbidities suggests the need for comprehensive implementation of
AF
prevention and management strategies.
Wake-Up Stroke Is Associated With Greater Nocturnal Mean Arterial Pressure Variability
Authors: Lundholm Michelle D. , Rooney Melissa , Maas Matthew B. , Attarian Hrayr , Prabhakaran Shyam
Published: April 2017

Background and Purpose—

Wake-up strokes (WUS) account for ≈20% to 30% of ischemic strokes. Studies have shown that increased autonomic instability as measured by blood pressure variability (BPV) is greater in stroke patients than nonstroke patients, but no studies have compared BPV in WUS versus non-WUS patients.

Methods—

From a single-center prospective registry, we identified consecutive ischemic stroke patients. BPV was calculated as the coefficient of variation of the mean arterial pressure during the first 24 hours after hospitalization. We assessed 24-hour BPV as a continuous measure and in quartiles in WUS versus non-WUS patients using univariable and multivariable statistics.

Results—

Among 369 patients (64.9±16.5 years; 50.1% male; 64.7% white), 78 were WUS (21.1%). Clinical characteristics and medical history were not different between WUS and non-WUS patients except WUS patients were older (69.0 versus 63.8 years;
P
=0.015) and more frequently had previous ischemic stroke (29.5% versus 17.2%;
P
=0.012). Initial 24-hour BPV (11.77 versus 10.76;
P
=0.098) was similar between groups. However, WUS patients had greater nocturnal BPV (10.50 versus 8.95;
P
=0.030), whereas daytime BPV was similar between groups (10.96 versus 10.47,
P
=0.459). In multivariate analysis, the highest quartile (≥11.48 mm Hg) of nocturnal BPV was independently associated with WUS (adjusted odds ratio, 1.95; confidence interval, 1.13–3.39;
P
=0.017).

Conclusions—

In this single-center study, we observed that greater nocturnal BPV during the first 24 hours after hospitalization occurred in WUS than non-WUS patients. Nocturnal autonomic instability warrants further study as a potential mechanism of WUS.
Early Endarterectomy Carries a Lower Procedural Risk Than Early Stenting in Patients With Symptomatic Stenosis of the Internal Carotid Artery
Authors: Rantner Barbara , Kollerits Barbara , Roubin Gary S. , Ringleb Peter A. , Jansen Olaf , Howard George , Hendrikse Jeroen , Halliday Alison , Gregson John , Eckstein Hans-Henning , Calvet David , Bulbulia Richard , Bonati Leo H. , Becquemin Jean-Pierre , Algra Ale , Brown Martin M. , Mas Jean-Louis , Brott Thomas G. , Fraedrich Gustav
Published: April 2017

Background and Purpose—

Patients undergoing carotid endarterectomy (CEA) for symptomatic stenosis of the internal carotid artery benefit from early intervention. Heterogeneous data are available on the influence of timing of carotid artery stenting (CAS) on procedural risk.

Methods—

We investigated the association between timing of treatment (0–7 days and >7 days after the qualifying neurological event) and the 30-day risk of stroke or death after CAS or CEA in a pooled analysis of individual patient data from 4 randomized trials by the Carotid Stenosis Trialists’ Collaboration. Analyses were done per protocol. To obtain combined estimates, logistic mixed models were applied.

Results—

Among a total of 4138 patients, a minority received their allocated treatment within 7 days after symptom onset (14% CAS versus 11% CEA). Among patients treated within 1 week of symptoms, those treated by CAS had a higher risk of stroke or death compared with those treated with CEA: 8.3% versus 1.3%, risk ratio, 6.7; 95% confidence interval, 2.1 to 21.9 (adjusted for age at treatment, sex, and type of qualifying event). For interventions after 1 week, CAS was also more hazardous than CEA: 7.1% versus 3.6%, adjusted risk ratio, 2.0; 95% confidence interval, 1.5 to 2.7 (
P
value for interaction with time interval 0.06).

Conclusions—

In randomized trials comparing stenting with CEA for symptomatic carotid artery stenosis, CAS was associated with a substantially higher periprocedural risk during the first 7 days after the onset of symptoms. Early surgery is safer than stenting for preventing future stroke.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00190398; URL:
http://www.controlled-trials.com
. Unique identifier: ISRCTN57874028; Unique identifier: ISRCTN25337470; URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00004732.
Long-Term Exposure to Ambient Air Pollution and Subclinical Cerebrovascular Disease in NOMAS (the Northern Manhattan Study)
Authors: Kulick Erin R. , Wellenius Gregory A. , Kaufman Joel D. , DeRosa Janet T. , Kinney Patrick L. , Cheung Ying Kuen , Wright Clinton B. , Sacco Ralph L. , Elkind Mitchell S.
Published: April 2017

Background and Purpose—

Long-term exposure to ambient air pollution is associated with higher risk of cardiovascular disease and stroke. We hypothesized that long-term exposure to air pollution would be associated with magnetic resonance imaging markers of subclinical cerebrovascular disease.

Methods—

Participants were 1075 stroke-free individuals aged ≥50 years drawn from the magnetic resonance imaging subcohort of the Northern Manhattan Study who had lived at the same residence for at least 2 years before magnetic resonance imaging. Cross-sectional associations between ambient air pollution and subclinical cerebrovascular disease were analyzed.

Results—

We found an association between distance to roadway, a proxy for residential exposure to traffic pollution, and white matter hyperintensity volume; however, after adjusting for risk factors, this relationship was no longer present. All other associations between pollutant measures and white matter hyperintensity volume were null. There was no clear association between exposure to air pollutants and subclinical brain infarcts or total cerebral brain volume.

Conclusions—

We found no evidence that long-term exposure to ambient air pollution is independently associated with subclinical cerebrovascular disease in an urban population-based cohort.
Classification of Bleeding Events
Authors: Neuberger Ulf , Möhlenbruch Markus Alfred , Herweh Christian , Ulfert Christian , Bendszus Martin , Pfaff Johannes
Published: April 2017

Background and Purpose—

Intracranial hemorrhage (ICH) after acute ischemic stroke treatments represents a feared complication with possible prognostic implications. In recent years, ICHs were commonly classified according to the ECASS (European Cooperative Acute Stroke Study). To improve the clinical applicability and relevance, the new Heidelberg Bleeding Classification (HBC) has been proposed in 2015. Here, we compared the ECASS and HBC classification with regard to observed events and prognostic relevance.

Methods—

A retrospective analysis of a prospectively compiled database of patients with acute ischemic stroke in the anterior circulation who received mechanical thrombectomy between February 2011 and March 2016 was performed. Presence of ICH after mechanical thrombectomy was evaluated on postinterventional computed tomographic imaging. ICHs were specified according to both ECASS III and HBC classification and analyzed with regard to their symptoms and outcome.

Results—

ICHs were observed in 156 of 768 patients (20.3%). Using ECASS III classification, 101 ICHs could be unambiguously assigned, of which 28 (27.7%; 3.6% of all treated patients) were symptomatic ICHs. Using HBC, 55 additional ICHs could be categorized. Of these total 156 ICHs, 29 (18.6%; 3.8% of all treated patients) were classified as symptomatic according to HBC.

Conclusions—

Classification of ICH by ECASS III and HBC criteria show distinct differences. These differences warrant special attention during interpretation and comparison of scientific publications.
Acupuncture Therapy and Incidence of Depression After Stroke
Authors: Lu Chung-Yen , Huang Hsin-Chia , Chang Hen-Hong , Yang Tsung-Hsien , Chang Chee-Jen , Chang Su-Wei , Chen Pei-Chun
Published: April 2017

Background and Purpose—

We investigated whether use of acupuncture within a 3-month poststroke period after hospital discharge is associated with reduced risk of depression.

Methods—

This cohort study included 16 046 patients aged ≥18 years with an initial hospitalization for stroke during 2000 and 2012 in the claims database of a universal health insurance program. Patients who had received acupuncture therapies within 3 months of discharge were defined as acupuncture users (n=1714). All patients were followed up for incidence of depression until the end of 2013. We assessed the association between use of acupuncture and incidence of depression using Cox proportional hazards models in all subjects and in propensity score–matched samples consisting of 1714 pairs of users and nonusers.

Results—

During the follow-up period, the incidence of depression per 1000 person-years was 11.1 and 9.7 in users and nonusers, respectively. Neither multivariable-adjusted Cox models (hazard ratio, 1.04; 95% confidence interval, 0.84–1.29) nor the propensity score-matching model (hazard ratio, 1.06; 95% confidence interval, 0.79–1.42) revealed an association between use of acupuncture and incidence of depression.

Conclusions—

In patients admitted to hospital for stroke, acupuncture therapy within 3 months after discharge was not associated with subsequent incidence of depression.
A Portrait of Biodiversity in Children’s Trade Books
Authors: Sousa Eunice , Quintino Victor , Teixeira José , Rodrigues Ana Maria
Published: April 2017

Indirect experiences are important in the public perception of nature and may influence attitudes towards conservation. Biodiversity and the environment are frequently presented in children’s books and promote children’s attitudes and emotions about biodiversity. We examined how biodiversity was portrayed in 164 books directed at six- to eight-year-old children. Living beings and habitats were found in 98% and 80% of the books, respectively, and included 441 different organisms in a total of 21,786 occurrences. The living beings in the books weren’t representative of the global biodiversity and were dominated by few iconic nonhuman organisms, mostly mammals, especially companion animals or other domesticated animals. The representations were strongly biased towards anthropomorphization of nonhuman animals who inhabited limited common habitats. This may contribute to the idea that all biodiversity lives in forests and humanized habitats, and is limited to nonhuman animals under human mastery or to few inaccessible megafauna.
Psychological Risk Factors for Childhood Nonhuman Animal Cruelty
Authors: Hawkins Roxanne D. , Hawkins Emma L. , Williams Joanne M.
Published: April 2017

Despite growing research into human-nonhuman animal relationships, little is known about childhood cruelty to nonhuman animals. The purpose of this review was to investigate the potential psychological risk factors for childhood cruelty to animals. The aim was to assemble, synthesize, and evaluate the quality and breadth of existing empirical research and highlight areas in need of further study. The review reveals a myriad of potential psychological risk factors associated with childhood animal cruelty, but highlights the decrease in publications on this topic over time and the lack of high-quality publications. Investigating the factors underlying cruel behavior toward animals has great implications for animal welfare and child wellbeing, and is vital for designing and implementing successful universal and targeted interventions to prevent cruelty to animals.
The crc of Unaccompanied Asylum Seekers in Finland
Authors: Kaukko Mervi
Published: April 2017

According to the un Convention on the Right of a Child (crc), all children in Finland have the right to participate in decision-making concerning them. This article shows how the conceptualisation of childhood affects the implementation of the crc, especially Article 12 on participation, focusing on unaccompanied asylum-seeking children in Finland. Universalist notions of childhood and children’s participatory rights overlook the specific socio-historical realities in which these rights exist. Therefore, this article adopts an intersectional view, in which children are seen not as future adults or citizens but as current rights-holders, and acknowledges the complexity of children’s reality where ethnicity, gender and past experiences are interrelated with the conception of childhood. Based on participatory action research with 12 unaccompanied girls, this article shows that they have justified views on their rights during the asylum process, and that those views should be heard and acted upon.
The Challenge of Space and the Technologies of Management of Ethno-Confessional Diversity in the Russian Empire
Authors: Mironov Boris
Published: April 2017

Territorial expansion led to the fact that Russia gradually developed into a multiethnic empire in which the titular nation was the minority. Long-term preservation of the unity of the multiethnic and multiconfessional Russian empire is explained by the relatively flexible ethno-confessional policy of imperial ethno-paternalism, which respected the status quo of an attached territory and the population living upon it; cooperated extensively with local elites; demonstrated religious and ethnic tolerance; instituted some advantages in the legal position of non-Russians compared with Russians; and offered indigenous peoples of annexed territories the right to be civilian actors equally with Russians. The principles of ethno-paternalism, which at first glance are not compatible with autocracy and serfdom, were in fact the reality and were dictated by a twofold need: the small proportion of those of strictly Russian ethnicity in the imperial population as whole and in some particular areas, and the lack of administrative and financial resources and the underdeveloped information and transportation infrastructures necessary for the rapid and thorough assimilation of the non-Orthodox borderlands. These principles represented a kind of “technology” of management of the ethno-confessional diversity in the empire, enabling the realization of both the “assembling” of imperial space, and the gradual, relatively flexible and non-linear integration and modernization of traditional society and “national borderlands” into the modern polity. When and where these imperial technologies were not applied with sufficient consistency, ethno-confessional conflict arose, as did issues with the loyalty of local ethnic communities and their leaders in relation to the imperial center, and problems with regard to general regional stability and security.
The Choice of Nationality Policy in Bashkiria, 1917–1925
Authors: Novozhilov Alexey
Published: April 2017

Several factors shaped nationality policy in Bashkiria in 1917–25: involvement of the central Bolshevik and regional White governments and activities of Muslim and Turko-Tatar elites, but Bashkir elites’ activism proved most significant. At first (1917–19) a long-range approach to practical organizational steps predominated. National activists in this period proceeded mainly on the higher elite level, proclaiming their principles and organizing national governing institutions; at the lower level they only disseminated propaganda of their views. In the second phase (1919–25), with Soviet power established in the Southern Urals a crucial struggle occurred concerning forms of national autonomy for Bashkiria and significant attention was paid to extending nationality policy to lower administrative levels. The main forms of struggle to achieve national autonomy’s objectives were convening congresses of deputies, forming assorted power structures based upon the congresses, establishing contacts with various governments but mainly with the Bolshevik government in Moscow, creating a national military, and struggling against alternative governments in Ufa and Orenburg. The major results of nationality policy in Bashkiria in 1917–25 can be summarized thus: legal formalization of the territorial integrity of a Bashkir autonomous entity and its relations with the federal center; inclusion of factory agglomerations in the autonomous region; granting of broad autonomous powers in education, culture, direct self-rule, and matters of justice; and creating conditions for development of all spheres of life involving the Bashkir language. Finally, the successes of indigenization policy and activity toward formation of a national intelligentsia are noteworthy.