bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral Intoxication of Mice with Shiga Toxin Type 2a (Stx2a) and Protection by Anti-Stx2a Monoclonal Antibody 11E10
Authors: Russo L. M. , Melton-Celsa A. R. , Smith M. A. , Smith M. J. , O'Brien A. D. 
Published: December 2013

ABSTRACTShiga toxin (Stx)-producingEscherichia coli(STEC) strains cause food-borne outbreaks of hemorrhagic colitis and, less commonly, a serious kidney-damaging sequela called the hemolytic uremic syndrome (HUS). Stx, the primary virulence factor expressed by STEC, is an AB5toxin with two antigenically distinct forms, Stx1a and Stx2a. Although both toxins have similar biological activities, Stx2a is more frequently produced by STEC strains that cause HUS than is Stx1a. Here we asked whether Stx1a and Stx2a act differently when delivered orally by gavage. We found that Stx2a had a 50% lethal dose (LD50) of 2.9 μg, but no morbidity occurred after oral intoxication with up to 157 μg of Stx1a. We also compared several biochemical and histological parameters in mice intoxicated orally versus intraperitoneally with Stx2a. We discovered that both intoxication routes caused similar increases in serum creatinine and blood urea nitrogen, indicative of kidney damage, as well as electrolyte imbalances and weight loss in the animals. Furthermore, kidney sections from Stx2a-intoxicated mice revealed multifocal, acute tubular necrosis (ATN). Of particular note, we detected Stx2a in kidney sections from orally intoxicated mice in the same region as the epithelial cell type in which ATN was detected. Lastly, we showed reduced renal damage, as determined by renal biomarkers and histopathology, and full protection of orally intoxicated mice with monoclonal antibody (MAb) 11E10 directed against the toxin A subunit; conversely, an irrelevant MAb had no therapeutic effect. Orally intoxicated mice could be rescued by MAb 11E10 6 h but not 24 h after Stx2a delivery.
The assessment and impact of sarcopenia in lung cancer: a systematic literature review
Authors: Collins Jemima , Noble Simon , Chester John , Coles Bernadette , Byrne Anthony 
Published: January 2014

ObjectivesThere is growing awareness of the relationship between sarcopenia (loss of muscle mass and function), and outcomes in cancer, making it a potential target for future therapies. In order to inform future research and practice, we undertook a systematic review of factors associated with loss of muscle mass, and the relationship between muscle function and muscle mass in lung cancer, a common condition associated with poor outcomes.DesignWe conducted a computerised systematic literature search on five databases. Studies were included if they explored muscle mass as an outcome measure in patients with lung cancer, and were published in English.SettingSecondary care.ParticipantsPatients with lung cancer.Primary outcomeFactors associated with loss of muscle mass and muscle function, or sarcopenia, and the clinical impact thereof in patients with lung cancer.ResultsWe reviewed 5726 citations, and 35 articles were selected for analysis. Sarcopenia, as defined by reduced muscle mass alone, was found to be very prevalent in patients with lung cancer, regardless of body mass index, and where present was associated with poorer functional status and overall survival. There were diverse studies exploring molecular and metabolic factors in the development of loss of muscle mass; however, the precise mechanisms that contribute to sarcopenia and cachexia remain uncertain. The effect of nutritional supplements and ATP infusions on muscle mass showed conflicting results. There are very limited data on the correlation between degree of sarcopenia and muscle function, which has a non-linear relationship in older non-cancer populations.ConclusionsLoss of muscle mass is a significant contributor to morbidity in patients with lung cancer. Loss of muscle mass and function may predate clinically overt cachexia, underlining the importance of evaluating sarcopenia, rather than weight loss alone. Understanding this relationship and its associated factors will provide opportunities for focused intervention to improve clinical outcomes.
End-of-life conversations and care: an asset-based model for community engagement
Authors: Matthiesen Mary , Froggatt Katherine , Owen Elaine , Ashton John R 
Published: January 2014

BackgroundPublic awareness work regarding palliative and end-of-life care is increasingly promoted within national strategies for palliative care. Different approaches to undertaking this work are being used, often based upon broader educational principles, but little is known about how to undertake such initiatives in a way that equally engages both the health and social care sector and the local communities. An asset-based community engagement approach has been developed that facilitates community-led awareness initiatives concerning end-of-life conversations and care by identifying and connecting existing skills and expertise.Aims(1) To describe the processes and features of an asset-based community engagement approach that facilitates community-led awareness initiatives with a focus on end-of-life conversations and care; and (2) to identify key community-identified priorities for sustainable community engagement processes.MethodsAn asset-based model of community engagement specific to end-of-life issues using a four-step process is described (getting started, coming together, action planning and implementation). The use of this approach, in two regional community engagement programmes, based across rural and urban communities in the northwest of England, is described.FindingsThe assets identified in the facilitated community engagement process encompassed people's talents and skills, community groups and networks, government and non-government agencies, physical and economic assets and community values and stories. Five priority areas were addressed to ensure active community engagement work: information, outreach, education, leadership and sustainability.ConclusionsA facilitated, asset-based approach of community engagement for end-of-life conversations and care can catalyse community-led awareness initiatives. This occurs through the involvement of community and local health and social care organisations as co-creators of this change across multiple sectors in a sustainable way. This approach provides a framework for other communities seeking to engage with public awareness in end-of-life issues.
Cerebral angioplasty using the Scepter XC dual lumen balloon for the treatment of vasospasm following intracranial aneurysm rupture
Authors: Heit Jeremy J , Choudhri Omar , Marks Michael P , Dodd Robert L , Do Huy M 
Published: January 2014

BackgroundCerebral vasospasm following subarachnoid hemorrhage (SAH) results in significant morbidity and mortality. Intra-arterial administration of calcium channel blockers or intracranial angioplasty may be performed when non-invasive medical management fails to prevent neurologic deterioration. Technical improvements in balloon catheters are expected to improve the success and safety of cerebral angioplasty.ObjectiveTo describe our initial experience with the new Scepter XC balloon catheter in cerebral vasospasm treatment following SAH.DesignAll patients who underwent cerebral angioplasty using the Scepter XC balloon for the treatment of medically refractory cerebral vasospasm after SAH were identified. Patient demographic information, procedural details, and outcome were obtained from electronic medical records.ResultsFive consecutive patients undergoing vasospasm treatment with cerebral angioplasty using the Scepter XC were identified. All treated patients had medically refractory vasospasm that was moderate or severe. Angioplasty of the supraclinoid internal carotid artery, the A1 and A2 segments of the anterior cerebral artery, the M1 and M2 segments of the middle cerebral artery, the V4 segment of the vertebral artery, and the basilar artery was performed. All angioplasty procedures were technically successful, and the degree of vasospasm improved significantly following angioplasty. There were no complications related to the cerebral angioplasty procedures.ConclusionsThe Scepter XC balloon catheter is safe and effective in the treatment of cerebral vasospasm following SAH. The excellent trackability and stability of the balloon catheter and the extra compliant design of the balloon represent technical advancements in the endovascular armamentarium in the treatment of cerebral vasospasm.
Unbiased Compound Screening Identifies Unexpected Drug Sensitivities and Novel Treatment Options for Gastrointestinal Stromal Tumors
Authors: Boichuk Sergei , Lee Derek J. , Mehalek Keith R. , Makielski Kathleen R. , Wozniak Agnieszka , Seneviratne Danushka S. , Korzeniewski Nina , Cuevas Rolando , Parry Joshua A. , Brown Matthew F. , Zewe James , Taguchi Takahiro , Kuan Shin-Fan , Schöffski Patrick , Debiec-Rychter Maria , Duensing Anette 
Published: January 2014

Abstract
Most gastrointestinal stromal tumors (GIST) are caused by oncogenic KIT or platelet-derived growth factor receptor activation, and the small molecule kinase inhibitor imatinib mesylate is an effective first-line therapy for metastatic or unresectable GIST. However, complete remissions are rare and most patients ultimately develop resistance, mostly because of secondary mutations in the driver oncogenic kinase. Hence, there is a need for novel treatment options to delay failure of primary treatment and restore tumor control in patients who progress under therapy with targeted agents. Historic data suggest that GISTs do not respond to classical chemotherapy, but systematic unbiased screening has not been performed. In screening a compound library enriched for U.S. Food and Drug Administration (FDA)–approved chemotherapeutic agents (NCI Approved Oncology Drugs Set II), we discovered that GIST cells display high sensitivity to transcriptional inhibitors and topoisomerase II inhibitors. Mechanistically, these compounds exploited the cells' dependency on continuous KIT expression and/or intrinsic DNA damage response defects, explaining their activity in GIST. Mithramycin A, an indirect inhibitor of the SP1 transcription factor, and mitoxantrone, a topoisomerase II inhibitor, exerted significant antitumor effects in mouse xenograft models of human GIST. Moreover, these compounds were active in patient-derived imatinib-resistant primary GIST cells, achieving efficacy at clinically relevant concentrations. Taken together, our findings reveal that GIST cells have an unexpectedly high and specific sensitivity to certain types of FDA-approved chemotherapeutic agents, with immediate implications for encouraging their clinical exploration. Cancer Res; 74(4); 1200–13. ©2014 AACR.
Efficacy and Safety of ETC-1002, a Novel Investigational Low-Density Lipoprotein-Cholesterol–Lowering Therapy for the Treatment of Patients With Hypercholesterolemia and Type 2 Diabetes Mellitus
Authors: Gutierrez Maria J. , Rosenberg Noah L. , MacDougall Diane E. , Hanselman Jeffrey C. , Margulies Janice R. , Strange Poul , Milad Mark A. , McBride Scott J. , Newton Roger S. 
Published: January 2014

Objective—
8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia. Additional cardiometabolic biomarkers, including glycemic measures, were also assessed.

Approach and Results—

A single-center, double-blind, placebo-controlled trial evaluated 60 patients with type 2 diabetes mellitus and elevated low-density lipoprotein-cholesterol. Patients discontinued all diabetes mellitus and lipid-regulating drugs and were randomized to receive ETC-1002 80 mg QD for 2 weeks followed by 120 mg QD for 2 weeks or placebo for 4 weeks. ETC-1002 lowered low-density lipoprotein-cholesterol levels by 43±2.6% (least squares mean±SE), compared with a reduction of 4±2.5% by placebo at day 29 (
P
<0.0001; primary end point). Non–high-density lipoprotein-cholesterol and total cholesterol were also significantly lowered by ETC-1002 compared with placebo (
P
<0.0001). High-sensitivity C-reactive protein was reduced by 41% (median) compared with a placebo reduction of 11% (
P
=0.0011). No clinically meaningful safety findings were observed.

Conclusions—
ETC-1002 lowered low-density lipoprotein-cholesterol and other lipids and demonstrated improvement in high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia without worsening glycemic control. ETC-1002 was well tolerated in this population.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT# 01607294.
d
‐Dimer Levels Over Time and the Risk of Recurrent Venous Thromboembolism: An Update of the Vienna Prediction Model
Authors: Eichinger Sabine , Heinze Georg , Kyrle Paul A. 
Published: January 2014

Background

Patients with unprovoked venous thromboembolism (
VTE
) can be stratified according to their recurrence risk based on their sex, the
VTE
location, and
d
‐dimer measured 3 weeks after anticoagulation by the
V
ienna Prediction Model. We aimed to expand the model to also assess the recurrence risk from later points on.

Methods and Results

Five hundred and fifty‐three patients with a first
VTE
were followed for a median of 68 months. We excluded patients with
VTE
provoked by a transient risk factor or female hormone intake, with a natural inhibitor deficiency, the lupus anticoagulant, or cancer. The study end point was recurrent
VTE
, which occurred in 150 patients.
d
‐Dimer levels did not substantially increase over time. Subdistribution hazard ratios (95% confidence intervals) dynamically changed from 2.43 (1.57 to 3.77) at 3 weeks to 2.27 (1.48 to 3.48), 1.98 (1.30 to 3.02) , and 1.73 (1.11 to 2.69) at 3, 9, and 15 months in men versus women, from 1.84 (1.00 to 3.43) to 1.68 (0.91 to 3.10), 1.49 (0.79 to 2.81) , and 1.44 (0.76 to 2.72) in patients with proximal deep vein thrombosis or pulmonary embolism compared with calf vein thrombosis, and from 1.30 (1.07 to 1.58) to 1.27 (1.06 to 1.51), 1.20 (1.02 to 1.41), and 1.13 (0.95 to 1.36) per doubling
d
‐dimer. Using a dynamic landmark competing risks regression approach, we generated nomograms and a web‐based calculator to calculate risk scores and recurrence rates from multiple times after anticoagulation.

Conclusions

Risk of recurrent
VTE
after discontinuation of anticoagulation can be predicted from multiple random time points by integrating the patient's sex, location of first
VTE
, and serial
d
‐dimer measurements.
Systematic Review and Meta-Analysis of Interventions Tested in Animal Models of Lacunar Stroke
Authors: Pedder Hugo , Vesterinen Hanna M. , Macleod Malcolm R. , Wardlaw Joanna M. 
Published: January 2014

Background and Purpose—
A total of 25% of strokes are lacunar, and these are pathophysiologically different from large artery strokes. Despite emerging evidence of a substantial impact on physical disability and dementia, little attention has been paid to the development of specific treatments. The optimal use of the animal models of lacunar stroke used to test candidate interventions is not known.

Methods—
We conducted a systematic review and meta-analysis of studies testing candidate interventions in animal models of lacunar stroke. We used random-effects meta-analysis to assess the impact of study characteristics and trim and fill to seek evidence of publication bias.

Results—
The efficacy of 43 distinct interventions was described in 57 publications. The median number of quality checklist items scored was 3 of 8 (interquartile range, 2–4). Many models reflected mechanisms of limited relevance to lacunar stroke. Meta-analysis of results from 27 studies showed that on average, infarct size and neurobehavioral outcome were improved by 34.2% (24.1–44.2) and 0.82 standardized mean difference (0.51–1.14), respectively. Four interventions improved both infarct size and neurobehavioral outcome but there were insufficient data for this finding to be considered robust. For infarct size, efficacy was lower in studies reporting blinding and higher in studies reporting randomization. For neurobehavior, efficacy was lower in randomized studies. For infarct size there was evidence of publication bias.

Conclusions—
No intervention has yet been tested in sufficient range and depth to support translation to clinical trial. There is limited reporting of measures to reduce the risk of bias and evidence for a substantial publications bias.
Cost-Effectiveness of Optimizing Acute Stroke Care Services for Thrombolysis
Authors: Penaloza-Ramos Maria Cristina , Sheppard James P. , Jowett Sue , Barton Pelham , Mant Jonathan , Quinn Tom , Mellor Ruth M. , Sims Don , Sandler David , McManus Richard J. ,   Birmingham and Black Country Collaborations for Leadership in Applied Health Research and Care investigators include:, Carr Peter , Greenfield Sheila , Helliwell Brin , Nand Cristina , Phillips Norman , Scott Rob , Singh Satinder , Ward Matthew 
Published: January 2014

Background and Purpose—
Thrombolysis in acute stroke is effective up to 4.5 hours after symptom onset but relies on early recognition, prompt arrival in hospital, and timely brain scanning. This study aimed to establish the cost-effectiveness of increasing thrombolysis rates through a series of hypothetical change strategies designed to optimize the acute care pathway for stroke.

Methods—
A decision-tree model was constructed, which relates the acute management of patients with suspected stroke from symptom onset to outcome. Current practice was modeled and compared with 7 change strategies designed to facilitate wider eligibility for thrombolysis. The model basecase consisted of data from consenting patients following the acute stroke pathway recruited in participating hospitals with data on effectiveness of treatment and costs from published sources.

Results—
All change strategies were cost saving while increasing quality-adjusted life years gained. Using realistic estimates of effectiveness, the change strategy with the largest potential benefit was that of better recording of onset time, which resulted in 3.3 additional quality-adjusted life years and a cost saving of US $46 000 per 100 000 population. All strategies increased the number of thrombolysed patients and the number requiring urgent brain imaging (by 9% to 21% dependent on the scenario). Assuming a willingness-to-pay of US $30 000 per quality-adjusted life year gained, the potential budget available to deliver the interventions in each strategy ranged from US $50 000 to US $144 000.

Conclusions—
These results suggest that any strategy that increases thrombolysis rates will result in cost savings and improved patient quality of life. Healthcare commissioners could consider this model when planning improvements in stroke care.
How Does El Niño Affect the Interannual Variability of the Boreal Summer Hadley Circulation?
Authors: Sun Yong , Zhou Tianjun 
Published: January 2014

Abstract
Analyses of 30-yr four reanalysis datasets [NCEP–NCAR reanalysis (NCEP1), NCEP–Department of Energy reanalysis (NCEP2), Japanese 25-year Reanalysis Project (JRA-25), and Interim ECMWF Re-Analysis (ERA-Interim)] reveal remarkably interannual variability of the Hadley circulation (HC) in boreal summer (June–August). The two leading modes of interannual variability of boreal summer HC are obtained by performing empirical orthogonal function (EOF) analysis on the mass streamfunction. A general intensification of boreal summer HC is seen in EOF-1 mode among NCEP1, NCEP2, and JRA-25 but the corresponding EOF-2 mode in ERA-Interim, while a weakened northern Hadley cell and remarkable regional variation of a southern Hadley cell are captured by the EOF-2 mode (from NCEP1, NCEP2, and JRA-25) and EOF-1 mode (from ERA-Interim), as evidenced by the enhanced (decreased) southern Hadley cell in the southern tropics (the northern tropics and southern subtropics). Both modes are driven by El Niño–like SST forcing in boreal summer, but are relevant to different phases of El Niño events. The EOF-1 (or EOF-2 derived from ERA-Interim) [EOF-2 (or EOF-1 derived from ERA-Interim)] mode is driven by SST anomalies in developing (decaying) El Niño summers. The interannual variations of the northern Hadley cell in both modes are driven by El Niño through modulating the interannual variations of the East Asian summer monsoon, while anomalous local Hadley circulation (LHC) in the regions 30°S–20°N, 110°E–180° and 30°S–20°N, 160°E–120°W in response to El Niño forcing largely determine the interannual variations of southern Hadley cell in both modes, respectively. The different behaviors of the southern Hadley cell between two leading modes can be well explained by the southward shift of the tropical heating center from north of 10°N in developing El Niño summers to south of 10°N in decaying El Niño summers.
Correlates of smokeless tobacco use among first year college students
Authors: Spangler John , Song Eunyoung , Pockey Jessica , Sutfin Erin L , Reboussin Beth A , Wagoner Kimberly , Wolfson Mark 
Published: January 2014

Objective: Smokeless tobacco (SLT) use is associated with specific adverse health effects. Knowledge of student tobacco use, including SLT, may guide inquiry into other risky health behaviors, and provide opportunities for health education of students. Design: An incentivized email invitation to complete a web-based survey was sent to students at 11 colleges and universities in North Carolina and Virginia. Methods: In autumn 2010, emails were sent to all first-year students ( n=29,536) at 11 colleges and universities in North Carolina and Virginia, inviting them to participate in a brief web-based survey to be used to establish a cohort for the parent study evaluating tobacco use over 4 years. Survey items elicited demographic characteristics, tobacco use and other health behaviors. Results: A total of 10,520 (36%) students responded. Past 30 day smoking and SLT use were 12% and 3%, respectively. Logistic regression analysis revealed that male gender (Adjusted Odds Ratio [AOR] = 11.6, 95% Confidence Interval [CI] = 8.16–16.59); current smoking (AOR = 5.5, 95% CI = 4.21–7.10), ever use of alcoholic energy drinks (AOR = 4.8, 95% CI = 3.63–6.43), and ≥ 5 days vs. < 3 days of physical activity a week (AOR = 1.5, 95% CI = 1.07–2.01) predicted risk of past 30 day SLT use. Conclusion: While SLT use is relatively uncommon, knowledge of significant correlations between student tobacco use, including SLT and other risky health behaviors, might guide clinicians’ inquiry and provide opportunities for health education of students.