bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving Door to Needle time in Patients for Thrombolysis
Authors: Fernandes Darren , Umasankar Udayaraj 
Published: August 2016

Ischaemic stroke can result in approximately 2 million brain neurones being damaged for each minute that it is left untreated. Various trials and studies such as the National Institute of Neurologic Disorders (NINDS) trial, the European Cooperative Acute Stroke Study (ECASS), ECASS II, and the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study have clearly demonstrated the beneficial effects of intravenous tissue plasminogen activator (tPA) for treatment of acute stroke.Therefore to minimise damage and improve clinical outcome, we need to identify patients who present within 4.5 hours of symptom onset and reduce the time taken to adminster a thrombolytic agent. This time is commonly referred to as the ‘door to needle’ (DTN) time.Our standard, set by the Clinical Commissioning Group (CCG) is to achieve a median time of scanning and thrombolysis within 55 minutes from the time that the patient enters the hospital. The aim of our QIP was to collect data on what the DTN time was during November 2015, December 2015, and January 2016 and to evaluate how this can be improved after each month.This Quality Improvement Project in the DTN time in patients for thrombolysis has identified areas in the pathway that leads to delays. One major contributing factor is the time for a doctor to come and assess and administer the thrombolytic agent to the patient. Change was implemented by ensuring that the core medical trainee on call is allocated to respond as a priority to all possible thrombolysis calls. This has resulted in a reduction of mean DTN time, from 74 minutes in November to 43 minutes in January. As well as improving patient outcomes, it is proposed that the implementation of change has benefitted the training experience and development of key skills of the core medical trainees.
Bioactive versus bare platinum coils for the endovascular treatment of intracranial aneurysms: systematic review and meta-analysis of randomized clinical trials
Authors: Broeders Joris A , Ahmed Ali Usama , Molyneux Andrew J , Poncyljusz Wojciech , Raymond Jean , White Phillip M , Steinfort Brendan 
Published: August 2016

BackgroundBioactive coils were introduced in 2002 in an attempt to improve aneurysm healing and durability of angiographic results. Evidence demonstrating superior efficacy to justify the routine use of bioactive coils over bare coils is limited. We compared the periprocedural and clinical outcome after bioactive and bare platinum coiling for intracranial aneurysms.MethodsMEDLINE, EMBASE, Cochrane Library, and ISI Web of Knowledge Conference Proceedings Citation Index—Science were searched for randomized clinical trials (RCTs) comparing bioactive and bare coils. The methodological quality was evaluated to assess bias risk. Periprocedural outcomes and mid-term outcomes were compared.ResultsFive independent RCTs comparing bioactive (n=1084) and bare coils (n=1084) were identified. Periprocedural outcome was similar for both groups. Bioactive coiling increased the rate of complete aneurysm occlusion (47% vs 40%; RR 1.17 (95% CI 1.05 to 1.31); p=0.006) and reduced the rate of residual aneurysm neck at 10 months compared with bare coiling in the mid-term (26% vs 31%; RR 0.82 (95% CI 0.70 to 0.96); p=0.01). There were no differences in aneurysm recurrence, aneurysm rupture, stroke, neurological death, modified Rankin Scale score and reinterventions. Subgroup analysis for the three RCTs on hydrogel coils demonstrated reduction of residual aneurysms compared with bare coiling (25% vs 34%; RR 0.76 (95% CI 0.58 to 0.99); p=0.04).ConclusionsBioactive coils ensure a higher rate of medium-term complete aneurysm occlusion while reducing the rate of residual neck aneurysms compared with bare coiling in the mid-term. Hydrogel coils reduce residual aneurysms compared with bare coils. While there is level 1a evidence to show more complete aneurysm occlusion, longer term follow-up is needed to determine if this translates into clinical significance.
Endovascular treatment of cribriform plate dural arteriovenous fistulas: technical difficulties and complications avoidance
Authors: Robert Thomas , Blanc Raphaël , Smajda Stanislas , Ciccio Gabriele , Redjem Hocine , Bartolini Bruno , Fahed Robert , Piotin Michel 
Published: August 2016

ObjectiveCribriform plate dural arteriovenous fistula (dAVF) is a rare pathology, for which the treatment of choice used to be neurosurgery. Technological advances in micro-catheters and embolic agents permitted new endovascular alternatives.MethodsWe included all patients treated endovascularly for a cribriform plate dAVF between 2008 and 2013. We retrospectively analysed data focusing on the type of treatment chosen.ResultsTen patients were treated by endovascular approach, with a need for an additional surgical exclusion of the fistula in two cases. Thirteen embolisation sessions were done. Embolisation of the fistula through an ethmoidal artery was the technique of choice; the catheterism of the ophthalmic artery was impossible in two cases and the embolic agent did not penetrate in four cases. The embolisation through the middle meningeal artery was successful in one case but the tortuosity of this artery prevented good penetration of the embolic agent. Venous approach was successful in all cases but was limited to fistulas with superficial venous drainage.ConclusionsEndovascular treatment of cribriform plate dAVF is safe and effective. The embolisation through ethmoidal artery is the method of choice. Branches of the middle meningeal artery are tortuous and prevent the penetration of embolic agent. Venous approach is effective but is limited to cases of failure of the arterial approach.
High HbA1c is associated with higher risk of ischaemic stroke in Pakistani population without diabetes
Authors: Nomani Ali Zohair , Nabi Sumaira , Ahmed Shahzad , Iqbal Mansoor , Rajput Haris Majid , Rao Suhail 
Published: August 2016

ContextThe role of glycated haemoglobin (HbA1c) in the prediction of ischaemic stroke in individuals without diabetes is underestimated.AimsWe performed a study to analyse the role of HbA1c in the risk prediction of ischaemic stroke in Pakistani population without diabetes. We further studied the difference between HbA1c values of individuals with diabetes and without diabetes with stroke.Settings and designSingle centre, case–control.Materials and methodsIn phase I, a total of 233 patients without diabetes with ischaemic stroke and 245 as controls were enrolled. Association of HbA1c levels, lipid profiles and blood pressure recordings with ischaemic stroke was analysed. In phase II, comparison was done between diabetics and non-diabetics with stroke.Statistical analysisComparison of the mean variables was performed with Student's t-tests. Logistic regression analysis with ischaemic stroke as the dependent variable was performed for phase I.ResultsIn phase I, the ischaemic stroke group had significantly higher HbA1c levels (5.9±2.9% vs 5.5±1.6%) compared with controls (p<0.05). Triglyceride cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure and HbA1c were the significant determinants of stroke (p<0.05). In phase II, mean HbA1c values were significantly higher in the diabetes group (7.6±2.1 vs 6.1±2.3) (p<0.05) but other parameters were not statistically significantly different (p>0.05).ConclusionsHigher HbA1c indicated a significantly increased risk for ischaemic stroke. An HbA1c value above 5.6% (prediabetic range) predicted future risk of stroke and efforts to maintain glucose level within the normal range (≤5.6%) in individuals with high cardiovascular risk are important.
Reducing uncertainty and risk through field-based studies
Authors: Bowman M. B. J. , Smyth Helen R. 
Published: August 2016

Abstract
Field-based studies, be they regional or basin-scale fieldwork, or the examination of outcrop analogues, have been an important component of petroleum system studies in the upstream oil and gas industry for many years. Recent technological advances, founded on traditional field methodologies, whether they are in digital outcrop characterization or developments in processing and computational capabilities, have fuelled a resurgence in such fieldwork. These studies enable the building of realistic models that allow the exploration or production geoscientist to navigate effectively from plate-to-play-to-pore. The interrogation of field data and resulting models provide a more informed means of benchmarking the subsurface, as well as a more realistic view of subsurface uncertainty and the management of associated risk in subsurface description and prediction.
This Special Publication records 12 papers given at a conference titled ‘Reducing Subsurface Uncertainty and Risk Through Field-Based Studies’ organized by the Petroleum Group of the Geological Society of London, and held in London from 4 to 6 March 2014. The observations drawn in this introductory paper reflect the authors’ experiences, presentations at the conference and manuscripts within this volume.
MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB
Authors: Rose April A.N. , Annis Matthew G. , Frederick Dennie T. , Biondini Marco , Dong Zhifeng , Kwong Lawrence , Chin Lynda , Keler Tibor , Hawthorne Thomas , Watson Ian R. , Flaherty Keith T. , Siegel Peter M. 
Published: August 2016

Abstract
Purpose: To determine if BRAF and/or MEK inhibitor–induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB.
Experimental Design: The Cancer Genome Atlas melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF-mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot, and FACS analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from patients with melanoma taken before, during, and after disease progression on MAPK inhibitor treatment. Subcutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth.
Results: A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor–treated melanoma cells and is also elevated in on-treatment versus pretreatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug conjugate targeting GPNMB, is effective in causing melanoma regression in preclinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone.
Conclusions: The combination of MAPK pathway inhibitors with an antibody-drug conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma. Clin Cancer Res; 22(24); 6088–98. ©2016 AACR.
Non-HDL Cholesterol and Triglycerides
Authors: Puri Rishi , Nissen Steven E. , Shao Mingyuan , Elshazly Mohamed B. , Kataoka Yu , Kapadia Samir R. , Tuzcu E. Murat , Nicholls Stephen J. 
Published: August 2016

Objectives—
Non–high-density lipoprotein cholesterol (non-HDLC) levels reflect the full burden of cholesterol transported in atherogenic lipoproteins. Genetic studies suggest a causal association between elevated triglycerides (TGs)-rich lipoproteins and atherosclerosis. We evaluated associations between achieved non-HDLC and TG levels on changes in coronary atheroma volume.

Approach and Results—

Data were analyzed from 9 clinical trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (ΔPAV) and were evaluated against on-treatment non-HDLC and TG levels. The effects of lower (<100 mg/dL) versus higher (≥100 mg/dL) achieved non-HDLC levels and lower (<200 mg/dL) versus higher (≥200 mg/dL) achieved TG levels were evaluated in populations with variable on-treatment low-density lipoprotein cholesterol (LDLC) </≥70 mg/dL and C-reactive protein </≥2 mg/L and in patients with or without diabetes mellitus. On-treatment non-HDLC levels linearly associated with ΔPAV. Overt PAV progression (ΔPAV>0) was associated with achieved TG levels >200 mg/dL, respectively. Lower on-treatment non-HDLC and TG levels associated with significant PAV regression compared with higher non-HDLC and TG levels across all levels of LDLC and C-reactive protein and irrespective of diabetic status (
P
<0.001 across all comparisons). ΔPAV were more strongly influenced by changes in non-HDLC (β=0.62;
P
<0.001) compared with changes in LDLC (β=0.51;
P
<0.001). Kaplan–Meier sensitivity analyses demonstrated significantly greater major adverse cardiovascular event rates in those with higher versus lower non-HDLC and TG levels, with an earlier separation of the non-HDLC compared with the LDLC curve.

Conclusions—
Achieved non-HDLC levels seem more closely associated with coronary atheroma progression than LDLC. Plaque progression associates with achieved TGs, but only above levels of 200 mg/dL. These observations support a more prominent role for non-HDLC (and possibly TG) lowering in combating residual cardiovascular risk.
β-Blocker Adherence in Familial Long QT Syndrome
Authors: Waddell-Smith Kathryn E. , Li Jian , Smith Warren , Crawford Jackie , Skinner Jonathan R. 
Published: August 2016

Background—
Long-term uninterrupted β-blockade significantly reduces cardiac events in long QT syndrome (LQTS). Despite this, data on nonadherence are scarce and quantified only on the day of cardiac arrest in LQTS literature. We aimed to describe β-blocker adherence, and predictors thereof, among patients with LQTS types 1 and 2.

Methods and Results—
Electronic health records and pharmacy dispensing data were reviewed for 90 patients with LQTS 1 and 2 who reside in Auckland, New Zealand, during a 34-month period. For each patient, the medication possession ratio (MPR: proportion of follow-up days patients were dispensed β-blocker) was calculated. Adequate adherence was characterized by an MPR ≥0.8 and ideal as MPR=1.0. Clinical and demographic features were assessed to determine whether they predicted adherence. Long-term β-blockers were prescribed to 74 patients (82%). Side effects were described as intolerable by 6 (8%) and their β-blockers were stopped. MPR was calculated in the remaining 68 patients >151.7 patient-years of follow-up. Median MPR was 0.79 (range, 0–1.3). Suboptimal adherence (MPR<0.8) was recorded in 35 (51%). Seven patients (10%) never took up a prescription (MPR=0). Adequate adherence was present in 33 (49%), including 9 (13%) who had ideal adherence. Age, sex, clinical presentation, family history of sudden death, ethnicity, and deprivation index did not predict adherence.

Conclusions—
Adherence to β-blockers in LQTS is suboptimal in half of those with LQTS 1 and 2. Risk factors for nonadherence could not be identified in our population. Further research into β-blocker adherence is imperative in this high-risk population.
Redefining the Blanking Period After Catheter Ablation for Paroxysmal Atrial Fibrillation
Authors: Willems Stephan , Khairy Paul , Andrade Jason G. , Hoffmann Boris A. , Levesque Sylvie , Verma Atul , Weerasooriya Rukshen , Novak Paul , Arentz Thomas , Deisenhofer Isabel , Rostock Thomas , Steven Daniel , Rivard Lena , Guerra Peter G. , Dyrda Katia , Mondesert Blandine , Dubuc Marc , Thibault Bernard , Talajic Mario , Roy Denis , Nattel Stanley , Macle Laurent 
Published: August 2016

Background—
Early recurrences (ERs) of atrial tachyarrhythmia are common after catheter ablation of atrial fibrillation. A 3-month blanking period is recommended by current guidelines. This study sought to investigate the significance of ER during the first 3 months post ablation in predicting late recurrences and determine whether it varies according to timing.

Methods and Results—

A total of 401 patients with paroxysmal atrial fibrillation undergoing pulmonary vein isolation were followed for 12 months with transtelephonic monitoring in the ADVICE (Adenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination) trial. Patients with atrial tachyarrhythmia ≥30 s within the 3-month blanking period were stratified according to the timing of ER. A total of 179 patients (44.6%) experienced their last episode of ER during the first (n=53), second (n=44), or third (n=82) month of the 3-month blanking period. One-year freedom from symptomatic atrial tachyarrhythmia was 77.2% in patients without ER compared with 62.6%, 36.4%, and 7.8% in patients with ER 1, 2, and 3 months post ablation, respectively (
P
<0.0001). Receiver operating curve analyses revealed a strong correlation between the timing of ER and late recurrence (area under the curve 0.82,
P
<0.0001). Corresponding hazard ratios for ER during the first, second, and third months were 1.84, 4.45, and 9.64, respectively.

Conclusions—
This study validates the use of a blanking period after catheter ablation for paroxysmal atrial fibrillation but calls into question the 90-day cut-off value. In particular, >90% of patients with ER during the third month post ablation experience late recurrence by 1 year. However, pending further study, repeat ablation before 90 days cannot be routinely advocated.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01058980.
Novel CPVT-Associated Calmodulin Mutation in
CALM3
(CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks
Authors: Gomez-Hurtado Nieves , Boczek Nicole J. , Kryshtal Dmytro O. , Johnson Christopher N. , Sun Jennifer , Nitu Florentin R. , Cornea Razvan L. , Chazin Walter J. , Calvert Melissa L. , Tester David J. , Ackerman Michael J. , Knollmann Björn C. 
Published: August 2016

Background—
Calmodulin (CaM) mutations are associated with severe forms of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). CaM mutations are found in 13% of genotype-negative long QT syndrome patients, but the prevalence of CaM mutations in genotype-negative CPVT patients is unknown. Here, we identify and characterize CaM mutations in 12 patients with genotype-negative but clinically diagnosed CPVT.

Methods and Results—

We performed mutational analysis of
CALM1
,
CALM2
, and
CALM3
gene-coding regions, in vitro measurement of CaM-Ca
2+
(Ca)-binding affinity, ryanodine receptor 2–CaM binding, Ca handling, L-type Ca current, and action potential duration. We identified a novel CaM mutation—A103V—in
CALM3
in 1 of 12 patients (8%), a female who experienced episodes of exertion-induced syncope since age 10, had normal QT interval, and displayed ventricular ectopy during stress testing consistent with CPVT. A103V modestly lowered CaM Ca-binding affinity (3-fold reduction versus WT-CaM), but did not alter CaM binding to ryanodine receptor 2. In permeabilized cardiomyocytes, A103V-CaM (100 nmol/L) promoted spontaneous Ca wave and spark activity, a cellular phenotype of ryanodine receptor 2 activation. Even a 1:3 mixture of A103V-CaM:WT-CaM activated Ca waves, demonstrating functional dominance. Compared with long QT syndrome D96V-CaM, A103V-CaM had significantly less effects on L-type Ca current inactivation, did not alter action potential duration, and caused delayed afterdepolarizations and triggered beats in intact cardiomyocytes.

Conclusions—

We discovered a novel CPVT mutation in the
CALM3
gene that shares functional characteristics with established CPVT-associated mutations in
CALM1
. A small proportion of A103V-CaM is sufficient to evoke arrhythmogenic Ca disturbances via ryanodine receptor 2 dysregulation, which explains the autosomal dominant inheritance.
Long-Term Outcomes of Catheter Ablation of Ventricular Tachycardia in Patients With Cardiac Sarcoidosis
Authors: Muser Daniele , Santangeli Pasquale , Pathak Rajeev K. , Castro Simon A. , Liang Jackson J. , Magnani Silvia , Hayashi Tatsuya , Garcia Fermin C. , Hutchinson Mathew D. , Supple Gregory E. , Frankel David S. , Riley Michael P. , Lin David , Schaller Robert D. , Desjardins Benoit , Dixit Sanjay , Callans David J. , Zado Erica S. , Marchlinski Francis E. 
Published: August 2016

Background—
Catheter ablation (CA) of ventricular tachycardia (VT) in patients with cardiac sarcoidosis can be challenging because of the complex underlying substrate. We sought to determine the long-term outcome of CA of VT in patients with cardiac sarcoidosis.

Methods and Results—
We enrolled 31 patients (age, 55±10 years) with diagnosis of cardiac sarcoidosis based on Heart Rhythm Society criteria and VT who underwent CA. In 23 (74%) patients, preprocedure cardiac magnetic resonance imaging and positron emission tomographic (PET) evaluation were performed. Preprocedure magnetic resonance imaging was positive for late gadolinium enhancement in 21 of 23 (91%) patients, whereas abnormal 18-fluorodeoxyglucose uptake was found in 15 of 23 (65%) cases. In 14 of 15 patients with positive PET at baseline, PET was repeated after 6.1±3.7-month follow-up. After a median follow-up of 2.5 (range, 0–10.5) years, 1 (3%) patient died and 4 (13%) underwent heart transplant. Overall VT-free survival was 55% at 2-year follow-up. Among the 16 (52%) patients with VT recurrences, CA resulted in a significant reduction of VT burden, with 8 (50%) having only isolated (1–3) VT episodes and only 1 patient with recurrent VT storm. The presence of late gadolinium enhancement at magnetic resonance imaging, a positive PET at baseline, and lack of PET improvement over follow-up were associated with increased risk of recurrent VT.

Conclusions—
In patients with cardiac sarcoidosis and VT, CA is effective in achieving long-term freedom from VT or improvement in VT burden in the majority of patients. The presence of late gadolinium enhancement at magnetic resonance imaging, a positive PET scan at baseline, or lack of improvement at repeat PET over follow-up predict worse arrhythmia-free survival.