bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastrointestinal Bleeding With Edoxaban Versus Warfarin
Authors: Aisenberg James , Chatterjee-Murphy Prapti , Friedman Flack Kathryn , Weitz Jeffrey I. , Ruff Christian T. , Nordio Francesco , Mercuri Michele F. , Choi Youngsook , Antman Elliott M. , Braunwald Eugene , Giugliano Robert P. 
Published: May 2018

Background:
The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction) compared higher-dose edoxaban regimen (HD-ER) and lower-dose edoxaban regimen with well-managed warfarin in 21 105 patients with atrial fibrillation. The risk factors and clinical impact of gastrointestinal bleeding (GIB) in this trial have not been described in detail.

Methods and Results:

This analysis was undertaken to identify risk factors for major GIB (MGIB) and compare the severity and outcomes of GIB with edoxaban and warfarin. During 2.8 years mean follow-up, there were 579 MGIB (1.22% per year), of which 63 were life-threatening or fatal (0.13% per year). Male sex, increased age, prior GIB, concomitant aspirin, lower baseline hemoglobin, renal dysfunction, and higher HAS-BLED and CHADS
2
scores were independently associated with the risk of MGIB. Whereas the annual rate of MGIB was higher with HD-ER than with warfarin (1.53% and 1.25%, respectively; hazard ratio, 1.23; 95% confidence interval, 1.02–1.48;
P
=0.033), the annual rates of life-threatening or fatal GIB were similar (0.15% and 0.18%, respectively). Several indicators of more severe GIB, including hemodynamic instability, hospitalization, ≥ 4 U transfusion, and hemoglobin loss ≥5 g/dL, were similar with HD-ER and warfarin, whereas surgery required to manage bleeding was less frequent with HD-ER. Lower-dose edoxaban regimen, which achieved 50% lower trough edoxaban levels, was associated with significantly less MGIB than warfarin.

Conclusions:
MGIB occurred more frequently with HD-ER than warfarin. The rates of life-threatening or fatal GIB were low and similar with both HD-ER and warfarin. Clinical outcomes were generally favorable. The correlation between dose, trough edoxaban level, and the risk of GIB risk suggests GIB is exposure-related.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00781391.
Variation in Lipid-Lowering Therapy Use in Patients With Low-Density Lipoprotein Cholesterol ≥190 mg/dL
Authors: Virani Salim S. , Kennedy Kevin F. , Akeroyd Julia M. , Morris Pamela B. , Bittner Vera A. , Masoudi Frederick A. , Stone Neil J. , Petersen Laura A. , Ballantyne Christie M. 
Published: May 2018

Background:
Patients with low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL are at high risk of atherosclerotic cardiovascular disease events. Treatment guidelines recommend intensive treatment in these patients. Variation in the use of lipid-lowering therapies (LLTs) in these patients in a national sample of cardiology practices is not known.

Methods and Results:
Using data from the American College of Cardiology National Cardiovascular Data Registry–Practice Innovation and Clinical Excellence registry, we assessed the proportion of patients with LDL-C ≥190 mg/dL (n=49 447) receiving statin, high-intensity statin, LLT associated with ≥50% LDL-C lowering, ezetimibe, or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor between January 2013 and December 2016. We assessed practice-level rates and variation in LLT use using median rate ratio (MRR) adjusted for patient and practice characteristics. MRRs represent the likelihood that 2 random practices would differ in treatment of identical patients with LDL-C ≥190 mg/dL. The proportion of patients receiving a statin, high-intensity statin, LLT associated with ≥50% LDL-C reduction, ezetimibe, or PCSK9 inhibitor were 58.5%, 31.9%, 34.6%, 8.5%, and 1.5%, respectively. Median practice-level rates and adjusted MRR for statin (56% [interquartile range, 47.3%–64.8%]; MRR, 1.20 [95% confidence interval [CI], 1.17–1.23]), high-intensity statin (30.2% [interquartile range, 12.1%–41.1%]; MRR, 2.31 [95% CI, 2.12–2.51]), LLT with ≥50% LDL-C lowering (31.8% [interquartile range, 15.3%–45.5%]; MRR, 2.12 [95% CI, 1.95–2.28]), ezetimibe (5.8% [interquartile range, 2.8%–9.8%]; MRR, 2.42 [95% CI, 2.21–2.63]), and PCSK9 inhibitors (0.16% [interquartile range, 0%–1.9%]; MRR, 2.38 [95% CI, 2.04–2.72]) indicated significant gaps and >200% variation in receipt of several of these medications for patients across practices. Among those without concomitant atherosclerotic cardiovascular disease, even larger treatment gaps were noted (proportion of patients on a statin, high-intensity statin, LLT with ≥50% LDL-C reduction, ezetimibe, or PCSK9 inhibitor were 50.8%, 25.25%, 26.8%, 4.9%, and 0.74%, respectively).

Conclusions:
Evidence-based LLT use remains low among patients with elevated LDL-C with significant variation in care. System-level interventions are needed to address these gaps and reduce variation in care of these high-risk patients.
Complete and Partial Lecithin:Cholesterol Acyltransferase Deficiency Is Differentially Associated With Atherosclerosis
Authors: Oldoni Federico , Baldassarre Damiano , Castelnuovo Samuela , Ossoli Alice , Amato Mauro , van Capelleveen Julian , Hovingh G. Kees , De Groot Eric , Bochem Andrea , Simonelli Sara , Barbieri Simone , Veglia Fabrizio , Franceschini Guido , Kuivenhoven Jan Albert , Holleboom Adriaan G. , Calabresi Laura 
Published: May 2018

Background:
Lecithin:cholesterol acyltransferase (LCAT) is the sole enzyme that esterifies cholesterol in plasma. Its role in the supposed protection from atherogenesis remains unclear because mutations in LCAT causing fish-eye disease (FED) or familial LCAT deficiency (FLD) have been reported to be associated with more or instead less carotid atherosclerosis, respectively. This discrepancy may be associated with the loss of cholesterol esterification on only apolipoprotein AI (FED) or on both apolipoprotein AI– and apolipoprotein B–containing lipoproteins (FLD), an aspect that has thus far not been investigated.

Methods:
Seventy-four heterozygotes for LCAT mutations recruited from Italy and the Netherlands were assigned to FLD (n=33) or FED (n=41) groups and compared with 280 control subjects. Subclinical atherosclerosis was assessed with carotid intima-media thickness.

Results:

Compared with control subjects, total cholesterol was lower by 16% (−32.9 mg/dL) and 7% (−14.9 mg/dL) and high-density lipoprotein cholesterol was lower by 29% (−16.7 mg/dL) and 36% (−20.7 mg/dL) in the FLD and FED groups, respectively. Subjects with FLD displayed a significant 18% lower low-density lipoprotein cholesterol compared with subjects with FED (101.9±35.0 versus 123.6±47.4 mg/dL;
P
=0.047) and control subjects (122.6±35.0 mg/dL;
P
=0.003). Remarkably, all 3 intima-media thickness parameters were lower in subjects with FLD compared with FED and control subjects (accounting for age, sex, body mass index, smoking, hypertension, family history of cardiovascular disease, and plasma lipids). After additional correction for nationality and ultrasonographic methods, average and maximum intima-media thickness remained significantly lower when subjects with FLD were compared with those with FED (0.59 versus 0.73 mm,
P
=0.003; and 0.87 versus 1.24 mm,
P
<0.001, respectively). In contrast, the common carotid intima-media thickness (corrected for age, sex, body mass index, smoking, hypertension, family history of cardiovascular disease, and plasma lipids) was higher in subjects with FED compared with control subjects (0.69 versus 0.65 mm;
P
=0.05), but this significance was lost after adjustment for nationality and ultrasonographic machine.

Conclusions:
In this head-to-head comparison, FLD and FED mutations were shown to be associated with decreased and increased atherosclerosis, respectively. We propose that this discrepancy is related to the capacity of LCAT to generate cholesterol esters on apolipoprotein B–containing lipoproteins. Although this capacity is lost in FLD, it is unaffected in FED. These results are important when considering LCAT as a target to decrease atherosclerosis.
Prognostic Significance of the Sodium Channel Blocker Test in Patients With Brugada Syndrome
Authors: Ueoka Akira , Morita Hiroshi , Watanabe Atsuyuki , Morimoto Yoshimasa , Kawada Satoshi , Tachibana Motomi , Miyamoto Masakazu , Nakagawa Koji , Nishii Nobuhiro , Ito Hiroshi 
Published: May 2018

Background

A drug provocation test using a sodium channel blocker (
SCB
) can unmask a type 1
ECG
pattern in patients with Brugada syndrome. However, the prognostic value of the results of an
SCB
challenge is limited in patients with non–type 1
ECG
. We investigated the associations of future risk for ventricular fibrillation with
SCB
‐induced
ECG
changes and ventricular tachyarrhythmias (
VTA
s).

Methods and Results

We administered intravenous pilsicainide to 245 consecutive patients with Brugada syndrome (181 patients with spontaneous type 1
ECG
, 64 patients with non–type 1
ECG
).
ECG
parameters before and after the test and occurrence of drug‐induced
VTA
s were evaluated. During a mean follow‐up period of 113±57 months, fatal
VTA
events occurred in 31 patients (sudden death: n=3, ventricular tachycardia/
ventricular fibrillation
: n=28). Symptomatic patients and spontaneous type 1
ECG
were associated with future fatal arrhythmic events. Univariable analysis of
ECG
parameters after the test showed that long
PQ
and
QRS
intervals, high
ST
level, and
SCB
‐induced
VTA
s were associated with later
VTA
events during follow‐up. Multivariable analysis showed that symptomatic patients, high
ST
level (V1) ≥0.3
mV
after the test, and
SCB
‐induced
VTA
s were independent predictors for future fatal arrhythmic events (hazard ratios: 3.28, 2.80, and 3.62, 95% confidence intervals: 1.54–7.47, 1.32–6.35, and 1.64–7.75, respectively;
P
<0.05).

Conclusions

SCB
‐induced
VTA
s and
ST
‐segment augmentation are associated with an increased risk of the development of ventricular tachycardia/
ventricular fibrillation
events during follow‐up in patients with Brugada syndrome.
Role of Myeloid Lineage Cell Autophagy in Ischemic Brain Injury
Authors: Kotoda Masakazu , Furukawa Hajime , Miyamoto Takeshi , Korai Masaaki , Shikata Fumiaki , Kuwabara Atsushi , Xiong Xiaoxing , Rutledge Caleb , Giffard Rona G. , Hashimoto Tomoki 
Published: May 2018

Background and Purpose—
Inflammatory cells play a significant role in secondary injury after ischemic stroke. Recent studies have suggested that a lack of autophagy in myeloid cells causes augmented proinflammatory cytokine release and prolonged inflammation after tissue injury. In this study, we investigated the roles of myeloid cell autophagy in ischemic brain injury.

Methods—
Focal cerebral ischemia was induced via transient middle cerebral artery occlusion in mice with autophagy-deficient myeloid lineage cells (Atg5flox/flox LysMCre+) and in their littermate controls (Atg5flox/flox). Infarct volume, neurological function, inflammatory cell infiltration, and proinflammatory cytokine expression levels were evaluated.

Results—

Mice lacking autophagy in myeloid lineage cells had a lower survival rate for 14 days than control mice (20% versus 70%;
P
<0.05). Although there was no difference in infarct volume at 12 hours between the 2 groups, mice lacking autophagy in myeloid lineage cells had larger infarct volumes at later time points (3 and 7 days after reperfusion) with worse neurological deficit scores and lower grip test scores. There were a higher number of ionized calcium binding adaptor molecule 1-positive cells and cells expressing M1 marker CD16/32 in mice lacking autophagy in myeloid cells at the later time points. Moreover, these mice had higher expression levels of proinflammatory cytokines at later time points; however, there was no difference in ionized calcium binding adaptor molecule 1-positive cells or mRNA levels of proinflammatory cytokines at the earlier time point (12 hours after reperfusion).

Conclusions—
These data suggest that the lack of myeloid cell autophagy aggravates secondary injury by augmenting and prolonging inflammation after ischemic stroke without affecting the initial injury.
Antiplatelet Treatment After Transient Ischemic Attack and Ischemic Stroke in Patients With Cerebral Microbleeds in 2 Large Cohorts and an Updated Systematic Review
Authors: Lau Kui Kai , Lovelock Caroline E. , Li Linxin , Simoni Michela , Gutnikov Sergei , Küker Wilhelm , Mak Henry Ka Fung , Rothwell Peter M. 
Published: May 2018

Background and Purpose—
In patients with transient ischemic attack/ischemic stroke, microbleed burden predicts intracerebral hemorrhage (ICH), and ischemic stroke, but implications for antiplatelet treatment are uncertain. Previous cohort studies have had insufficient follow-up to assess the time course of risks, have not stratified risks by antithrombotic use, and have not reported extracranial bleeds or functional outcome of ICH versus ischemic stroke.

Methods—
In 2 independent prospective cohorts with transient ischemic attack/ischemic stroke (Oxford Vascular Study/mainly white; University of Hong Kong/mainly Chinese), antiplatelet treatment was started routinely irrespective of microbleed burden. Risks, time course and outcome of ICH, extracranial bleeds, and recurrent ischemic events were determined and stratified by microbleed burden (0 versus 1, 2–4, and ≥5), adjusting for age, sex, and vascular risk factors.

Results—

Microbleeds were more frequent in the Chinese cohort (450 of 1003 versus 165 of 1080;
P
<0.0001), but risk associations were similar during 7433 patient-years of follow-up. Among 1811 patients on antiplatelet drugs, risk of major extracranial bleeds was unrelated to microbleed burden (
P
trend
=0.87), but the 5-year risk of ICH was steeply related (
P
trend
<0.0001), with 11 of 15 (73%) of ICH in 140 of 1811 (7.7%) patients with ≥5 microbleeds. However, risk of ischemic stroke also increased with microbleed burden (
P
trend
=0.013), such that risk of ischemic stroke and coronary events exceeded ICH and major extracranial bleeds during the first year, even among patients with ≥5 microbleeds (11.6% versus 3.9%). However, this ratio changed over time, with risk of hemorrhage (11.2%) matching that of ischemic events (12.0%) after 1 year. Moreover, whereas the association between microbleed burden and risk of ischemic stroke was due mainly to nondisabling events (
P
trend
=0.007), the association with ICH was accounted for (
P
trend
<0.0001) by disabling/fatal events (≥5 microbleeds: 82% disabling/fatal ICH versus 40% disabling/fatal ischemic stroke;
P
=0.035).

Conclusions—
In white and Chinese patients with ≥5 microbleeds, withholding antiplatelet drugs during the first year after transient ischemic attack/ischemic stroke may be inappropriate. However, the risk of ICH may outweigh any benefit thereafter.
Intravenous Recombinant Tissue-Type Plasminogen Activator
Authors: Ferrigno Marc , Bricout Nicolas , Leys Didier , Estrade Laurent , Cordonnier Charlotte , Personnic Thomas , Kyheng Maeva , Henon Hilde 
Published: May 2018

Background and Purpose—
Intravenous thrombolysis (IVT) followed by mechanical thrombectomy (MT) improves functional outcome in patients with ischemic stroke related to proximal-vessel occlusion in the anterior circulation. Whether MT alone is as effective as IVT/MT remains controversial. We aimed at evaluating the influence of IVT in patients with large anterior circulation artery occlusion treated with MT.

Methods—
We did a prospective observational cohort study in patients with stroke related to large anterior circulation artery occlusion treated by MT who were admitted to Lille University Hospital, Lille, France. We evaluated the influence of IVT on favorable functional outcome (defined as a modified Rankin Scale score 0–2 or similar to the prestroke modified Rankin Scale) and on mortality at month 3. Between-group comparisons in outcomes were adjusted for prespecified confoundors by using a propensity score–adjusted approach.

Results—
From January 2012 to January 2017, we included 485 patients (median age, 68 years; 46% men; 348 [72%] in the IVT/MT group; 137 [28%] in the MT group). In MT group, 22% of patients had a favorable outcome versus 35% in IVT/MT group (adjusted relative risk, 1.76; 95% confidence interval, 1.23–2.55). Mortality within 3 months occurred less frequently in IVT/MT group (14% versus 32%; adjusted relative risk, 0.46; 95% confidence interval, 0.31–0.70). Successful reperfusion (Thrombolysis in Cerebral Infarction scale 2b-3) was more frequent in IVT/MT group (75% versus 60%; adjusted relative risk, 1.30; 95% confidence interval, 1.11–1.53). There was no difference between groups on hemorrhagic complications.

Conclusions—
In this population, previous IVT improved functional outcome and survival at 3 months in patients treated by MT. While waiting for randomized controlled trials, this result encourages not to avoid IVT before MT.
Marked intra-genomic variation and pseudogenes in the ITS1-5.8S-ITS2 rDNA of Symphurus plagiusa (Pleuronectiformes: Cynoglossidae)
Authors: Gong Li , Shi Wei , Yang Min , Kong Xiaoyu 
Published: May 2018

AbstractThe eukaryotic ribosomal DNA (rDNA) cluster consists of multiple copies of three genes (18S, 5.8S, and 28S rDNA) and two internal transcribed spacers (ITS1 and ITS2). In recent years, an increasing number of rDNA sequence polymorphisms have been identified in numerous species. In the present study, we provide 33 complete ITS (ITS1-5.8S-ITS2) sequences from twoSymphurus plagiusaindividuals. To the best of our knowledge, these sequences are the first detailed information on ITS sequences in Pleuronectiformes. Here, two divergent types (Type A and B) of the ITS1-5.8S-ITS2 rDNA sequence were found, which mainly differ in sequence length, GC content, nucleotide diversity (π), secondary structure and minimum free energy. The ITS1-5.8S-ITS2 rDNA sequence of Type B was speculated to be a putative pseudogene according to pseudogene identification criteria. Cluster analysis showed that sequences from the same type clustered into one group and two major groups were formed. The high degree of ITS1-5.8S-ITS2 sequence polymorphism at the intra-specific level indicated that theS. plagiusagenome has evolved in a non-concerted evolutionary manner. These results not only provide useful data for ribosomal pseudogene identification, but also further contribute to the study of rDNA evolution in teleostean genomes.
NU-WRF Aerosol Transport Simulation over West Africa: Effects of Biomass Burning on Smoke Aerosol Distribution
Authors: Iguchi Takamichi , Matsui Toshihisa , Tao Zhining , Kim Dongchul , Ichoku Charles M. , Ellison Luke , Wang Jun 
Published: May 2018

AbstractSeries of aerosol transport hindcasts for West Africa were conducted using the Weather Research and Forecasting (WRF) Model coupled to chemistry within the NASA-Unified WRF (NU-WRF) framework. The transport of biomass-burning aerosols in April and December 2009 was investigated over two types of simulation domains. One-month simulations with 9-km grid spacing for April or December 2009 covered most of North and West Africa and were evaluated by comparison with measurements of the total-column aerosol optical depth, Ångström exponent, and horizontal wind components at various pressure levels. The horizontal wind components at 700 hPa were identified as key factors in determining the transport patterns of biomass-burning aerosols from sub-Saharan West Africa to the Sahel. The vertical accumulation of biomass-burning aerosols close to 700 hPa was demonstrated in 1-day simulations with 1-km horizontal grid spacing. A new simple parameterization for the effects of heat release by biomass burning was designed for this resolution and tested together with the conventional parameterization based on fixed smoke injection heights. The aerosol vertical profiles were somewhat sensitive to the selection of parameterization, except for cases with the assumption of excessive heating by biomass burning. The new parameterization works reasonably well and offers flexibility to relate smoke transport to biomass-burning plume rise that can be correlated with the satellite fire radiative power measurements, which is advantageous relative to the conventional parameterization.
‘The Worldly Advantage It Gives … ’ Missionary Education, Migration and Intergenerational Mobility in the Long Nineteenth Century, Ceylon and Malaya 1816–1916
Authors: Wal Kristina Hodelin-ter 
Published: May 2018

During the mid-nineteenth century, many Tamils in Ceylon sent their children to Protestant missionary schools while some adults went to work for missionaries to gain education and employment. Though the ties to the Vellalar caste were strong, the gains of colonial employment and education were more influential to those of the Vellalar caste intermingling with Christian missionaries. Interaction with British and American missionaries in the early to late nineteenth century ultimately led to the migration of this group to British Malaya. Circumstances in Ceylon, as well as the drive for resources such as education and employment, led to the push away from the old colony of Ceylon to the frontier colony of Malaya. This article will showcase the agency of the Ceylonese Tamils within British Ceylon and Malaya during the late colonial era. In order to understand the clout of Ceylonese Tamils in the frontier colony of Malaya, an examination of the agency they held onto in British Ceylon is essential for review. The transfer of educational and religious networks from one colony to the other is the core of comprehending the migratory experiences and intergenerational mobility over generations in colonial to post-colonial Malaya/Malaysia. JEL: N00, Z12, Z10
Diagnostic accuracy of simplified ultrasound hand examination protocols for detection of inflammation and disease burden in patients with rheumatoid arthritis
Authors: Sivakumaran Priyanka , Hussain Sidra , Attipoe Laura , Ciurtin Coziana 
Published: May 2018

Background There is no consensus regarding the minimum number of joints that should be included in an ultrasound (US) scoring system to reliably assess for disease activity in rheumatoid arthritis (RA). Purpose To assess whether simplified US protocols for hand examination are as informative as the examination of 22 joints in patients with RA, and to correlate the US parameters with disease activity (DAS-28). Material and Methods This is a cross-sectional study of 224 RA patients stratified based on their DAS-28 scores and assessed using eight preselected US examination protocols, including 22, 18, 16, 14, ten, eight, and two different combinations of four joints, respectively. Results We found a significant difference between US hand scores regarding their ability to detect active inflammation and erosions. DAS-28 scores correlated very well with the power Doppler (PD) scores generated by all eight US examination protocols (r = 0.89–1, P < 0.05), irrespective of patients' disease activity. Simplified US scores missed information on presence of PD in 20.6–40.2% patients ( P < 0.05) and misdiagnosed non-erosive hand RA in 12–38.4% patients ( P < 0.05), depending on the number of joints excluded from US hand examination. Conclusion Preselected simplified US scores are less reliable in appreciating the disease burden when compared with an extended protocol for 22 joint US examination, raising clinicians' awareness regarding the need to comprehensively assess multiple hand joints to reliably rule out subclinical inflammation.