bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sublingual Adjuvant Delivery by a Live Attenuated Vibrio cholerae-Based Antigen Presentation Platform
Authors: Liao Julie , Gibson Jacob A. , Pickering Bradley S. , Watnick Paula I. 
Published: December 2018

Diarrheal disease is the most common infectious disease of children in the developing world. Our goal is to develop a diarrheal antigen presentation platform based on whole
Vibrio cholerae
cells that does not depend on protein purification. We have previously shown the feasibility of genetically fusing antigens to the
V. cholerae
biofilm matrix protein RbmA for presentation on the cell surface. A mucosal adjuvant could improve immunogenicity of such a vaccine at the mucosal surface. Here we engineer a live attenuated
V. cholerae
vaccine to constitutively synthesize mmCT, a nontoxic form of cholera toxin. When this vaccine is delivered sublingually,
in vivo
-synthesized mmCT acts as both an adjuvant and antigen. This could greatly increase the magnitude and duration of the immune response elicited by codelivered heterologous antigens.
Diffusion-Weighted Imaging Hyperintensities in Subtypes of Acute Intracerebral Hemorrhage
Authors: Boulanger Marion , Schneckenburger Romain , Join-Lambert Claire , Werring David J. , Wilson Duncan , Hodel Jérome , Zuber Mathieu , Touzé Emmanuel 
Published: December 2018

Background and Purpose—
Diffusion-weighted imaging (DWI) hyperintensities in intracerebral hemorrhage (ICH) are associated with increased risk of recurrent ICH, cognitive impairment, and death, but whether these lesions are specific to a subtype of ICH remains uncertain. We investigated the association between DWI lesions and ICH subtype and explored the risk factors for DWI lesions.

Methods—
In a systematic review of ICH studies, we identified those reporting prevalence of DWI lesions. Two reviewers independently assessed study eligibility and risk of bias and collected data. We determined the pooled prevalence of DWI lesions within 90 days after ICH onset for cerebral amyloid angiopathy- and hypertensive angiopathy-related ICH using random-effects meta-analysis. We calculated odds ratios to compare prevalence of DWI lesions by ICH subtype and to assess risk factors for DWI lesions.

Results—
Eleven studies (1910 patients) were included. The pooled prevalence of DWI lesions was 18.9% (95% CI, 11.1–26.7) in cerebral amyloid angiopathy- and 21.0% (95% CI, 15.3–26.6) in hypertensive angiopathy-related ICH. There was no difference in the prevalence of DWI lesions between cerebral amyloid angiopathy- (64/292 [21.9%]) and hypertensive angiopathy-related ICH (79/370 [21.4%]; odds ratio, 1.25; 95% CI, 0.73–2.15) in the 5 studies reporting data on both ICH pathogeneses. In all ICH, presence of DWI lesions was associated with neuroimaging features of microangiopathy (leukoaraiosis extension, previous ICH, and presence, and number of microbleeds) but not with vascular risk factors or the use of antithrombotic therapies.

Conclusions—
Prevalence of DWI lesions in acute ICH averages 20%, with no difference between cerebral amyloid angiopathy- and hypertensive angiopathy-related ICH. Detection of DWI lesions may add valuable information to assess the progression of the underlying microangiopathy.
Change in Cardiorespiratory Fitness and Risk of Stroke and Death
Authors: Prestgaard Erik , Mariampillai Julian , Engeseth Kristian , Erikssen Jan , Bodegård Johan , Liestøl Knut , Gjesdal Knut , Kjeldsen Sverre , Grundvold Irene , Berge Eivind 
Published: December 2018

Background and Purpose—
Low cardiorespiratory fitness is associated with increased risk of cardiovascular disease. The present study aims to assess whether change of fitness over time has any impact on long-term risk of stroke and death.

Methods—
We recruited healthy men aged 40 to 59 years in 1972 to 1975, and followed them until 2007. Physical fitness was assessed with a bicycle ECG test at baseline and again at 7 years, by dividing the total exercise work by body weight. Participants were categorized as remained fit, became unfit, remained unfit, or became fit, depending on whether fitness remained or crossed the median values from baseline to the 7-year visit. Outcome data were collected up to 35 years, from study visits, hospital records, and the National Cause of Death Registry. Risks of stroke and death were estimated by Cox regression analyses and expressed as hazard ratios (HRs) with 95% CIs.

Results—
Of 2014 participants, 1403 were assessed both at baseline and again at 7 years, and were followed for a mean of 23.6 years. Compared with the became unfit group, risk of stroke was 0.85 (0.54–1.36) for the remained unfit, 0.43 (0.28–0.67) for the remained fit, and 0.34 (0.17–0.67) for the became fit group. For all-cause death, risks were 0.99 (0.76–1.29), 0.57 (0.45–0.74), and 0.65 (0.46–0.90), respectively. Among those with high fitness at baseline, the became unfit group had a significantly higher risk of stroke (HR, 2.35; CI, 1.49–3.63) and death (HR, 1.74; CI, 1.35–2.23) than those who remained fit. Among those who had low fitness at baseline, the became fit group had a significantly lower risk of stroke (HR, 0.40; CI, 0.21–0.72) and death (HR, 0.66; CI, 0.50–0.85) than participants in the remained unfit group.

Conclusions—
Cardiorespiratory fitness at baseline and change in fitness was associated with large changes in long-term risk of stroke and death. These findings support the encouragement of regular exercise as a stroke prevention strategy.
Loss of Ribosomal RACK1 (Receptor for Activated Protein Kinase C 1) Induced by Phosphorylation at T50 Alleviates Cerebral Ischemia-Reperfusion Injury in Rats
Authors: Li Xiang , Li Jinquan , Qian Jinhong , Zhang Dongping , Shen Haitao , Li Xiang , Li Haiying , Chen Gang 
Published: December 2018

Background and Purpose—
RACK1 (receptor for activated protein kinase C 1) is an integral component of ribosomes with neuroprotective functions. The goal of this study was to determine the role of RACK1 in cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms.

Methods—
A middle cerebral artery occlusion/reperfusion model in adult male Sprague Dawley rats (250–280 g) was established, and cultured neurons were exposed to oxygen-glucose deprivation/reoxygenation to mimic I/R injury in vitro. Expression vectors encoding wild-type RACK1 and RACK1 with T50A mutation (T50A) were constructed and administered to rats by intracerebroventricular injection.

Results—
The potential role of RACK1 in cerebral I/R injury was confirmed by the decreased protein levels of RACK1 within penumbra tissue, especially of neurons. Second, there was an increase in the phosphorylation ratio of RACK1 at the threonine/serine residues at 1.5 hours after middle cerebral artery occlusion onset. Third, based on site-specific mutagenesis, we identified T50 as a key site for RACK1 phosphorylation during I/R. Fourth, wild-type RACK1 overexpression reduced infarct size, neuronal death, neuronal tissue loss, and neurobehavioral dysfunction, while RACK1 (T50A) overexpression exerted opposite effects. Finally, we found that RACK1 phosphorylation at T50 induced a loss of ribosomal RACK1, which switched RACK1 from beclin-1 translation inhibition to autophagy induction following I/R.

Conclusions—
RACK1 phosphorylation may be a potential intervention target for neurons during I/R; thus, exogenous supplementation of RACK1 may be a novel approach for ameliorating I/R injury.
Crossed Cerebellar Atrophy in Perinatal Stroke
Authors: Craig Brandon T. , Olsen Cheyanne , Mah Sarah , Carlson Helen L. , Wei Xing-Chang , Kirton Adam 
Published: December 2018

Background and Purpose—
Perinatal stroke causes most hemiparetic cerebral palsy and lifelong disability. Crossed cerebellar atrophy (CCA) is chronic cerebellar volume loss following contralateral motor pathway injury. We hypothesized that CCA is quantifiable in perinatal stroke and associated with poor motor outcome.

Methods—
Term-born children with perinatal stroke, magnetic resonance imaging beyond 6 months of age, and no additional neurological disorders were recruited. Blinded scorers measured cerebellar volumes expressed as ratios (contralesional/ipsilesional), with values <1 suggesting CCA. Motor outcomes including perinatal stroke outcome measure (PSOM) motor and cognitive scores (good/poor), Assisting Hand Assessment, and Melbourne Assessment were compared with cerebellar volume measures.

Results—

Seventy-three children met criteria (53% male). Mean cerebellar ratios were <1.0 (0.975±0.04; range, 0.885–1.079;
P
<0.001) suggesting occurrence of CCA. Cerebellar ratios did not differ between stroke types or across PSOM motor outcomes. Larger ipsilesional cerebellar volume was associated with poor PSOM cognitive outcome (
P
=0.042), possibly with poor PSOM motor outcome (
P
=0.063), and overall PSOM score (
P
=0.034).

Conclusions—
CCA occurs in perinatal stroke but is not strongly associated with motor outcome. However, ipsilesional cerebellar volume is associated with poor cognitive and overall outcomes.
Risk of Radiation-Induced Cancer From Computed Tomography Angiography Use in Imaging Surveillance for Unruptured Cerebral Aneurysms
Authors: Malhotra Ajay , Wu Xiao , Chugh Aditya , Mustafa Adel , Matouk Charles C. , Gandhi Dheeraj , Sanelli Pina 
Published: December 2018

Background and Purpose—
Although computed tomography angiography (CTA) is an excellent, noninvasive imaging modality for surveillance of intracranial aneurysms, radiation concerns have been cited to restrict its use in surveillance imaging. The goal of this study was to estimate distributions of radiation-induced central nervous system cancer incidence from CTA surveillance for intracranial aneurysms, and the impact of frequency and duration of surveillance imaging using follow-up CTAs.

Methods—
Simulation-modeling approach was performed using data on CTA associated radiation risk. We used the Radiation Risk Assessment Tool, based on the data using the BEIR VII report (BEIR VII). Each CTA was assigned as a separate exposure event. Men and women, respectively, starting surveillance imaging at 30, 40, and 50 years and receiving annual CTAs were considered as separate subgroups. As a comparison, we also calculated the radiation-induced cancer risk in the same groups of patients but receiving CTAs every 2 and 5 years, respectively.

Results—
CTA-associated excess cancer risk per exposure increases relatively more rapidly with the first 10 exposures and plateaus after the 44th exposure. On average, per CTA incurs ≈0.0026% in excess lifetime cancer risk. Receiving CTA follow-up at a younger age, more frequent follow-up, longer surveillance period, and men are the major factors contributing to an elevated excess lifetime risk. In the highest risk group, male patient receiving annual CTA follow-ups from the age of 30 years, the excess lifetime risk is 0.115% at the age of 81 years.

Conclusions—
Radiation-induced brain cancer incidence associated with unruptured intracranial aneurysm surveillance strategies using CTA is low relative to the risk for aneurysmal rupture. Further cost-effectiveness/utility analyses might help assess this risk in the context of aneurysmal ruptures prevented by surveillance imaging.
Higher Pulsatility in Cerebral Perforating Arteries in Patients With Small Vessel Disease Related Stroke, a 7T MRI Study
Authors: Geurts Lennart J. , Zwanenburg Jaco J.M. , Klijn Catharina J.M. , Luijten Peter R. , Biessels Geert Jan 
Published: December 2018

Background and Purpose—
Cerebral small vessel disease (SVD) is a major cause of stroke and dementia, but underlying disease mechanisms are still largely unknown, partly because of the difficulty in assessing small vessel function in vivo. We developed a method to measure blood flow velocity pulsatility in perforating arteries in the basal ganglia and semioval center. We aimed to determine whether this novel method could detect functional abnormalities at the level of the small vessels in patients with stroke attributable to SVD.

Methods—
We investigated 10 patients with lacunar infarction (mean age 61 years, 80% men), 11 patients with deep intracerebral hemorrhage (ICH) considered to be caused by SVD (ICH, mean age 58 years, 82% men) and 18 healthy controls that were age- and sex-matched. We performed 2-dimensional phase contrast magnetic resonance imaging at 7 T to measure time-resolved blood flow velocity in cerebral perforating arteries of the semioval center and the basal ganglia. We compared the number of detected arteries, pulsatility index and mean velocity between the patient groups and controls.

Results—

In the basal ganglia, the number of detected perforators was lower in lacunar infarction (26±9,
P
=0.01) and deep ICH patients (28±6,
P
=0.02) than in controls (35±7). The pulsatility index in the basal ganglia was higher in lacunar infarction (1.07±0.13,
P
=0.03), and deep ICH patients (1.02±0.11,
P
=0.11), than in controls (0.94±0.10). Observations in the semioval center were similar. Number of detected perforators was lower in lacunar infarction (32±18,
P
=0.06), and deep ICH patients (28±18,
P
=0.02), than in controls (45±16). The pulsatility index was higher in lacunar infarction (1.18±0.15,
P
=0.02), and deep ICH patients (1.17±0.14,
P
=0.045) than in controls (1.08±0.07). No velocity differences were detected.

Conclusions—
This exploratory study shows that SVD can be expressed in terms of functional measures, such as pulsatility index, which are derived directly from the small vessels themselves. Future studies may use this technique to further unravel the mechanisms underlying SVD.
Prognostic Significance of Plasma CLEC-2 (C-Type Lectin-Like Receptor 2) in Patients With Acute Ischemic Stroke
Authors: Zhang Xia , Zhang Wei , Wu Xuechun , Li Hui , Zhang Chunyuan , Huang Zhichao , Shi Rongfang , You Tao , Shi Jijun , Cao Yongjun 
Published: December 2018

Background and Purpose—
CLEC-2 (C-type lectin-like receptor 2) is a C-type lectin receptor highly expressed on platelets with the prominent involvement in platelet activation, which was increased in coronary heart disease. Given the role of platelet activation in ischemic stroke and the connections between coronary heart disease and ischemic stroke, CLEC-2 might be a candidate marker of ischemic stroke. Here, we aimed to examine the prognostic significance of CLEC-2 in patients with acute ischemic stroke (AIS).

Methods—
Three hundred fifty-two patients with AIS within 7 days and 112 healthy controls were prospectively studied. Plasma CLEC-2 (pCLEC-2) and some conventional risk factors of stroke were examined. Stroke progression was defined as any new neurological symptoms/signs or any neurological worsening within 7 days after stroke onset, and poor prognosis was defined as modified Rankin Scale scores >2 at 90 days. The association between pCLEC-2 and stroke progression/prognosis was evaluated using regression models.

Results—

Patients with AIS had a significantly higher level of pCLEC-2 than that of healthy controls (
P
<0.05). Patients with AIS with progressive stroke or poor prognosis had a much higher level of pCLEC-2 compared with those with stable stroke or good prognosis (all
P
<0.05). Increasing pCLEC-2 was significantly associated with an increased risk of stroke progression (odds ratio, 1.97; 95% CI, 1.11–3.50;
P
=0.021) and poor prognosis (odds ratio, 1.70; 95% CI, 1.17–2.48;
P
=0.006). Patients with the highest pCLEC-2 level were 7- to 8-fold more likely to have stroke progression compared with the lowest quartile (odds ratio, 7.69; 95% CI, 1.43–41.41). Patients with the highest pCLEC-2 level were also more likely to have poor prognosis at 90 days (odds ratio, 5.58; 95% CI, 1.76–17.68). The optimal cutoff points of pCLEC-2 for predicting stroke progression and poor prognosis were 235.48 and 207.08 pg/mL, respectively.

Conclusions—
Increased pCLEC-2 was associated with stroke progression and poor prognosis at 90 days significantly, which indicates the prognostic role of pCLEC-2 in AIS. However, it needs to be confirmed in large-scale studies.
Scoring System to Optimize Pioglitazone Therapy After Stroke Based on Fracture Risk
Authors: Viscoli Catherine M. , Kent David M. , Conwit Robin , Dearborn Jennifer L. , Furie Karen L. , Gorman Mark , Guarino Peter D. , Inzucchi Silvio E. , Stuart Amber , Young Lawrence H. , Kernan Walter N. ,   for the IRIS Trial Investigators
Published: December 2018

Background and Purpose—
The insulin sensitizer, pioglitazone, reduces cardiovascular risk in patients after an ischemic stroke or transient ischemic attack but increases bone fracture risk. We conducted a secondary analysis of the IRIS trial (Insulin Resistance Intervention After Stroke) to assess the effect of pretreatment risk for fracture on the net benefits of pioglitazone therapy.

Methods—
IRIS was a randomized placebo-controlled trial of pioglitazone that enrolled patients with insulin resistance but without diabetes mellitus within 180 days of an ischemic stroke or transient ischemic attack. Participants were recruited at 179 international centers from February 2005 to January 2013 and followed for a median of 4.8 years. Fracture risk models were developed from patient characteristics at entry. Within fracture risk strata, we quantified the effects of pioglitazone compared with placebo by estimating the relative risks and absolute 5-year risk differences for fracture and stroke or myocardial infarction.

Results—
The fracture risk model included points for age, race-ethnicity, sex, body mass index, disability, and medications. The relative increment in fracture risk with pioglitazone was similar in the lower (<median point score) and higher (≥ median point score) risk strata. However, the absolute risk difference (ARD) for fracture was less in the low-risk group (5.8% in pioglitazone group versus 4.0% in placebo group; ARD, 1.8%; 95% CI, −0.7% to 4.4%) compared with high-risk group (18.0% versus 11.6%; ARD, 6.4%; 95% CI, 3.2% to 9.6%). Reductions in risk for stroke or myocardial infarction did not vary by fracture risk (low-risk ARD, −3.7%; high-risk ARD, −3.5%). In low-risk patients, pioglitazone prevented 2.0 strokes or myocardial infarctions for each fracture caused, compared with 0.5 among those at high risk.

Conclusions—
A simple point score identifying patients at low risk for fracture may assist in selecting patients with a favorable benefit-risk profile for pioglitazone therapy after ischemic stroke or transient ischemic attack.
Outcomes After Use of Standard- and Low-Dose Non–Vitamin K Oral Anticoagulants in Asian Patients With Atrial Fibrillation
Authors: Cho Min Soo , Yun Ji Eun , Park Ji Jeong , Kim Yun Jung , Lee Jessie , Kim Hyungmin , Park Duk-Woo , Nam Gi-Byoung 
Published: December 2018

Background and Purpose—
Limited data are available describing the relative effectiveness, safety, and optimal dosing of non–vitamin K antagonist oral anticoagulants (NOACs) for treatment of nonvalvular atrial fibrillation in East Asian patients. We tried to compare effectiveness and safety outcomes of standard- and low-dose NOACs and warfarin in this population.

Methods—

Using nationwide administrative claims-based datasets from the Korean National Health Insurance Service Database (July 1, 2015, to December 31, 2016), this study comprised 56 504 anticoagulation-naive nonvalvular atrial fibrillation patients with high thromboembolic risk (CHA
2
DS
2
-VASc score, ≥2) treated with oral anticoagulants. Main study outcomes included thromboembolic events (ischemic stroke or systemic embolism), major bleeding, and mortality.

Results—
Among the study patients, 10 409 (18.4%) received warfarin and 46 095 (81.6%) were treated with NOACs: dabigatran (n=12 593; 22.3%), rivaroxaban (n=21 000; 37.2%), and apixaban (n=12 502; 22.1%). Low-dose NOAC (75.1% dabigatran, 59.7% rivaroxaban, and 62.7% apixaban) was more frequently used than standard-dose NOAC. During median follow-up of 15.0 months, each NOAC was associated with significantly lower risk of thromboembolic events (hazard ratio [HR], 0.76; 95% CI, 0.75–0.81 for dabigatran; HR, 0.74; 95% CI, 0.65–0.83 for rivaroxaban; and HR, 0.68; 95% CI, 0.59–0.78 for apixaban). Regarding safety outcomes, dabigatran (HR, 0.81; CI, 0.69–0.95) and apixaban (HR, 0.67; CI, 0.56–0.79) were associated with lower risk of major bleeding but not with rivaroxaban (HR, 0.96; CI, 0.84–1.11). Among adults <75 years of age without chronic kidney disease, use of low-dose apixaban did not demonstrate clinical benefit over warfarin with respect to thromboembolic events (HR, 0.99; CI, 0.76–1.28) and mortality (HR, 0.85; CI, 0.62–1.16).

Conclusions—
In this cohort of East Asian patients with nonvalvular atrial fibrillation, NOACs were associated with better effectiveness and safety outcomes versus warfarin. Lower NOAC doses were more often used, but an unjustified underdosing of apixaban seems to result in lower clinical benefit.
Stroke and Cerebrovascular Disease in Pregnancy
Authors: Liu Shiliang , Chan Wee-Shian , Ray Joel G. , Kramer Michael S. , Joseph K.S. ,   for the Canadian Perinatal Surveillance System (Public Health Agency of Canada)
Published: December 2018

Background and Purpose—
Few studies have examined the epidemiology of stroke in pregnancy, despite the high associated burden of death and disability. We aimed to quantify the incidence, temporal trends, risk factors, and case fatality associated with stroke and cerebrovascular disease in pregnancy.

Methods—
All antepartum, peripartum, and postpartum hospitalizations and readmissions within 42 days of delivery in Canada (except Quebec) were obtained from the Canadian Institute of Health Information for the years 2003 to 2016. We assessed temporal trends in stroke and quantified associated risk factors using logistic regression.

Results—

Five hundred twenty-four stroke cases were identified among 3 907 262 deliveries (13.4 per 100 000). The majority of cases were hemorrhagic strokes (307 cases, 58.6%) and most occurred in the postpartum period (270 cases, 51.5%). The case fatality rate was 7.4%. Stroke incidence rose from 10.8 per 100 000 in 2003 to 2004 to 16.6 per 100 000 deliveries in 2015 to 2016 (
P
=0.002). Risk factors for stroke included older maternal (age ≥40 years; adjusted odds ratio [AOR], 1.7; 95% CI, 1.1–2.6), preeclampsia (AOR, 7.1; 95% CI, 5.3–9.6), eclampsia (AOR, 65.9; 95% CI, 43.6–99.6), maternal congenital heart disease (AOR, 38.1; 95% CI, 22.1–65.8), connective tissue disorders (AOR, 12.6; 95% CI, 6.1–26.9), sepsis (AOR, 7.6; 95% CI, 3.6–16.2), severe postpartum hemorrhage (AOR, 4.7; 95% CI, 2.8–8.0), and thrombophilia (AOR, 4.2; 95% CI, 1.5–12.1).

Conclusions—
The rising incidence of stroke in pregnancy, especially during the postpartum period, and its strong association with hypertensive disorders of pregnancy (especially preeclampsia) suggest that follow-up of severe hypertensive patients is required after delivery.