bluuebunny/crossref_metadata_2025 huggingface dataset:
Aortic Valve Stenosis
Authors: Goody Philip Roger , Hosen Mohammed Rabiul , Christmann Dominik , Niepmann Sven Thomas , Zietzer Andreas , Adam Matti , Bönner Florian , Zimmer Sebastian , Nickenig Georg , Jansen Felix
Published: March 2020

Aortic valve stenosis is the most prevalent heart valve disease worldwide. Although interventional treatment options have rapidly improved in recent years, symptomatic aortic valve stenosis is still associated with high morbidity and mortality. Calcific aortic valve stenosis is characterized by a progressive fibro-calcific remodeling and thickening of the aortic valve cusps, which subsequently leads to valve obstruction. The underlying pathophysiology is complex and involves endothelial dysfunction, immune cell infiltration, myofibroblastic and osteoblastic differentiation, and, subsequently, calcification. To date, no pharmacotherapy has been established to prevent aortic valve calcification. However, novel promising therapeutic targets have been recently identified. This review summarizes the current knowledge of pathomechanisms involved in aortic valve calcification and points out novel treatment strategies.
Mechanisms of Arterial Stiffening
Authors: Lacolley Patrick , Regnault Véronique , Laurent Stéphane
Published: March 2020

Arterial stiffness is a major independent risk factor for cardiovascular complications causing isolated systolic hypertension and increased pulse pressure in the microvasculature of target organs. Stiffening of the arterial wall is determined by common mechanisms including reduced elastin/collagen ratio, production of elastin cross-linking, reactive oxygen species–induced inflammation, calcification, vascular smooth muscle cell stiffness, and endothelial dysfunction. This brief review will discuss current biological mechanisms by which other cardiovascular risk factors (eg, aging, hypertension, diabetes mellitus, and chronic kidney disease) cause arterial stiffness, with a particular focus on recent advances regarding nuclear mechanotransduction, mitochondrial oxidative stress, metabolism and dyslipidemia, genome mutations, and epigenetics. Targeting these different molecular pathways at different time of cardiovascular risk factor exposure may be a novel approach for discovering drugs to reduce arterial stiffening without affecting artery strength and normal remodeling.
Activated Platelets Induce Endothelial Cell Inflammatory Response in Psoriasis via COX-1
Authors: Garshick Michael S. , Tawil Michael , Barrett Tessa J. , Salud-Gnilo Charissa M. , Eppler Michael , Lee Angela , Scher Jose U. , Neimann Andrea L. , Jelic Sanja , Mehta Nehal N. , Fisher Edward A. , Krueger James G. , Berger Jeffrey S.
Published: March 2020

Objective:

Patients with psoriasis have impaired vascular health and increased cardiovascular disease (CVD). Platelets are key players in the pathogenesis of vascular dysfunction in cardiovascular disease and represent therapeutic targets in cardiovascular prevention. The object of this study was to define the platelet phenotype and effector cell properties on vascular health in psoriasis and evaluate whether aspirin modulates the platelet-induced phenotype.

Approach and Results:

Platelets from psoriasis patients (n=45) exhibited increased platelet activation (relative to age- and gender-matched controls, n=18), which correlated with psoriasis skin severity. Isolated platelets from psoriasis patients demonstrated a 2- to 3-fold (
P
<0.01) increased adhesion to human aortic endothelial cells and induced proinflammatory transcriptional changes, including upregulation of
IL 8
(interleukin 8),
IL1β
, and Cox (cyclooxygenase)-2 Platelet RNA sequencing revealed an interferon signature and elevated expression of
COX-1
, which correlated with psoriasis disease severity (
r
=0.83,
P
=0.01). In a randomized trial of patients with psoriasis, 2 weeks of 81 mg low-dose aspirin, a COX-1 inhibitor, reduced serum thromboxane (Tx) B
2
and reduced brachial vein endothelial proinflammatory transcript expression >70% compared with the no-treatment group (
P
<0.01). Improvement in brachial vein endothelial cell inflammation significantly correlated with change in serum TxB
2
(
r
=0.48,
P
=0.02).

Conclusions:

In patients with psoriasis, platelets are activated and induce endothelial cell inflammation. Low-dose aspirin improved endothelial cell health in psoriasis via platelet COX-1 inhibition. These data demonstrate a previously unappreciated role of platelets in psoriasis and endothelial cell inflammation and suggests that aspirin may be effective in improving vascular health in patients with psoriasis.

Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT03228017.
Untargeted Lipidomics Reveals a Specific Enrichment in Plasmalogens in Epicardial Adipose Tissue and a Specific Signature in Coronary Artery Disease
Authors: Barchuk Magali , Dutour Anne , Ancel Patricia , Svilar Ljubica , Miksztowicz Veronica , Lopez Graciela , Rubio Miguel , Schreier Laura , Nogueira Juan Patricio , Valéro René , Béliard Sophie , Martin Jean Charles , Berg Gabriela , Gaborit Bénédicte
Published: March 2020

Objective:

Epicardial adipose tissue (EAT) is an active endocrine organ that could contribute to the pathophysiology of coronary artery disease (CAD) through the paracrine release of proatherogenic mediators. Numerous works have analyzed the inflammatory signature of EAT, but scarce informations on its lipidome are available. Our objective was first to study the differences between EAT and subcutaneous adipose tissue (SAT) lipidomes and second to identify the specific untargeted lipidomic signatures of EAT and SAT in CAD.

Approach and Results:

Subcutaneous and EAT untargeted lipidomic analysis was performed in 25 patients with CAD and 14 patients without CAD and compared with paired plasma lipidomic analysis of isolated VLDL (very low-density lipoprotein) and HDL (high-density lipoprotein). Lipidomics was performed on a C18 column hyphenated to a Q-Exactive plus mass spectrometer, using both positive and negative ionization mode. EAT and SAT had independent lipidomic profile, with 95 lipid species differentially expressed and phosphatidylethanolamine 18:1p/22:6 twenty-fold more expressed in EAT compared with SAT false discovery rate =3×10
−4
). Patients with CAD exhibited more ceramides (
P
=0.01), diglycerides (
P
=0.004; saturated and nonsaturated), monoglycerides (
P
=0.013) in their EAT than patients without CAD. Conversely, they had lesser unsaturated TG (triglycerides;
P
=0.02). No difference was observed in the 295 lipid species found in SAT between patients with and without CAD. Fifty-one lipid species were found in common between EAT and plasma lipoproteins. TG 18:0/18:0/18:1 was found positively correlated (
r
=0.45,
P
=0.019) in EAT and HDL and in EAT and VLDL (
r
=0.46,
P
=0.02).

Conclusions:

CAD is associated with specific lipidomic signature of EAT, unlike SAT. Plasma lipoprotein lipidome only partially reflected EAT lipidome.
Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes
Authors: Tazmini Kiarash , Frisk Michael , Lewalle Alexandre , Laasmaa Martin , Morotti Stefano , Lipsett David B. , Manfra Ornella , Skogestad Jonas , Aronsen Jan M. , Sejersted Ole M. , Sjaastad Ivar , Edwards Andrew G. , Grandi Eleonora , Niederer Steven A. , Øie Erik , Louch William E.
Published: March 2020

Rationale:

Hypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes.

Objective:

To investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes.

Methods and Results:

Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K
+
] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca
2+
overload and increased generation of both spontaneous Ca
2+
waves and delayed afterdepolarizations. However, similar Ca
2+
-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na
+
-K
+
ATPase and Na
+
-Ca
2+
exchanger proteins within these structures, as reduction in Na
+
pump activity locally inhibited Ca
2+
extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca
2+
overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca
2+
quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na
+
current, as they were rapidly blocked by tetrodotoxin. Na
+
current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K
+
current (I
Kur
); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes.

Conclusions:

Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology.
Celastrol Attenuates Angiotensin II–Induced Cardiac Remodeling by Targeting STAT3
Authors: Ye Shiju , Luo Wu , Khan Zia A. , Wu Gaojun , Xuan Lina , Shan Peiren , Lin Ke , Chen Taiwei , Wang Jingying , Hu Xiang , Wang Shengjie , Huang Weijian , Liang Guang
Published: March 2020

Rationale:

Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II–induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure.

Objective:

We have examined the potential effect of celastrol—a bioactive compound derived from the Celastraceae family—on Ang II–induced cardiac dysfunction.

Methods and Results:

In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II–induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II–challenged and transverse aortic constriction–challenged mice by inhibiting cardiac fibrosis and hypertrophy.

Conclusions:

Our studies show that celastrol inhibits Ang II–induced cardiac dysfunction by inhibiting STAT3 activity.
Nfatc1 Promotes Interstitial Cell Formation During Cardiac Valve Development in Zebrafish
Authors: Gunawan Felix , Gentile Alessandra , Gauvrit Sébastien , Stainier Didier Y.R. , Bensimon-Brito Anabela
Published: March 2020

Rationale:

The transcription factor NFATC1 (nuclear factor of activated T-cell 1) has been implicated in cardiac valve formation in humans and mice, but we know little about the underlying mechanisms. To gain mechanistic understanding of cardiac valve formation at single-cell resolution and insights into the role of NFATC1 in this process, we used the zebrafish model as it offers unique attributes for live imaging and facile genetics.

Objective:

To understand the role of Nfatc1 in cardiac valve formation.

Methods and Results:

Using the zebrafish atrioventricular valve, we focus on the valve interstitial cells (VICs), which confer biomechanical strength to the cardiac valve leaflets. We find that initially atrioventricular endocardial cells migrate collectively into the cardiac jelly to form a bilayered structure; subsequently, the cells that led this migration invade the ECM (extracellular matrix) between the 2 endocardial cell monolayers, undergo endothelial-to-mesenchymal transition as marked by loss of intercellular adhesion, and differentiate into VICs. These cells proliferate and are joined by a few neural crest–derived cells. VIC expansion and a switch from a promigratory to an elastic ECM drive valve leaflet elongation. Functional analysis of Nfatc1 reveals its requirement during VIC development. Zebrafish
nfatc1
mutants form significantly fewer VICs due to reduced proliferation and impaired recruitment of endocardial and neural crest cells during the early stages of VIC development. With high-speed microscopy and echocardiography, we show that reduced VIC formation correlates with valvular dysfunction and severe retrograde blood flow that persist into adulthood. Analysis of downstream effectors reveals that Nfatc1 promotes the expression of
twist1b
—a well-known regulator of epithelial-to-mesenchymal transition.

Conclusions:

Our study sheds light on the function of Nfatc1 in zebrafish cardiac valve development and reveals its role in VIC formation. It also further establishes the zebrafish as a powerful model to carry out longitudinal studies of valve formation and function.
Phosphoproteomic Analysis of Neonatal Regenerative Myocardium Revealed Important Roles of Checkpoint Kinase 1 via Activating Mammalian Target of Rapamycin C1/Ribosomal Protein S6 Kinase b-1 Pathway
Authors: Fan Yi , Cheng Yiwei , Li Yafei , Chen Bingrui , Wang Zimu , Wei Tianwen , Zhang Hao , Guo Yueshuai , Wang Qiming , Wei Yongyue , Chen Feng , Sha Jiahao , Guo Xuejiang , Wang Liansheng
Published: March 2020

Background:

In mammals, regenerative therapy after myocardial infarction is hampered by the limited regenerative capacity of adult heart, whereas a transient regenerative capacity is maintained in the neonatal heart. Systemic phosphorylation signaling analysis on ischemic neonatal myocardium might be helpful to identify key pathways involved in heart regeneration. Our aim was to define the kinase-substrate network in ischemic neonatal myocardium and to identify key pathways involved in heart regeneration after ischemic insult.

Methods:

Quantitative phosphoproteomics profiling was performed on infarct border zone of neonatal myocardium, and kinase-substrate network analysis revealed 11 kinases with enriched substrates and upregulated phosphorylation levels, including checkpoint kinase 1 (CHK1) kinase. The effect of CHK1 on cardiac regeneration was tested on Institute of Cancer Research CD1 neonatal and adult mice that underwent apical resection or myocardial infarction.

Results:

In vitro, CHK1 overexpression promoted whereas CHK1 knockdown blunted cardiomyocyte proliferation. In vivo, inhibition of CHK1 hindered myocardial regeneration on resection border zone in neonatal mice. In adult myocardial infarction mice, CHK1 overexpression on infarct border zone upregulated mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway, promoted cardiomyocyte proliferation, and improved cardiac function. Inhibiting mammalian target of rapamycin activity by rapamycin blunted the neonatal cardiomyocyte proliferation induced by CHK1 overexpression in vitro.

Conclusions:

Our study indicates that phosphoproteome of neonatal regenerative myocardium could help identify important signaling pathways involved in myocardial regeneration. CHK1 is found to be a key signaling responsible for neonatal regeneration. Myocardial overexpression of CHK1 could improve cardiac regeneration in adult hearts by activating the mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway. Thus, CHK1 might serve as a potential novel target in myocardial repair after myocardial infarction.
Evidence From Family Studies for Autoimmunity in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Caforio Alida L.P. , Re Federica , Avella Andrea , Marcolongo Renzo , Baratta Pasquale , Seguso Mara , Gallo Nicoletta , Plebani Mario , Izquierdo-Bajo Alvaro , Cheng Chun-Yan , Syrris Petros , Elliott Perry M. , d’Amati Giulia , Thiene Gaetano , Basso Cristina , Gregori Dario , Iliceto Sabino , Zachara Elisabetta
Published: March 2020

Background:

Serum anti-heart autoantibodies (AHAs) and anti-intercalated disk autoantibodies (AIDAs) are autoimmune markers in myocarditis. Myocarditis has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC). To provide evidence for autoimmunity, we searched for AHAs and AIDAs in ARVC.

Methods:

We studied: 42 ARVC probands, 23 male, aged 42, interquartile range 33–49, 20 from familial and 22 nonfamilial pedigrees; 37 clinically affected relatives (ARs), 24 male aged 35, interquartile range 18–46; and 96 healthy relatives, 49 male, aged 27, interquartile range 17–45. Serum AHAs and AIDAs were tested by indirect immunofluorescence on human myocardium and skeletal muscle in 171 of the 175 ARVC individuals and in controls with noninflammatory cardiac disease (n=160), ischemic heart failure (n=141), and healthy blood donors (n=270). Screening of 5 desmosomal genes was performed in probands; when a sequence variant was identified, cascade family screening followed, blind to immunologic results.

Results:

AHA frequency was higher (36.8%) in probands, ARs (37.8%), and healthy relatives (25%) than in noninflammatory cardiac disease (1%), ischemic heart failure (1%), or healthy blood donors (2.5%;
P
=0.0001). AIDA frequency was higher in probands (8%,
P
=0.006), in ARs (21.6%,
P
=0.00001), and in healthy relatives (14.6%,
P
=0.00001) than in noninflammatory cardiac disease (3.75%), ischemic heart failure (2%), or healthy blood donors (0.3%). AHA-positive status was associated with higher frequency of palpitation (
P
=0.004), implantable cardioverter defibrillator implantation (
P
=0.021), lower left ventricular ejection fraction (
P
=0.004), AIDA-positive status with both lower right ventricular and left ventricular ejection fractions (
P
=0.027 and
P
=0.027, respectively). AHA- and/or AIDA-positive status in the proband and at least one of the respective relatives was more common in familial (17/20, 85%) than in sporadic (10/22, 45%) pedigrees (
P
=0.007).

Conclusions:

The presence of AHAs and AIDAs provides evidence of autoimmunity in the majority of familial and in almost half of sporadic ARVC. In probands and in ARs, these antibodies were associated with features of disease severity. Longitudinal studies are needed to clarify whether they may predict ARVC development in healthy relatives or if they be a result of manifest ARVC.
Low-Attenuation Noncalcified Plaque on Coronary Computed Tomography Angiography Predicts Myocardial Infarction
Authors: Williams Michelle C. , Kwiecinski Jacek , Doris Mhairi , McElhinney Priscilla , D’Souza Michelle S. , Cadet Sebastien , Adamson Philip D. , Moss Alastair J. , Alam Shirjel , Hunter Amanda , Shah Anoop S.V. , Mills Nicholas L. , Pawade Tania , Wang Chengjia , Weir McCall Jonathan , Bonnici-Mallia Michael , Murrills Christopher , Roditi Giles , van Beek Edwin J.R. , Shaw Leslee J. , Nicol Edward D. , Berman Daniel S. , Slomka Piotr J. , Newby David E. , Dweck Marc R. , Dey Damini
Published: March 2020

Background:

The future risk of myocardial infarction is commonly assessed using cardiovascular risk scores, coronary artery calcium score, or coronary artery stenosis severity. We assessed whether noncalcified low-attenuation plaque burden on coronary CT angiography (CCTA) might be a better predictor of the future risk of myocardial infarction.

Methods:

In a post hoc analysis of a multicenter randomized controlled trial of CCTA in patients with stable chest pain, we investigated the association between the future risk of fatal or nonfatal myocardial infarction and low-attenuation plaque burden (% plaque to vessel volume), cardiovascular risk score, coronary artery calcium score or obstructive coronary artery stenoses.

Results:

In 1769 patients (56% male; 58±10 years) followed up for a median 4.7 (interquartile interval, 4.0–5.7) years, low-attenuation plaque burden correlated weakly with cardiovascular risk score (
r
=0.34;
P
<0.001), strongly with coronary artery calcium score (
r
=0.62;
P
<0.001), and very strongly with the severity of luminal coronary stenosis (area stenosis,
r
=0.83;
P
<0.001). Low-attenuation plaque burden (7.5% [4.8–9.2] versus 4.1% [0–6.8];
P
<0.001), coronary artery calcium score (336 [62–1064] versus 19 [0–217] Agatston units;
P
<0.001), and the presence of obstructive coronary artery disease (54% versus 25%;
P
<0.001) were all higher in the 41 patients who had fatal or nonfatal myocardial infarction. Low-attenuation plaque burden was the strongest predictor of myocardial infarction (adjusted hazard ratio, 1.60 (95% CI, 1.10–2.34) per doubling;
P
=0.014), irrespective of cardiovascular risk score, coronary artery calcium score, or coronary artery area stenosis. Patients with low-attenuation plaque burden greater than 4% were nearly 5 times more likely to have subsequent myocardial infarction (hazard ratio, 4.65; 95% CI, 2.06–10.5;
P
<0.001).

Conclusions:

In patients presenting with stable chest pain, low-attenuation plaque burden is the strongest predictor of fatal or nonfatal myocardial infarction. These findings challenge the current perception of the supremacy of current classical risk predictors for myocardial infarction, including stenosis severity.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01149590.
Association of Intensive Lifestyle Intervention, Fitness, and Body Mass Index With Risk of Heart Failure in Overweight or Obese Adults With Type 2 Diabetes Mellitus
Authors: Pandey Ambarish , Patel Kershaw V. , Bahnson Judy L. , Gaussoin Sarah A. , Martin Corby K. , Balasubramanyam Ashok , Johnson Karen C. , McGuire Darren K. , Bertoni Alain G. , Kitzman Dalane , Berry Jarett D. ,   Look AHEAD Research Group
Published: March 2020

Background:

Type 2 diabetes mellitus (T2DM) is associated with a higher risk for heart failure (HF). The impact of a lifestyle intervention and changes in cardiorespiratory fitness (CRF) and body mass index on risk for HF is not well established.

Methods:

Participants from the Look AHEAD trial (Action for Health in Diabetes) without prevalent HF were included. Time-to-event analyses were used to compare the risk of incident HF between the intensive lifestyle intervention and diabetes support and education groups. The associations of baseline measures of CRF estimated from a maximal treadmill test, body mass index, and longitudinal changes in these parameters with risk of HF were evaluated with multivariable adjusted Cox models.

Results:

Among the 5109 trial participants, there was no significant difference in the risk of incident HF (n=257) between the intensive lifestyle intervention and the diabetes support and education groups (hazard ratio, 0.96 [95% CI, 0.75–1.23]) over a median follow-up of 12.4 years. In the most adjusted Cox models, the risk of HF was 39% and 62% lower among moderate fit (tertile 2: hazard ratio, 0.61 [95% CI, 0.44–0.83]) and high fit (tertile 3: hazard ratio, 0.38 [95% CI, 0.24–0.59]) groups, respectively (referent group: low fit, tertile 1). Among HF subtypes, after adjustment for traditional cardiovascular risk factors and interval incidence of myocardial infarction, baseline CRF was not significantly associated with risk of incident HF with reduced ejection fraction. In contrast, the risk of incident HF with preserved ejection fraction was 40% lower in the moderate fit group and 77% lower in the high fit group. Baseline body mass index also was not associated with risk of incident HF, HF with preserved ejection fraction, or HF with reduced ejection fraction after adjustment for CRF and traditional cardiovascular risk factors. Among participants with repeat CRF assessments (n=3902), improvements in CRF and weight loss over a 4-year follow-up were significantly associated with lower risk of HF (hazard ratio per 10% increase in CRF, 0.90 [95% CI, 0.82–0.99]; per 10% decrease in body mass index, 0.80 [95% CI, 0.69–0.94]).

Conclusions:

Among participants with type 2 diabetes mellitus in the Look AHEAD trial, the intensive lifestyle intervention did not appear to modify the risk of HF. Higher baseline CRF and sustained improvements in CRF and weight loss were associated with lower risk of HF.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00017953.
Redefined Measure of Early Neurological Improvement Shows Treatment Benefit of Alteplase Over Placebo
Authors: Agarwal Shashank , Scher Erica , Lord Aaron , Frontera Jennifer , Ishida Koto , Torres Jose , Rostanski Sara , Mistry Eva , Mac Grory Brian , Cutting Shawna , Burton Tina , Silver Brian , Liberman Ava L. , Lerario Mackenzie P. , Furie Karen , Grotta James , Khatri Pooja , Saver Jeffrey , Yaghi Shadi
Published: March 2020

Background and Purpose—

The first of the 2 NINDS (National Institute of Neurological Disorders and Stroke) Study trials did not show a significant increase in early neurological improvement, defined as National Institutes of Health Stroke Scale (NIHSS) improvement by ≥4, with alteplase treatment. We hypothesized that early neurological improvement defined as a percentage change in NIHSS (percent change NIHSS) at 24 hours is superior to other definitions in predicting 3-month functional outcomes and using this definition there would be treatment benefit of alteplase over placebo at 24 hours.

Methods—

We analyzed the NINDS rt-PA Stroke Study (Parts 1 and 2) trial data. Percent change NIHSS was defined as ([admission NIHSS score−24-hour NIHSS score]×100/admission NIHSS score] and delta NIHSS as (admission NIHSS score−24-hour NIHSS score). We compared early neurological improvement using these definitions between alteplase versus placebo patients. We also used receiver operating characteristic curve to determine the predictive association of early neurological improvement with excellent 3-month functional outcomes (Barthel Index score of 95–100 and modified Rankin Scale score of 0–1), good 3-month functional outcome (modified Rankin Scale score of 0–2), and 3-month infarct volume.

Results—

There was a significantly greater improvement in the 24-hour median percent change NIHSS among patients treated with alteplase compared with the placebo group (28% versus 15%;
P
=0.045) but not median delta NIHSS (3 versus 2;
P
=0.471). Receiver operating characteristic curve comparison showed that percent change NIHSS (ROC
percent
) was better than delta NIHSS (ROC
delta
) and admission NIHSS (ROC
admission
) with regards to excellent 3-month Barthel Index (ROC
percent
, 0.83; ROC
delta
, 0.76; ROC
admission
, 0.75), excellent 3-month modified Rankin Scale (ROC
percent
, 0.83; ROC
delta
, 0.74; ROC
admission
, 0.78), and good 3-month modified Rankin Scale (ROC
percent
, 0.83; ROC
delta
, 0.76; ROC
admission
, 0.78).

Conclusions—

In the NINDS rt-PA trial, alteplase was associated with a significant percent change improvement in NIHSS at 24 hours. Percent change in NIHSS may be a better surrogate marker of thrombolytic activity and 3-month outcomes.
Dabigatran Treatment of Acute Noncardioembolic Ischemic Stroke
Authors: Butcher Ken S. , Ng Kelvin , Sheridan Patrick , Field Thalia S. , Coutts Shelagh B. , Siddiqui Muzzafar , Gioia Laura C. , Buck Brian , Hill Michael D. , Miller Jodi , Klahr Ana C. , Sivakumar Leka , Benavente Oscar R. , Hart Robert G. , Sharma Mike
Published: March 2020

Background and Purpose—

Patients with transient ischemic attack (TIA) and minor ischemic stroke are at risk for early recurrent cerebral ischemia. Anticoagulants are associated with reduced recurrence but also increased hemorrhagic transformation (HT). The safety of the novel oral anticoagulant dabigatran in acute stroke has not been evaluated.

Methods—

DATAS II (Dabigatran Treatment of Acute Stroke II) was a phase II prospective, randomized open label, blinded end point trial. Patients with noncardioembolic stroke/transient ischemic attack (National Institutes of Health Stroke Scale score, ≤9; infarct volume, ≤25 mL) were randomized to dabigatran or aspirin. Magnetic resonance imaging was performed before randomization and repeated at day 30. Imaging end points were ascertained centrally by readers blinded to treatment. The primary end point was symptomatic HT within 37 days of randomization.

Results—

A total of 305 patients, mean age 66.59±13.21 years, were randomized to dabigatran or aspirin a mean of 42.00±17.31 hours after symptom onset. The qualifying event was a transient ischemic attack in 21%, and ischemic stroke in 79% of patients. Median National Institutes of Health Stroke Scale (interquartile range) was 1 (0–2), and mean infarct volume 3.2±6.5 mL. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (relative risk, 2.301 [95% CI, 0.778–6.802]). Baseline infarct volume predicted incident HT (odds ratio, 1.07 [95% CI, 1.03–1.12];
P
=0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran-assigned and 14/142 (9.8%) of aspirin-assigned patients (relative risk, 0.62 [95% CI, 0.26, 1.48]).

Conclusions—

Dabigatran was associated with a risk of HT similar to aspirin in acute minor noncardioembolic ischemic stroke/transient ischemic attack.

Registration—

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02295826.
Selective Serotonin Reuptake Inhibitors and Intracerebral Hemorrhage Risk and Outcome
Authors: Liu Li , Fuller Matthew , Behymer Tyler P. , Ng Yisi , Christianson Thomas , Shah Shreyansh , King Nicolas Kon Kam , Woo Daniel , James Michael L.
Published: March 2020

Background and Purpose—

Selective serotonin reuptake inhibitors (SSRIs) have a well-established association with bleeding complications and conflicting reports on outcome after stroke. We sought to evaluate whether pre–intracerebral hemorrhage (ICH) SSRI use increased ICH risk and post-ICH SSRI use improved ICH outcome.

Methods—

Through post hoc analysis of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage), SSRI use was categorized into no use, pre-ICH only, pre- and post-ICH use (termed “continuous”), and post-ICH only (termed “new”). Using multivariable modeling, associations were sought between pre-ICH SSRI use and ICH risk in the case-control set, and associations between post-ICH SSRI use and 3-month outcome were analyzed in the ICH case set. Exploratory analyses sought to assess influence of race/ethnicity in models.

Results—

The final study cohort consisted of 2287 ICH cases and 2895 controls. Pre-ICH SSRI use was not associated with ICH risk (odds ratio, 0.824 [95% CI, 0.632–1.074]) nor potentiation of ICH risk with anticoagulant or antiplatelet use. New post-ICH SSRI use was associated with unfavorable modified Rankin Scale score at 3 months after ICH (odds ratio, 1.673 [95% CI, 1.162–2.408];
P
=0.006) in multivariable analyses. Additional propensity score analysis indicated a similar trend but did not reach statistical significance (
P
=0.107). When stratified by race/ethnicity, multivariable modeling demonstrated reduced ICH risk with pre-ICH SSRI use in Hispanics (odds ratio, 0.513 [95% CI, 0.301–0.875];
P
=0.014), but not non-Hispanic whites or blacks, and no associations between post-ICH SSRI use and 3-month outcome in any racial/ethnic group.

Conclusions—

In a large multiethnic cohort, pre-ICH SSRI use was not associated with increased ICH risk, but post-ICH SSRI use was associated with unfavorable 3-month neurological outcome after ICH.

Registration—

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01202864.
SELECTION OF FUEL SUPPLIER FOR TRANSPORT FIRMS BY USING THE AHP
Authors: GÖRÇÜN Ömer Faruk
Published: March 2020

Selection of proper fuel supplier is extremely important for companies that carry out transportation activities and it can be evaluated as a critical decision to obtain competitive advantages in the transportation market. A structural and systematic frame is suggested in this paper in order to solve the decision problems for fuel supplier selection. In order to determine the selection criteria, the board of experts was constructed and a large number of roundtable meetings that realized in the way of brainstorm were organized with them. One of the most important questions can be asked as what are the selection criteria and decision options for the fuel supplier selection process? Experts who are a decision maker in their companies tried to seek a rational answer to this question. At the end of these meetings, obtained results were re-evaluated by the members of the board and selection criteria and decision options that will use for evaluation process were determined. The decision alternatives are Brand-P, Brand-B, Brand-S, and Brand-O. The selection criteria can be sorted as: fuel price per liter, product quality, service quality, easy terms of payment, brand awareness, environmental sensitivity. Actually, selection of fuel and fuel supplier has an extremely complex characteristic and it is a multi-criteria decision-making problem.  In this paper, the analytic hierarchy process theory was selected as a multi-criteria decision making problem in order to solve the decision making problem concerning with fuel and fuel supplier selection process. By using this methodology, decision makers can select the best fuel brand and fuel supplier by comparing variables such as selection criteria and decision alternatives in a mathematical model.
A Survey on Deep Learning for Multimodal Data Fusion
Authors: Gao Jing , Li Peng , Chen Zhikui , Zhang Jianing
Published: March 2020

With the wide deployments of heterogeneous networks, huge amounts of data with characteristics of high volume, high variety, high velocity, and high veracity are generated. These data, referred to multimodal big data, contain abundant intermodality and cross-modality information and pose vast challenges on traditional data fusion methods. In this review, we present some pioneering deep learning models to fuse these multimodal big data. With the increasing exploration of the multimodal big data, there are still some challenges to be addressed. Thus, this review presents a survey on deep learning for multimodal data fusion to provide readers, regardless of their original community, with the fundamentals of multimodal deep learning fusion method and to motivate new multimodal data fusion techniques of deep learning. Specifically, representative architectures that are widely used are summarized as fundamental to the understanding of multimodal deep learning. Then the current pioneering multimodal data fusion deep learning models are summarized. Finally, some challenges and future topics of multimodal data fusion deep learning models are described.
The Decolonisation of Children’s Rights and the Colonial Contours of the Convention on the Rights of the Child
Authors: Faulkner Elizabeth A. , Nyamutata Conrad
Published: March 2020

The United Nations Convention on the Rights of the Child (uncrc) 1989 has been celebrated for its universal acceptance. However, questions still arise around its provenance and representation. In particular, the Convention is deemed to enshrine Western notions of childhood upon which its rights were constructed. However, the legacy of the colonial contours of the new world order are often excluded within the context of children’s rights. It has been suggested that the new imperialism brandished under the guise of “children’s rights” serves as an effective tool to “beat” the Global South, deflecting from the continued Western dominance within the field of children’s rights. This paper interrogates the power dynamics and colonial legacy upon which views of children are formed, centralising the multitude of issues in the arena of children’s rights in the wake of what can be identified as Hokusai’s wave.
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The Affinity between Alghazali’s Intentions of the Philosophers and Maimonides’ Philosophy, According to Shalom Anabi
Authors: Elior Ofer
Published: March 2020

Beginning in the late 13th century, readers of Alghazali’s Intentions of the Philosophers in the Provençal, Spanish and Italian Jewish spheres viewed this treatise as belonging to the same tradition to which the philosophical stances of Maimonides, or at least some of them, belong. Readers who espoused this view were sometimes also of the opinion that the Intentions was the direct source for Maimonides’ ideas. These views, coupled with an understanding that the tradition in question differs from the philosophical tradition whose representative is Averroes, led students of Maimonides’ philosophy to examine his stances on issues about which the two traditions were in dispute. The present Zuta shows that the same opinions and approaches were adopted and expressed by Shalom Anabi, one of the leading scholars of the Jewish intellectual community of Constantinople in the 15th century.
A Note on an Old Jewish Bibliotaphos
Authors: Rosenzweig Claudia
Published: March 2020

In the editio princeps of the Mayse-bukh (Basel 1602) are circa 250 stories. The last one is a translation/reworking of a story that appears in Sefer Hasidim, and is about a bibliotaphos, someone who is ready to bury his books, but not to lend them. In this short paper, I try to show the differences between the Yiddish and the Hebrew source, suggesting that these differences can hint at historical and social transformations of the reading public of Yiddish texts in the Early Modern era.
Computational Analysis of Historical Hebrew Newspapers: Proof of Concept
Authors: Soffer Oren , Segal Zef , Greidinger Nurit , Rusinek Sinai , Silber-Varod Vered
Published: March 2020

This article focuses on one decade, 1874–1883, in the relatively long lifespan of the Hebrew weekly Ha-Tzefirah, which was founded in Warsaw in 1862. Applying computational tools to the study of the early Hebrew press requires a unique effort. The Hebrew language in general is distinct in its characters, morphological structure, and word order. The contribution of this proof-of-concept study is two-fold: First, computational analysis provides a long-term indication of trends in the discourse that cannot be attained through qualitative study. The second contribution is on the micro level: Computational analysis can potentially shed light, in a diachronic perspective, on the use of a specific term or the discussion of a specific geographical location.
Long-Lead Predictions of Warm Season Droughts in South Korea Using North Atlantic SST
Authors: Myoung Boksoon , Rhee Jinyoung , Yoo Changhyun
Published: March 2020

Understanding and predicting warm season (May–October) droughts is critically important in South Korea for agricultural productivity and water resource management. Using a 6-month standardized precipitation index ending in October (SPI6_Oct), we investigate the interannual variability of warm season droughts and the related large-scale atmospheric circulations for the most recent 20-yr period (1995–2014). Cyclonic (anticyclonic) circulations to the east of Japan (in the North Pacific) tend to induce warm season droughts (wetness) by suppressing (enhancing) moist water transport from the south of the Korean Peninsula. These circulation patterns to the east of Japan are linked to a barotropic Rossby wave–like teleconnection pattern from the North Atlantic to East Asia, which is found to be responsible for the interannual variability of SPI6_Oct. This teleconnection pattern is highly correlated with the difference in sea surface temperature (SST) between the Norwegian Sea and the Barents Sea (referred to as NA_dipole) in January–March (r = 0.68), which modulates the snow depth over the Ural Mountains in spring and the sea ice concentration over the Barents Sea during the entire warm season. Two drought prediction models, an empirical model and a hybrid machine learning model, are developed and tested for their predictive skills for South Korea. An empirical prediction model using NA_dipole as one of the predictors is found to accurately capture the interannual variability of SPI6_Oct (r2 = 53%). NA_dipole is found to improve the predictive skills of the hybrid machine learning drought prediction model, especially for longer lead times. Our results emphasize the significant role of North Atlantic SST anomalies in warm season medium-range droughts in South Korea.
The Effects of Recency and Numerical Uncertainty Estimates on Overcautiousness
Authors: Demnitz Raoni , Joslyn Susan
Published: March 2020

The four experiments reported here tested the impact of recent negative events on decision-making. Participants were given a virtual budget to spend on crops of varying costs and payoffs that, in some cases, depended on drought conditions. Participants made 46 decisions based on either deterministic or probabilistic seasonal climate predictions. Participants experienced a sequence of droughts either immediately prior to the target trials (recent condition) or early in the sequence (distant condition). In experiment 1, participants made overly cautious crop choices when droughts were experienced recently. Subsequent experiments probed the cognitive mechanisms involved. The effect of recency on overcautiousness was reduced by a midexperiment message, although it did not matter whether the message described a changed or consistent venue and time period. This suggests that overcautiousness was not caused by deducing a climatic trend in the particular area. Instead, we argue that availability—events that are easier to recall are judged to be more likely—was the major cause for increased cautiousness following recent droughts. Importantly, probabilistic predictions attenuated the impact of recency, inspired greater trust, and allowed participants to make better decisions overall than did deterministic predictions. Implications are discussed.
Correlative Microscopy and Spectroscopy Workflow for Microplastics
Authors: Sarau George , Kling Lasse , Oßmann Barbara E. , Unger Ann-Katrin , Vogler Frank , Christiansen Silke H.
Published: March 2020

Microplastics (MPs) have been reported in various environmental compartments and their number is continuously increasing because of degradation into smaller fragments down to nanoplastics. Humans are exposed to these small-sized MPs through food and air with potential health consequences that still need to be determined. This requires, in the first place, efficient and detailed visualization, relocalization, and characterization of the same MPs with complementary analytical methods. Here, we show the first application of a correlative microscopy and spectroscopy workflow to MPs that meets these demands. For this purpose, standard MP particles on aluminum-coated polycarbonate membrane filters were investigated by an optical zoom microscope and a hyphenated scanning electron microscopy (SEM)-Raman system. By merging the obtained data in one software, it is possible to navigate on the entire filters’ surface and correlate at identical locations MP morphology at the spatial resolutions of electron (1.6 nm at 1 kV for the used SEM, ∼100 nm minimum MP size in this study) and optical (∼1–10 µm) microscopies with chemical identification by micro-Raman spectroscopy. Moreover, we observed that low-voltage SEM works without a conductive coating of MPs, causes no detectable charging and structural changes, and provides high-resolution surface imaging of single and clustered MP particles, thus enabling subsequent Raman measurements. We believe that further work on the accurate identification and quantification of micro- and nanoplastics in real samples can potentially profit from this workflow.
Advances in microcellular injection moulding
Authors: Llewelyn Gethin , Rees Andrew , Griffiths Christian A , Scholz Steffen G.
Published: March 2020

Injection moulding is a well-established replication process for the cost-effective manufacture of polymer-based components. The process has different applications in fields such as medical, automotive and aerospace. To expand the use of polymers to meet growing consumer demands for increased functionality, advanced injection moulding processes have been developed that modifies the polymer to create microcellular structures. Through the creation of microcellular materials, additional functionality can be gained through polymer component weight and processing energy reduction. Microcellular injection moulding shows high potential in creating innovation green manufacturing platforms. This review article aims to present the significant developments that have been achieved in different aspects of microcellular injection moulding. Aspects covered include core-back, gas counter pressure, variable thermal tool moulding and other advanced technologies. The resulting characteristics of creating microcellular injection moulding components through both plasticising agents and nucleating agents are presented. In addition, the article highlights potential areas for research exploitation. In particular, acoustic and thermal applications, nano-cellular injection moulding parts and developments of more accurate simulations.
Preliminary Evidence on How the Dual Control Model Predicts Female Sexual Response to a Bogus Negative Feedback
Authors: Granados Reina , Carvalho Joana , Sierra Juan Carlos
Published: March 2020

The Dual Control Model of sexual response has been mostly tested with men. As such, there is a lack of evidence on how such model applies to women’s experience of sexual arousal, particularly when they face a threatening situation such as the threat of sexual performance failure. The aim of the current study was to test whether the Dual Control Model dimensions predict women’s sexual responses to a bogus negative feedback about their sexual performance. In addition, 22 women were exposed to a sexually explicit film clip, while their genital arousal was being measured. During this presentation, a bogus negative feedback, aimed at increasing women’s anxiety about their sexual performance, was provided. Vaginal photopletismography and self-report questions were used as means to evaluate women’s genital and subjective sexual arousal, respectively. The Sexual Excitation/Sexual Inhibition Inventory for Women was further used to capture women’s sexual dynamics. Regression analysis on the high-order factors revealed that sexual excitation proneness was the only predictor of the subjective sexual responses, while none of the factors has predicted genital arousal. “Arousability” and “Concerns about sexual function” dimensions predicted subjective sexual arousal. Sexual arousability may prevent women of lowering their subjective sexual responses in a sexually demanding situation, while “Concerns about sexual function” may have the opposite role, thus being a target of clinical interest. This work provides new data on the Dual Control Model of sexual response, and particularly on its role in women’s sexual functioning.