bluuebunny/crossref_metadata_2025_split huggingface dataset:
CML Hematopoietic Stem Cells Expressing IL1RAP Can Be Targeted by Chimeric Antigen Receptor–Engineered T Cells
Authors: Warda Walid , Larosa Fabrice , Neto Da Rocha Mathieu , Trad Rim , Deconinck Eric , Fajloun Ziad , Faure Cyril , Caillot Denis , Moldovan Marius , Valmary-Degano Severine , Biichle Sabeha , Daguindau Etienne , Garnache-Ottou Francine , Tabruyn Sebastien , Adotevi Olivier , Deschamps Marina , Ferrand Christophe 
Published: December 2018

Abstract

Chronic myeloid leukemia (CML) is a chronic disease resulting in myeloid cell expansion through expression of the BCR-ABL1 fusion transcript. Tyrosine kinase inhibitors (TKI) have significantly increased survival of patients with CML, and deep responders may consider stopping the treatment. However, more than 50% of patients relapse and restart TKI, subsequently suffering unknown toxicity. Because CML is a model immune system–sensitive disease, we hypothesize that chimeric antigen receptor (CAR) T cells targeting IL1 receptor-associated protein (IL1RAP) in quiescent CML stem cells may offer an opportunity for a permanent cure. In this study, we produced and molecularly characterized a specific monoclonal anti-IL1RAP antibody from which fragment antigen-binding nucleotide coding sequences were cloned as a single chain into a lentiviral backbone and secured with the suicide gene iCASP9/rimiducid system. Our CAR T-cell therapy exhibited cytotoxicity against both leukemic stem cells and, to a lesser extent, monocytes expressing IL1RAP, with no apparent effect on the hematopoietic system, including CD34+ stem cells. This suggests IL1RAP as a tumor-associated antigen for immunotherapy cell targeting. IL1RAP CAR T cells were activated in the presence of IL1RAP+ cell lines or primary CML cells, resulting in secretion of proinflammatory cytokines and specifically killing in vitro and in a xenograft murine model. Overall, we demonstrate the proof of concept of a CAR T-cell immunotherapy approach in the context of CML that is applicable for young patients and primary TKI-resistant, intolerant, or allograft candidate patients.

Significance:
These findings present the first characterization and proof of concept of a chimeric antigen receptor directed against IL1RAP expressed by leukemic stem cells in the context of CML.
Evidence for Incomplete Neutralization in Chilean Spanish
Authors: Bolyanatz Mariška A. 
Published: December 2018

AbstractBackground/Aims:In Chilean Spanish, syllable- and word-final /s/ are frequently weakened to an [h]-like segment or completely deleted. In word-final position, /s/ serves as the plural morpheme, so its deletion renders a site for potential neutralization with singular items. Chilean scholars have previously described differences in the vowel preceding weakened or deleted /s/ distinguishing it from non-/s/-final words, but this putative incomplete neutralization has not yet been acoustically verified, nor have its conditioning factors been explored. The primary purpose of this study was to assess via phonetic analysis of spontaneous speech whether neutralization of final vowels in singular words and plural words in Chilean Spanish is indeed incomplete, as hypothesized by scholars during the 20th century. Additionally, these vowels were also compared to the vowels of monomorphemic /s/-final words in order to ensure that the attested singular-versus-plural differences were not simply indicative of closed syllable laxing processes.Methods:Vowels were extracted from the spontaneous speech of 20 Chilean Spanish speakers and acoustically analyzed via VoiceSauce.Results:The results revealed that final /a/ vowels of plural words were found to be breathier than singular vowels but less breathy than the final vowels of monomorphemic words, and that plural /o/ was significantly fronted. They also demonstrated increased breathiness on /e/ vowels closed by /s/, regardless of morphological status.Conclusion:These results provide the first account of incomplete neutralization of plural vowel correlates in spontaneous speech in Chilean Spanish, and they offer evidence for closed syllable processes in this particular dialect, in alignment with an exemplar-theoretic approach.
Twelve‐Lead ECG Optimization of Cardiac Resynchronization Therapy in Patients With and Without Delayed Enhancement on Cardiac Magnetic Resonance Imaging
Authors: Gage Ryan M. , Khan Akbar H. , Syed Imran S. , Bajpai Ambareesh , Burns Kevin V. , Curtin Antonia E. , Blanchard Amanda L. , Gillberg Jeffrey M. , Ghosh Subham , Bank Alan J. 
Published: December 2018

Background

Delayed enhancement (
DE
) on magnetic resonance imaging is associated with ventricular arrhythmias, adverse events, and worse left ventricular mechanics. We investigated the impact of
DE
on cardiac resynchronization therapy (
CRT
) outcomes and the effect of
CRT
optimization.

Methods and Results

We studied 130 patients with ejection fraction (
EF
) ≤40% and
QRS
≥120 ms, contrast cardiac magnetic resonance imaging, and both pre‐ and 1‐year post‐
CRT
echocardiograms. Sixty‐three (48%) patients did not have routine optimization of
CRT
. The remaining patients were optimized for wavefront fusion by 12‐lead
ECG
. The primary end point in this study was change in
EF
following
CRT
. To investigate the association between electrical dyssynchrony and
EF
outcomes, the standard deviation of activation times from body‐surface mapping was calculated during native conduction and selected device settings in 52 of the optimized patients. Patients had no
DE
(n=45), midwall septal stripe (n=30), or scar (n=55). Patients without
DE
had better ∆
EF
(13±10 versus 4±10 units;
P
<0.01). Optimized patients had greater ∆
EF
in midwall stripe (2±9 versus 12±12 units;
P
=0.01) and scar (0±7 versus 5±10;
P
=0.04) groups, but not in the no‐
DE
group. Patients without
DE
had greater native standard deviation of activation times (
P
=0.03) and greater ∆standard deviation of activation times with standard programming (
P
=0.01). Device optimization reduced standard deviation of activation times only in patients with
DE
(
P
<0.01).

Conclusions

DE
on magnetic resonance imaging is associated with worse
EF
outcomes following
CRT
. Device optimization is associated with improved
EF
and reduced electrical dyssynchrony in patients with
DE
.
CD40L Priming of Platelets via NF‐κB Activation is CD40‐ and TAK1‐Dependent
Authors: Kojok Kevin , Akoum Souhad El , Mohsen Mira , Mourad Walid , Merhi Yahye 
Published: December 2018

Background
CD40 ligand (CD40L) is a thromboinflammatory molecule that predicts cardiovascular events. CD40L is a strong activator of nuclear factor kappa B (NF‐κB) in platelets that primes and enhances platelet activation in response to thrombotic stimuli. In addition to its classical receptor CD40, CD40L binds αIIbβ3, α5β1, and αMβ2 in various cell types. However, the function of the different CD40L receptors on platelets remains unexplored. The present study aims to identify the receptors of CD40L, involved in platelet NF‐κB activation, their downstream signaling and their implication in platelet aggregation.

Methods and Results

We showed that platelets express CD40, αIIbβ3, and α5β1 and release CD40L in response to sCD40L stimulation. sCD40L alone dose‐dependently induced platelet NF‐κB activation; this effect was absent in CD40
−/−
mouse platelets and inhibited by the CD40 blockade, but was unaffected by the αIIbβ3 or α5β1 blockade in human platelets. sCD40L/CD40 axis activates transforming growth factor‐β‐activated kinase 1 upstream of NF‐κB. In functional studies, sCD40L alone did not affect platelet aggregation but potentiated the aggregation response in the presence of suboptimal doses of thrombin; this effect was abolished by CD40, transforming growth factor‐β‐activated kinase 1, and NF‐κB inhibitors.

Conclusions
CD40L primes platelets via signaling pathways involving CD40/transforming growth factor‐β‐activated kinase 1/NF‐κB, which predisposes platelets to enhanced activation and aggregation in response to thrombotic stimuli.
Associations of Smoke‐Free Policies in Restaurants, Bars, and Workplaces With Blood Pressure Changes in the CARDIA Study
Authors: Mayne Stephanie L. , Jacobs David R. , Schreiner Pamela J. , Widome Rachel , Gordon‐Larsen Penny , Kershaw Kiarri N. 
Published: December 2018

Background

Smoke‐free legislation has been associated with reductions in secondhand smoke exposure and cardiovascular disease. However, it remains unknown whether smoke‐free policies are associated with reductions in blood pressure (
BP
).

Methods and Results

Longitudinal data from 2606 nonsmoking adult participants of the
CARDIA
(Coronary Artery Risk Development in Young Adults) Study (1995–2011) were linked to state, county, and local‐level 100% smoke‐free policies in bars, restaurants, and/or nonhospitality workplaces based on participants’ census tract of residence. Mixed‐effects models estimated associations of policies with
BP
and hypertension trajectories over 15 years of follow‐up. Fixed‐effects regression estimated associations of smoke‐free policies with within‐person changes in systolic and diastolic
BP
and hypertension. Models were adjusted for sociodemographic, health‐related, and policy/geographic covariates. Smoke‐free policies were associated with between‐person differences and within‐person changes in systolic
BP
. Participants living in areas with smoke‐free policies had lower systolic
BP
on average at the end of follow‐up compared with those in areas without policies (adjusted predicted mean differences [in mm Hg]: restaurant: −1.14 [95% confidence interval: −2.15, −0.12]; bar: −1.52 [−2.48, −0.57]; workplace: −1.41 [−2.32, −0.50]). Smoke‐free policies in restaurants and bars were associated with mean within‐person reductions in systolic
BP
of −0.85 (−1.61, −0.09) and −1.08 (−1.82, −0.34), respectively. Only restaurant policies were associated with a significant within‐person reduction in diastolic
BP
, of −0.58 (−1.15, −0.01).

Conclusions
While the magnitude of associations was small at the individual level, results suggest a potential mechanism through which reductions in secondhand smoke because of smoke‐free policies may improve population‐level cardiovascular health.
Increased Vulnerability to Atrial Fibrillation Is Associated With Increased Susceptibility to Alternans in Old Sheep
Authors: Pearman Charles M. , Madders George W.P. , Radcliffe Emma J. , Kirkwood Graeme J. , Lawless Michael , Watkins Amy , Smith Charlotte E.R. , Trafford Andrew W. , Eisner David A. , Dibb Katharine M. 
Published: December 2018

Background

Atrial fibrillation (
AF
) is common in the elderly, but rare in the young; however, the changes that occur with age that promote
AF
are not fully understood. Action potential (
AP
) alternans may be involved in the initiation of
AF
. Using a translationally relevant model, we investigated whether age‐associated atrial vulnerability to
AF
was associated with susceptibility to
AP
alternans.

Methods and Results

AF
was induced in conscious young and old sheep using 50 Hz burst pacing. Old sheep were more vulnerable to
AF
. Monophasic and cellular
AP
s were recorded from the right atrium in vivo and from myocytes isolated from the left and right atrial appendages.
AP
alternans occurred at lower stimulation frequencies in old sheep than young in vivo (old, 3.0±0.1 Hz; young, 3.3±0.1 Hz;
P
<0.05) and in isolated myocytes (old, 1.6±0.1 Hz; young, 2.0±0.1 Hz;
P
<0.05). Simultaneous recordings of [Ca
2+
]
i
and membrane potential in myocytes showed that alternans of
AP
s and [Ca
2+
]
i
often occurred together. However, at low stimulation rates [Ca
2+
]
i
alternans could occur without
AP
alternans, whereas at high stimulation rates
AP
alternans could still be observed despite disabling Ca
2+
cycling using thapsigargin.

Conclusions

We have shown, for the first time in a large mammalian model, that aging is associated with increased duration of
AF
and susceptibility to
AP
alternans. We suggest that instabilities in Ca
2+
handling initiate alternans at low stimulation rates, but that
AP
restitution alone can sustain alternans at higher rates.
Long‐Term Follow‐Up of Patients With Short QT Syndrome: Clinical Profile and Outcome
Authors: El‐Battrawy Ibrahim , Besler Johanna , Liebe Volker , Schimpf Rainer , Tülümen Erol , Rudic Boris , Lang Siegfried , Wolpert Christian , Zhou Xiaobo , Akin Ibrahim , Borggrefe Martin 
Published: December 2018

Background

Short
QT
syndrome (
SQTS
) is a rare inheritable disease associated with sudden cardiac death. Data on long‐term outcomes of families with SQTS are limited.

Methods and Results

Seventeen patients with
SQTS
in 7 independent families (48% men; median age, 42.4 years; corrected QT interval, 324.9±40.8 ms) were followed up for 13.5±2.5 years. A history of sudden cardiac death was documented in 71% of families. A large number of them showed sudden cardiac deaths at a younger age, with a predominance of men (67%). Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or atrial flutter. An
SQTS
‐related gene was found in 76% of the patients as follows:
KCNH
2 (
SQTS
1) in 4,
CACNA
1C (
SQTS
4) in 3, and
CACN
b2 (
SQTS
5) in 6. Five patients (29%) received an implantable cardioverter‐defibrillator and 5 patients received long‐term prophylaxis with hydroquinidine. During follow‐up, 1 patient received an appropriate implantable cardioverter‐defibrillator shock attributable to ventricular fibrillation. The patient received no further implantable cardioverter‐defibrillator shocks after treatment with hydroquinidine.

Conclusions

The risk of sudden cardiac death in
SQTS
families is high. However, after appropriate risk assessment and individualized treatment options (hydroquinidine and/or implantable cardioverter‐defibrillator), the long‐term outcome is relatively benign when patients are seen at a reference center.
Gait Speed and 1‐Year Mortality Following Cardiac Surgery: A Landmark Analysis From the Society of Thoracic Surgeons Adult Cardiac Surgery Database
Authors: Afilalo Jonathan , Sharma Abhinav , Zhang Shuaiqi , Brennan J. Matthew , Edwards Fred H. , Mack Michael J. , McClurken James B. , Cleveland Joseph C. , Smith Peter K. , Shahian David M. , Peterson Eric D. , Alexander Karen P. 
Published: December 2018

Background
In older adults undergoing cardiac surgery, prediction of downstream risk is critical. Our objective was to determine the association of 5‐m gait speed with 1‐year mortality and repeat hospitalization following cardiac surgery.

Methods and Results

In this prospective cohort of patients undergoing cardiac surgery at centers participating in the Society of Thoracic Surgeons Database with gait speed recorded, we examined all‐cause mortality using a landmark analysis at 0 to 30, 30 to 365, and >365 days, as well as repeat hospitalization. The cohort consisted of 8287 patients (median age, 74 years; 32% females). At 1 year, survival was 90% in the slow (<0.83 m/s), 95% in the middle (0.83–1.00 m/s), and 97% in the fast (>1.00 m/s) gait speed tertiles, and risk of hospitalization was 45%, 33%, and 27%, respectively (both
P
<0.0001). After adjustment, gait speed remained predictive of mortality (hazard ratio, 2.16 per 0.1‐m/s decrease in gait speed; 95% confidence interval, 1.59–2.93) and rehospitalization (hazard ratio, 1.71 per 0.1‐m/s decrease in gait speed; 95% confidence interval, 1.45–2.0). In a landmark analysis, the effect of slow gait speed on mortality was most marked from 30 to 365 days after surgery, where each decline in 0.1 m/s of gait speed conferred a 2‐fold increased risk of mortality.

Conclusions
Gait speed is a simple tool to screen for frailty and identify older adults at risk for adverse events in the early and midterm postoperative periods.
A Nurse‐Led Limited Risk Factor Modification Program to Address Obesity and Obstructive Sleep Apnea in Atrial Fibrillation Patients
Authors: Yaeger Amaryah , Cash Nancy R. , Parham Tara , Frankel David S. , Deo Rajat , Schaller Robert D. , Santangeli Pasquale , Nazarian Saman , Supple Gregory E. , Arkles Jeffrey , Riley Michael P. , Garcia Fermin C. , Lin David , Epstein Andrew E. , Callans David J. , Marchlinski Francis E. , Kolansky Daniel M. , Mora Jorge I. , Amaro Anastassia , Schwab Richard , Pack Allan , Dixit Sanjay 
Published: December 2018

Background

Obesity and obstructive sleep apnea (
OSA
) are associated with atrial fibrillation (
AF
), yet these conditions remain inadequately treated. We report on the feasibility and efficacy of a nurse‐led risk factor modification program utilizing a pragmatic approach to address obesity and
OSA
in
AF
patients.

Methods and Results

AF
patients with obesity (body mass index ≥30 kg/m
2
) and/or the need for
OSA
management (high risk per Berlin Questionnaire or untreated
OSA
) were voluntarily enrolled for risk factor modification, which comprised patient education, lifestyle modification, coordination with specialists, and longitudinal management. Weight loss and
OSA
treatment were monitored by monthly follow‐up calls and/or continuous positive airway pressure (
CPAP
) unit downloads. Quality of life and arrhythmia symptoms were assessed with the
SF
‐36 and
AF
Severity Scale at baseline and at 6 months. From November 1, 2016 to October 31, 2017, 252 patients (age 63±11 years; 71% male; 57% paroxysmal
AF
) were enrolled, 189 for obesity and 93 for
OSA
. Obese patients who enrolled lost significantly greater percent body weight than those who declined (3% versus 0.3%;
P
<0.05). Among 93 patients enrolled for
OSA
, 70 completed sleep studies,
OSA
was confirmed in 50, and the majority (76%) started
CPAP
therapy. All components of quality of life and arrhythmia symptoms improved significantly from baseline to 6 months among enrolled patients.

Conclusions

A nurse‐led risk factor modification program is a potentially sustainable and generalizable model that can improve weight loss and
OSA
in
AF
patients, translating into improved quality of life and arrhythmia symptoms.
Anti‐Inflammatory Effects of a Vegan Diet Versus the American Heart Association–Recommended Diet in Coronary Artery Disease Trial
Authors: Shah Binita , Newman Jonathan D. , Woolf Kathleen , Ganguzza Lisa , Guo Yu , Allen Nicole , Zhong Judy , Fisher Edward A. , Slater James 
Published: December 2018

Background
Dietary interventions may play a role in secondary cardiovascular prevention. hsCRP (High‐sensitivity C‐reactive protein) is a marker of risk for major adverse cardiovascular outcomes in coronary artery disease.

Methods and Results

The open‐label, blinded end‐point, EVADE CAD (Effects of a Vegan Versus the American Heart Association‐Recommended Diet in Coronary Artery Disease) trial randomized participants (n=100) with coronary artery disease to 8 weeks of a vegan or American Heart Association–recommended diet with provision of groceries, tools to measure dietary intake, and dietary counseling. The primary end point was high‐sensitivity C‐reactive protein. A linear regression model compared end points after 8 weeks of a vegan versus American Heart Association diet and adjusted for baseline concentration of the end point. Significance levels for the primary and secondary end points were set at 0.05 and 0.0015, respectively. A vegan diet resulted in a significant 32% lower high‐sensitivity C‐reactive protein (β, 0.68, 95% confidence interval [0.49–0.94];
P
=0.02) when compared with the American Heart Association diet. Results were consistent after adjustment for age, race, baseline waist circumference, diabetes mellitus, and prior myocardial infarction (adjusted β, 0.67 [0.47–0.94],
P
=0.02). The degree of reduction in body mass index and waist circumference did not significantly differ between the 2 diet groups (adjusted β, 0.99 [0.97–1.00],
P
=0.10; and adjusted β, 1.00 [0.98–1.01],
P
=0.66, respectively). There were also no significant differences in markers of glycemic control between the 2 diet groups. There was a nonsignificant 13% reduction in low‐density lipoprotein cholesterol with the vegan diet when compared with the American Heart Association diet (adjusted β, 0.87 [0.78–0.97],
P
=0.01). There were no significant differences in other lipid parameters.

Conclusions
In patients with coronary artery disease on guideline‐directed medical therapy, a vegan diet may be considered to lower high‐sensitivity C‐reactive protein as a risk marker of adverse outcomes.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
02135939.
Expansion Hyoidthyroidpexy: Combined Hyoid Surgery Techniques for Obstructive Sleep Apnea: All in One
Authors: Askar Sherif M. , El‐Anwar Mohammad Waheed , Awad Ali 
Published: December 2018

We provide expansion hyoidthyroidpexy as a novel surgical procedure for obstructive sleep apnea (OSA) that could combine different techniques of hyoid bone surgery in 1 procedure. This case series included patients with OSA who had an apnea‐hypopnea index (AHI) >15 and showed predominant lateral wall hypopharyngeal collapse. In 21 patients, the procedure was performed smoothly without technical difficulties or operative adverse events, resulting in lateral expansion of each horn of the hyoid bone by ≥1 cm without early or late complications. At 6 months postoperatively, both AHI and the mean lowest oxygen saturation level were significantly improved (P <. 0001). The new expansion hyoidthyroidpexy technique is a reliable, easy, and effective procedure with good surgical outcomes in patients with OSA. It is feasible to be employed in the protocol of multilevel surgery for OSA.
Ayesha Memorial Hospital (B)
Authors: Bashir Mohsin 
Published: December 2018

The case is divided into two parts, and an epilogue is provided to the students at the end of the discussion. Case A discusses the protagonist’s arrival at a hospital that is affected by a hidden power struggle between opposing parties. In an attempt to exercise his influence and improve the hospital’s operations, the protagonist introduces reforms and changes to the hospital’s processes. However, as a result of his increasing influence and knack for not respecting the status quo, he realizes that there are people in the management who feel threatened by his influence and plan to damage his status in the hospital. At the conclusion of Case A, he has been handed a letter that informs him of a disciplinary committee case against him on serious allegations of misuse of authority, torture and even sexual harassment. He is concerned that he has been set up by his opponents, who have resources and credibility that might make it difficult for him to escape from this situation unscathed. Thus, in the given situation the protagonist weighs his possible options. Case B concerns how the protagonist responds to his disciplinary committee case. Policy changes previously initiated by the protagonist and his alliance with the vice-president serve as important tools. They neutralize the resources that are used by the protagonist’s opponents in an investigation against him. In the end, the protagonist, Murtaza; therefore, successfully comes out of this situation unscathed. The epilogue discusses how the protagonist’s initial alliance with the vice-president, in light of changing circumstances, begins to wither away as the mutual opposition they both once shared also begins to weaken.