bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Effectiveness of Interventions for Stroke Prevention in Atrial Fibrillation: A Network Meta‐Analysis
Authors: Tereshchenko Larisa G. , Henrikson Charles A. , Cigarroa Joaquin , Steinberg Jonathan S. 
Published: May 2016

Background

The goal of this study was to compare the safety and effectiveness of individual antiembolic interventions in nonvalvular atrial fibrillation (
AF
): novel oral anticoagulants (
NOAC
s) (apixaban, dabigatran, edoxaban, and rivaroxaban); vitamin K antagonists (
VKA
); aspirin; and the Watchman device.

Methods and Results

A network meta‐analysis of randomized, clinical trials (
RCT
s) was performed.
RCT
s that included patients with prosthetic cardiac valves or mitral stenosis, mean or median follow‐up <6 months, <200 participants, without published report in English language, and
NOAC
phase
II
studies were excluded. The placebo/control arm received either placebo or no treatment. The primary efficacy outcome was the combination of stroke (of any type) and systemic embolism. All‐cause mortality served as a secondary efficacy outcome. The primary safety outcome was the combination of major extracranial bleeding and intracranial hemorrhage. A total of 21
RCT
s (96 017 nonvalvular
AF
patients; median age, 72 years; 65% males; median follow‐up, 1.7 years) were included. In comparison to placebo/control, use of aspirin (odds ratio [
OR
], 0.75 [95%
CI
, 0.60–0.95]),
VKA
(0.38 [0.29–0.49]), apixaban (0.31 [0.22–0.45]), dabigatran (0.29 [0.20–0.43]), edoxaban (0.38 [0.26–0.54]), rivaroxaban (0.27 [0.18–0.42]), and the Watchman device (0.36 [0.16–0.80]) significantly reduced the risk of any stroke or systemic embolism in nonvalvular
AF
patients, as well as all‐cause mortality (aspirin:
OR
, 0.82 [0.68–0.99];
VKA
: 0.69 [0.57–0.85]; apixaban: 0.62 [0.50–0.78]; dabigatran: 0.62 [0.50–0.78]; edoxaban: 0.62 [0.50–0.77]; rivaroxaban: 0.58 [0.44–0.77]; and the Watchman device: 0.47 [0.25–0.88]). Apixaban (0.89 [0.80–0.99]), dabigatran (0.90 [0.82–0.99]), and edoxaban (0.89 [0.82–0.96]) reduced risk of all‐cause death as compared to
VKA
.

Conclusions

The entire spectrum of therapy to prevent thromboembolism in nonvalvular
AF
significantly reduced stroke/systemic embolism events and mortality.
Carotid Artery Vascular Mechanics Serve as Biomarkers of Cognitive Dysfunction in Aortic‐Banded Miniature Swine That Can Be Treated With an Exercise Intervention
Authors: Olver T. Dylan , Klakotskaia Diana , Ferguson Brian S. , Hiemstra Jessica A. , Schachtman Todd R. , Laughlin M. Harold , Emter Craig A. 
Published: May 2016

Background
Cognitive impairment in the setting of heart failure with preserved ejection fraction remains poorly understood. Using aortic‐banded miniature swine displaying pathological features of human heart failure with preserved ejection fraction, we tested the hypothesis that increased carotid artery stiffness and altered carotid blood flow control are associated with impaired memory independent of decreased cardiac output. Furthermore, we hypothesized that chronic exercise prevents carotid artery vascular restructuring and preserves normal blood flow control and cognition in heart failure with preserved ejection fraction.

Methods and Results
Yucatan pigs aged 8 months were divided into 3 groups: control (n=7), aortic‐banded sedentary (n=7), and aortic‐banded exercise trained (n=7). At 6 months following aortic‐banded or control conditions, memory was evaluated using a spatial hole‐board task. Carotid artery vascular mechanics and blood flow were assessed at rest, and blood flow control was examined during transient vena cava occlusion. Independent of decreased cardiac output, the aortic‐banded group exhibited impaired memory that was associated with carotid artery vascular stiffening, elevated carotid artery vascular resistance, and exaggerated reductions in carotid artery blood flow during vena cava occlusion. Chronic exercise augmented memory scores, normalized blood flow control, and improved indices of carotid artery vascular stiffening. Indices of vascular stiffening were significantly correlated with average memory score.

Conclusions
Carotid artery stiffness and altered vasomotor control correlate with impaired cognition independent of cardiac systolic dysfunction. Carotid artery vascular mechanics may serve as a biomarker for vascular cognitive impairment in heart failure with preserved ejection fraction. Chronic low‐intensity exercise reduces vascular stiffening and improves cognition, highlighting the utility of exercise therapy for treating vascular cognitive impairment in heart failure with preserved ejection fraction.
Efficacy and Safety of Edoxaban in Elderly Patients With Atrial Fibrillation in the ENGAGE AF–TIMI 48 Trial
Authors: Kato Eri Toda , Giugliano Robert P. , Ruff Christian T. , Koretsune Yukihiro , Yamashita Takeshi , Kiss Robert Gabor , Nordio Francesco , Murphy Sabina A. , Kimura Tetsuya , Jin James , Lanz Hans , Mercuri Michele , Braunwald Eugene , Antman Elliott M. 
Published: May 2016

Background

Elderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the
ENGAGE AF
‐
TIMI
48 trial, we evaluate clinical outcomes with edoxaban versus warfarin according to age.

Methods and Results

Twenty‐one thousand one‐hundred and five patients enrolled in the
ENGAGE AF
‐
TIMI
48 trial were stratified into 3 prespecified age groups: <65 (n=5497), 65 to 74 (n=7134), and ≥75 (n=8474) years. Older patients were more likely to be female, with lower body weight and reduced creatinine clearance, leading to higher rates of edoxaban dose reduction (10%, 18%, and 41% for the 3 age groups,
P
<0.001). Stroke or systemic embolic event (1.1%, 1.8%, and 2.3%) and major bleeding (1.8%, 3.3%, and 4.8%) rates with warfarin increased across age groups (
P
trend
<0.001 for both). There were no interactions between age group and randomized treatment in the primary efficacy and safety outcomes. In the elderly (≥75 years), the rates of stroke/systemic embolic event were similar with edoxaban versus warfarin (hazard ratio 0.83 [0.66–1.04]), while major bleeding was significantly reduced with edoxaban (hazard ratio 0.83 [0.70–0.99]). The absolute risk difference in major bleeding (−82 events/10 000 pt‐yrs) and in intracranial hemorrhage (−73 events/10 000 pt‐yrs) both favored edoxaban over warfarin in older patients.

Conclusions
Age has a greater influence on major bleeding than thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with edoxaban provides an even greater absolute reduction in safety events over warfarin, compared to treatment with edoxaban versus warfarin in younger patients.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov/
. Unique identifier:
NCT
00781391.
Cingulate GABA levels inversely correlate with the intensity of ongoing chronic knee osteoarthritis pain
Authors: Reckziegel Diane , Raschke Felix , Cottam William J , Auer Dorothee P 
Published: May 2016

Background This study aims to investigate the role of the mid-anterior cingulate cortex γ-aminobutyric acid levels in chronic nociceptive pain. The molecular mechanisms of pain chronification are not well understood. In fibromyalgia, low mid-anterior cingulate cortex γ-aminobutyric acid was associated with high pain suggesting a role of prefrontal disinhibition. We hypothesize that mid-anterior cingulate cortex GABAergic disinhibition may underpin chronic pain independent of the pain etiology and comorbid negative affect. Proton magnetic resonance spectra were acquired at 3T from the mid-anterior cingulate cortex in 20 patients with chronic painful knee osteoarthritis, and 19 healthy pain-free individuals using a point resolved spectroscopy sequence optimized for detection of γ-aminobutyric acid. Participants underwent questionnaires for negative affect (depression and anxiety) and psychophysical pain phenotyping. Results No differences in mid-anterior cingulate cortex γ-aminobutyric acid or other metabolite levels were detected between groups. Ratings of perceived intensity of ongoing osteoarthritis pain were inversely correlated with γ-aminobutyric acid ( r = −0.758, p < 0.001), but no correlations were seen for negative affect or pain thresholds. The pain γ-aminobutyric acid interrelation remained strong when controlling for depression ( r = −0.820, p < 0.001). Combined levels of glutamine and glutamate were unrelated to psychometric or to pain thresholds. Conclusion Our study supports mid-anterior cingulate cortex γ-aminobutyric acid as a potential marker of pain severity in chronic nociceptive pain states independent of negative affect. The findings suggest that GABAergic disinhibition of the salience network may underlie sensitization to averse stimuli as a mechanism contributing to pain chronification.
Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies
Authors: Sun Chuang , Dotti Gianpietro , Savoldo Barbara 
Published: May 2016

AbstractHematologic malignancies provide a suitable testing environment for cell-based immunotherapies, which were pioneered by the development of allogeneic hematopoietic stem cell transplant. All types of cell-based therapies, from donor lymphocyte infusion to dendritic cell vaccines, and adoptive transfer of tumor-specific cytotoxic T cells and natural killer cells, have been clinically translated for hematologic malignancies. The recent success of chimeric antigen receptor–modified T lymphocytes in B-cell malignancies has stimulated the development of this approach toward other hematologic tumors. Similarly, the remarkable activity of checkpoint inhibitors as single agents has created enthusiasm for potential combinations with other cell-based immune therapies. However, tumor cells continuously develop various strategies to evade their immune-mediated elimination. Meanwhile, the recruitment of immunosuppressive cells and the release of inhibitory factors contribute to the development of a tumor microenvironment that hampers the initiation of effective immune responses or blocks the functions of immune effector cells. Understanding how tumor cells escape from immune attack and favor immunosuppression is essential for the improvement of immune cell–based therapies and the development of rational combination approaches.
Toxicities of chimeric antigen receptor T cells: recognition and management
Authors: Brudno Jennifer N. , Kochenderfer James N. 
Published: May 2016

Abstract
Chimeric antigen receptor (CAR) T cells can produce durable remissions in hematologic malignancies that are not responsive to standard therapies. Yet the use of CAR T cells is limited by potentially severe toxicities. Early case reports of unexpected organ damage and deaths following CAR T-cell therapy first highlighted the possible dangers of this new treatment. CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction. CRS is the most common type of toxicity caused by CAR T cells. Neurologic toxicity due to CAR T cells might in some cases have a different pathophysiology than CRS and requires different management. Aggressive supportive care is necessary for all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. Interleukin-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. Corticosteroids should be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the antimalignancy activity of the CAR T cells. This review describes the toxicities caused by CAR T cells and reviews the published approaches used to manage toxicities. We present guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy.
Efficient analysis of large datasets and sex bias with ADMIXTURE
Authors: Shringarpure Suyash S. , Bustamante Carlos D. , Lange Kenneth , Alexander David H. 
Published: May 2016

Abstract
Background
A number of large genomic datasets are being generated for studies of human ancestry and diseases. The ADMIXTURE program is commonly used to infer individual ancestry from genomic data.

Results
We describe two improvements to the ADMIXTURE software. The first enables ADMIXTURE to infer ancestry for a new set of individuals using cluster allele frequencies from a reference set of individuals. Using data from the 1000 Genomes Project, we show that this allows ADMIXTURE to infer ancestry for 10,920 individuals in a few hours (a 5 × speedup). This mode also allows ADMIXTURE to correctly estimate individual ancestry and allele frequencies from a set of related individuals. The second modification allows ADMIXTURE to correctly handle X-chromosome (and other haploid) data from both males and females. We demonstrate increased power to detect sex-biased admixture in African-American individuals from the 1000 Genomes project using this extension.

Conclusions
These modifications make ADMIXTURE more efficient and versatile, allowing users to extract more information from large genomic datasets.
Molecular and behavioral profiling of Dbx1-derived neurons in the arcuate, lateral and ventromedial hypothalamic nuclei
Authors: Sokolowski Katie , Tran Tuyen , Esumi Shigeyuki , Kamal Yasmin , Oboti Livio , Lischinsky Julieta , Goodrich Meredith , Lam Andrew , Carter Margaret , Nakagawa Yasushi , Corbin Joshua G. 
Published: May 2016

Abstract

Background
Neurons in the hypothalamus function to regulate the state of the animal during both learned and innate behaviors, and alterations in hypothalamic development may contribute to pathological conditions such as anxiety, depression or obesity. Despite many studies of hypothalamic development and function, the link between embryonic development and innate behaviors remains unexplored. Here, focusing on the embryonically expressed homeodomain-containing gene Developing Brain Homeobox 1 (Dbx1), we explored the relationship between embryonic lineage, post-natal neuronal identity and lineage-specific responses to innate cues. We found that Dbx1 is widely expressed across multiple developing hypothalamic subdomains. Using standard and inducible fate-mapping to trace the Dbx1-derived neurons, we identified their contribution to specific neuronal subtypes across hypothalamic nuclei and further mapped their activation patterns in response to a series of well-defined innate behaviors.

Results

Dbx1-derived neurons occupy multiple postnatal hypothalamic nuclei including the lateral hypothalamus (LH), arcuate nucleus (Arc) and the ventral medial hypothalamus (VMH). Within these nuclei, Dbx1
+ progenitors generate a large proportion of the Pmch-, Nesfatin-, Cart-, Hcrt-, Agrp- and ERα-expressing neuronal populations, and to a lesser extent the Pomc-, TH- and Aromatase-expressing populations. Inducible fate-mapping reveals distinct temporal windows for development of the Dbx1-derived LH and Arc populations, with Agrp+ and Cart+ populations in the Arc arising early (E7.5-E9.5), while Pmch+ and Hcrt+ populations in the LH derived from progenitors expressing Dbx1 later (E9.5-E11.5). Moreover, as revealed by c-Fos labeling, Dbx1-derived cells in male and female LH, Arc and VMH are responsive during mating and aggression. In contrast, Dbx1-lineage cells in the Arc and LH have a broader behavioral tuning, which includes responding to fasting and predator odor cues.

Conclusion
We define a novel fate map of the hypothalamus with respect to Dbx1 expression in hypothalamic progenitor zones. We demonstrate that in a temporally regulated manner, Dbx1-derived neurons contribute to molecularly distinct neuronal populations in the LH, Arc and VMH that have been implicated in a variety of hypothalamic-driven behaviors. Consistent with this, Dbx1-derived neurons in the LH, Arc and VMH are activated during stress and other innate behavioral responses, implicating their involvement in these diverse behaviors.
Impact of frequent cerebrospinal fluid sampling on Aβ levels: systematic approach to elucidate influencing factors
Authors: Van Broeck Bianca , Timmers Maarten , Ramael Steven , Bogert Jennifer , Shaw Leslie M. , Mercken Marc , Slemmon John , Van Nueten Luc , Engelborghs Sebastiaan , Streffer Johannes Rolf 
Published: May 2016

Abstract
Background
Cerebrospinal fluid (CSF) amyloid-beta (Aβ) peptides are predictive biomarkers for Alzheimer’s disease and are proposed as pharmacodynamic markers for amyloid-lowering therapies. However, frequent sampling results in fluctuating CSF Aβ levels that have a tendency to increase compared with baseline. The impact of sampling frequency, volume, catheterization procedure, and ibuprofen pretreatment on CSF Aβ levels using continuous sampling over 36 h was assessed.

Methods
In this open-label biomarker study, healthy participants (n = 18; either sex, age 55 − 85 years) were randomized into one of three cohorts (n = 6/cohort; high-frequency sampling). In all cohorts except cohort 2 (sampling started 6 h post catheterization), sampling through lumbar catheterization started immediately post catheterization. Cohort 3 received ibuprofen (800 mg) before catheterization. Following interim data review, an additional cohort 4 (n = 6) with an optimized sampling scheme (low-frequency and lower volume) was included. CSF Aβ1–37, Aβ1–38, Aβ1–40, and Aβ1–42 levels were analyzed.

Results
Increases and fluctuations in mean CSF Aβ levels occurred in cohorts 1–3 at times of high-frequency sampling. Some outliers were observed (cohorts 2 and 3) with an extreme pronunciation of this effect. Cohort 4 demonstrated minimal fluctuation of CSF Aβ both on a group and an individual level. Intersubject variability in CSF Aβ profiles over time was observed in all cohorts.

Conclusions
CSF Aβ level fluctuation upon catheterization primarily depends on the sampling frequency and volume, but not on the catheterization procedure or inflammatory reaction. An optimized low-frequency sampling protocol minimizes or eliminates fluctuation of CSF Aβ levels, which will improve the capability of accurately measuring the pharmacodynamic read-out for amyloid-lowering therapies.

Trial registration
ClinicalTrials.gov NCT01436188. Registered 15 September 2011.
The scalp as a donor site for skin grafting in burns: retrospective study on complications
Authors: Roodbergen Dorota Teresa , Vloemans Adrianus Fredericus Petrus Maria , Rashaan Zjir Mezjda , Broertjes Jacob Cornelis , Breederveld Roelf Simon 
Published: May 2016

Abstract

Background
Split skin grafting (SSG) is the cornerstone in the treatment of deep burns and large skin defects. Frequently used donor sites are the thigh, abdomen and buttocks. The scalp is less common while considered as a reliable donor site. Advantages are a large surface area, rapid wound healing, cosmetically favourable results and multiple harvests from the same donor site. Complications include scab formation, chronic folliculitis and alopecia but have been recorded sporadically in previous studies. This article evaluates the complication rate of the scalp donor site in the treatment of deep burns in the Beverwijk Burn Centre.

Methods
A retrospective study was performed of all patients who received a skin graft from the scalp at the Beverwijk Burn Centre between January 2004 and December 2012. Data were collected from medical files of included patients, including gender, age, type of burn (scald, flame, other) and total body surface area (TBSA) burned at the time of first surgery. Postoperative variables were healing time of the donor site and incidence of complications. During follow-up, the incidence of late complications was reviewed.

Results
A total number of 105 grafts were analysed in 93 patients: 58 males (62 %) and 35 females (38 %), with a median age of 2 years and 3 months old. Of the patients, 30 (32 %) had flame burns and 57 (61 %) had scald burns. Eighty-seven percent of patients had a TBSA burned of 5 % or less. All donor sites healed within 14 days. No alopecia or scar hypertrophy developed at the donor sites. Two patients (2.2 %) developed folliculitis; one patient (1.1 %) showed scab formation.

Conclusions
The scalp as a donor site in our Burn Centre shows a comparable short-term complication rate to the previous literature, with quick healing and no long-term complications. Therefore, we propose the consideration of the scalp as a primary donor site, especially in young children, where the scalp offers a larger donor site area than the buttocks or thighs.
The role of antioxidant micronutrients in the rate of recovery of burn patients: a systematic review
Authors: Adjepong Mary , Agbenorku Pius , Brown Patricia , Oduro Ibok 
Published: May 2016

Abstract
Burn injury can be detrimental to the health of individuals, meanwhile victims lose proteins and micronutrients in wound exudates. Victims also experience extensive protein catabolism. These make them prone to malnutrition. Burn patients also suffer a lot of emotional trauma that reduce nutrient intake. The aim of this paper was to review primary evidence on the effect of antioxidant micronutrients on the recovery rate of burn patients. Electronic databases such as PubMed, BioMed, and Cochrane were systematically searched between January 1, 2014, and January 30, 2014. Keywords include vitamin A, vitamin C, vitamin E, ascorbic acid, zinc, copper, selenium, tocopherol, carotenoids, dietary intake, supplementation, wound healing, infection, recovery rate, and burn patients. The systematic search was done to retrieve all published data from 1990 to 2013. A total of 518 journal articles were obtained, and after the removal of duplicates, reviews, commentaries, and studies with non-human subjects, 11 papers were accepted for review. The review considered only papers that were published, and there might be some unpublished data that may have been omitted. Generally, the wound healing time and infection rates were reduced by the administration of the antioxidant micronutrients. The review revealed that there was no such published work in developing countries and children were excluded from most studies. It was also stated clearly that there was no uniformity in burn management; hence, there is a need for more studies on burn management in various populations.
EPAC1 activation by cAMP stabilizes CFTR at the membrane by promoting its interaction with NHERF1
Authors: Lobo Miguel J. , Amaral Margarida D. , Zaccolo Manuela , Farinha Carlos M. 
Published: May 2016

ABSTRACT
Cyclic AMP (cAMP) activates protein kinase A (PKA) but also the guanine nucleotide exchange factor ‘exchange protein directly activated by cAMP’ (EPAC1; also known as RAPGEF3). Although phosphorylation by PKA is known to regulate CFTR channel gating – the protein defective in cystic fibrosis – the contribution of EPAC1 to CFTR regulation remains largely undefined. Here, we demonstrate that in human airway epithelial cells, cAMP signaling through EPAC1 promotes CFTR stabilization at the plasma membrane by attenuating its endocytosis, independently of PKA activation. EPAC1 and CFTR colocalize and interact through protein adaptor NHERF1 (also known as SLC9A3R1). This interaction is promoted by EPAC1 activation, triggering its translocation to the plasma membrane and binding to NHERF1. Our findings identify a new CFTR-interacting protein and demonstrate that cAMP activates CFTR through two different but complementary pathways – the well-known PKA-dependent channel gating pathway and a new mechanism regulating endocytosis that involves EPAC1. The latter might constitute a novel therapeutic target for treatment of cystic fibrosis.