bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia
Authors: Shih Alan H. , Meydan Cem , Shank Kaitlyn , Garrett-Bakelman Francine E. , Ward Patrick S. , Intlekofer Andrew M. , Nazir Abbas , Stein Eytan M. , Knapp Kristina , Glass Jacob , Travins Jeremy , Straley Kim , Gliser Camelia , Mason Christopher E. , Yen Katharine , Thompson Craig B. , Melnick Ari , Levine Ross L. 
Published: February 2017

Abstract
Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, including TET2 and IDH2. Here, we show that models of AML resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output and resulted in a reduction in leukemic blasts consistent with antileukemic activity. These therapeutic benefits were associated with restoration of leukemic cell differentiation, and the normalization of hematopoiesis was derived from mutant cells. By contrast, combining AG-221 or 5-azacytidine with FLT3 inhibition resulted in a reduction in mutant allele burden, progressive recovery of normal hematopoiesis from non-mutant stem-progenitor cells, and reversal of dysregulated DNA methylation and transcriptional output. Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.
Significance: AMLs with mutations in TET2 or IDH2 are sensitive to epigenetic therapy through inhibition of DNA methyltransferase activity by 5-azacytidine or inhibition of mutant IDH2 through AG-221. These inhibitors induce a differentiation response and can be used to inform mechanism-based combination therapy. Cancer Discov; 7(5); 494–505. ©2017 AACR.
See related commentary by Thomas and Majeti, p. 459.
See related article by Yen et al., p. 478.
This article is highlighted in the In This Issue feature, p. 443
Differences in Presentation and Outcomes Between Children With Familial Dilated Cardiomyopathy and Children With Idiopathic Dilated Cardiomyopathy
Authors: Rusconi Paolo , Wilkinson James D. , Sleeper Lynn A. , Lu Minmin , Cox Gerald F. , Towbin Jeffrey A. , Colan Steven D. , Webber Steven A. , Canter Charles E. , Ware Stephanie M. , Hsu Daphne T. , Chung Wendy K. , Jefferies John L. , Cordero Christina , Lipshultz Steven E. 
Published: February 2017

Background—
Research comparing the survival of children with familial dilated cardiomyopathy (FDCM) to that of children with idiopathic dilated cardiomyopathy (IDCM) has produced conflicting results.

Methods and Results—

We analyzed data from children with FDCM or IDCM using the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry. Compared to children with IDCM (n=647), children with FDCM (n=223) were older (mean 6.2 versus 4.5 years,
P
<0.001), less often had heart failure (64% versus 78%,
P
<0.001), had less-depressed mean left ventricular fractional shortening
z
scores (−7.85±3.98 versus −9.06±3.89,
P
<0.001) and lower end-diastolic dimension
z
scores (4.12±2.61 versus 4.91±2.57,
P
<0.001) at diagnosis. The cumulative incidence of death was lower for patients with FDCM compared with IDCM (
P
=0.04; hazard ratio 0.64,
P
=0.06), but no difference in risk of transplant or the combined death or transplant outcome. There was no difference in the proportion of children with echocardiographic normalization at 3 years of follow-up (FDCM, 30% versus IDCM, 26%;
P
=0.33). Multivariable analysis showed no difference in outcomes between FDCM and IDCM but for both groups older age, congestive heart failure, and increased left ventricular end-systolic dimension
z
score at diagnosis were independently associated with an increased risk of death or heart transplantation (all
P
s<0.001).

Conclusions—
There was no survival difference between FDCM and IDCM after adjustment for other factors. Older age, congestive heart failure, and greater left ventricular dilation at diagnosis were independently associated with increased risk of the combined end point of death or transplantation.

Clinical Trial Registration—

URL:
https://clinicaltrials.gov
. Unique identifier: NCT00005391
Sex Differences in the Clinical Impact of High Platelet Reactivity After Percutaneous Coronary Intervention With Drug-Eluting Stents
Authors: Yu Jennifer , Mehran Roxana , Baber Usman , Ooi Sze-Yuan , Witzenbichler Bernhard , Weisz Giora , Rinaldi Michael J. , Neumann Franz-Josef , Metzger D. Christopher , Henry Timothy D. , Cox David A. , Duffy Peter L. , Mazzaferri Ernest L. , Brodie Bruce R. , Stuckey Thomas D. , Maehara Akiko , Xu Ke , Ben-Yehuda Ori , Kirtane Ajay J. , Stone Gregg W. 
Published: February 2017

Background—
Sex differences in the outcomes after percutaneous coronary intervention with drug-eluting stents and in the response to clopidogrel therapy have been reported; however, the differential risk of high platelet reactivity (HPR) on clopidogrel in women versus men is unknown.

Methods and Results—

We compared 8448 patients enrolled in the ADAPT-DES study (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) according to sex and the presence/absence of HPR on clopidogrel (defined as P2Y12 reactivity units >208). Study end points were definite and probable stent thrombosis (ST), clinically relevant bleeding, all-cause mortality, myocardial infarction, and major adverse cardiac events (comprising mortality, myocardial infarction, and target lesion revascularization). HPR was more common among women (1118/2163, 51.7%) than men (2491/6285, 39.6%). HPR was associated with a roughly double risk of 1-year ST in both women and men (women with versus without HPR: 1.4% versus 0.7%; hazard ratio [HR], 2.02; 95% confidence interval [CI], 0.82–4.95;
P
=0.12; and men: 1.2% versus 0.5%; HR, 2.42; 95% CI, 1.36–4.30;
P
=0.002;
P
interaction
=0.73). HPR was associated with almost half the rate of clinically relevant bleeding in women (women: HPR versus no HPR, 5.3% versus 9.8%; HR, 0.54; 95% CI, 0.40–0.74;
P
<0.001), whereas men had similar rates of bleeding regardless of HPR status (men: HPR versus no HPR, 5.7% versus 5.9%; HR, 0.96; 95% CI, 0.78–1.18;
P
=0.70;
P
interaction
=0.003). In propensity-adjusted models, HPR was an independent predictor of ST and myocardial infarction in men; although both associations were nonsignificant among women, no interaction was observed in the associations between HPR and either ST or myocardial infarction. Conversely, HPR was an independent predictor of reduced bleeding only in women (women: adjusted HR, 0.58; 95% CI, 0.41–0.82;
P
=0.002; and men: adjusted HR, 0.83; 95% CI, 0.65–1.04;
P
=0.11;
P
interaction
=0.01).

Conclusions—
In the current analysis, the associated risk of HPR for ST was similar in both sexes. However, HPR was associated with significantly reduced bleeding only among women.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00638794.
Aspirin Desensitization in Patients With Coronary Artery Disease
Authors: Rossini Roberta , Iorio Annamaria , Pozzi Roberto , Bianco Matteo , Musumeci Giuseppe , Leonardi Sergio , Lettieri Corrado , Bossi Irene , Colombo Paola , Rigattieri Stefano , Dossena Cinzia , Anzuini Angelo , Capodanno Davide , Senni Michele , Angiolillo Dominick J. 
Published: February 2017

Background—
There are limited data on aspirin (ASA) desensitization for patients with coronary artery disease. The aim of the present study was to assess the safety and efficacy of a standard rapid desensitization protocol in patients with ASA sensitivity undergoing coronary angiography.

Methods and Results—
This is a prospective, multicenter, observational study including 7 Italian centers including patients with a history of ASA sensitivity undergoing coronary angiography with intent to undergo percutaneous coronary intervention. A total of 330 patients with history of ASA sensitivity with known/suspected stable coronary artery disease or presenting with an acute coronary syndrome, including ST-segment–elevation myocardial infarction were enrolled. Adverse effects to aspirin included urticaria (n=177, 53.6%), angioedema (n=69, 20.9%), asthma (n=65, 19.7%), and anaphylactic reaction (n=19, 5.8%). Among patients with urticaria/angioedema, 13 patients (3.9%) had a history of idiopathic chronic urticaria. All patients underwent a rapid ASA (5.5 hours) desensitization procedure. The desensitization procedure was performed before cardiac catheterization in all patients, except for those (n=78, 23.6%) presenting with ST-segment–elevation myocardial infarction who underwent the desensitization after primary percutaneous coronary intervention. Percutaneous coronary intervention was performed in 235 patients (71%) of the overall study population. The desensitization procedure was successful in 315 patients (95.4%) and in all patients with a history of anaphylactic reaction. Among the 15 patients (4.6%) who did not successfully respond to the desensitization protocol, adverse reactions were minor and responded to treatment with corticosteroids and antihistamines. Among patients with successful in-hospital ASA desensitization, 253 patients (80.3%) continued ASA for at least 12 months. Discontinuation of ASA in the 62 patients (19.7%) who had responded to the desensitization protocol was because of medical decision and not because of hypersensitivity reactions.

Conclusions—
A standard rapid desensitization protocol is safe and effective across a broad spectrum of patients, irrespective of the type of aspirin sensitivity manifestation, with indications to undergo coronary angiography with intent to perform percutaneous coronary intervention.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02848339.
Incidence and Survival After In-Hospital Cardiopulmonary Resuscitation in Nonelderly Adults
Authors: Mallikethi-Reddy Sagar , Briasoulis Alexandros , Akintoye Emmanuel , Jagadeesh Kavyashri , Brook Robert D. , Rubenfire Melvyn , Afonso Luis , Grines Cindy L. 
Published: February 2017

Background—
Survival trends after in-hospital cardiopulmonary resuscitation (ICPR) for cardiac arrest in nonelderly adults is not well known. Influence of cardiopulmonary resuscitation guidelines on nationwide survival after ICPR is yet to be well elucidated.

Methods and Results—

We examined survival trends and factors associated with survival after ICPR in nonelderly adults aged 18 to 64 years, using Healthcare Utilization Project Nationwide Inpatient Sample Database from 2007 through 2012 in the United States. Furthermore, we studied the impact of 2010 American Heart Association cardiopulmonary resuscitation guidelines on survival. We identified 235 959 patients who underwent ICPR after cardiac arrest. Overall, 30.4% patients survived to hospital discharge. Survival improved from 27.4% in 2007 to 32.8% in 2012 (
P
trend
<0.001). Shockable arrest rhythms were noted in 23.3% of patients. Incidence of ICPR increased from 1.81 per 1000 hospitalizations in 2007 to 2.37 per 1000 hospitalizations in 2012 (
P
trend
<0.001). There was no statistically significant change in survival trends before and after 2010 cardiopulmonary resuscitation guidelines. Female sex and shockable rhythms were associated with higher adjusted odds of survival, whereas black race, lack of health insurance, age, and weekend admission were associated with lower adjusted odds of survival.

Conclusions—
Among nonelderly adults, survival after ICPR improved significantly from 2007 through 2012, with an overall survival rate of 30.4%. Incidence of ICPR increased significantly during the study period. There was no statistically significant change in survival before and after 2010 cardiopulmonary resuscitation guidelines. Female sex and black race were associated with higher and lower odds of survival, respectively.
Genome-Wide Analysis of the Circulating miRNome After Cerebral Ischemia Reveals a Reperfusion-Induced MicroRNA Cluster
Authors: Uhlmann Stefan , Mracsko Eva , Javidi Ehsan , Lamble Sarah , Teixeira Ana , Hotz-Wagenblatt Agnes , Glatting Karl-Heinz , Veltkamp Roland 
Published: February 2017

Background and Purpose—
Circulating microRNAs (miRNAs) are emerging biomarkers for stroke because of their high stability in the bloodstream and association with pathophysiologic conditions. However, the circulating whole-genome miRNAs (miRNome) has not been characterized comprehensively in the acute phase of stroke.

Methods—
We profiled the circulating miRNome in mouse models of acute ischemic and hemorrhagic stroke by next-generation sequencing. Stroke models were compared with sham-operated and naive mice to identify deregulated circulating miRNAs. Top-ranked miRNAs were validated and further characterized by quantitative reverse transcription polymerase chain reaction.

Results—
We discovered 24 circulating miRNAs with an altered abundance in the circulation 3 hours after ischemia, whereas the circulating miRNome was not altered after intracerebral hemorrhage compared with sham-operated mice. Among the upregulated miRNAs in ischemia, the top-listed miR-1264/1298/448 cluster was strongly dependent on reperfusion in different ischemia models. A time course experiment revealed that the miR-1264/1298/448 cluster peaked in the circulation around 3 hours after reperfusion and gradually decreased thereafter.

Conclusions—
Alteration of the miRNome in the circulation is associated with cerebral ischemia/reperfusion, but not hemorrhage, suggesting a potential to serve as biomarkers for reperfusion in the acute phase. The pathophysiological role of reperfusion-inducible miR-1264/1298/448 cluster, which is located on chromosome X within the introns of the serotonin receptor HTR2C, requires further investigation.
《翻譯老乞大·朴通事》與明代官話入聲調的分化
Authors: Dong Jianjiao 
Published: February 2017

提要
《翻譯老乞大•朴通事》右音入聲調存在按主元音高低分化的現象。本文結合粵語、閩南語、晉語和江淮官話等方言中元音差異影響入聲調和入聲尾演變的情況，證明《翻譯老乞大•朴通事》右音入聲調分化模式可能是有實際語音依據的，崔世珍記錄的十六世紀漢語官話入聲調消變的過程中出現過按主元音分化的現象，和現代江淮官話六安、舒城方言最為接近。這種相似性可能說明十六世紀官話和江淮官話之間存在某種淵源關係，但更可能只是相同音理導致的類型上的一致。
The Effect of Vertical Baroclinicity Concentration on Atmospheric Macroturbulence Scaling Relations
Authors: Yuval Janni , Kaspi Yohai 
Published: February 2017

Abstract
Motivated by the expectation that under global warming upper-level meridional temperature gradients will increase while lower-level temperature gradients will decrease, the relations between the vertical structure of baroclinicity and eddy fields are investigated. The sensitivity of eddies and the relation between the mean available potential energy and eddy quantities are studied for cases where the vertical structure of the lapse rate and meridional temperature gradient are modified. To investigate this systematically, an idealized general circulation model with a Newtonian cooling scheme that has a very short relaxation time for the mean state and a long relaxation time for eddies is used. This scheme allows for any chosen zonally mean state to be obtained with good precision. The results indicate that for similar change in the lapse rate or meridional temperature gradient, eddies are more sensitive to changes in baroclinicity where it is already large. Furthermore, when the vertical structure of the lapse rate or the meridional temperature gradient is modified, there is no universal linear relation between the mean available potential energy and eddy quantities.
Role of Rain as Perception Aid in Assessing Wind Speeds and Associated Personal Risks
Authors: Agdas Duzgun , Masters Forrest J. , Webster Gregory D. 
Published: February 2017

Abstract
Extreme event perception drives personal risks and, consequently, dictates household decision-making before, during, and after extreme events. Given this, increasing the extreme event perception accuracy of the public is important to improving decision-making in extreme event scenarios; however, limited research has been done on this subject. Results of a laboratory experiment, in which 76 human participants were exposed to hurricane-strength weather conditions and asked to estimate their intensities and associated personal risks, are presented in this article. Participants were exposed to a range of identical wind speeds [20, 40, 60 mph (1 mph = 1.61 km h−1)] with [8 in. h−1 (1 in. = 2.54 cm)] and without rain. They then provided estimates of the perceived wind and rain (when present) speeds, and associated personal risks on a nominal scale of 0 to 10. Improvements in the accuracy of wind speed perception at higher speeds were observed when rain was present in the wind field (41.5 and 69.1 mph) than when it was not (45.2 and 75.8 mph) for 40- and 60-mph wind speed exposures, respectively. In contrast, risk perceptions were similar for both rain and nonrain conditions. This is particularly interesting because participants failed to estimate rain intensities (both horizontal and wind-driven rain) by a significant margin. The possible implications of rain as a perception aid to wind and the viability of using perception aids to better convey extreme weather risks are discussed. The article concludes by revisiting discussions about the implications of past hurricane experience on wind intensity perception, personal risk assessment, and future directions in extreme weather risk perception research.
Efficacy of a universal smoking cessation intervention initiated in inpatient psychiatry and continued post-discharge: A randomised controlled trial
Authors: Metse Alexandra P , Wiggers John , Wye Paula , Wolfenden Luke , Freund Megan , Clancy Richard , Stockings Emily , Terry Margarett , Allan John , Colyvas Kim , Prochaska Judith J , Bowman Jenny A 
Published: February 2017

Objective: Interventions are required to redress the disproportionate tobacco-related health burden experienced by persons with a mental illness. This study aimed to assess the efficacy of a universal smoking cessation intervention initiated within an acute psychiatric inpatient setting and continued post-discharge in reducing smoking prevalence and increasing quitting behaviours. Method: A randomised controlled trial was undertaken across four psychiatric inpatient facilities in Australia. Participants ( N = 754) were randomised to receive either usual care ( n = 375) or an intervention comprising a brief motivational interview and self-help material while in hospital, followed by a 4-month pharmacological and psychosocial intervention ( n = 379) upon discharge. Primary outcomes assessed at 6 and 12 months post-discharge were 7-day point prevalence and 1-month prolonged smoking abstinence. A number of secondary smoking-related outcomes were also assessed. Subgroup analyses were conducted based on psychiatric diagnosis, baseline readiness to quit and nicotine dependence. Results: Seven-day point prevalence abstinence was higher for intervention participants (15.8%) than controls (9.3%) at 6 months post-discharge (odds ratio = 1.07, p = 0.04), but not at 12 months (13.4% and 10.0%, respectively; odds ratio = 1.03, p = 0.25). Significant intervention effects were not found on measures of prolonged abstinence at either 6 or 12 months post-discharge. Differential intervention effects for the primary outcomes were not detected for any subgroups. At both 6 and 12 months post-discharge, intervention group participants were significantly more likely to smoke fewer cigarettes per day, have reduced cigarette consumption by ⩾50% and to have made at least one quit attempt, relative to controls. Conclusions: Universal smoking cessation treatment initiated in inpatient psychiatry and continued post-discharge was efficacious in increasing 7-day point prevalence smoking cessation rates and related quitting behaviours at 6 months post-discharge, with sustained effects on quitting behaviour at 12 months. Further research is required to identify strategies for achieving longer term smoking cessation.
Sexuality education delivery in Australian regional secondary schools: A qualitative case study
Authors: Hulme Chambers Alana , Tomnay Jane , Clune Samantha , Roberts Sarah 
Published: February 2017

Background: Factors affecting the delivery of sexuality education to school students include government policy, school leadership and teacher confidence. Objective: The aim of this paper was to understand, from the perspective of regional education, health and welfare sector professionals, what is needed to support good sexual health for secondary school students. Methods: A qualitative study that took place in ‘Fairview’, a regional location in Victoria, Australia. Five focus groups, totalling 37 participants, were conducted in 2015. An inductive analysis was used to identify key themes. Findings: The main theme was the inconsistent presence and delivery of sexuality education curriculum in Fairview schools. This was attributed to factors such as perceived lack of commitment at government level to sexuality education, lack of importance in comparison with other subjects and variation in inclusion across year levels. Teachers and the delivery of sexuality education and the role of school leadership in supporting sexuality education were the two sub-themes present within the broader narrative. Teacher capacity to deliver sexuality education was ascribed to lack of training. Perceptions concerning the use of external providers to deliver sexuality education differed, as did opinions about the role of school leadership in supporting sexuality education. Conclusion: Sexuality education in schools could be improved through clearer government policy direction. This would signal the importance of sexuality education to school leaders and, if supported via resources such as training for teachers, could assist in achieving the aim of improving students’ sexual health and well-being.
Prevention of Tracheostomy‐Related Hospital‐Acquired Pressure Ulcers
Authors: O’Toole Thomas R. , Jacobs Natalie , Hondorp Brian , Crawford Laura , Boudreau Lisa R. , Jeffe Jill , Stein Brian , LoSavio Phillip 
Published: February 2017

ObjectiveTo determine if standardization of perioperative tracheostomy care procedures decreased the incidence of hospital‐acquired tracheostomy‐related pressure ulcers.MethodsAll patients at least 18 years old who underwent placement of a tracheostomy tube in the operating room from July 1, 2014, through June 30, 2015, were cared for postoperatively through an institutionally adopted quality improvement protocol. This included 4 elements: (1) placement of a hydrocolloid dressing underneath the tracheostomy flange in the postoperative period, (2) removal of plate sutures within 7 days of the tracheostomy procedure, (3) placement of a polyurethane foam dressing after suture removal, and (4) neutral positioning of the head. One year after the bundle was initiated, a retrospective analysis was performed to compare the percentage of tracheostomy patients who developed pressure ulcers versus the preintervention period.ResultsThe incidence of tracheostomy‐related pressure ulcers decreased from 20 of 183 tracheostomies (10.93%) prior to use of the standardized protocol to 2 of 155 tracheostomies (1.29%). Chi‐square analysis showed a significant difference between the groups, with a P value of. 0003.DiscussionAdoption of this care bundle at our institution resulted in a significant reduction in the incidence of hospital‐acquired tracheostomy‐related pressure ulcers. The impact of any single intervention within our protocol was not assessed and could be an area of further investigation.Implications for PracticeAdoption of a standardized posttracheostomy care bundle at the institution level may result in the improved care of patients with tracheostomies and specifically may reduce the incidence of pressure ulcers.