bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia
Authors: Ye Lin , Wang Jiaming , Tan Yuting , Beyer Ashley I. , Xie Fei , Muench Marcus O. , Kan Yuet Wai 
Published: September 2016

Significance
We designed this study to elevate fetal hemoglobin for the treatment of β-thalassemia and sickle cell disease (SCD). It has long been known that some individuals who are compound heterozygotes of β-thalassemia or SCD with deletional hereditary persistence of fetal hemoglobin (HPFH) have minimal hematological abnormalities and mild clinical manifestation compared with the homozygous patients. We used CRISPR-Cas9 to modify normal bone marrow hematopoietic stem and progenitor cells (HSPCs) to the deletional HPFH genotype. The erythroid cells derived from such modified HSPCs showed significantly higher γ-globin expression compared with the nondeletion-modified cells. This study provides proof of concept for developing a potential new approach to autologous transplantation therapy for the treatment of homozygous β-thalassemia and SCD.
Episodic specificity induction impacts activity in a core brain network during construction of imagined future experiences
Authors: Madore Kevin P. , Szpunar Karl K. , Addis Donna Rose , Schacter Daniel L. 
Published: September 2016

Significance
Recent behavioral studies using an episodic specificity induction—training in recollecting details of past experiences—have suggested a role for episodic memory in imagining future events, solving problems, and thinking creatively. The present fMRI study examines the brain regions impacted by the specificity induction. The experiment shows that receiving a specificity induction led to increased activity in key brain regions previously implicated in detailed event construction, including the hippocampus and inferior parietal lobule, when participants imagined future events. These results provide insights into the influence of episodic memory beyond simple remembering, and may help to guide potential applications for individuals from populations characterized by overgeneralized memory and imagination, such as healthy aging and clinical depression.
eIF4B stimulates translation of long mRNAs with structured 5′ UTRs and low closed-loop potential but weak dependence on eIF4G
Authors: Sen Neelam Dabas , Zhou Fujun , Harris Michael S. , Ingolia Nicholas T. , Hinnebusch Alan G. 
Published: September 2016

Significance
Protein synthesis initiates in eukaryotes when the 40S ribosomal subunit, loaded with initiator tRNA, attaches to the 5′ end of the mRNA, scans the 5′ UTR, and selects the AUG start codon. Ribosome attachment and scanning are impeded by structures in the 5′ UTR that can be resolved by RNA helicases Ded1 and eukaryotic translation initiation factor 4A (eIF4A), with cofactors eIF4B and eIF4G. We show that eIF4B can stimulate translation independently of eIF4A and that eIF4B, eIF4A, and Ded1 are preferentially required for translating long mRNAs, burdened with 5′ UTR structures, that inefficiently form the closed-loop intermediate with the mRNA ends joined by eIF4G. In contrast, eIF4G appears to be most crucial for closed-loop assembly on short, highly translated, and unstructured mRNAs.
Improving Antimicrobial Stewardship by Antibiotic Allergy Delabeling: Evaluation of Knowledge, Attitude, and Practices Throughout the Emerging Infections Network
Authors: Trubiano Jason A. , Beekmann Susan E. , Worth Leon J. , Polgreen Philip M. , Thursky Karin A. , Slavin Monica A. , Grayson M. Lindsay , Phillips Elizabeth J. 
Published: September 2016

Abstract
Antibiotic allergy testing (AAT) practices of Emerging Infections Network infectious disease physicians were surveyed. Although AAT was perceived to be necessary for removal of inappropriate or unnecessary allergy labels, there was limited access to any form of testing. In this study, we discuss current antibiotic allergy knowledge gaps and the development of AAT practices within antimicrobial stewardship programs, which will potentially improve antimicrobial prescribing.
Range and Innovation in Jonson’s Staging
Authors: Happé Peter 
Published: September 2016

Abstract
This review of Jonson’s staging methods in eight plays over 34 years in five theatres suggests that he was persistently innovative and creative. He adapted his plays to different types of theatre and made his decisions about staging match the differing objectives he set himself within the plays. It shows that he could write on a large scale as well as for intimate situations, and that he created stage events which involved complex movement and intricate actions. He was always aware of the need to entertain his audiences as well as being concerned to stimulate their thinking, and in order to do this he used a range of staging devices including metatheatrical presentation, onstage commentary, and the creation of an imagined space offstage. Such devices could be simple and adaptable to different situations, but at times he also located stage action quite specifically to real places in London.
Effects of Heavy Exercise and Restricted Diet Regimes on Nitrogen Balance and Body Composition
Authors: Huelsemann Frank , Koehler Karsten , Flenker Ulrich 
Published: September 2016

Abstract
In the past people led far more strenuous, active lives than industrialized, sedentary populations do today, and conditions could be far harsher, for instance during frigid glacial conditions. These factors carry significant implications for human energy requirements and metabolism. Endurance athletes undergoing strenuous physical regimes can serve as models for such demanding conditions. This chapter reviews the influences of strenuous activity and dietary restrictions on energy and protein metabolism. The thesis is illustrated by describing a semi-controlled experiment of an expedition across a hostile environment, monitored by means of nutritional and activity records, and stable nitrogen isotope ratios (15N/14N) in hair. The results demonstrate that under demanding conditions both energy balance and protein intake lead to 15N-enrichment; dietary and metabolic effects cannot be separated. They suggest that physically demanding lifestyles, especially under harsh conditions, must be considered in the interpretation of human 15N/14N values for dietary reconstructions.
‘Discourse on Rivers, and Fish and Fishing’
Authors: Mitchell Peter 
Published: September 2016

Abstract
Freshwater fish are often identified as a major resource for past hunter-gatherers, and their exploitation has been implicated in both the emergence of the capacity for modern behaviour and the evolution of sociopolitical complexity. Archaeological attention has mostly been directed at higher latitude groups, but southern Africa is one of several middle and lower latitude regions in which freshwater fish were also procured, sometimes on a large scale. This chapter considers their exploitation in Africa south of the Zambezi over the longue durée of the past 70,000 years, discusses the ways in which they were captured, and evaluates claims that they helped sustain higher population densities, reduced mobility, seasonal aggregation, and the development of more ‘delayed return’ economies during the late Holocene.
Faculty Talk About Teaching at the Community College
Authors: Finley Diane L. , Kinslow Sherry L. 
Published: September 2016

Abstract
This article examines what it means to teach at a community college from the viewpoint of two experienced faculty members. The comprehensive community college holds a unique place in American higher education, as it performs many functions, including workforce development, transfer education, and often developmental (remedial) education. The open-admissions nature of the community college gives anyone access to a college education or other training. That access results in a classroom that is different from those at four-year institutions. This article examines what it means to teach at the community college level by examining the community college and its place in American higher education. It includes an exploration of how open admission affects the classroom and the teacher. It discusses how the multiple missions of the community college, as well as political and funding issues, influence the faculty and their primary responsibility of teaching.
The Characteristics of International Medical Graduates Who Have Been Disciplined by Professional Regulatory Colleges in Canada: A Retrospective Cohort Study
Authors: Alam Asim , Matelski John J. , Goldberg Hanna R. , Liu Jessica J. , Klemensberg Jason , Bell Chaim M. 
Published: September 2016

Purpose
This study evaluated the proportion and characteristics of international medical graduates (IMGs) who have been disciplined by professional regulatory colleges in Canada in comparison with disciplined North American medical graduates (NAMGs).

Method
The authors compiled a database of the nature of professional misconduct and penalties incurred by disciplined physicians from January 2000 to May 2015 using public records. They compared discipline data for IMGs versus those for NAMGs, and calculated risk ratios (RRs) and 95% confidence intervals (CIs) for select outcomes.

Results
There were 794 physicians disciplined; 922 disciplinary cases during the 15-year study period. IMGs composed an average of 23.4% (standard deviation = 1.1%) of the total physician population and represented one-third of disciplined physicians and discipline cases. The overall disciplinary rate for all Canadian physicians was 8.52 cases per 10,000 physician years (95% CI [7.77, 9.31]). This rate per group was higher for IMGs than for NAMGs (12.91 [95% CI (11.50, 14.43)] vs. 8.16 [95% CI (7.53, 8.82)] cases per 10,000 physician years, P < .01, and RR 1.58 (95% CI [1.38, 1.82]). IMGs were disciplined at significantly higher rates than NAMGs if they were trained in South Africa (RR 1.73 [95% CI (1.14, 2.51), P < .01), Egypt (RR 3.59 [95% CI (2.18, 5.52)], P < .01), or India (RR 1.66 [95% CI (1.01, 2.55)], P = .03).

Conclusions
IMGs are disciplined at a higher rate than NAMGs. Future initiatives should be focused to delineate the exact cause of this observation.
Health Care Disparity and State-Specific Pregnancy-Related Mortality in the United States, 2005–2014
Authors: Moaddab Amirhossein , Dildy Gary A. , Brown Haywood L. , Bateni Zhoobin H. , Belfort Michael A. , Sangi-Haghpeykar Haleh , Clark Steven L. 
Published: September 2016

OBJECTIVE:
To investigate factors associated with differential state maternal mortality ratios and to quantitate the contribution of various demographic factors to such variation.

METHODS:
In a population-level analysis study, we analyzed data from the Centers for Disease Control and Prevention National Center for Health Statistics database and the Detailed Mortality Underlying Cause of Death database (CDC WONDER) that contains mortality and population counts for all U.S. counties. Bivariate correlations between maternal mortality ratio and all maternal demographic, lifestyle, health, and medical service utilization characteristics were calculated. We performed a maximum likelihood factor analysis with varimax rotation retaining variables that were significant (P<.05) in the univariate analysis to deal with multicollinearity among the existing variables.

RESULTS:
The United States has experienced a continued increase in maternal mortality ratio since 2007 with rates of 21–22 per 100,000 live births in 2013 and 2014. This increase in mortality was most dramatic in non-Hispanic black women. There was a significant correlation between state mortality ranking and the percentage of non-Hispanic black women in the delivery population. Cesarean deliveries, unintended births, unmarried status, percentage of non-Hispanic black deliveries, and four or less prenatal visits were significantly (P<.05) associated with increased maternal mortality ratio.

CONCLUSION:
Interstate differences in maternal mortality ratios largely reflect a different proportion of non-Hispanic black or unmarried patients with unplanned pregnancies. Racial disparities in health care availability, access, or utilization by underserved populations are an important issue faced by states in seeking to decrease maternal mortality.
Distinguishing Arterial Ischemic Stroke From Hypoxic–Ischemic Encephalopathy in the Neonate at Birth
Authors: Adami Rebecca R. , Grundy Maureen E. , Poretti Andrea , Felling Ryan J. , Lemmon Monica , Graham Ernest M. 
Published: September 2016

OBJECTIVE:
To identify perinatal risk factors that can distinguish arterial ischemic stroke from hypoxic–ischemic encephalopathy at birth.

METHODS:
This is a cohort study of all neonates born at 35 weeks of gestation or greater admitted to our neonatal intensive care unit from January 1, 2010, to December 31, 2015, that compares neonates with stroke with those with hypoxic–ischemic encephalopathy undergoing whole-body hypothermia with abnormal brain magnetic resonance imaging.

RESULTS:
During this 6-year period, there were 22 neonates with stroke and 47 with hypoxic–ischemic encephalopathy undergoing whole-body hypothermia with abnormal magnetic resonance imaging. Three neonates triaged to hypothermia initially thought to have hypoxic–ischemic encephalopathy were later diagnosed with stroke. All neonates with stroke had a negative thrombophilia workup. Neonates with stroke had a significantly higher incidence of seizures and increased initial platelet counts on univariate analysis. A multivariable model of variables with P<.1 on univariate analysis present within 6 hours of birth found significant increases in nonreassuring fetal heart rate tracings, sentinel events, low Apgar score at 5 minutes, and metabolic acidosis at birth with hypoxic–ischemic encephalopathy. Stroke was associated with a significantly increased initial platelet count.

CONCLUSION:
Stroke is associated with increased initial platelet counts and is not associated with cesarean delivery for nonreassuring fetal heart rate tracings, sentinel events, or perinatal metabolic acidosis. Stroke is a form of neonatal brain injury not associated with perinatal risk factors that allow early identification.
Maternal Marijuana Use and Adverse Neonatal Outcomes
Authors: Conner Shayna N. , Bedell Victoria , Lipsey Kim , Macones George A. , Cahill Alison G. , Tuuli Methodius G. 
Published: September 2016

OBJECTIVE:
To estimate whether marijuana use in pregnancy increases risks for adverse neonatal outcomes and clarify if any increased risk is attributable to marijuana use itself or to confounding factors such as tobacco use.

DATA SOURCES:
Two authors performed a search of the data through August 2015 utilizing PubMed, Embase, Scopus, Cochrane reviews, ClinicalTrials.gov, and Cumulative Index to Nursing and Allied Health.

METHODS OF STUDY SELECTION:
We looked at observational studies that compared rates of prespecified adverse neonatal outcomes in women who used marijuana during pregnancy with women who did not.

TABULATION, INTEGRATION, AND RESULTS:
Two authors independently extracted data from the selected studies. Primary outcomes were low birth weight (less than 2,500 g) and preterm delivery at less than 37 weeks of gestation. Secondary outcomes were birth weight, gestational age at delivery, small for gestational age, level II or greater nursery admission, stillbirth, spontaneous abortion, low Apgar score, placental abruption, and perinatal death. DerSimonian-Laird random-effects models were used. We assessed heterogeneity using the Q test and I
2 statistic. Stratified analyses were performed for the primary outcomes and pooled adjusted estimates were calculated. We included 31 studies that assessed the effects of maternal marijuana use on adverse neonatal outcomes. Based on pooled unadjusted data, marijuana use during pregnancy was associated with an increased risk of low birth weight (15.4% compared with 10.4%, pooled relative risk [RR] 1.43, 95% confidence interval [CI] 1.27–1.62) and preterm delivery (15.3% compared with 9.6%, pooled RR 1.32, 95% CI 1.14–1.54). However, pooled data adjusted for tobacco use and other confounding factors showed no statistically significant increased risk for low birth weight (pooled RR 1.16, 95% CI 0.98–1.37) or preterm delivery (pooled RR 1.08, 95% CI 0.82–1.43).

CONCLUSION:
Maternal marijuana use during pregnancy is not an independent risk factor for adverse neonatal outcomes after adjusting for confounding factors. Thus, the association between maternal marijuana use and adverse outcomes appears attributable to concomitant tobacco use and other confounding factors.
Extended adjuvant endocrine therapy in hormone-receptor-positive early breast cancer
Authors: O’Leary Connor G. , Ellis Haley , Higgins Michaela 
Published: September 2016

Purpose of review
The risk of relapse associated with oestrogen receptor-positive early breast cancer persists for at least 15 years after diagnosis. Several large clinical trials have examined extended adjuvant endocrine therapy.

Recent findings
The MA.17 trial demonstrated improved disease-free survival (DFS) with use of letrozole for 5 years after some years of tamoxifen and an overall survival advantage for this approach in women with node-positive oestrogen receptor-positive cancer at diagnosis. The subsequent adjuvant tamoxifen – to offer more? and adjuvant tamoxifen: longer against shorter trials demonstrated a DFS advantage for 10 years of tamoxifen over 5 years. The recently reported MA.17R trial randomized women who had already completed 5 years of aromatase inhibitor therapy with or without previous tamoxifen to further 5 years of letrozole or placebo. DFS was significantly improved in the extended letrozole group, quality of life was similar but bone fracture rates were higher. The absolute benefit in terms of reduced distant recurrences in these studies is modest, and tolerability and compliance challenges remain.

Summary
Physicians and patients now have multiple evidence-based treatment options for women who complete 5 years of adjuvant endocrine therapy. Extended therapy with either tamoxifen or letrozole should be considered for all and decision based on menopausal status, individual risk, tolerance and magnitude of potential benefit.
Extended anti-HER2 therapy in early breast cancer: longer beats shorter?
Authors: Refae Sadal , Pistilli Barbara , Delaloge Suzette 
Published: September 2016

Purpose of review
One-year duration of adjuvant trastuzumab is the gold standard since 2005. During the last decade many attempts have been made to both increase and reduce the treatment duration. The purpose of this article is to review the current available evidence regarding alternative anti-HER2 therapy durations in the (neo)adjuvant treatment of HER2-positive localized breast cancer patients.

Recent findings
According to the majority of published data, shorter trastuzumab schedule has shown a decreased benefit in the overall HER2 population, whereas extending adjuvant trastuzumab, beyond 1 year, does not improve the outcome and is associated with increased cardiac toxicity. However, new challenging questions are raised by the recent results of ExteNet trial, in which sequential introduction of 1 year neratinib after standard trastumab-based therapy improved the outcome, especially in the estrogen receptor-positive subset of patients.

Summary
To date the standard duration of adjuvant trastuzumab remains 1 year in the adjuvant setting. It is likely that ongoing trials will clarify which patients could benefit from a shorter or a longer treatment. Taking into account patient's specific risk/benefit ratio and new biomarkers, in future, a ‘personalized’ treatment duration would be warranted.
Practical implications of integrated glioma classification according to the World Health Organization classification of tumors of the central nervous system 2016
Authors: Malzkorn Bastian , Reifenberger Guido 
Published: September 2016

Purpose of review
Morphological features identifiable by light microscopy have been the basis of brain tumor diagnostics for many decades. The revised WHO classification of tumors of the central nervous system 2016 combines histological and molecular features for an integrated classification. This new approach builds upon advances in brain tumor molecular genetics and has important practical implications.

Recent findings
Molecular genetic studies revealed distinct glioma entities with specific genetic and epigenetic profiles. Evidence has been accumulated that molecular classification more reliably discriminates glioma entities and better predicts patient outcome than histological classification. Major glioma entities can be distinguished by four molecular biomarkers included in the new WHO classification, namely isocitrate dehydrogenase mutation, codeletion of chromosome arms 1p and 19q, codon 27 lysine-to-methionine mutation in H3 histones, and C11orf95-RELA gene fusions. Each is detectable by common techniques in routinely processed tissue specimens. Their integration into glioma classification greatly improves diagnostic accuracy but also has practical implications concerning establishment and quality control of novel techniques, increased costs and prolonged time to diagnosis.

Summary
We summarize the relevant changes in the revised WHO classification of gliomas, outline the integrated approach, and discuss its practical implications and potential challenges.
A Systematic Review of Local Excision After Neoadjuvant Therapy for Rectal Cancer: Are ypT0 Tumors the Limit?
Authors: Hallam Sally , Messenger David E. , Thomas Michael G. 
Published: September 2016

BACKGROUND:
Neoadjuvant therapy reduces local recurrence after radical surgery for rectal cancer with complete pathological response in 15% to 25% of patients. Radical surgery is associated with significant morbidity that may be avoided by local excision in selected cases.

OBJECTIVE:
This systematic review aimed to determine the oncological outcomes and morbidity of local excision after neoadjuvant therapy.

DATA SOURCES:
Data sources included MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases.

STUDY SELECTION:
A systematic search of the databases using validated terms for rectal cancer, neoadjuvant therapy, and local excision was conducted.

INTERVENTIONS:
Neoadjuvant therapy and local excision were the included interventions.

MAIN OUTCOME MEASURES:
Pooled local recurrence, median survival, and pooled morbidity were measured.

RESULTS:
Twenty unique studies were included (14 cohort, 5 comparative cohort, and 1 randomized controlled trial), describing 1068 patients. Patient choice, prohibitive comorbidity, good clinical response, and early stage disease were the most frequent indications for local excision. Pretreatment T2 and T3 tumors accounted for 46.4% and 30.7% of cases. Long-course treatment was administered in all of the studies, except to a cohort of 64 patients who received short-course radiotherapy. Pooled complete clinical response was 45.8% (95% CI, 31.4%–60.5%), and pooled complete pathological response was 44.2% (95% CI, 36.4%–52.0%). Median follow-up was 54 months (range, 12–81 months). ypT0 tumors had a pooled local recurrence rate of 4.0% (95% CI, 1.9%–6.9%) and a median disease-free survival rate of 95.0% (95% CI, 87.4%–100%). Pooled local recurrence and median disease-free survival rates for ypT1 tumors or higher were 21.9% (95% CI, 15.9%–28.5%) and 68.0% (58.3%–69.0%). Pooled incidence of complications was 23.2% (95% CI, 15.7%–31.7%), with suture-line dehiscence reported in 9.9% (95% CI, 4.8%–16.7%).

LIMITATIONS:
Limitations included study quality, high risk of selection bias and detection bias in study designs, and limited sample sizes.

CONCLUSIONS:
Local excision after neoadjuvant therapy should only be considered a curative treatment if complete pathological response is obtained. Given the high rate of local recurrence among incomplete responders, future studies should focus on predicting patients who will achieve complete pathological response.