bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reexamination of a Battlefield Trauma Golden Hour Policy
Authors: Howard Jeffrey T. , Kotwal Russ S. , Santos-Lazada Alexis R. , Martin Matthew J. , Stockinger Zsolt T. 
Published: October 2017

BACKGROUND
Most combat casualties who die, do so in the prehospital setting. Efforts directed toward alleviating prehospital combat trauma death, known as killed in action (KIA) mortality, have the greatest opportunity for eliminating preventable death.

METHODS
Four thousand five hundred forty-two military casualties injured in Afghanistan from September 11, 2001, to March 31, 2014, were included in this retrospective analysis to evaluate proposed explanations for observed KIA reduction after a mandate by Secretary of Defense Robert M. Gates that transport of injured service members occur within 60 minutes. Using inverse probability weighting to account for selection bias, data were analyzed using multivariable logistic regression and simulation analysis to estimate the effects of (1) gradual improvement, (2) damage control resuscitation, (3) harm from inadequate resources, (4) change in wound pattern, and (5) transport time on KIA mortality.

RESULTS
The effect of gradual improvement measured as a time trend was not significant (adjusted odds ratio [AOR], 0.99; 95% confidence interval [CI], 0.94–1.03; p = 0.58). For casualties with military Injury Severity Score of 25 or higher, the odds of KIA mortality were 83% lower for casualties who needed and received prehospital blood transfusion (AOR, 0.17; 95% CI, 0.06–0.51; p = 0.002); 33% lower for casualties receiving initial treatment by forward surgical teams (AOR, 0.67; 95% CI, 0.58–0.78; p < 0.001); 70%, 74%, and 87% lower for casualties with dominant injuries to head (AOR, 0.30; 95% CI, 0.23–0.38; p < 0.001), abdomen (AOR, 0.26, 95% CI, 0.19–0.36; p < 0.001) and extremities (AOR, 0.13; 95% CI, 0.09–0.17; p < 0.001); 35% lower for casualties categorized with blunt injuries (AOR, 0.65; 95% CI, 0.46–0.92; p = 0.01); and 39% lower for casualties transported within one hour (AOR, 0.61; 95% CI, 0.51–0.74; p < 0.001). Results of simulations in which transport times had not changed after the mandate indicate that KIA mortality would have been 1.4% higher than observed, equating to 135 more KIA deaths (95% CI, 105–164).

CONCLUSION
Reduction in KIA mortality is associated with early treatment capabilities, blunt mechanism, select body locations of injury, and rapid transport.

LEVEL OF EVIDENCE
Therapy, level III.
Don’t call me crazy! Delirium occurs outside of the intensive care unit
Authors: Cahill Anthony , Pearcy Christopher , Almahmoud Khalid , Agrawal Vaidehi , Mani Usha , Sladek Phillip , Truitt Michael S. 
Published: October 2017

Introduction
Delirium has been well studied among patients in the intensive care unit (ICU); however, data beyond the ICU is limited. The purpose of this study is to prospectively evaluate the incidence and associated risk factors for delirium in noncritical care areas (NCCA).

Methods
After institutional review board approval, a prospective cohort study was conducted at our urban Level I Trauma Center from December 2015 to February 2016. All patients admitted to the designated study area by a trauma surgeon were included. The Confusion Assessment Method (CAM) was administered every 12 hours until discharge. Delirious patients (CAM+) were administered the CAM-S to quantify the severity of delirium. Demographics, laboratory data, and inpatient medication lists were analyzed.

Results
Of 148 participants, 12 (8%) were CAM+ and 136 (92%) were CAM−. The average CAM-S of CAM+ patients was 7 ± 3. Included patients were aged 52 ± 20 years and 45% were men. Of patients 65 years or older, 9 (21%) were CAM+. Medications associated with delirium were: albuterol (p = 0.01), atorvastatin (p = 0.01), duloxetine (p = 0.04), sertraline (p = 0.04), folic acid (p = 0.01), thiamine (p = 0.01), vitamin D (p < 0.001), haloperidol (p = 0.04), metoprolol (p = 0.02), and vancomycin (p = 0.02). Abnormal laboratory values associated with delirium included: Albumin (p = 0.03; odds ratio [OR], 7.94, 95% confidence interval [CI], 1.1–63.20), Calcium (p = 0.01; OR, 4.95; 95% CI, 1.5–16.7), Sodium (p = 0.04; OR, 3.91; 95% CI, 1.13–13.5), hematocrit (p = 0.04), and mean corpuscular hemoglobin concentration (p < 0.05; OR, 5.29; 95% CI, 1.19–23.46).

Conclusions
Our study demonstrated an 8% incidence of delirium overall in NCCA, increasing to 21% in patients 65 years or older. Many risk factors identified among NCCA patients are consistent with the ICU literature; however, our CAM+ patients had additional risk factors which have not been previously associated with the development of delirium. Screening of NCCA patients for delirium should be considered.

Level of Evidence
Prognostic and Epidemological, level IV.
Recent development of nanoparticles for molecular imaging
Authors: Kim Jonghoon , Lee Nohyun , Hyeon Taeghwan 
Published: October 2017

Molecular imaging enables us to non-invasively visualize cellular functions and biological processes in living subjects, allowing accurate diagnosis of diseases at early stages. For successful molecular imaging, a suitable contrast agent with high sensitivity is required. To date, various nanoparticles have been developed as contrast agents for medical imaging modalities. In comparison with conventional probes, nanoparticles offer several advantages, including controllable physical properties, facile surface modification and long circulation time. In addition, they can be integrated with various combinations for multimodal imaging and therapy. In this opinion piece, we highlight recent advances and future perspectives of nanomaterials for molecular imaging.This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Current status and future challenges for molecular imaging
Authors: Anderson Carolyn J. , Lewis Jason S. 
Published: October 2017

Molecular imaging (MI), used in its wider sense of biology at the molecular level, is a field that lies at the intersection of molecular biology and traditional medical imaging. As advances in medicine have exponentially expanded over the last few decades, so has our need to better understand the fundamental behaviour of living organisms in a non-invasive and timely manner. This commentary draws from topics the authors addressed in their presentations at the 2017 Royal Society Meeting ‘Challenges for chemistry in molecular imaging’, as well as a discussion of where MI is today and where it is heading in the future.This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Multimodal nanoparticle imaging agents: design and applications
Authors: Burke Benjamin P. , Cawthorne Christopher , Archibald Stephen J. 
Published: October 2017

Molecular imaging, where the location of molecules or nanoscale constructs can be tracked in the body to report on disease or biochemical processes, is rapidly expanding to include combined modality or multimodal imaging. No single imaging technique can offer the optimum combination of properties (e.g. resolution, sensitivity, cost, availability). The rapid technological advances in hardware to scan patients, and software to process and fuse images, are pushing the boundaries of novel medical imaging approaches, and hand-in-hand with this is the requirement for advanced and specific multimodal imaging agents. These agents can be detected using a selection from radioisotope, magnetic resonance and optical imaging, among others. Nanoparticles offer great scope in this area as they lend themselves, via facile modification procedures, to act as multifunctional constructs. They have relevance as therapeutics and drug delivery agents that can be tracked by molecular imaging techniques with the particular development of applications in optically guided surgery and as radiosensitizers. There has been a huge amount of research work to produce nanoconstructs for imaging, and the parameters for successful clinical translation and validation of therapeutic applications are now becoming much better understood. It is an exciting time of progress for these agents as their potential is closer to being realized with translation into the clinic. The coming 5–10 years will be critical, as we will see if the predicted improvement in clinical outcomes becomes a reality. Some of the latest advances in combination modality agents are selected and the progression pathway to clinical trials analysed.
This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Using experience to improve: How errors shape behavior and brain activity in monkeys
Authors: Pardo-Vazquez Jose L. , Acuña Carlos 
Published: October 2017

AbstractPrevious works have shown that neurons from the ventral premotor cortex (PMv) represent several elements of perceptual decisions. One of the most striking findings was that, after the outcome of the choice is known, neurons from PMv encode all the information necessary for evaluating the decision process. These results prompted us to suggest that this cortical area could be involved in shaping future behavior. In this work, we have characterized neuronal activity and behavioral performance as a function of the outcome of the previous trial. We found that the outcome of the immediately previous trial (n-1) significantly changes, in the current trial (n), the activity of single cells and behavioral performance. The outcome of trial n-2, however, does not affect either behavior or neuronal activity. Moreover, the outcome of difficult trials had a greater impact on performance and recruited more PMv neurons than the outcome of easy trials. These results give strong support to our suggestion that PMv neurons evaluate the decision process and use this information to modify future behavior.
A Major Role for Common Genetic Variation in Anxiety Disorders
Authors: Purves Kirstin L. , Coleman Jonathan R. I. , Meier Sandra M. , Rayner Christopher , Davis Katrina A. S. , Cheesman Rosa , Bækvad-Hansen Marie , Børglum Anders D. , Cho Shing Wan , Deckert Jürgen , Gaspar Héléna A. , Bybjerg-Grauholm Jonas , Hettema John M. , Hotopf Matthew , Hougaard David , Hübel Christopher , Kan Carol , McIntosh Andrew M. , Mors Ole , Mortensen Preben Bo , Nordentoft Merete , Werge Thomas , Nicodemus Kristin K. , Mattheisen Manuel , Breen Gerome , Eley Thalia C. 
Published: October 2017

AbstractAnxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (n = 83 565) and an additional Current Anxiety Symptoms (n= 77 125) analysis. The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.
Amplification-free, CRISPR-Cas9 Targeted Enrichment and SMRT Sequencing of Repeat-Expansion Disease Causative Genomic Regions
Authors: Tsai Yu-Chih , Greenberg David , Powell James , Höijer Ida , Ameur Adam , Strahl Maya , Ellis Ethan , Jonasson Inger , Mouro Pinto Ricardo , Wheeler Vanessa C. , Smith Melissa L. , Gyllensten Ulf , Sebra Robert , Korlach Jonas , Clark Tyson A. 
Published: October 2017

AbstractTargeted sequencing has proven to be an economical means of obtaining sequence information for one or more defined regions of a larger genome. However, most target enrichment methods require amplification. Some genomic regions, such as those with extreme GC content and repetitive sequences, are recalcitrant to faithful amplification. Yet, many human genetic disorders are caused by repeat expansions, including difficult to sequence tandem repeats.We have developed a novel, amplification-free enrichment technique that employs the CRISPR-Cas9 system for specific targeting multiple genomic loci. This method, in conjunction with long reads generated through Single Molecule, Real-Time (SMRT) sequencing and unbiased coverage, enables enrichment and sequencing of complex genomic regions that cannot be investigated with other technologies. Using human genomic DNA samples, we demonstrate successful targeting of causative loci for Huntington’s disease (HTT; CAG repeat), Fragile X syndrome (FMR1; CGG repeat), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (C9orf72; GGGGCC repeat), and spinocerebellar ataxia type 10 (SCA10) (ATXN10; variable ATTCT repeat). The method, amenable to multiplexing across multiple genomic loci, uses an amplification-free approach that facilitates the isolation of hundreds of individual on-target molecules in a single SMRT Cell and accurate sequencing through long repeat stretches, regardless of extreme GC percent or sequence complexity content. Our novel targeted sequencing method opens new doors to genomic analyses independent of PCR amplification that will facilitate the study of repeat expansion disorders.
Non-invasive detection of upper tract urothelial carcinomas through the analysis of driver gene mutations and aneuploidy in urine
Authors: Springer Simeon , Chen Chung-Hsin , Li Lu , Douville Chris , Wang Yuxuan , Cohen Josh , Afsari Bahman , Danilova Ludmila , Silliman Natalie , Schaeffer Joy , Ptak Janine , Dobbyn Lisa , Papoli Maria , Kinde Isaac , Huang Chao-Yuan , Shun Chia-Tung , Karchin Rachel , Netto George J. , Turesky Robert J. , Yun Byeong Hwa , Rosenquist Thomas A. , Hruban Ralph H. , Pu Yeong-Shiau , Grollman Arthur P. , Tomasetti Cristian , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Dickman Kathleen G. 
Published: October 2017

AbstractUpper tract urothelial carcinomas (UTUC) of the renal pelvis or ureter can be difficult to detect and challenging to diagnose. Here, we report the development and application of a non-invasive test for UTUC based on molecular analyses of DNA recovered from cells shed into the urine. The test, called UroSEEK, incorporates assays for mutations in eleven genes frequently mutated in urologic malignancies and for allelic imbalances on 39 chromosome arms. At least one genetic abnormality was detected in 75% of urinary cell samples from 56 UTUC patients but in only 0.5% of 188 samples from healthy individuals. The assay was considerably more sensitive than urine cytology, the current standard-of-care. UroSEEK therefore has the potential to be used for screening or to aid in diagnosis in patients at increased risk for UTUC, such as those exposed to herbal remedies containing the carcinogen aristolochic acid.
p53 suppresses mutagenic RAD52 and POLθ pathways by orchestrating DNA replication restart homeostasis
Authors: Roy Sunetra , Tomaszowski Karl-Heinz , Luzwick Jessica , Park Soyoung , Li Jun , Murphy Maureen , Schlacher Katharina 
Published: October 2017

ABSTRACTClassically, p53 tumor-suppressor acts in transcription, apoptosis, and cell-cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks driving genomic instability independent of transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53 suppression of replication genome instability.
highroadis induced by retinoids and clears mutant Rhodopsin-1 inDrosophilaRetinitis Pigmentosa models
Authors: Huang Huai-Wei , Brown Brian , Chung Jaehoon , Domingos Pedro M. , Ryoo Hyung Don 
Published: October 2017

AbstractThe light detecting protein, Rhodopsin, requires retinoid chromophores for their function. In vertebrates, retinoids also serve as signaling molecules, but whether these molecules similarly regulate gene expression inDrosophilaremains unclear. Here, we report the identification of a retinoid-inducible gene inDrosophila,highroad, which is required for photoreceptors to clear folding-defective mutant Rhodopsin-1 proteins. Specifically, we identifiedhighroadthrough an in vivo RNAi based genetic interaction screen with one such folding defective Rhodopsin-1 mutant,ninaEG69D. CRISPR-Cas9-mediated deletion ofhighroadresults in the stabilization of folding-defective mutant Rhodopsin-1 proteins, and acceleration of the age-related retinal degeneration phenotype ofninaEG69Dmutants. Elevatedhighroadtranscript levels are detectedninaEG69Dflies, and interestingly, deprivation of retinoids in the fly diet blocks this effect. Consistently, mutations in the retinoid transportersanta mariaimpairs the induction ofhighroadinninaEG69Dflies. In cultured S2 cells,highroadexpression is induced by retinoic acid treatment. These results indicate that cellular quality control mechanism against misfolded Rhodopsin-1 involves regulation of gene expression by retinoids.
Enhanced wort fermentation withde novolager hybrids adapted to high ethanol environments
Authors: Krogerus Kristoffer , Holmström Sami , Gibson Brian 
Published: October 2017

AbstractInterspecific hybridization is a valuable tool for developing and improving brewing yeast in a number of industry-relevant aspects. However, the genomes of newly formed hybrids can be unstable. Here, we exploited this trait by adapting four brewing yeast strains, three of which werede novointerspecific lager hybrids with different ploidy levels, to high ethanol concentrations in an attempt to generate variant strains with improved fermentation performance in high-gravity wort. Through a batch fermentation-based adaptation process and selection based on a two-step screening process, we obtained eight variant strains which we compared to the wild-type strains in 2L-scale wort fermentations replicating industrial conditions. The results revealed that the adapted variants outperformed the strains from which they were derived, and the majority also possessed several desirable brewing-relevant traits, such as increased ester formation and ethanol tolerance, as well as decreased diacetyl formation. The variants obtained from the polyploid hybrids appeared to show greater improvements in fermentation performance. Interestingly, it was not only the hybrid strains, but also theS. cerevisiaeparent strain, that appeared to adapt and showed considerable changes in genome size. Genome sequencing and ploidy analysis revealed that changes had occurred both at chromosome and single nucleotide level in all variants. Our study demonstrates the possibility of improvingde novolager yeast hybrids through adaptive evolution by generating stable and superior variants that possess traits relevant to industrial lager beer fermentation.ImportanceRecent studies have shown that hybridization is a valuable tool for creating new and diverse strains of lager yeast. Adaptive evolution is another strain development tool that can be applied in order to improve upon desirable traits. Here we apply adaptive evolution to newly created lager yeast hybrids by subjecting them to environments containing high ethanol levels. We isolate and characterize a number of adapted variants, which possess improved fermentation properties and ethanol tolerance. Genome analysis revealed substantial changes in the variants compared to the original strains. These improved variants strains were produced without any genetic modification, and are suitable for industrial lager beer fermentations.
Transcranial alternating current stimulation induces long-term augmentation of neural connectivity and sustained anxiety reduction
Authors: Clancy Kevin J. , Baisley Sarah K. , Albizu Alejandro , Kartvelishvili Nicholas , Ding Mingzhou , Li Wen 
Published: October 2017

ABSTRACTAlthough transcranial alternating current stimulation (tACS) has demonstrated short-term effects in modulating neural oscillations, potential clinical efficacy of tACS for treating “oscillopathies” (disorders associated with aberrant neural oscillations) hinges on its ability to generate long-term neural plasticity, which can translate into lasting behavioral changes. Administering alpha-frequency tACS over 4 consecutive days, we evaluated short- and long-term (> 24 hours) effects of α-tACS on local alpha power and oscillatory connectivity, along with behavioral outcomes in anxious arousal and affective sensory perception. The α-tACS (vs. sham stimulation) group exhibited increases in posterior alpha power immediately and 30 minutes post-stimulation but not 24 hours post-stimulation, suggesting transient effects on local neuronal synchrony. Strikingly, long-range alpha-frequency Granger causal connectivity (posterior→frontal) increased not only immediately and 30 minutes but also 24 hours post-stimulation, paralleled by sustained reductions in anxious arousal and aversion to auditory stimuli. Therefore, tACS is capable of eliciting long-term plasticity in long-range oscillatory connectivity with direct, lasting behavioral consequences, while leaving endogenous local oscillations unaltered. This temporal disparity in local and network effects favors the view of large-scale network strengthening by tACS, calling for research attention to the circuit and network impacts of tACS. Critically, with the growing recognition of large-scale network dysfunctions as a transdiagnostic pathophysiology of psychiatric disorders, this connectivity plasticity advocates for the clinical application of tACS with its unique advantage in tackling network pathologies.
A class of GATA3 mutation reprograms the breast cancer transcriptional network through gain and loss of function
Authors: Takaku Motoki , Grimm Sara A. , Roberts John D. , Chrysovergis Kaliopi , Bennett Brian D. , Myers Page , Perera Lalith , Tucker Charles J. , Perou Charles M. , Wade Paul A. 
Published: October 2017

AbstractGATA3 is frequently mutated in breast cancer; these mutations are widely presumed to be loss of function. Here, we address molecular alterations downstream of a novel class of GATA3 mutations, revealing both gain and loss of function. Mutation of one allele of GATA3 led to loss of binding and decreased expression at a subset of genes, including Progesterone Receptor. At other loci, associated with epithelial to mesenchymal transition, gain of binding at a novel sequence motif correlated with increased gene expression. These results demonstrate that not all GATA3 mutations are equivalent and that these mutations impact breast cancer through gain and loss of function.