bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dexmedetomidine for the Treatment of Hyperactive Delirium Refractory to Haloperidol in Nonintubated ICU Patients: A Nonrandomized Controlled Trial*
Authors: Carrasco Genís , Baeza Nacho , Cabré Lluís , Portillo Eugenia , Gimeno Gemma , Manzanedo David , Calizaya Milagros 
Published: March 2016

Objectives:
To evaluate the clinical effectiveness, safety, and cost of dexmedetomidine for the treatment of agitated delirium refractory to haloperidol in nonintubated critically ill patients.

Design:
Nonrandomized, controlled trial.

Setting:
Intensive care department of a tertiary care nonprofit hospital.

Patients:
All consecutive admissions to a medical-surgical ICU with a diagnosis of agitated delirium.

Interventions:
Initial haloperidol titration: all patients received IV bolus doses of haloperidol until agitation was controlled (Richmond Agitation Sedation Scale scoring range, 0 to −2) or reaching the maximum daily dose. Group comparison: patient responders to haloperidol (control group) were compared with nonresponders (dexmedetomidine group).

Measurements and Main Results:
A total of 132 nonintubated patients were treated with haloperidol in the initial haloperidol titration phase. Forty-six patients (34.8%; 95% CI, 26.0–43.1%) did not respond to haloperidol, and 86 patients (65.2%; 95% CI, 56.3–73.0%) were responders. During the group comparison phase, dexmedetomidine achieved a higher percentage of time in satisfactory sedation levels than did haloperidol (92.7% [95% CI, 84.5–99.8%] vs 59.3% [95% CI, 48.6–69.3%], respectively; p = 0.0001). Haloperidol was associated with 10 cases (11.6% [95% CI, 6.5–21.2%]) of oversedation and two (2.0% [0.4–8%]) of corrected QT lengthening. Direct cost of dexmedetomidine was 17 times greater than haloperidol, but it achieved a mean savings of $4,370 per patient due to the reduction in length of ICU stay.

Conclusions:
In the study conditions, dexmedetomidine shows to be useful as a rescue drug for treating agitation due to delirium in nonintubated patients in whom haloperidol has failed, and it seems to have a better effectiveness, safety, and cost-benefit profile than does haloperidol.
Knowledge, Behavior, and Free-Living Amoebae Contamination of Cosmetic Contact Lens Among University Wearers in Thailand: A Cross-Sectional Study
Authors: Mahittikorn Aongart , Kittichathanakul Thanuntorn , To-Im Jongdee , Nacapunchai Duangporn 
Published: March 2016

Objective:
To assess the general knowledge, behavior, and presence of potentially pathogenic amoebae in cosmetic contact lens (CCL) wearers.

Methods:
One hundred CCL asymptomatic wearers were randomly selected. A questionnaire regarding their lens use, and a pair of their CCL was obtained. Identification of free-living amoeba (FLA) strains was based on morphological diagnosis, enflagellation tests (for non-Acanthamoeba strains), and sequencing of the small-subunit rRNA gene fragments.

Results:
Most (92%) of the participants surveyed were women, and the average age of the participants was 21.5±0.2 years. The CCL wearers generally showed a moderate (47%) or good (35%) level of knowledge, and good (51%) or excellent (40%) use of CCL. Two CCL samples were positive for Acanthamoeba genotype T3 or Vahlkampfia. The Acanthamoeba-contaminated CCL was from a wearer who used saline for treating lenses, and the Vahlkampfia-contaminated CCL was from a wearer who used CCL while swimming.

Conclusions:
This is the first report of the presence of potentially pathogenic FLA in used CCL from asymptomatic wearers in Thailand. Although there was satisfactory knowledge and practice of lens care use, the public should be aware of CCL contaminated with potentially pathogenic FLA that can directly or indirectly cause keratitis.
Characteristics of Ocular Pain Complaints in Patients With Idiopathic Dry Eye Symptoms
Authors: Kalangara Jerry P. , Galor Anat , Levitt Roy C. , Covington Derek B. , McManus Katherine T. , Sarantopoulos Constantine D. , Felix Elizabeth R. 
Published: March 2016

Objective:
The purpose of this study was to examine the severity and quality of ocular pain complaints in patients with dry eye symptoms.

Methods:
Subjects with clinically relevant dry eye symptoms (dryness, discomfort, tearing) of unknown origin seen in the Miami Veterans Affairs eye clinic were administered questionnaires for dry eye symptoms and ocular pain and underwent a standardized ocular examination. Qualities and severity ratings of ocular pain in subjects with idiopathic dry eye were compared with similar measures from published data in other chronic pain populations.

Results:
The study sample consisted of 154 subjects, of which 91% were men and ranged in age from 27 to 89 (mean age=61). Fifty-three percent of participants reported an average ocular pain of at least moderate intensity (numerical rating scale≥4), with specific characteristics (i.e., “burning” spontaneous pain) reported at frequencies comparable to prevalent chronic neuropathic pain syndromes as reported in the literature. Significant correlations were found between ocular pain metrics and dry eye symptom severity scores (r=0.57–0.66). Dry eye signs, however, did not generally correlate with ocular pain severity.

Conclusions:
A significant proportion of subjects with idiopathic dry eye symptoms reported moderate or greater ocular pain intensity, with most endorsing descriptors commonly used by patients with nonocular neuropathic pain conditions. Identifying subgroups of dry eye patients based on the presence and characteristics of ocular pain complaints may improve dry eye subclassification and better individualize treatment strategies.
Efficacy of Epithelium-Off and Epithelium-On Corneal Collagen Cross-Linking in Pediatric Keratoconus
Authors: Eraslan Muhsin , Toker Ebru , Cerman Eren , Ozarslan Deniz 
Published: March 2016

Objectives:
To evaluate the efficacy of riboflavin/ultraviolet A epithelium-off (epi-off) and epithelium-on (epi-on) corneal collagen cross-linking (CXL) in progressive pediatric keratoconus.

Methods:
Thirty-six eyes of 27 patients aged 18 years or younger (12–18 years) diagnosed with progressive keratoconus and treated with epi-off (n=18 eyes) or epi-on (n=18 eyes) CXL were included in this study. All patients were followed up for 24 months postoperatively.

Results:
At 24-month follow-up, the mean corrected distance visual acuity (CDVA) improved from 0.24±0.17 to 0.17±0.11 logMAR in the epi-off group (P=0.032). In the epi-on group, CDVA improved from 0.33±0.23 to 0.26±0.20 logMAR (P=0.012), but the improvement was not significantly different between groups (P>0.05). In the epi-off group, all mean K values improved: K1 (Δ=−0.63 D, P=0.024), K2 (Δ=−0.73 D, P=0.008), and Kmax (Δ=−1.4 D, P=0.035), whereas in the epi-on group, Kmax and K2 did not change significantly and K1 (Δ=0.68 D, P=0.029) significantly worsened. Postoperative mild corneal haze occurred in 5 eyes (28%) in the epi-off group. No postoperative complications were observed in the epi-on group. In 94.4% of the epi-off group, keratoconus regressed (44.4%) or stabilized (50.0%), whereas in the epi-on group, only 66.6% regressed (33.3%) or stabilized (33.3%), and the difference was significant (P=0.038).

Conclusions:
The efficacy of the epi-on procedure in terms of its ability to halt keratoconus progression appears to be 0.70 of the efficacy of epi-off CXL.
Multiple genetic changes underlie the evolution of long-tailed forest deer mice
Authors: Kingsley Evan P. , Kozak Krzysztof M. , Pfeifer Susanne P. , Yang Dou-Shuan , Hoekstra Hopi E. 
Published: March 2016

ABSTRACTUnderstanding both the role of selection in driving phenotypic change and its underlying genetic basis remain major challenges in evolutionary biology. Here we focus on a classic system of local adaptation in the North American deer mouse,Peromyscus maniculatus, which occupies two main habitat types, prairie and forest. Using historical collections we demonstrate that forest-dwelling mice have longer tails than those from non-forested habitats, even when we account for individual and population relatedness. Based on genome-wide SNP capture data, we find that mice from forested habitats in the eastern and western parts of their range form separate clades, suggesting that increased tail length evolved independently from a short-tailed ancestor. Two major changes in skeletal morphology can give rise to longer tails—increased number and increased length of vertebrae—and we find that forest mice in the east and west have both more and longer caudal vertebrae, but not trunk vertebrae, than nearby prairie forms. Using a second-generation intercross between a prairie and forest pair, we show that the number and length of caudal vertebrae are not correlated in this recombinant population, suggesting that variation in these traits is controlled by separate genetic loci. Together, these results demonstrate convergent evolution of the long-tailed forest phenotype through multiple, distinct genetic mechanisms (controlling vertebral length and vertebral number), thus suggesting that these morphological changes—either independently or together—are adaptive.
A Bayesian approach for analysis of whole-genome bisulphite sequencing data identifies disease-associated changes in DNA methylation
Authors: Rackham Owen J.L. , Langley Sarah R. , Oates Thomas , Vradi Eleni , Harmston Nathan , Srivastava Prashant K. , Behmoaras Jacques , Dellaportas Petros , Bottolo Leonardo , Petretto Enrico 
Published: March 2016

ABSTRACTDNA methylation is a key epigenetic modification involved in gene regulation whose contribution to disease susceptibility remains to be fully understood. Here, we present a novel Bayesian smoothing approach (called ABBA) to detect differentially methylated regions (DMRs) from whole-genome bisulphite sequencing (WGBS). We also show how this approach can be leveraged to identify disease-associated changes in DNA methylation, suggesting mechanisms through which these alterations might affect disease. From a data modeling perspective, ABBA has the distinctive feature of automatically adapting to different correlation structures in CpG methylation levels across the genome whilst taking into account the distance between CpG sites as a covariate. Our simulation study shows that ABBA has greater power to detect DMRs than existing methods, providing an accurate identification of DMRs in the large majority of simulated cases. To empirically demonstrate the method’s efficacy in generating biological hypotheses, we performed WGBS of primary macrophages derived from an experimental rat system of glomerulonephritis and used ABBA to identify >1,000 disease-associated DMRs. Investigation of these DMRs revealed differential DNA methylation localized to a 600bp region in the promoter of theIfitm3gene. This was confirmed by ChIP-seq and RNA-seq analyses, showing differential transcription factor binding at theIfitm3promoter by JunD (an established determinant of glomerulonephritis) and a consistent change inIfitm3expression. Our ABBA analysis allowed us to propose a new role forIfitm3in the pathogenesis of glomerulonephritis via a mechanism involving promoter hypermethylation that is associated withIfitm3repression in the rat strain susceptible to glomerulonephritis.
Personalized Risk Prediction for Type 2 Diabetes: the Potential of Genetic Risk Scores
Authors: Läll Kristi , Mägi Reedik , Morris Andrew , Metspalu Andres , Fischer Krista 
Published: March 2016

AbstractPurposeThe study aims to develop a Genetic Risk Score (GRS) for the prediction of Type 2 Diabetes (T2D) that could be used for risk assessment in general population.MethodsUsing the results of genome-wide association studies, we develop adoubly-weightedGRS for the prediction of T2D risk, aiming to capture the effect of 1000 single nucleotide polymorphisms. The GRS is evaluated in the Estonian Biobank cohort (n=10273), analysing its effect on prevalent and incident T2D, while adjusting for other predictors. We assessed the effect of GRS on all-cause and cardiovascular mortality and its association with other T2D risk factors, and conducted the reclassification analysis.ResultsThe adjusted hazard for incident T2D is 1.90 (95% CI 1.48, 2.44) times higher and for cardiovascular mortality 1.27 (95% CI 1.10, 1.46) times higher in the highest GRS quintile compared to the rest of the cohort. No significant association between BMI and GRS is found in T2D-free individuals. Adding GRS to the prediction model for 5-year T2D risks results in continuous Net Reclassification Improvement of 0.26 (95% CI 0.15, 0.38).ConclusionThe proposed GRS would considerably improve the accuracy of T2D risk prediction when added to the set of predictors used so far.
Conformational dynamics of Tau in the cell quantified by an intramolecular FRET biosensor in physiological and pathological context
Authors: Di Primio C , Quercioli V , Siano G , Kovacech B , Novak M , Cattaneo A 
Published: March 2016

ABSTRACTImpaired interactions of Tau protein with microtubules (MT) and Tau misfolding play a key role in Alzheimer disease (AD) and other neurodegenerative diseases collectively named Tauopathies. However, little is known about the molecular conformational changes that underlie Tau misfolding and aggregation in pathological conditions, due to the difficulty of studying structural aspects of this intrinsically unfolded protein, particularly in the context of living cells.Here we developed a new Conformational-Sensitive Tau sensor (CST), based on human Tau full length protein, to investigate the changes in 3D conformation and aggregation state of Tau upon modulation of its interactions with MTs in living cells, in physiological and pathological conditions. After showing that the CST fully preserves functional Tau activities in living cells, we demonstrated that MT-bound Tau displays a loop-like conformation, while soluble Tau assumes a relaxed conformation.The imaging readout based on CST allowed to discover new conformational properties of full length Tau in living cells, when challenged with Alzheimer-relevant seeds from different sources, and to learn about different ways to induce the self-aggregation of full length Tau in cells. Furthermore, it allowed to investigate the contribution to the pathology of point mutations known to alter Tau/MTs interaction.SIGNIFICANCEThe microtubule-associated protein Tau regulates the stability of microtubules (MT) and its alteration and misfolding plays an important role in Alzheimer disease (AD) and in several other neurodegenerative diseases collectively named Tauopathies. However, little is known about the molecular mechanism that modulate the conformational changes of Tau in pathological conditions. Here, we developed a conformational sensitive Tau biosensor providing insights into the 3D conformation of Tau in living cells. This new tool showed that MT-bound Tau displays a loop-like conformation, while soluble Tau assume a relaxed conformation, which might be more prone to aggregation. Furthermore the CST was used to develop an assay to screen molecules and mutations involved in Tau self-aggregation in living cells. Remarkably, the imaging tool developed allowed to demonstrate that Aβ oligomers induced Tau aggregation in living cells.
Sensitive red protein calcium indicators for imaging neural activity
Authors: Dana Hod , Mohar Boaz , Sun Yi , Narayan Sujatha , Gordus Andrew , Hasseman Jeremy P. , Tsegaye Getahun , Holt Graham T. , Hu Amy , Walpita Deepika , Patel Ronak , Macklin John J , Bargmann Cornelia I. , Ahrens Misha B. , Schreiter Eric R. , Jayaraman Vivek , Looger Loren L. , Svoboda Karel , Kim Douglas S. 
Published: March 2016

AbstractGenetically encoded calcium indicators (GECIs) allow measurement of activity in large populations of neurons and in small neuronal compartments, over times of milliseconds to months. Although GFP-based GECIs are widely used forin vivoneurophysiology, GECIs with red-shifted excitation and emission spectra have advantages forin vivoimaging because of reduced scattering and absorption in tissue, and a consequent reduction in phototoxicity. However, current red GECIs are inferior to the state-of-the-art GFP-based GCaMP6 indicators for detecting and quantifying neural activity. Here we present improved red GECIs based on mRuby (jRCaMP1a, b) and mApple (jRGECO1a), with sensitivity comparable to GCaMP6. We characterized the performance of the new red GECIs in cultured neurons and in mouse,Drosophila, zebrafish andC. elegans in vivo. Red GECIs facilitate deep-tissue imaging, dual-color imaging together with GFP-based reporters, and the use of optogenetics in combination with calcium imaging.
Assessment of Circulating Copy Number Variant Detection for Cancer Screening
Authors: Molparia Bhuvan , Nichani Eshaan , Torkamani Ali 
Published: March 2016

ABSTRACTCurrent high-sensitivity cancer screening methods suffer from false positive rates that lead to numerous unnecessary procedures and questionable public health benefit overall. Detection of circulating tumor DNA (ctDNA) has the potential to transform cancer screening. Thus far, nearly all ctDNA studies have focused on detection of tumor-specific point mutations. However, ctDNA point mutation detection methods developed to date lack either the scope or sensitivity necessary to be useful for cancer screening, due to the extremely low (<1%) ctDNA fraction derived from early stage tumors. We suggest that tumor-derived copy number variant (CNV) detection is theoretically a superior means of ctDNA-based cancer screening for many tumor types, given that, relative to point mutations, each individual tumor CNV contributes a much larger number of ctDNA fragments to the overall pool of circulating DNA. Here we perform an in silico assessment of the potential for ctDNA CNV-based cancer screening across many common cancers.
Dissecting resistance mechanisms in melanoma combination therapy
Authors: Kim Eunjung , Anderson Alexander 
Published: March 2016

AbstractWe present a compartment model that explains melanoma cell response and resistance to mono and combination therapies. Model parameters were estimated by utilizing an optimization algorithm to identify parameters that minimized the difference between predicted cell populations and experimentally measured cell numbers. The model was then validated within vitroexperimental data. Our simulations show that although a specific timing of the combination therapy is effective in controlling tumor cell populations over an extended period of time, the treatment eventually fails. We subsequently predict a more optimal combination therapy that incorporates an additional drug at the right moment.
Vcfanno: fast, flexible annotation of genetic variants
Authors: Pedersen Brent S. , Layer Ryan M. , Quinlan Aaron R. 
Published: March 2016

ABSTRACTBackgroundThe integration of genome annotations and reference databases is critical to the identification of genetic variants that may be of interest in studies of disease or other traits. However, comprehensive variant annotation with diverse file formats is difficult with existing methods.ResultsWe have developedvcfannoas a flexible toolset that simplifies the annotation of genetic variants in VCF format.Vcfannocan extract and summarize multiple attributes from one or more annotation files and append the resulting annotations to the INFO field of the original VCF file.Vcfannoalso integrates the lua scripting language so that users can easily develop custom annotations and metrics. By leveraging a new parallel “chromosome sweeping” algorithm, it enables rapid annotation of both whole-exome and whole-genome datasets. We demonstrate this performance by annotating over 85.3 million variants in less than 17 minutes (>85,000 variants per second) with 50 attributes from 17 commonly used genome annotation resources.ConclusionsVcfannois a flexible software package that provides researchers with the ability to annotate genetic variation with a wide range of datasets and reference databases in diverse genomic formats.AvailabilityThevcfannosource code is available athttps://github.com/brentp/vcfannounder the MIT license, and platform-specific binaries are available athttps://github.com/brentp/vcfanno/releases. Detailed documentation is available athttp://brentp.github.io/vcfanno/, and the code underlying the analyses presented can be found athttps://github.com/brentp/vcfanno/tree/master/scripts/paper.
Evidence for selective attention in the insect brain
Authors: de Bivort Benjamin L. , van Swinderen Bruno 
Published: March 2016

AbstractThe capacity for selective attention appears to be required for any animal responding to an environment containing multiple objects, although this has been difficult to study in smaller animals such as insects. Clear operational characteristics of attention however make study of this crucial brain function accessible to any animal model. Whereas earlier approaches have relied on freely behaving paradigms placed in an ecologically relevant context, recent tethered preparations have focused on brain imaging and electrophysiology in virtual reality environments. Insight into brain activity during attention-like behavior has revealed key elements of attention in the insect brain. Surprisingly, a variety of brain structures appear to be involved, suggesting that even in the smallest brains attention might involve widespread coordination of neural activity.HighlightsInsect behavior shows attention-like filtering and allows concurrent neural recordingRecent work finds compelling correlates of visual attention in the central complexPutative goal-directed stimulus-filtering is present in neuropils across the brain
FIT2D: a multi-purpose data reduction, analysis and visualization program
Authors: Hammersley A. P. 
Published: March 2016

FIT2D is one of the principal area detector data reduction, analysis and visualization programs used at the European Synchrotron Radiation Facility and is also used by more than 400 research groups worldwide, including many other synchrotron radiation facilities. It has been developed for X-ray science, but is applicable to other structural techniques and is used in analysing electron diffraction data and microscopy, and neutron diffraction and scattering data.FIT2D works for both interactive and `batch'-style data processing. Calibration and correction of detector distortions, integration of two-dimensional data to a variety of one-dimensional scans, and one- and two-dimensional model fitting are the main uses. Many other general-purpose image processing and image visualization operations are available. Commands are available through a `graphical user interface' and operations common to certain types of analysis are grouped within `interfaces'. Executable versions for most workstation and personal computer systems, and web page documentation, are available at http://www.esrf.eu/computing/scientific/FIT2D.