bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical Development of EBI-005: An IL-1 Receptor-1 Inhibitor for the Topical Ocular Treatment of Ocular Surface Inflammatory Diseases
Authors: Kovalchin Joseph , King Bracken , Masci Allyson , Hopkins Elizabeth , Fry Jeremy , Hou Jay , Li Christian , Tenneson Kelly , Weber Steve , Wolfe Gary , Collins Kathy , Furfine Eric S. 
Published: July 2017

Objective:
Topical interleukin (IL)-1 receptor (R)1 blockade is therapeutically active in reducing signs and symptoms of dry eye disease. Herein, we describe in vitro and in vivo nonclinical Investigational New Drug (IND)-enabling studies of EBI-005, a novel protein chimera of IL-1β and IL-1 receptor antagonist (IL-1Ra or anakinra) that potently binds IL-1R1 and blocks signaling. These studies provide an assessment of receptor affinity, drug bioavailability, immunogenic response, safety, and tolerability in mice and rabbits.

Methods:
In vitro and in silico along with Good Laboratory Practices (GLP) and non-GLP in vivo studies in mice and rabbits assessed the topical ocular and systemic immunogenicity and toxicology of EBI-005. Animals were treated with EBI-005 once daily subcutaneously or four times daily by topical ocular administration for up to 6 weeks (with 2-week recovery phase).

Results:
EBI-005 has 500 times higher affinity than anakinra to IL-1R1. Predictive immunogenicity testing suggested that EBI-005 is not more immunogenic. Systemic bioavailability of EBI-005 is low (1.4% in mice and 0.2% in rabbits) after topical ocular administration. EBI-005 penetrated into the anterior ocular tissues within 15 min of topical ocular administration. However, it is low or undetectable after 4 hr and does not form a depot after repeated topical ocular administration. EBI-005 was safe and well tolerated, and exposure to drug was maintained despite an antidrug antibody response after systemic administration, based on IND-enabling toxicology and safety pharmacology studies.

Conclusions:
Ocular doses of EBI-005 at 50 mg/mL in mice and rabbits totaling 0.15 mg/eye in mice and 1.5 mg/eye in rabbits, administered 4 times daily, did not produce adverse effects, and demonstrated excellent bioavailability in target tissues with low systemic exposure. In addition, immunogenic response to the drug did not cause adverse effects or diminish the drug's activity in most cases. The results support drug administration of the highest anticipated human clinical study dose of a 20 mg/mL solution (40 μL 3 times daily in each eye).
Increase in intracranial pressure by application of a rigid cervical collar: a pilot study in healthy volunteers
Authors: Maissan Iscander M. , Ketelaars Rein , Vlottes Boris , Hoeks Sanne E. , den Hartog Dennis , Stolker Robert J. 
Published: July 2017

Objectives
Rigid cervical collars are known to increase intracranial pressure (ICP) in severe traumatic brain injury (TBI). Cerebral blood flow might decrease according to the Kellie Monroe doctrine. For this reason, the use of the collar in patients with severe TBI has been abandoned from several trauma protocols in the Netherlands. There is no evidence on the effect of a rigid collar on ICP in patients with mild or moderate TBI or indeed patients with no TBI. As a first step we tested the effect in healthy volunteers with normal ICPs and intact autoregulation of the brain.

Methods
In this prospective blinded cross-over study, we evaluated the effect of application of a rigid cervical collar in 45 healthy volunteers by measuring their optical nerve sheath diameter (ONSD) by transocular sonography. Sonographic measurement of the ONSD behind the eye is an indirect noninvasive method to estimate ICP and pressure changes.

Results
We included 22 male and 23 female volunteers. In total 360 ONSD measurements were performed in these 45 volunteers. Application of a collar resulted in a significant increase in ONSD in both the left (β=0.06, 95% confidence interval: 0.05–0.07, P<0.001) and the right eye (β=0.01, 95% confidence interval: 0.00–0.02, P=0.027)

Conclusion
Application of a rigid cervical collar significantly increases the ONSD in healthy volunteers with intact cerebral autoregulation. This suggests that ICP may increase after application of a collar. In healthy volunteers, this seems to be of minor importance. On the basis of our findings the effect of a collar on ONSD and ICP in patients with mild and moderate TBI needs to be determined.
Rising Incidence of Paediatric Inflammatory Bowel Disease in Canterbury, New Zealand, 1996–2015
Authors: Lopez Robert N. , Appleton Laura , Gearry Richard B. , Day Andrew S. 
Published: July 2017

ABSTRACTBackground:The incidence of paediatric inflammatory bowel disease (IBD) around the world is increasing. Canterbury, New Zealand, has one of the highest Crohn disease (CD) incidence rates published. The present study aimed to document the incidence of paediatric IBD in Canterbury between 1996 and 2015.Methods:All patients diagnosed with IBD in Canterbury, while younger than 16 years, between January 1, 1996 and December 31, 2015 were identified. Demographic and disease phenotypic details were collected and entered into a secure database. Age‐specific population data for Canterbury were obtained and annual incidence rates were then calculated.Results:The mean annual incidence rate over the 20‐year period was 7.18/100,000 (95% confidence interval 5.55–8.81) children. There was a 4‐fold increase in the incidence of paediatric IBD in Canterbury between 1996 and 2015. The ratio of CD to ulcerative colitis (UC) diagnosed was 8.4:1. Disease phenotype of CD and UC, based on the Paris classification, were comparable with other studies.Conclusions:The incidence of paediatric IBD in Canterbury has increased dramatically during the last 2 decades. Some of the observed incidence rates are among the highest documented anywhere in the world. The preponderance of CD over UC in the present study is the highest published.
Complementary and Alternative Medicine Use and Symptom Burden in Women Undergoing Chemotherapy for Breast Cancer in Malaysia
Authors: Chui Ping Lei , Abdullah Khatijah Lim , Wong Li Ping , Taib Nur Aishah 
Published: July 2017

Background:
Complementary and alternative medicine (CAM) is commonly used for cancer- and chemotherapy-related symptoms. Nurses are likely to encounter many CAM users in their practice.

Objective:
The aims of this study were to assess CAM use and examine the symptom burden of CAM and non-CAM users among patients with breast cancer who are undergoing chemotherapy.

Methods:
A CAM use questionnaire and the Side-Effect Burden Scale were administered to 546 patients. Complementary and alternative medicine use was categorized as mind-body practices (MBPs), natural products (NPs), or traditional medicine (TM).

Results:
We identified 386 CAM users (70.7%) in this study. The CAM users reported a higher marginal mean total symptom burden score (40.39 ± 2.6) than non-CAM users (36.93 ± 3.21), although this difference was not statistically significant (P = .09). Triple-modality (MBP-NP-TM) CAM users had a significantly higher marginal mean total symptom burden score (47.44 ± 4.12) than single-modality (MBP) users (34.09 ± 4.43). The risk of having a high total symptom burden score was 12.9-fold higher among the MBP-NP-TM users than among the MBP users.

Conclusions:
Complementary and alternative medicine use is common among Malaysian patients who are undergoing chemotherapy for breast cancer. However, CAM and non-CAM users reported similar symptom burdens, although single-modality use of MBP is likely associated with a lower symptom burden.

Implications for Practice:
Nurses should keep abreast of current developments and trends in CAM use. Understanding CAM use and the related symptom burden will allow nurses to initiate open discussion and guide their patients in seeking additional information or referrals for a particular therapy.
Clinical Application of a Transurethral Holmium Laser Excision of Exposed Polypropylene Mesh at Lower Urinary Tract: Single Surgeon Experience With Long-term Follow-up
Authors: Lee Chan Ho , Ku Ja Yoon , Lee Kyoung , Lee Jeong Zoo , Shin Dong Gil 
Published: July 2017

Purpose
The aim of this study was to evaluate the clinical application of a transurethral holmium laser excision of exposed polypropylene mesh as an effective minimally invasive surgical approach in patients with lower urinary tract mesh erosion following the transvaginal placement of polypropylene mesh.

Methods
A retrospective analysis was conducted on the data of 22 patients with exposed polypropylene mesh in the lower urinary tract that was managed using the transurethral holmium laser technique. The patients were divided into 2 groups based on the type of mesh surgery: a midurethral sling (MUS) group (n = 18) and a pelvic organ prolapse (POP) group (n = 4). The surgical outcomes were compared.

Results
The mean time follow-up after the first surgery was 23.2 months, and 14 patients (64%) reported symptomatic improvement. During outpatient follow-up, eroded residual mesh and failed re-epithelialization were discovered in 6 patients. The recurrence rates in the MUS and POP groups after the first surgery were 22% and 50%, respectively. The recurrence-free periods of each group were 30.5 versus 13.5 months, respectively. Whereas 5 patients had successful epithelialization of the surgical wound following the second endoscopic surgery, 1 patient in the POP group required a third endoscopic surgery because of persistent mesh erosion.

Conclusions
The excision of exposed polypropylene mesh using a transurethral holmium laser following MUS appears to be a feasible option because of potentially low rates of complication and recurrent stress incontinence. However, minimally invasive approach using holmium laser may not be as successful for mesh erosion after transvaginal mesh repair for POP.
Lessons and recommendations from three decades as an NSF REU Site: A call for systems-based assessment
Authors: McDevitt Andrew L. , Patel Manisha V. , Ellison Aaron M. 
Published: July 2017

AbstractNSF’s Research Experiences for Undergraduates (REU) program supports thousands of undergraduate researchers annually. REU sites operate independently with regards to their research mission and structure, leading to a complex educational milieu distinct from traditional classrooms and labs. Overall, REU sites are perceived as providing highly formative experiences for developing researchers. However, given improved assessment practices over REU’s three decades, best practices for student learning and evaluation of long-term impacts remain limited. To address this limitation, we recommend the use of systems-based theoretical frameworks when studying REU programs. We outline how one such framework, cultural-historical activity theory (CHAT), could inform the collection of assessment data. Among other strengths, CHAT guides collection of quantitative and qualitative information that can help characterize REU programs in an educationally meaningful context. Adoption of CHAT and similar approaches by REU Sites could improve dialogue among programs, encourage collaborations, and improve evidence-based practices.
Engineered CRISPR-Cas9 system enables noiseless, fine-tuned and multiplexed repression of bacterial genes
Authors: Vigouroux Antoine , Oldewurtel Enno , Cui Lun , Teeffelen Sven van , Bikard David 
Published: July 2017

AbstractOver the past few years, tools that make use of the Cas9 nuclease have led to many breakthroughs, including in the control of gene expression. The catalytically dead variant of Cas9 known as dCas9 can be guided by small RNAs to block transcription of target genes, in a strategy also known as CRISPRi. Here, we reveal that the level of complementarity between the guide RNA and the target controls the rate at which dCas9 successfully blocks the RNA polymerase. We use this mechanism to precisely and robustly reduce gene expression by defined relative amounts. We demonstrate broad applicability of this method to the study of genetic regulation and cellular physiology. First, we characterize feedback strength of a model auto-repressor. Second, we study the impact of copy-number variations of cell-wall synthesizing enzymes on cell morphology. Finally, we demonstrate that this system can be multiplexed to obtain any combination of fractional repression of two genes.
Defining the synaptic mechanisms that tune CA3-CA1 reactivation during sharp-wave ripples
Authors: Malerba Paola , Jones Matt W. , Bazhenov Maxim A. 
Published: July 2017

AbstractDuring non-REM sleep, memory consolidation is driven by a dialogue between hippocampus and cortex involving the reactivation of specific neural activity sequences (‘replay’). In the hippocampus, replay occurs during sharp-wave ripples (SWRs), short bouts of excitatory activity in area CA3 which induce high frequency oscillations in the inhibitory interneurons of area CA1. Despite growing evidence for the functional importance of replay, its neural mechanisms remain poorly understood. Here, we develop a novel theoretical model of hippocampal spiking during SWRs. In our model, noise-induced activation of CA3 pyramidal cells triggered an excitatory cascade capable of inducing local ripple events in CA1. Ripples occurred stochastically, with Schaffer Collaterals driving their coordination, so that localized sharp waves in CA3 produced consistently localized CA1 ripples. In agreement with experimental data, the majority of pyramidal cells in the model showed low reactivation probabilities across SWRs. We found, however, that a subpopulation of pyramidal cells had high reactivation probabilities, which derived from fine-tuning of the network connectivity. In particular, the excitatory inputs along synaptic pathway(s) converging onto cells and cell pairs controlled emergent single cell and cell pair reactivation, with inhibitory inputs and intrinsic cell excitability playing differential roles in CA3 vs. CA1. Our model predicts (1) that the hippocampal network structure driving the emergence of SWR is also able to generate and modulate reactivation, (2) inhibition plays a particularly prominent role in CA3 reactivation and (3) CA1 sequence reactivation is reliant on CA3-CA1 interactions rather than an intrinsic CA1 process.
Different mechanisms drive the maintenance of polymorphism at loci subject to strong versus weak fluctuating selection
Authors: Bertram Jason , Masel Joanna 
Published: July 2017

AbstractThe long-running debate about the role of selection in maintaining genetic variation has been given new impetus by the discovery of hundreds of seasonally oscillating polymorphisms in wildDrosophila,possibly stabilized by an alternating summer-winter selection regime. Historically there has been skepticism about the potential of temporal variation to balance polymorphism, because selection must be strong to have a meaningful stabilizing effect — unless dominance also varies over time (“reversal of dominance”). Here we develop a simplified model of seasonally variable selection that simultaneously incorporates four different stabilizing mechanisms, including two genetic mechanisms (“cumulative overdominance” and reversal of dominance), as well as ecological “storage” (“protection from selection” and boom-bust demography). We use our model to compare the stabilizing effects of these mechanisms. Although reversal of dominance has by far the greatest stabilizing effect, we argue that the three other mechanisms could also stabilize polymorphism under plausible conditions, particularly when all three are present. With many loci subject to diminishing returns epistasis, reversal of dominance stabilizes many alleles of small effect. This makes the combination of the other three mechanisms, which are incapable of stabilizing small effect alleles, a better candidate for stabilizing the detectable frequency oscillations of large effect alleles.
Conditionally rare taxa contribute but do not account for prokaryotic community changes in soils
Authors: Kaminsky Rachel , Morales Sergio E. 
Published: July 2017

AbstractConditionally rare taxa (CRT) are thought to greatly impact microbial community turnover across many environments, but little is known about their role in soils. Here, we investigate the contribution of CRT to whole community variation over space and time in a series of geographically distinct soils dedicated to three agricultural practices of differing intensities and sampled over a full seasonal cycle. We demonstrate that soil CRT do not account for observed total community changes, but that these rare taxa can be modified by spatiotemporal filters.
Full-length mRNA sequencing uncovers a widespread coupling between transcription and mRNA processing
Authors: Anvar Seyed Yahya , Allard Guy , Tseng Elizabeth , Sheynkman Gloria , de Klerk Eleonora , Vermaat Martijn , Yin Raymund H. , Johansson Hans E. , Ariyurek Yavuz , den Dunnen Johan T. , Turner Stephen W. , 't Hoen Peter A.C. 
Published: July 2017

ABSTRACTThe multifaceted control of gene expression requires tight coordination of regulatory mechanisms at transcriptional and post-transcriptional level. Here, we studied the interdependence of transcription, splicing and polyadenylation events on single mRNA molecules by full-length mRNA sequencing. In MCF-7 breast cancer cells, we found 2,700 genes with interdependent alternative transcription, splicing and polyadenylation events, both in proximal and distant parts of mRNA molecules. The analysis of three human primary tissues revealed similar patterns of interdependency between transcription and mRNA processing events. We predict thousands of novel Open Reading Frames from the sequence of full-length mRNAs and obtained evidence for their translation by shotgun proteomics. The mapping database rescued 358 previously unassigned peptides and improved the assignment of others. By recognizing sample-specific amino-acid changes and novel splicing patterns, full-length mRNA sequencing improved proteogenomics analysis of MCF-7 cells. Our findings demonstrate that our understanding of transcriptome complexity is far from complete and provides a basis to reveal largely unresolved mechanisms that coordinate transcription and mRNA processing.
Correcting batch effects in single-cell RNA sequencing data by matching mutual nearest neighbours
Authors: Haghverdi Laleh , Lun Aaron T. L. , Morgan Michael D. , Marioni John C. 
Published: July 2017

AbstractThe presence of batch effects is a well-known problem in experimental data analysis, and single- cell RNA sequencing (scRNA-seq) is no exception. Large-scale scRNA-seq projects that generate data from different laboratories and at different times are rife with batch effects that can fatally compromise integration and interpretation of the data. In such cases, computational batch correction is critical for eliminating uninteresting technical factors and obtaining valid biological conclusions. However, existing methods assume that the composition of cell populations are either known or the same across batches. Here, we present a new strategy for batch correction based on the detection of mutual nearest neighbours in the high-dimensional expression space. Our approach does not rely on pre-defined or equal population compositions across batches, only requiring that a subset of the population be shared between batches. We demonstrate the superiority of our approach over existing methods on a range of simulated and real scRNA-seq data sets. We also show how our method can be applied to integrate scRNA-seq data from two separate studies of early embryonic development.
Wikipedia as a gateway to biomedical research: The relative distribution and use of citations in the English Wikipedia
Authors: Maggio Lauren A. , Willinsky John M. , Steinberg Ryan M. , Mietchen Daniel , Wass Joseph L. , Dong Ting 
Published: July 2017

AbstractWikipedia is a gateway to knowledge. However, the extent to which this gateway ends at Wikipedia or continues via supporting citations is unknown. Wikipedia’s gateway functionality has implications for information design and education, notably in medicine. This study aims to establish benchmarks for the relative distribution and referral (click) rate of citations—as indicated by presence of a Digital Object Identifier (DOI)—from Wikipedia, with a focus on medical citations.DOIs referred from the English Wikipedia in August 2016 were obtained from Crossref.org. Next, based on a DOI’s presence on a WikiProject Medicine page, all DOIs in Wikipedia were categorized as medical (WP:MED) or non-medical (non-WP:MED). Using this categorization, referred DOIs were classified as WP:MED, non-WP:MED, or BOTH, meaning the DOI may have been referred from either category. Data were analyzed using descriptive and inferential statistics.Out of 5.2 million Wikipedia pages, 4.42% (n=229,857) included at least one DOI. 68,870 were identified as WP:MED, with 22.14% (n=15,250) featuring one or more DOIs. WP:MED pages featured on average 8.88 DOI citations per page, whereas non-WP:MED pages had on average 4.28 DOI citations. For DOIs only on WP:MED pages, a DOI was referred every 2,283 pageviews and for non-WP-MED pages every 2,467 pageviews. DOIs from BOTH pages accounted for 12% (n=58,475) of referrals, making determining a referral rate for BOTH impossible.While these results cannot provide evidence of greater citation referral from WP:MED than non-WP:MED, they do provide benchmarks to assess strategies for changing referral patterns. These changes might include editors adopting new methods for designing and presenting citations or the introduction of teaching strategies that address the value of consulting citations as a tool for extending learning.