bluuebunny/crossref_metadata_2025_split huggingface dataset:
SigSeeker: a peak-calling ensemble approach for constructing epigenetic signatures
Authors: Lichtenberg Jens , Elnitski Laura , Bodine David M 
Published: April 2017

Abstract

Motivation
Epigenetic data are invaluable when determining the regulatory programs governing a cell. Based on use of next-generation sequencing data for characterizing epigenetic marks and transcription factor binding, numerous peak-calling approaches have been developed to determine sites of genomic significance in these data. Such analyses can produce a large number of false positive predictions, suggesting that sites supported by multiple algorithms provide a stronger foundation for inferring and characterizing regulatory programs associated with the epigenetic data. Few methodologies integrate epigenetic based predictions of multiple approaches when combining profiles generated by different tools.

Results
The SigSeeker peak-calling ensemble uses multiple tools to identify peaks, and with user-defined thresholds for peak overlap and signal strength it retains only those peaks that are concordant across multiple tools. Peaks predicted to be co-localized by only a very small number of tools, discovered to be only marginally overlapping, or found to represent significant outliers to the approximation model are removed from the results, providing concise and high quality epigenetic datasets. SigSeeker has been validated using established benchmarks for transcription factor binding and histone modification ChIP-Seq data. These comparisons indicate that the quality of our ensemble technique exceeds that of single tool approaches, enhances existing peak-calling ensembles, and results in epigenetic profiles of higher confidence.

Availability and implementation
http://sigseeker.org

Supplementary information
Supplementary data are available at Bioinformatics online.
What does a Deductible Do? The Impact of Cost-Sharing on Health Care Prices, Quantities, and Spending Dynamics*
Authors: Brot-Goldberg Zarek C. , Chandra Amitabh , Handel Benjamin R. , Kolstad Jonathan T. 
Published: April 2017

Abstract
Measuring consumer responsiveness to medical care prices is a central issue in health economics and a key ingredient in the optimal design and regulation of health insurance markets. We leverage a natural experiment at a large self-insured firm that required all of its employees to switch from an insurance plan that provided free health care to a nonlinear, high-deductible plan. The switch caused a spending reduction between 11.8% and 13.8% of total firm-wide health spending. We decompose this spending reduction into the components of (i) consumer price shopping, (ii) quantity reductions, and (iii) quantity substitutions and find that spending reductions are entirely due to outright reductions in quantity. We find no evidence of consumers learning to price shop after two years in high-deductible coverage. Consumers reduce quantities across the spectrum of health care services, including potentially valuable care (e.g., preventive services) and potentially wasteful care (e.g., imaging services). To better understand these changes, we study how consumers respond to the complex structure of the high-deductible contract. Consumers respond heavily to spot prices at the time of care, reducing their spending by 42% when under the deductible, conditional on their true expected end-of-year price and their prior year end-of-year marginal price. There is no evidence of learning to respond to the true shadow price in the second year post-switch.
Iron Loading Exaggerates the Inflammatory Response to the Toll-like Receptor 4 Ligand Lipopolysaccharide by Altering Mitochondrial Homeostasis
Authors: Hoeft Konrad , Bloch Donald B. , Graw Jan A. , Malhotra Rajeev , Ichinose Fumito , Bagchi Aranya 
Published: April 2017

Abstract

Background
Perioperative and critically ill patients are often exposed to iron (in the form of parenteral-iron administration or blood transfusion) and inflammatory stimuli, but the effects of iron loading on the inflammatory response are unclear. Recent data suggest that mitochondrial reactive oxygen species have an important role in the innate immune response and that increased mitochondrial reactive oxygen species production is a result of dysfunctional mitochondria. We tested the hypothesis that increased intracellular iron potentiates lipopolysaccharide-induced inflammation by increasing mitochondrial reactive oxygen species levels.

Methods
Murine macrophage cells were incubated with iron and then stimulated with lipopolysaccharide. C57BL/6 wild-type mice were intraperitoneally injected with iron and then with lipopolysaccharide. Markers of inflammation and mitochondrial superoxide production were examined. Mitochondrial homeostasis (the balance between mitochondrial biogenesis and destruction) was assessed, as were mitochondrial mass and the proportion of nonfunctional to total mitochondria.

Results
Iron loading of mice and cells potentiated the inflammatory response to lipopolysaccharide. Iron loading increased mitochondrial superoxide production. Treatment with MitoTEMPO, a mitochondria-specific antioxidant, blunted the proinflammatory effects of iron loading. Iron loading increased mitochondrial mass in cells treated with lipopolysaccharide and increased the proportion of nonfunctional mitochondria. Iron loading also altered mitochondrial homeostasis to favor increased production of mitochondria.

Conclusions
Acute iron loading potentiates the inflammatory response to lipopolysaccharide, at least in part by disrupting mitochondrial homeostasis and increasing the production of mitochondrial superoxide. Improved understanding of iron homeostasis in the context of acute inflammation may yield innovative therapeutic approaches in perioperative and critically ill patients.
Evidence-based Recommendations for Pediatric Orthopaedic Practice
Authors: Mulpuri Kishore , Schaeffer Emily K. , Graham H. Kerr , Kocher Mininder S. , Sanders James , Zaltz Ira 
Published: April 2017

Background:
Evidence-based medicine has become the cornerstone to guide clinical practice decision-making. Evidence-based medicine integrates the strongest available evidence with clinical expertise to make decisions about clinical care. The quality of the evidence depends upon the soundness of the study methodology to allow for meaningful interpretation of the clinical results. The purpose of this review is to analyze the methodological design and clinical findings of published pediatric orthopaedic studies to determine their ability to change or influence clinical practice.

Methods:
This is the first in a series of evidence-based reviews in pediatric orthopaedics. The pediatric orthopaedic literature was reviewed for randomized controlled trials (RCTs) published in 2013 to 2014. Two RCTs were selected from the Journal of Bone and Joint Surgery for in depth methodological review and analysis. Methodological reviews were performed by 2 orthopaedic surgeons with advanced research degrees. Following this, 2 clinical experts reviewed the articles to rate the clinical impact or value of each study. Methodological and clinical reviews were compiled, and a final recommendation on impact to change clinical practice was made based on both review components at the consensus of the panel.

Results:
The first study reviewed investigated the impact of physical therapy on function following supracondylar humeral fractures in children. The reviewers deemed the superiority study to of sound design, and conclusions appropriate for the methodology used and clinical findings. The results do not compel a recommendation to change clinical practice. The second study investigated the impact of Botulinum Toxin A with casting for the treatment of idiopathic toe-walking in children. Although of relatively sound design, the sample size was too small to appropriately perform some statistical comparisons. No recommendation to change clinical practice could be made.

Conclusion:
Both RCTs reviewed were superiority studies with a negative result. No recommendation to change clinical practice could be made.

Significance:
Interpretation of superiority studies with nonsignificant findings must be done with caution. The findings of both of these RCTs highlight the need for more noninferiority trials in the pediatric orthopaedic literature in order to appropriately demonstrate no difference between 2 treatment options.
Intraoperative Change in Defect Size during Maxillary Reconstruction Using Surgical Guides Created by CAD/CAM
Authors: Morita Daiki , Numajiri Toshiaki , Nakamura Hiroko , Tsujiko Shoko , Sowa Yoshihiro , Yasuda Makoto , Hirano Shigeru 
Published: April 2017

Summary:
Surgical osteotomy guides created by computer-aided design/computer-aided manufacturing (CAD/CAM) have been developed and are now widely used in maxillofacial reconstruction. However, there are no standard procedures for dealing with an intraoperative change in defect size. We report on a case in which we used our CAD/CAM guides to deal with an intraoperative change in defect size in a maxillary reconstruction. We planned the maxillary reconstruction using a free fibula flap because of left maxillary sinus cancer in a 73-year-old man. In Japan, we cannot use commercially supplied CAD/CAM guides because these have not been approved by the government. We created novel CAD/CAM guides by using free software and a low-cost 3D printer. We performed model surgery to check the accuracy of the design and to prebend the titanium plates before the operation. The actual defect in the maxilla was found to be smaller than that used in preoperative planning. It was therefore necessary to rearrange the fibular segments and to rebend the plates. Comparison between the preoperative and postoperative 3D images showed that the deviation was 2–4 mm. In case that the CAD/CAM guides become inapplicable because of an intraoperative change in defect size, rearranging both the ends of set-up fibular segments and rebending the plates in situ allows us to deal with the situation. However, because extra time is needed to rearrange and rebend, the total operation and flap ischemic times are not shortened.
Antimicrobial Resistant Streptococcus pneumoniae: Prevalence, Mechanisms, and Clinical Implications
Authors: Cherazard Regine , Epstein Marcia , Doan Thien-Ly , Salim Tanzila , Bharti Sheena , Smith Miriam A. 
Published: April 2017

Background:

Streptococcus pneumoniae is a major cause of pneumonia, meningitis, sepsis, bacteremia, and otitis media. S. pneumoniae has developed increased resistance to multiple classes of antibiotics.

Study Design:
Systematic literature review of prevalence, mechanisms, and clinical implications in S. pneumoniae resistance.

Areas of Uncertainty:
Since S. pneumoniae resistance to penicillin was first reported with subsequent development of resistance to other classes of drugs, selection of appropriate antibiotic treatment is challenging.

Data Sources:
We searched PubMed (English language) for citations to antibiotic resistance in S. pneumoniae published before March 1, 2016.

Results:
We present a review of S. pneumoniae resistance to beta-lactams, macrolides, lincosamides, fluoroquinolones, tetracyclines, and trimethoprim-sulfamethoxazole (TMP-SMX). There has been a steady decline in susceptibility of S. pneumoniae to commonly used beta-lactams. Phenotypic expression of penicillin resistance occurs as a result of a genetic structural modification in penicillin-binding proteins. Between 20% and 40% of S. pneumoniae isolates are resistant to macrolides. Macrolide resistance mechanisms include ribosomal target site alteration, alteration in antibiotic transport, and modification of the antibiotic. Approximately 22% of S. pneumoniae isolates are resistant to clindamycin. Similar to macrolide resistance, clindamycin involves a target site alteration. The prevalence of fluoroquinolone resistance is low, although increasing. S. pneumoniae resistance to fluoroquinolones occurs by accumulated mutations within the bacterial genome, increased efflux, or acquisition of plasmid-encoded genes. S. pneumoniae resistance has also increased for the tetracyclines. The primary mechanism is mediated by 2 genes that confer ribosomal protection. The prevalence of TMP-SMX resistance is around 35%. As with fluoroquinolones, resistance to TMP-SMX is secondary to mutations in the bacterial genome.

Conclusions:
Effective treatment of resistant S. pneumoniae is a growing concern. New classes of drugs, newer formulations of older drugs, combination antibiotic therapy, nonantibiotic modalities, better oversight of antibiotic usage, and enhanced preventive measures hold promise.
Prescriber Compliance With Liver Monitoring Guidelines for Pazopanib in the Postapproval Setting: Results From a Distributed Research Network
Authors: Shantakumar Sumitra , Nordstrom Beth L. , Hall Susan A. , Djousse Luc , van Herk-Sukel Myrthe P.P. , Fraeman Kathy H. , Gagnon David R. , Chagin Karen , Nelson Jeanenne J. 
Published: April 2017

Objectives
Pazopanib received US Food and Drug Administration approval in 2009 for advanced renal cell carcinoma. During clinical development, liver chemistry abnormalities and adverse hepatic events were observed, leading to a boxed warning for hepatotoxicity and detailed label prescriber guidelines for liver monitoring. As part of postapproval regulatory commitments, a cohort study was conducted to assess prescriber compliance with liver monitoring guidelines.

Methods
Over a 4-year period, a distributed network approach was used across 3 databases: US Veterans Affairs Healthcare System, a US outpatient oncology community practice database, and the Dutch PHARMO Database Network. Measures of prescriber compliance were designed using the original pazopanib label guidelines for liver monitoring.

Results
Results from the VA (n = 288) and oncology databases (n = 283) indicate that prescriber liver chemistry monitoring was less than 100%: 73% to 74% compliance with baseline testing and 37% to 39% compliance with testing every 4 weeks. Compliance was highest near drug initiation and decreased over time. Among patients who should have had weekly testing, the compliance was 56% in both databases. The more serious elevations examined, including combinations of liver enzyme elevations meeting the laboratory definition of Hy’s law were infrequent but always led to appropriate discontinuation of pazopanib. Only 4 patients were identified for analysis in the Dutch database; none had recorded baseline testing.

Conclusions
In this population-based study, prescriber compliance was reasonable near pazopanib initiation but low during subsequent weeks of treatment. This study provides information from real-world community practice settings and offers feedback to regulators on the effectiveness of label monitoring guidelines.
Multilateral Functional Alterations of Human Neutrophils in Sepsis: From the Point of Diagnosis to the Seventh Day
Authors: Endo Akira , Okamura Miko , Yoshikawa Shunsuke , Otomo Yasuhiro , Morio Tomohiro 
Published: April 2017

ABSTRACT
Neutrophil functional changes caused by sepsis itself and their time-course variation have not been fully elucidated because previous studies targeted patients who had received therapeutic interventions. We explored the multilateral functions of circulating neutrophils in patients with severe sepsis or septic shock who had not yet undergone interventions, and followed their changes. Patients were treated based on the Surviving Sepsis Campaign Guidelines 2012. Neutrophil functions were evaluated on days 0 (before therapeutic intervention), 3, and 7 in 59 septic patients. The clinical severity score (APACHE II and SOFA) and serum pro-/anti-inflammatory cytokine concentrations of the patients were significantly increased on day 0 and normalized on day 3. However, neutrophil priming state, estimated by measuring the fMLP-stimulated reactive oxygen species, was significantly elevated on day 0, further augmented on day 3, and then returned to day 0 levels on day 7 despite general resolution of the inflammatory response. The expression of CXC chemokine receptor 2 and paired immunoglobulin-like receptor α, assessed as surrogate markers of transmigration and adhesion potency, was suppressed most strongly on day 0 and gradually recovered. To conclude, contrary to the patient's clinical course, neutrophil priming state was augmented most strongly at 3 days after diagnosis of sepsis. Impaired transmigration and excessive adhesion potency were observed most prominently at diagnosis. These observations would partially explain the mechanism of development of multiple organ dysfunction of the host who is subjected to a secondary insult, and may provide an important perspective for the implementation of additional immune-modulating therapy in sepsis.
The Impact of a Dedicated Robotic Team on Robotic-Assisted Sacrocolpopexy Outcomes
Authors: Carter-Brooks Charelle M. , Du Angela L. , Bonidie Michael J. , Shepherd Jonathan P. 
Published: April 2017

Background
Robotic-assisted sacrocolpopexy has been criticized for high cost. A strategy to increase operating room efficiency and decrease cost is implementation of a dedicated robotic team. Our objective was to determine if a dedicated robotic team decreases operative time.

Study Design
This institutional review board–approved retrospective cohort study included all robotic-assisted sacrocolpopexy performed from June 2010 to August 2015 by a single surgeon at 2 institutions in 1 health system. One hospital had a dedicated robotic team, whereas the other did not. To assess baseline differences, χ2 and t tests were used. Multivariable linear regression identified factors impacting operative time.

Results
Eighty-eight robotic-assisted sacrocolpopexy cases met inclusion criteria. Subjects were primarily white (92.8%) and postmenopausal (85.5%) with stage III prolapse (71.1%). Mean age was 60.6 ± 9.0 years, and BMI was 28.5 ± 5.1 kg/m2. Seventeen cases (19.3%) had a dedicated team. In the 71 cases without a dedicated team, there were 16 different surgical technologist and no advanced practice providers. Groups had similar baseline characteristics (all P > 0.05).
Mean operative time for the dedicated team was significantly less (131.8 vs 160.2 minutes, P < 0.001), a 17.7% time reduction. The decrease persisted on multivariable regression (β = −25.98 minutes, P < 0.001) after adjusting for case order on the day (β = −8.6 minutes, P = 0.002) and prior to hysterectomy (β = −36.1 minutes, P < 0.001). Operative complications and prolapse recurrence were low overall and not different between the dedicated and nondedicated teams (0% vs 2.9%, P = 0.50; 0% vs 7.5%, P = 0.29).

Conclusions
A dedicated robotic team during robotic-assisted sacrocolpopexy significantly decreased operative time by 26 minutes, a 17.7% reduction at our institution.
Awareness Regarding Perineal Protection, Obstetric Anal Sphincter Injury, and Episiotomy Among Obstetrics and Gynecology Residents; Effects of an Educational Workshop
Authors: Stecher Anna M. , Yeung Jennifer , Crisp Catrina C. , Pauls Rachel N. 
Published: April 2017

Objectives
Appropriate perineal protection may reduce rates of obstetric anal sphincter injuries (OASIS). We sought to investigate the knowledge and attitudes of obstetrics and gynecology residents concerning perineal protection, OASIS, and episiotomy before and after an educational workshop.

Methods
This was an institutional review board–approved cross-sectional survey study of obstetrics and gynecology residents. Two experts in perineal protection, whose methods have been shown to reduce OASIS by 50%, provided 1 week of education. Residents were taught in hands-on workshops and labor and delivery wards. Residents were surveyed regarding experiences, knowledge, and opinions of perineal protection, OASIS, and episiotomy. Surveys were administered immediately before and after the workshop and at 3 months following.

Results
All 31 residents participated. Almost all (97%) felt it was possible to reduce the incidence of OASIS prior to the workshop. Statistically significant increases were noted following training in the number that felt it was “very effective” to use the 2-handed technique taught in the workshop (P = 0.002), as well as those that reported most commonly performing a mediolateral episiotomy (protective against OASIS, if used selectively) when episiotomy was indicated (P = 0.001). The percent that reported feeling “comfortable” or “very comfortable” performing episiotomies increased from 45% to 77% immediately after the workshop (P = 0.002); this declined to 55% at 3 months. A large majority (77%) reported that the workshop was beneficial; 65% described an impact to patient care.

Conclusions
A workshop targeting perineal protection improved awareness and changed clinical practice in this group of residents. Ongoing education regarding perineal protection and episiotomy may reinforce behavior modifications.
The Effect of Lithotomy Position on Nerve Stretch: A Cadaveric Study
Authors: Deveneau Nicolette E. , Forbis Courtney , Lipetskaia Lioudmilla , Kinman Casey L. , Agrawal Anubhav , Herring Nicole R. , Francis Sean L. 
Published: April 2017

Objective
The objective of our study was to design a method to measure nerve stretch in cadaveric subjects and then use the method to assess femoral nerve stretch in the lithotomy position with varying degrees of flexion and extension.

Methods
A university-based, cadaveric observational study of femoral nerve stretch was conducted. In 6 cadaveric subjects, femoral nerve near the inguinal ligament was dissected in each cadaveric subject. The nerve was marked, and digital images of the nerve were obtained in the supine position and lithotomy position in both flexion and extension. Distances were calculated using the ratio of pixels to millimeter specific for each image. The average distance for each set of images was then used to calculate the percent change from supine for each position.

Results
We were able to assess nerve stretch using photo-editing software. For extended position, all nerves showed some degree of stretch with the mean percent change in nerve length being 10.35%. For all other positions, most showed a decrease of nerve length. There was not a significant relation between degree of extension and stretch (Pearson r, P < 0.05).

Conclusions
Hip extension between 10 and 20 degrees consistently stretches the femoral nerve greater than 5%. The potential for femoral nerve stretch and avoiding hip extension should be considered when positioning a patient in lithotomy for surgical procedures.
Increasing suppression of saccade-related transients along the human visual hierarchy
Authors: Golan Tal , Davidesco Ido , Meshulam Meir , Groppe David M , Mégevand Pierre , Yeagle Erin M , Goldfinger Matthew S , Harel Michal , Melloni Lucia , Schroeder Charles E , Deouell Leon Y , Mehta Ashesh D , Malach Rafael 
Published: April 2017

AbstractA key hallmark of visual perceptual awareness is robustness to instabilities arising from unnoticeable eye and eyelid movements. In previous human intracranial (iEEG) work (Golan et al., 2016) we found that excitatory broadband high-frequency activity transients, driven by eye blinks, are suppressed in higher-level but not early visual cortex. Here, we utilized the broad anatomical coverage of iEEG recordings in 12 eye-tracked neurosurgical patients to test whether a similar stabilizing mechanism operates following small saccades. We compared saccades (1.3°-3.7°) initiated during inspection of large individual visual objects with similarly-sized external stimulus displacements. Early visual cortex sites responded with positive transients to both conditions. In contrast, in both dorsal and ventral higher-level sites the response to saccades (but not to external displacements) was suppressed. These findings indicate that early visual cortex is highly unstable compared to higher-level visual regions which apparently constitute the main target of stabilizing extra-retinal oculomotor influences.