bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving compound–protein interaction prediction by building up highly credible negative samples
Authors: Liu Hui , Sun Jianjiang , Guan Jihong , Zheng Jie , Zhou Shuigeng
Published: June 2015

Motivation: Computational prediction of compound–protein interactions (CPIs) is of great importance for drug design and development, as genome-scale experimental validation of CPIs is not only time-consuming but also prohibitively expensive. With the availability of an increasing number of validated interactions, the performance of computational prediction approaches is severely impended by the lack of reliable negative CPI samples. A systematic method of screening reliable negative sample becomes critical to improving the performance of in silico prediction methods.

Results: This article aims at building up a set of highly credible negative samples of CPIs via an in silico screening method. As most existing computational models assume that similar compounds are likely to interact with similar target proteins and achieve remarkable performance, it is rational to identify potential negative samples based on the converse negative proposition that the proteins dissimilar to every known/predicted target of a compound are not much likely to be targeted by the compound and vice versa. We integrated various resources, including chemical structures, chemical expression profiles and side effects of compounds, amino acid sequences, protein–protein interaction network and functional annotations of proteins, into a systematic screening framework. We first tested the screened negative samples on six classical classifiers, and all these classifiers achieved remarkably higher performance on our negative samples than on randomly generated negative samples for both human and Caenorhabditis elegans. We then verified the negative samples on three existing prediction models, including bipartite local model, Gaussian kernel profile and Bayesian matrix factorization, and found that the performances of these models are also significantly improved on the screened negative samples. Moreover, we validated the screened negative samples on a drug bioactivity dataset. Finally, we derived two sets of new interactions by training an support vector machine classifier on the positive interactions annotated in DrugBank and our screened negative interactions. The screened negative samples and the predicted interactions provide the research community with a useful resource for identifying new drug targets and a helpful supplement to the current curated compound–protein databases.

Availability: Supplementary files are available at: http://admis.fudan.edu.cn/negative-cpi/.

Contact:  sgzhou@fudan.edu.cn

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Reconstructing gene regulatory dynamics from high-dimensional single-cell snapshot data
Authors: Ocone Andrea , Haghverdi Laleh , Mueller Nikola S. , Theis Fabian J.
Published: June 2015

Motivation: High-dimensional single-cell snapshot data are becoming widespread in the systems biology community, as a mean to understand biological processes at the cellular level. However, as temporal information is lost with such data, mathematical models have been limited to capture only static features of the underlying cellular mechanisms.

Results: Here, we present a modular framework which allows to recover the temporal behaviour from single-cell snapshot data and reverse engineer the dynamics of gene expression. The framework combines a dimensionality reduction method with a cell time-ordering algorithm to generate pseudo time-series observations. These are in turn used to learn transcriptional ODE models and do model selection on structural network features. We apply it on synthetic data and then on real hematopoietic stem cells data, to reconstruct gene expression dynamics during differentiation pathways and infer the structure of a key gene regulatory network.

Availability and implementation: C++ and Matlab code available at https://www.helmholtz-muenchen.de/fileadmin/ICB/software/inferenceSnapshot.zip.

Contact:  fabian.theis@helmholtz-muenchen.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Gene network inference by fusing data from diverse distributions
Authors: Žitnik Marinka , Zupan Blaž
Published: June 2015

Motivation: Markov networks are undirected graphical models that are widely used to infer relations between genes from experimental data. Their state-of-the-art inference procedures assume the data arise from a Gaussian distribution. High-throughput omics data, such as that from next generation sequencing, often violates this assumption. Furthermore, when collected data arise from multiple related but otherwise nonidentical distributions, their underlying networks are likely to have common features. New principled statistical approaches are needed that can deal with different data distributions and jointly consider collections of datasets.

Results: We present FuseNet, a Markov network formulation that infers networks from a collection of nonidentically distributed datasets. Our approach is computationally efficient and general: given any number of distributions from an exponential family, FuseNet represents model parameters through shared latent factors that define neighborhoods of network nodes. In a simulation study, we demonstrate good predictive performance of FuseNet in comparison to several popular graphical models. We show its effectiveness in an application to breast cancer RNA-sequencing and somatic mutation data, a novel application of graphical models. Fusion of datasets offers substantial gains relative to inference of separate networks for each dataset. Our results demonstrate that network inference methods for non-Gaussian data can help in accurate modeling of the data generated by emergent high-throughput technologies.

Availability and implementation: Source code is at https://github.com/marinkaz/fusenet.

Contact:  blaz.zupan@fri.uni-lj.si

Supplementary information:  Supplementary information is available at Bioinformatics online.
Knowledge-driven geospatial location resolution for phylogeographic models of virus migration
Authors: Weissenbacher Davy , Tahsin Tasnia , Beard Rachel , Figaro Mari , Rivera Robert , Scotch Matthew , Gonzalez Graciela
Published: June 2015

Summary: Diseases caused by zoonotic viruses (viruses transmittable between humans and animals) are a major threat to public health throughout the world. By studying virus migration and mutation patterns, the field of phylogeography provides a valuable tool for improving their surveillance. A key component in phylogeographic analysis of zoonotic viruses involves identifying the specific locations of relevant viral sequences. This is usually accomplished by querying public databases such as GenBank and examining the geospatial metadata in the record. When sufficient detail is not available, a logical next step is for the researcher to conduct a manual survey of the corresponding published articles.

Motivation: In this article, we present a system for detection and disambiguation of locations (toponym resolution) in full-text articles to automate the retrieval of sufficient metadata. Our system has been tested on a manually annotated corpus of journal articles related to phylogeography using integrated heuristics for location disambiguation including a distance heuristic, a population heuristic and a novel heuristic utilizing knowledge obtained from GenBank metadata (i.e. a ‘metadata heuristic’).

Results: For detecting and disambiguating locations, our system performed best using the metadata heuristic (0.54 Precision, 0.89 Recall and 0.68 F-score). Precision reaches 0.88 when examining only the disambiguation of location names. Our error analysis showed that a noticeable increase in the accuracy of toponym resolution is possible by improving the geospatial location detection. By improving these fundamental automated tasks, our system can be a useful resource to phylogeographers that rely on geospatial metadata of GenBank sequences.

Contact:  davy.weissenbacher@asu.edu
Reconstruction of clonal trees and tumor composition from multi-sample sequencing data
Authors: El-Kebir Mohammed , Oesper Layla , Acheson-Field Hannah , Raphael Benjamin J.
Published: June 2015

Motivation: DNA sequencing of multiple samples from the same tumor provides data to analyze the process of clonal evolution in the population of cells that give rise to a tumor.

Results: We formalize the problem of reconstructing the clonal evolution of a tumor using single-nucleotide mutations as the variant allele frequency (VAF) factorization problem. We derive a combinatorial characterization of the solutions to this problem and show that the problem is NP-complete. We derive an integer linear programming solution to the VAF factorization problem in the case of error-free data and extend this solution to real data with a probabilistic model for errors. The resulting AncesTree algorithm is better able to identify ancestral relationships between individual mutations than existing approaches, particularly in ultra-deep sequencing data when high read counts for mutations yield high confidence VAFs.

Availability and implementation: An implementation of AncesTree is available at: http://compbio.cs.brown.edu/software.

Contact:  braphael@brown.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Misassembly detection using paired-end sequence reads and optical mapping data
Authors: Muggli Martin D. , Puglisi Simon J. , Ronen Roy , Boucher Christina
Published: June 2015

Motivation: A crucial problem in genome assembly is the discovery and correction of misassembly errors in draft genomes. We develop a method called misSEQuel that enhances the quality of draft genomes by identifying misassembly errors and their breakpoints using paired-end sequence reads and optical mapping data. Our method also fulfills the critical need for open source computational methods for analyzing optical mapping data. We apply our method to various assemblies of the loblolly pine, Francisella tularensis, rice and budgerigar genomes. We generated and used stimulated optical mapping data for loblolly pine and F.tularensis and used real optical mapping data for rice and budgerigar.

Results: Our results demonstrate that we detect more than 54% of extensively misassembled contigs and more than 60% of locally misassembled contigs in assemblies of F.tularensis and between 31% and 100% of extensively misassembled contigs and between 57% and 73% of locally misassembled contigs in assemblies of loblolly pine. Using the real optical mapping data, we correctly identified 75% of extensively misassembled contigs and 100% of locally misassembled contigs in rice, and 77% of extensively misassembled contigs and 80% of locally misassembled contigs in budgerigar.

Availability and implementation:  misSEQuel can be used as a post-processing step in combination with any genome assembler and is freely available at http://www.cs.colostate.edu/seq/.

Contact:  muggli@cs.colostate.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Genome-wide detection of intervals of genetic heterogeneity associated with complex traits
Authors: Llinares-López Felipe , Grimm Dominik G. , Bodenham Dean A. , Gieraths Udo , Sugiyama Mahito , Rowan Beth , Borgwardt Karsten
Published: June 2015

Motivation: Genetic heterogeneity, the fact that several sequence variants give rise to the same phenotype, is a phenomenon that is of the utmost interest in the analysis of complex phenotypes. Current approaches for finding regions in the genome that exhibit genetic heterogeneity suffer from at least one of two shortcomings: (i) they require the definition of an exact interval in the genome that is to be tested for genetic heterogeneity, potentially missing intervals of high relevance, or (ii) they suffer from an enormous multiple hypothesis testing problem due to the large number of potential candidate intervals being tested, which results in either many false positives or a lack of power to detect true intervals.

Results: Here, we present an approach that overcomes both problems: it allows one to automatically find all contiguous sequences of single nucleotide polymorphisms in the genome that are jointly associated with the phenotype. It also solves both the inherent computational efficiency problem and the statistical problem of multiple hypothesis testing, which are both caused by the huge number of candidate intervals. We demonstrate on Arabidopsis thaliana genome-wide association study data that our approach can discover regions that exhibit genetic heterogeneity and would be missed by single-locus mapping.

Conclusions: Our novel approach can contribute to the genome-wide discovery of intervals that are involved in the genetic heterogeneity underlying complex phenotypes.

Availability and implementation: The code can be obtained at: http://www.bsse.ethz.ch/mlcb/research/bioinformatics-and-computational-biology/sis.html.

Contact:  felipe.llinares@bsse.ethz.ch

Supplementary information  :  Supplementary data are available at Bioinformatics online.
PAGER: constructing PAGs and new PAG–PAG relationships for network biology
Authors: Yue Zongliang , Kshirsagar Madhura M. , Nguyen Thanh , Suphavilai Chayaporn , Neylon Michael T. , Zhu Liugen , Ratliff Timothy , Chen Jake Y.
Published: June 2015

In this article, we described a new database framework to perform integrative “gene-set, network, and pathway analysis” (GNPA). In this framework, we integrated heterogeneous data on pathways, annotated list, and gene-sets (PAGs) into a PAG electronic repository (PAGER). PAGs in the PAGER database are organized into P-type, A-type and G-type PAGs with a three-letter-code standard naming convention. The PAGER database currently compiles 44 313 genes from 5 species including human, 38 663 PAGs, 324 830 gene–gene relationships and two types of 3 174 323 PAG–PAG regulatory relationships—co-membership based and regulatory relationship based. To help users assess each PAG’s biological relevance, we developed a cohesion measure called Cohesion Coefficient (CoCo), which is capable of disambiguating between biologically significant PAGs and random PAGs with an area-under-curve performance of 0.98. PAGER database was set up to help users to search and retrieve PAGs from its online web interface. PAGER enable advanced users to build PAG–PAG regulatory networks that provide complementary biological insights not found in gene set analysis or individual gene network analysis. We provide a case study using cancer functional genomics data sets to demonstrate how integrative GNPA help improve network biology data coverage and therefore biological interpretability. The PAGER database can be accessible openly at http://discovery.informatics.iupui.edu/PAGER/.

Contact:  jakechen@iupui.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
Using collective expert judgements to evaluate quality measures of mass spectrometry images
Authors: Palmer Andrew , Ovchinnikova Ekaterina , Thuné Mikael , Lavigne Régis , Guével Blandine , Dyatlov Andrey , Vitek Olga , Pineau Charles , Borén Mats , Alexandrov Theodore
Published: June 2015

Motivation: Imaging mass spectrometry (IMS) is a maturating technique of molecular imaging. Confidence in the reproducible quality of IMS data is essential for its integration into routine use. However, the predominant method for assessing quality is visual examination, a time consuming, unstandardized and non-scalable approach. So far, the problem of assessing the quality has only been marginally addressed and existing measures do not account for the spatial information of IMS data. Importantly, no approach exists for unbiased evaluation of potential quality measures.

Results: We propose a novel approach for evaluating potential measures by creating a gold-standard set using collective expert judgements upon which we evaluated image-based measures. To produce a gold standard, we engaged 80 IMS experts, each to rate the relative quality between 52 pairs of ion images from MALDI-TOF IMS datasets of rat brain coronal sections. Experts’ optional feedback on their expertise, the task and the survey showed that (i) they had diverse backgrounds and sufficient expertise, (ii) the task was properly understood, and (iii) the survey was comprehensible. A moderate inter-rater agreement was achieved with Krippendorff’s alpha of 0.5. A gold-standard set of 634 pairs of images with accompanying ratings was constructed and showed a high agreement of 0.85. Eight families of potential measures with a range of parameters and statistical descriptors, giving 143 in total, were evaluated. Both signal-to-noise and spatial chaos-based measures performed highly with a correlation of 0.7 to 0.9 with the gold standard ratings. Moreover, we showed that a composite measure with the linear coefficients (trained on the gold standard with regularized least squares optimization and lasso) showed a strong linear correlation of 0.94 and an accuracy of 0.98 in predicting which image in a pair was of higher quality.

Availability and implementation: The anonymized data collected from the survey and the Matlab source code for data processing can be found at: https://github.com/alexandrovteam/IMS_quality.

Contact:  theodore.alexandrov@embl.de
SoloDel: a probabilistic model for detecting low-frequent somatic deletions from unmatched sequencing data
Authors: Kim Junho , Kim Sanghyeon , Nam Hojung , Kim Sangwoo , Lee Doheon
Published: June 2015

Motivation: Finding somatic mutations from massively parallel sequencing data is becoming a standard process in genome-based biomedical studies. There are a number of robust methods developed for detecting somatic single nucleotide variations However, detection of somatic copy number alteration has been substantially less explored and remains vulnerable to frequently raised sampling issues: low frequency in cell population and absence of the matched control samples.

Results: We developed a novel computational method SoloDel that accurately classifies low-frequent somatic deletions from germline ones with or without matched control samples. We first constructed a probabilistic, somatic mutation progression model that describes the occurrence and propagation of the event in the cellular lineage of the sample. We then built a Gaussian mixture model to represent the mixed population of somatic and germline deletions. Parameters of the mixture model could be estimated using the expectation-maximization algorithm with the observed distribution of read-depth ratios at the points of discordant-read based initial deletion calls. Combined with conventional structural variation caller, SoloDel greatly increased the accuracy in classifying somatic mutations. Even without control, SoloDel maintained a comparable performance in a wide range of mutated subpopulation size (10–70%). SoloDel could also successfully recall experimentally validated somatic deletions from previously reported neuropsychiatric whole-genome sequencing data.

Availability and implementation: Java-based implementation of the method is available at http://sourceforge.net/projects/solodel/

Contact:  swkim@yuhs.ac or dhlee@biosoft.kaist.ac.kr

Supplementary information:  Supplementary data are available at Bioinformatics online.
The expanding family of regulatory B cells
Authors: Mauri Claudia , Menon Madhvi
Published: June 2015

Over the last decade it has become evident that in addition to producing antibody, B cells activate the immune system by producing cytokines and via antigen presentation. In addition, B cells also exhibit immunosuppressive functions via diverse regulatory mechanisms. This subset of B cells, known as regulatory B cells (Bregs), contributes to the maintenance of tolerance, primarily via the production of IL-10. Studies in experimental animal models, as well as in patients with autoimmune diseases, have identified multiple Breg subsets exhibiting diverse mechanisms of immune suppression. In this review, we describe the different Breg subsets identified in mice and humans, and their diverse mechanisms of suppression in different disease settings.
A weak lensing comparability study of galaxy mergers that host AGNs
Authors: Harvey D. , Courbin F.
Published: June 2015

We compared the total mass density profiles of three different types of galaxies using weak gravitational lensing: (i) 29 galaxies that host quasars at $\bar{z}\sim 0.32$ that are in a post-starburst quasar (PSQ) phase with high star formation indicating recent merger activity, (ii) 22 large elliptical galaxies from the Sloan Lens ACS Survey (SLACS) sample that do not host a quasar at $\bar{z}\sim 0.23$, and (iii) 17 galaxies that host moderately luminous quasars at $\bar{z}\sim 0.36$ powered by disc instabilities, but with no intense star formation. In an initial test we found no evidence for a connection between the merger state of a galaxy and the profile of the halo, with the PSQ profile comparable to that of the other two samples and consistent with the Leauthaud et al. study of moderately luminous quasars in Cosmic Evolution Survey (COSMOS). Given the compatibility of the two quasar samples, we combined these and found no evidence for any connection between black hole activity and the dark matter halo. All three mass profiles remained compatible with isothermality given the present data.
Cosmic ray penetration in diffuse clouds
Authors: Morlino G. , Gabici S.
Published: June 2015

Cosmic rays are a fundamental source of ionization for molecular and diffuse clouds, influencing their chemical, thermal, and dynamical evolution. The amount of cosmic rays inside a cloud also determines the gamma-ray flux produced by hadronic collisions between cosmic rays and cloud material. We study the spectrum of cosmic rays inside and outside of a diffuse cloud by solving the stationary transport equation for cosmic rays including diffusion, advection, and energy losses due to ionization of neutral hydrogen atoms. We found that the cosmic ray spectrum inside a diffuse cloud differs from the one in the interstellar medium (ISM) for energies smaller than Ebr ≈ 100 MeV, irrespective of the model details. Below Ebr, the spectrum is harder (softer) than that in the ISM if the latter is a power law ∝p−s with s larger (smaller) than ∼0.42.
Necrotizing Fasciitis in Hematological Patients: Enterobacteriaceae Predominance and Limited Utility of Laboratory Risk Indicator for Necrotizing Fasciitis Score
Authors: Foo Rui Min , Tung Moon Ley , Poon Li Mei , Chan Douglas , Smitasin Nares , Koh Liang Piu , Chng Wee Joo , Chai Louis Yi Ann
Published: June 2015

Immune suppression is a recognized risk factor for necrotizing fasciitis. In patients with hematological malignancies, a profoundly immunocompromised group, the predominant causative organisms are Gram negative. Clinical presentation and outcomes in these patients are similar to the immunocompetent. The Laboratory Risk Indicator for Necrotizing Fasciitis score is not reliable for risk stratification of the disease.
Use of Simulation to Test Systems and Prepare Staff for a New Hospital Transition
Authors: Adler Mark D. , Mobley Bonnie L. , Eppich Walter J. , Lappe Molly , Green Michaeleen , Mangold Karen
Published: June 2015

Objective

To describe the development and key outcomes arising from the use of simulation as a method to test systems and prepare staff for a transition to a new hospital.

Methods

We describe a simulation program developed by key parties with the goal of reducing latent safety threats present at the opening of a new hospital and to train staff in new workflows. Issues identified were collected and reported to leadership. Outcomes included the number of learners reached, issues identified (grouped by theme), and results of a postmove survey of hospital-based staff.

Results

Approximately 258 hours of simulation were conducted, impacting 514 participants. We conducted 64 hours of system testing and 196 hours of training during the main orientation process. Approximately 641 unique issues were identified (175 equipment, 136 code alarm, 174 barriers to care, and 156 incorrect signage). In a hospital-wide survey, 38% reported simulation as part of their training (39% of nurses and 23% of physicians). 43% of survey respondents reported multidisciplinary simulations; 55% of simulation attendees felt that the simulation was helpful and eased their transition to the new hospital.

Conclusions

Systems testing and education using simulation can play a meaningful role in new facility training. Key lessons included early planning, allocation of resources to the effort, flexibility to adapt to changes, and planned integration with other training activities. A formal a priori plan to address issues identified during the process is necessary.
Additional Medical Costs Due to Hospital-Acquired Falls
Authors: Hirose Masahiro , Nakabayashi Narue , Fukuda Seiji , Yamaguchi Shuhei , Igawa Mikio , Egami Koichi , Honda Junichi , Shima Hiroji
Published: June 2015

Objectives

To explore the additional medical costs (AMCs) due to hospital-acquired falls (falls), as well as their impact on clinical services within hospitals under the nationally uniform universal health insurance system in Japan.

Methods

With the use of administrative profiling data based on accounting systems linked with the Japanese social insurance medical fee schedule, we analyzed data from 2 teaching hospitals: Shimane University Hospital (SUH) and St. Mary's Hospital (SMH). We extracted 588 fall cases from 4669 incident reports in SUH and 1168 fall cases from 7717 incident reports in SMH that potentially incurred AMCs.

Results

Additional medical costs were 364 ± 2129 USD for minor injuries and 4336 ± 3645 USD for major injuries at SUH (P < 0.001) and 114 ± 124 USD for minor injuries and 2267 ± 2811 USD for major injuries at SMH (P < 0.001). Among the clinical services provided, imaging services were the most frequently used, with 89.9% (n = 205) of 228 minor injuries at SUH and 86.7% (n = 339) of 391 minor injuries at SMH; imaging services were used in all major injury cases at both hospitals. Although the number of cases using additional procedure/surgery services was lower than those using imaging services at both hospitals, AMCs for procedure/surgery services accounted for the highest proportions of total AMCs in both hospitals.

Conclusions

Although falls with minor injuries outnumbered falls with major injuries, fall-related AMCs for the latter were higher at both teaching hospitals because procedure/surgery services were required for cases with major injuries such as femoral neck and trochanteric fractures. The findings suggest that hospital administrators and policy makers have to take appropriate measures to prevent major injuries inpatients due to hospital-acquired falls.
Critical Value Reporting at Egyptian Laboratories
Authors: Mosallam Rasha , Ibrahim Samaa Zenhom
Published: June 2015

Objectives

To examine critical value reporting policies and practices and to identify critical value ranges for selected common laboratory assays at inpatient division of laboratories of Alexandria hospitals.

Methods

A cross-sectional descriptive study design was used. Subjects were from inpatient division of all laboratories of Alexandria hospitals (40 laboratories). Data were collected using a questionnaire composed of 4 sections. The first section explored hospital and laboratory characteristics. The second section assessed policies and procedures of critical value reporting. The third section explored the reporting process. The fourth section explored critical value ranges for selected common laboratory assays.

Results

Written procedure for reporting of critical values was present in 77.5% of laboratories and a comprehensive list of critical values in 72.55%. For laboratories having a critical value list, the number of tests in the list ranged from 7 to 40. Three-fifths of laboratories had a policy for assessing the timeliness of reporting and 3 quarters stated that the laboratory policy requires feedback (60.0% and 75.0%, respectively). The hospital laboratory physician was responsible for critical value reporting followed by the laboratory technician (75.0% and 50.0%, respectively). The call is received mainly by nurses and physicians ordering the test (67.5% and 55.0%, respectively) and the channel of reporting is mainly the telephone or through sending test report to the ward (67.5% and 50.0%, respectively). Wireless technologies are used in reporting in only 10.0% of hospitals. The cutoff limits for reporting different assays showed considerable interlaboratory variation.

Conclusions

Critical value policies and practices showed interinstitutional variation with deficiencies in some reporting practices. Selection of critical assays for notification and setting the limits of notification exhibited wide variation as well.
Improving Adherence to Practice Guidelines for Anticoagulation in Patients Receiving Neuraxial Anesthesia Using an Electronic Order Entry Alert System
Authors: Jajosky Jessica , Howell Stephen M. , Honaker John , Moriarty Allison , Shea Joy Marie
Published: June 2015

Objectives

Epidural analgesia is frequently used to alleviate postoperative pain. Though rare, epidural hematoma continues to be a feared complication of neuraxial analgesia. The risk of epidural hematoma is likely increased when certain regimens are used for prophylaxis/treatment of venous thromboembolism. To help decrease the risk, we developed an alert in our electronic medical record to assist providers with adherence to published guidelines addressing neuraxial analgesia and anticoagulation.

Methods

Patient data were collected retrospectively 3 months before and 3 months after the initiation of the computerized alert to assess the effectiveness of the alert. Patients were included if they had a procedure code associated with epidural analgesia. Pregnant patients and children were excluded. Type and frequency of antithrombotic medications were recorded for comparison to published practice guidelines.

Results

Using Poisson regression to describe the data, patients with epidurals after the best practice alert observed a 61% decrease in the expected number of days of exposure to inappropriate doses of anticoagulation versus patients treated before implementation of the alert.

Conclusion

Unapproved antithrombotic administration was significantly reduced after initiation of the alert system. This simple electronic alert was found to have a protective effect for patients receiving both anticoagulation and epidural analgesia.
A Systematic Review of Systemic Cobaltism After Wear or Corrosion of Chrome-Cobalt Hip Implants
Authors: Gessner Bradford D. , Steck Thomas , Woelber Erik , Tower Stephen S.
Published: June 2015

Objectives

We sought to synthesize data on systemic arthroprosthetic cobaltism, a recently described syndrome that results from wear or corrosion of chrome-cobalt hip components.

Methods

We conducted a systematic literature review to identify all reported cases of systemic arthroprosthetic cobaltism. To assess the epidemiologic link between blood cobalt levels (B[Co]), we developed a symptom scoring tool that evaluated 9 different symptom categories and a category of medical utilization.

Results

We identified 25 patients reported between 2001 and 2014 with a substantial increase in case reports over the past 3 years. Symptoms were diverse and involved the hip (84%), cardiovascular system (60%), audiovestibular system (52%), peripheral motor-sensory system (48%), thyroid (48%), psychological functioning (32%), visual system (32%), and the hematological, oncological, or immune system (20%). The mean latency from implantation to presentation or revision was 41 months (range, 9–99 months). The mean B[Co] was 324 μg/L and 4 patients had levels less than 20 μg/L. The B[Co] but not blood chromium level was highly associated with a quantitative measure of overall symptom severity (r
2, 0.81; P < 0.001). Mean B[Co] and symptom scores were substantially higher in patients with revisions of failed ceramic-on-ceramic prostheses than those with primary metal-on-metal prostheses.

Conclusions

Systemic arthroprosthetic cobaltism is an increasingly recognized complication of wear or corrosion of chrome-cobalt hip implants, may involve a large number of organ systems, and may occur with relatively low B[Co]. There is an urgent need to better define the overall scope of the problem and to develop screening and management strategies.
MERS-CoV recombination: implications about the reservoir and potential for adaptation
Authors: Dudas Gytis , Rambaut Andrew
Published: June 2015

Recombination is a process that unlinks neighbouring loci allowing for independent evolutionary trajectories within genomes of many organisms. If not properly accounted for, recombination can compromise many evolutionary analyses. In addition, when dealing with organisms that are not obligately sexually reproducing, recombination gives insight into the rate at which distinct genetic lineages come into contact. Since June, 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has caused 1106 laboratory-confirmed infections, with 421 MERS-CoV associated deaths as of April 16, 2015. Although bats are considered as the likely ultimate source of zoonotic betacoronaviruses, dromedary camels have been consistently implicated as the source of current human infections in the Middle East. In this paper we use phylogenetic methods and simulations to show that MERS-CoV genome has likely undergone numerous recombinations recently. Recombination in MERS-CoV implies frequent co-infection with distinct lineages of MERS-CoV, probably in camels given the current understanding of MERS-CoV epidemiology.
Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis
Authors: Weckselblatt Brooke , Hermetz Karen E. , Rudd M. Katharine
Published: June 2015

Unbalanced translocations are a relatively common type of copy number variation and a major contributor to neurodevelopmental disorders. We analyzed the breakpoints of 57 unique unbalanced translocations to investigate the mechanisms of how they form. Fifty-one are simple unbalanced translocations between two different chromosome ends, and six rearrangements have more than three breakpoints involving two to five chromosomes. Sequencing 37 breakpoint junctions revealed that simple translocations have between 0 and 4 base pairs (bp) of microhomology (n = 26), short inserted sequences (n = 8), or paralogous repeats (n = 3) at the junctions, indicating that translocations do not arise primarily from nonallelic homologous recombination but instead form most often via nonhomologous end joining or microhomology-mediated break-induced replication. Three simple translocations fuse genes that are predicted to produce in-frame transcripts of SIRPG-WWOX, SMOC2-PROX1, and PIEZO2-MTA1, which may lead to gain of function. Three complex translocations have inversions, insertions, and multiple breakpoint junctions between only two chromosomes. Whole-genome sequencing and fluorescence in situ hybridization analysis of two de novo translocations revealed at least 18 and 33 breakpoints involving five different chromosomes. Breakpoint sequencing of one maternally inherited translocation involving four chromosomes uncovered multiple breakpoints with inversions and insertions. All of these breakpoint junctions had 0–4 bp of microhomology consistent with chromothripsis, and both de novo events occurred on paternal alleles. Together with other studies, these data suggest that germline chromothripsis arises in the paternal genome and may be transmitted maternally. Breakpoint sequencing of our large collection of chromosome rearrangements provides a comprehensive analysis of the molecular mechanisms behind translocation formation.
YCF1: A Green TIC: Response to the de Vries et al. Commentary
Authors: Nakai Masato
Published: June 2015

This response to a recent Commentary article by de Vries et al. highlights critical errors in the annotation and identification of Ycf1 homologs in the sequenced chloroplast genomes. Contrary to what is reported by de Vries et al., the majority of chloroplast genomes sequenced to date appear to have retained a typical Ycf1 sequence (i.e., including the N-terminal 6TM domain and a variable hydrophilic C-terminal domain) as my group previously reported. Our evidence continues to support the model that Ycf1 forms an essential component of a “green TIC” that is largely conserved among the Chlorophyta and land plants. Since the establishment of this green TIC with Tic20 as the core component, some cases of loss of Ycf1 during the evolution of the green lineages might be regarded as modifications or alterations of the complex. Here, I discuss our working model that the presence of an alternative “nonphotosynthetic-type” or “ancestral-type” TIC might explain other (or specific) cases of the lack of Ycf1, not only in early lineages, including Glaucophyta and Rhodophyta, but also in the grasses.
Sarcomatoid carcinoma arising in the congenital pigmented nevus after treatment with carbon dioxide snow freezing method
Authors: Nakajima Rina , Komine Mayumi , Miyamoto Yukiko , Fusumae Takayuki , Fujita Yurika , Maekawa Takeo , Murata Satoru , Fukushima Noriyoshi , Ohtsuki Mamitaro
Published: June 2015

We report a case of sarcomatoid carcinoma of the skin in a 63‐year‐old man who was treated with the carbon dioxide snow freezing method for a huge congenital pigmented nevus that extended from the right upper extremity to the right trunk during childhood. He had an exophytic red tumor on the nevus in the right upper extremity that grew slowly for 4 years and rapidly recently. Histological and immunohistochemical studies revealed both epithelial and mesenchymal malignancy in the same tumor. The epithelial component was composed of basaloid cells forming multiple nests with peripheral palisading, positive for keratins and BerEP4, implying basal cell carcinoma. The mesenchymal component was composed of spindle‐shaped cells negative for keratins and positive for vimentin, suggesting sarcoma. This is, to our knowledge, the first report of sarcomatoid carcinoma arising in the primary pigmented nevus that had been treated by the carbon dioxide snow freezing method.
Successful treatment of hypertrophic herpes simplex genitalis in HIV‐infected patient with topical imiquimod
Authors: Deza Gustavo , Martin‐Ezquerra Gemma , Curto‐Barredo Laia , Villar García Judit , Pujol Ramon M.
Published: June 2015

Hypertrophic herpes simplex genitalis is an atypical presentation of genital herpes described in the context of immunosuppression, particularly HIV‐positive patients. This situation can become a diagnostic and therapeutic challenge. For this reason, alternative therapies are currently being discussed in the literature. We report a case of hypertrophic genital herpes in a HIV‐positive patient who was successfully treated with topical 5% imiquimod after treatment failures with oral and i.v. antivirals.
Case of H syndrome with massive skin involvement, retroperitoneal fibrosis and Raynaud's phenomenon with a novel mutation in the SLC29A3 gene
Authors: Fujita Etsuko , Komine Mayumi , Tsuda Hidetoshi , Adachi Akimasa , Murata Satoru , Kamata Yasuyuki , Minota Seiji , Ohtsuki Mamitaro
Published: June 2015

We describe a case of H syndrome with massive skin involvement, retroperitoneal fibrosis and Raynaud's phenomenon. A 48‐year‐old man with parents of a consanguineous marriage, first appeared with decreased urine output, skin sclerosis on his inner thighs and short stature (142 cm, 47 kg). The patient had suffered from hearing loss since the age of 1 year, and his secondary sexual characteristics had not developed. Computed tomography showed periaortic fibrosis, bilateral ureteral stenosis, hydronephrosis and sclerosis of the germinal cords. A biopsy from the retroperitoneal mass revealed remarkable fibrosis with chronic inflammatory cells. Biopsies from the skin lesion showed thick collagen bundles through the dermis and lymphohistiocytic infiltration with numerous plasma cells. Serum inflammatory markers, such as C‐reactive protein, vascular endothelial factor, transforming growth factor‐β and soluble interleukin‐2 receptor, were elevated. Prednisolone was effective in treating skin lesions and in lowering serum inflammatory markers. After a long period of follow up, genomic DNA of the patient was obtained, and we identified a homozygous mutation in exon 5, c.625G>A, which caused transition of glycine to arginine, p.Gly208Arg, in the patient, but not in DNA samples from another 50 healthy individuals. This is the first case of H syndrome with Raynaud's phenomenon and retroperitoneal fibrosis, and the first Japanese case of H syndrome reported in the English published work with a novel mutation in the SLC29A3 gene.
Reliability and validity assessment of the revised Symptom Checklist 90 for alopecia areata patients in China
Authors: Tan Huan , Lan Xue‐mei , Yu Nan‐lan , Yang Xi‐chuan
Published: June 2015

No study has tested the reliability and validity of the revised Symptom Checklist 90 (SCL‐90‐R) for patients with alopecia areata (AA), and few have used it to evaluate the mental health of AA patients. To assess the psychological status in Chinese AA patients using the SCL‐90‐R, and to evaluate its reliability and validity, the psychological status of 168 patients and 100 controls was evaluated with the Chinese‐version SCL‐90‐R. From this study, we found that The Global Severity Index and nine subscale scores on the SCL‐90‐R were significantly higher in AA patients than that in the controls. Moreover, The Global Severity Index and nine subscale scores on the SCL‐90‐R were associated with disease duration, age of onset, sex and type of AA. In addition, the SCL‐90‐R presented good internal consistency (whole scale α = 0.98 and split‐half coefficient = 0.95). The intercorrelations between the nine subscales and their correlations with the total scale were 0.58–0.93. Factor analysis produced 22 factors with eigenvalues more than 1.0; the first factor explained 33.88% of the variance. Only hostility and paranoid ideation merged into one factor. Taken together, our data indicated that Chinese AA patients demonstrate greater psychopathology than healthy controls. The SCL‐90‐R can be used to assess global psychological distress in AA patients with good reliability and validity.
On the variety of methods for calculating confidence intervals by bootstrapping
Authors: Puth Marie‐Therese , Neuhäuser Markus , Ruxton Graeme D.
Published: June 2015

Researchers often want to place a confidence interval around estimated parameter values calculated from a sample. This is commonly implemented by bootstrapping. There are several different frequently used bootstrapping methods for this purpose.

Here we demonstrate that authors of recent papers frequently do not specify the method they have used and that different methods can produce markedly different confidence intervals for the same sample and parameter estimate.

We encourage authors to be more explicit about the method they use (and number of bootstrap resamples used).

We recommend the bias corrected and accelerated method as giving generally good performance; although researchers should be warned that coverage of bootstrap confidence intervals is characteristically less than the specified nominal level, and confidence interval evaluation by any method can be unreliable for small samples in some situations.
Tax Avoidance and the Implications of Weak Internal Controls
Authors: Bauer Andrew M.
Published: June 2015

I examine whether corporate tax avoidance is associated with internal control weaknesses (ICWs) disclosed under the Sarbanes‐Oxley Act (SOX). ICWs disclosed under SOX are frequently related to a firm's tax function. When pervasive ICWs exist, the likelihood increases that these frequent tax‐related ICWs spill over from financial reporting issues to tax avoidance objectives. Thus, my research helps corporate stakeholders understand the implications of internal controls beyond simply financial reporting objectives. Results indicate that, on average, firms with a tax‐related ICW have a 4 percent higher three‐year cash effective tax rate relative to firms without any such weaknesses. Further estimates reveal that this negative relation stems from pervasive, company‐level tax ICWs. Analysis of remediation suggests a causal link. I find that after remediating tax‐related ICWs, firms report higher levels of tax avoidance in the future. Broadly, these findings support that internal control quality represents a proxy for internal governance, and thus the strength of alignment between managers and shareholders. Furthermore, tax‐related internal controls represent an important underlying determinant of tax avoidance with significant cash flow effects, and implications beyond financial reporting.
The Effect of Investor Status on Investors' Susceptibility to Earnings Fixation
Authors: Harris Ling L. , Hobson Jessen L. , Jackson Kevin E.
Published: June 2015

This study investigates whether an individual's status as a current or a prospective investor affects the investor's susceptibility to earnings fixation and proposes a mechanism to reduce earnings fixation. Our experimental results suggest that current investors are more susceptible to earnings fixation than prospective investors, and that current investors can reduce earnings fixation by explicitly forecasting future earnings as part of their evaluation process. We provide theory‐consistent evidence that current investors' prevention focus makes them elevate the importance of summary earnings in their evaluation of a company. However, after forecasting future earnings, current investors view summary earnings as only one of several similarly important evaluation inputs rather than as one substantially more important input (relative to its components). Our study contributes to research on earnings fixation and investor status. We also contribute to practice by documenting the moderating effect of investor status on earnings fixation and by identifying a simple mechanism that current investors can use to reduce their susceptibility to earnings fixation.
When Do Ineffective Audit Committee Members Experience Turnover?
Authors: Kachelmeier Steven J. , Rasmussen Stephanie J. , Schmidt Jaime J.
Published: June 2015

We use information extracted from a major proxy advisory service to test predictions from institutional theory regarding when and why audit committee (AC) members experience turnover because of evidence of ineffective governance. First, we broadly categorize AC ineffectiveness concerns as either (i) financial reporting failures or (ii) characteristics of individual AC members. Institutional theory suggests that the visible nature of the first category is more likely to threaten perceptions of AC legitimacy and hence prompt turnover, which is what we find. We then enrich the analysis by interacting the AC‐member ineffectiveness indicators with the extent of shareholder protest votes, finding that shareholder dissent elevates the turnover effects of both categories of ineffectiveness, as institutional theory would predict. Finally, we find that otherwise effective AC members face an increased likelihood of turnover if they serve on the AC when financial reporting failures are discovered, even if they were not on the AC when the events precipitating the failures occurred. Overall, our findings support the institutional theoretic premise that boards take remedial actions when necessary to restore perceived legitimacy.