bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of an Advanced Imaging Utilization Review Program on Downstream Health Care Utilization and Costs for Low Back Pain
Authors: Graves Janessa M. , Fulton-Kehoe Deborah , Jarvik Jeffrey G. , Franklin Gary M. 
Published: April 2018

Background:
Early magnetic resonance imaging (MRI) for acute low back pain (LBP) has been associated with increased costs, greater health care utilization, and longer disability duration in workers’ compensation claimants.

Objectives:
To assess the impact of a state policy implemented in June 2010 that required prospective utilization review (UR) for early MRI among workers’ compensation claimants with LBP.

Research Design:
Interrupted time series.

Subjects:
In total, 76,119 Washington State workers’ compensation claimants with LBP between 2006 and 2014.

Measures:
Proportion of workers receiving imaging per month (MRI, computed tomography, radiographs) and lumbosacral injections and surgery; mean total health care costs per worker; mean duration of disability per worker. Measures were aggregated monthly and attributed to injury month.

Results:
After accounting for secular trends, decreases in early MRI [level change: −5.27 (95% confidence interval, −4.22 to −6.31); trend change: −0.06 (−0.01 to −0.12)], any MRI [−4.34 (−3.01 to −5.67); −0.10 (−0.04 to −0.17)], and injection [trend change: −0.12 (−0.06 to −0.18)] utilization were associated with the policy. Radiograph utilization increased in parallel [level change: 2.46 (1.24–3.67)]. In addition, the policy resulted in significant decreasing changes in mean costs per claim, mean disability duration, and proportion of workers who received disability benefits. The policy had no effect on computed tomography or surgery utilization.

Conclusions:
The UR policy had discernable effects on health care utilization, costs, and disability. Integrating evidence-based guidelines with UR can improve quality of care and patient outcomes, while reducing use of low-value health services.
Risk Factors for Pneumocystis jirovecii Pneumonia in Patients With Rheumatoid Arthritis and a Prophylactic Indication of Trimethoprim/Sulfamethoxazole
Authors: Yukawa Kazutoshi , Nagamoto Yasutsugu , Watanabe Hirofumi , Funaki Masamoto , Iwahashi Mitsuhiro , Yamana Jiro , Sasaki Rie , Yamana Seizo 
Published: April 2018

Background/Objectives
Immunosuppressant medications (ISPs) increase the occurrence of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients. The prophylactic administration of trimethoprim/sulfamethoxazole (TMP/SMX) for PCP is effective but has serious adverse effects and so should be selectively used for patients at high risk. The aims of this study were to clarify the risk factors for PCP in RA patients and to establish the indications for administering TMP/SMX.

Methods
This retrospective cohort study analyzed data from 2640 patients (2010–2014) diagnosed as having RA who had not received a prophylactic administration of TMP/SMX. The risk factors for PCP were evaluated by comparing the clinical parameters between patients with PCP (PCP group, n = 19) and those without (non-PCP group, n = 2621).

Results
The PCP group was older (70 vs. 64 years), received higher doses of prednisolone (6.2 vs. 2.4 mg/d) and methotrexate (7.7 vs. 5.2 mg/wk), and had a greater number of ISPs (1.3 vs. 0.8) (p < 0.05). We stratified the PCP risk using a scoring system based on odds ratios (ORs) calculated for these parameters (methotrexate ≥6 mg/wk OR = 4.5, 1 point; age ≥65 years, OR = 3.7, 1 point; ≥2 ISPs, OR = 3.7, 1 point; prednisolone ≥5 mg/d, OR = 12.4, 3 points). The incidence of PCP among patients scoring 0 to 2 points was 0.04%; 3 to 4 points, 2.3%; and 5 points or more, 5.8%.

Conclusions
The prophylactic administration of TMP/SMX for PCP is recommended for RA patients who score at least 5 points with our system.
Exons as units of phenotypic impact for truncating mutations in autism
Authors: Chiang Andrew H. , Chang Jonathan , Wang Jiayao , Vitkup Dennis 
Published: April 2018

AbstractAutism spectrum disorders (ASD) are a group of related neurodevelopmental diseases displaying significant genetic and phenotypic heterogeneity1–4. Despite recent progress in understanding ASD genetics, the nature of phenotypic heterogeneity across probands remains unclear5, 6. Notably, likely gene-disrupting (LGD) de novo mutations affecting the same gene often result in substantially different ASD phenotypes. Nevertheless, we find that truncating mutations that affect the same exon frequently lead to strikingly similar intellectual phenotypes in unrelated ASD probands. Analogous patterns are observed for two independent proband cohorts and several other important ASD-associated phenotypes. We find that exons biased towards prenatal and postnatal expression preferentially contribute to ASD cases with lower and higher IQ phenotypes, respectively. These results suggest that exons, rather than genes, often represent a unit of effective phenotypic impact for truncating mutations in autism. The observed phenotypic effects are likely mediated by nonsense-mediated decay (NMD) of splicing isoforms, with autism phenotypes usually triggered by relatively mild (15-30%) decreases in overall gene dosage. We find that each gene with recurrent ASD mutations can be described by a parameter, phenotype dosage sensitivity (PDS), which characterizes the quantitative relationship between changes in a gene’s dosage and changes in a given disease phenotype. We further demonstrate analogous relationships between LGD mutations and changes in gene expression across human tissues. Therefore, similar phenotypic patterns may be also observed in multiple other systems and genetic disorders.
Whole-brain calcium imaging during physiological vestibular stimulation in larval zebrafish
Authors: Migault Geoffrey , Panier Thomas , Candelier Raphaël , Debrégeas Georges , Bormuth Volker 
Published: April 2018

AbstractDuring in vivo functional imaging, animals are head-fixed and thus deprived from vestibular inputs, which severely hampers the design of naturalistic virtual environments. To overcome this limitation, we developed a miniaturized ultra-stable light-sheet microscope that can be dynamically rotated during imaging along with a head-restrained zebrafish larva. We demonstrate that this system enables whole-brain functional imaging at single-cell resolution under controlled vestibular stimulation. We recorded for the first time the dynamic whole-brain response of a vertebrate to physiological vestibular stimulation. This development largely expands the potential of virtual-reality systems to explore complex multisensory-motor integration in 3D.
Festa: FLexible EXon-Based SPlicing And TRanscription ANnotation
Authors: Alfredo Rago , John K. Cobourne 
Published: April 2018

AbstractWe introduce FESTA, an R based algorithm that allows detection of alternative splicing based on experiment-specific exon expression data. FESTA disentangles alternative splicing signal from whole-gene transcription, facilitating the discovery and characterization of novel regulatory events even in the absence of transcript annotations or paired-end data. We also include customization options to increase its applicability on different platforms and experimental designs as well as a tool for the conversion from transcript expression to inclusion ratios.
Direct Small Molecule Activation of Mitofusins
Authors: Zacharioudakis Emmanouil , Biris Nikolaos , Garner Thomas P. , Chen Yun , Pekson Ryan , Dhingra Rimpy , Santulli Gaetano , Kirshenbaum Lorrie A. , Kitsis Richard N. , Gavathiotis Evripidis 
Published: April 2018

SummaryMitochondrial fusion is a physiological process that is regulated by mitofusins on the outer mitochondrial membrane. Conformational plasticity between anti- and pro-tethering conformations of mitofusins permits mitochondrial tethering and subsequent fusion. Here we developed a pharmacophore-based model to rationally manipulate the conformational plasticity of mitofusin 2 and perfomed an in silico small-molecule screen. This enabled the discovery of a direct activator of mitofusins, MASM7, capable of potently promoting mitochondrial fusion. The specificity of the MASM7-mitofusin 2 interaction is highlighted by structure-activity relationships of MASM7 analogues, FRET, NMR and mitochondrial fusion studies using mitofusin mutants. Our study identified the first-in-class direct activator of mitofusins, demonstrating a new paradigm for chemical modulation of mitochondrial fusion and downstream processes.
Development and validation of a triplex qPCR assay to detect efflux pump-mediated antibiotic resistance inBurkholderia pseudomallei
Authors: Webb Jessica R. , Price Erin P. , Somprasong Nawarat , Schweizer Herbert P. , Baird Robert W. , Currie Bart J. , Sarovich Derek S. 
Published: April 2018

ABSTRACTBurkholderia pseudomallei, the causative agent of the deadly tropical disease melioidosis, is intrinsically resistant to many antibiotics, leaving few effective treatment options. Trimethoprim-sulfamethoxazole (SXT), meropenem (MEM) and doxycycline (DOX) are valuable antibiotics for melioidosis treatment due to inherently low or no primary resistance. Although considered rare, upregulation of one or more resistance-nodulation-division (RND) efflux pumps is now known to lead to acquired resistance towards these drugs inB. pseudomallei.Here, we developed a triplex quantitative PCR assay to detect upregulation of the three clinically relevant RND efflux systems: AmrAB-OprA, BpeB-OprB and BpeEF-OprC. The triplex assay was tested on seven clinically-derivedB. pseudomalleiisogenic pairs, where the latter strain of each pair had altered regulator activity and exhibited reduced susceptibility to SXT, MEM or DOX. The triplex assay accurately detected efflux pump upregulation between isogenic pairs, which corresponded with decreased antibiotic susceptibility. We further verified assay performance on eight laboratory-generatedB. pseudomalleimutants encoding efflux pump regulator mutations. Targeting antibiotic resistance inB. pseudomalleiusing molecular genotyping provides clinicians with a rapid tool to identify potential treatment failure in near real-time, enabling informed alteration of treatment during an infection and improved patient outcomes.IMPORTANCEThe melioidosis bacteriumBurkholderia pseudomalleiis intrinsically resistant to many antibiotics, limiting treatment options to a handful of drugs including meropenem, doxycycline and trimethoprim-sulfamethoxazole. Although rare, there have now been several documented melioidosis cases where resistance to these antibiotics has developed during an infection, leading to treatment failure and increased mortality rates. Interestingly, all strains resistant to these drugs exhibit increased efflux pump expression, representing a shared molecular signature that can be exploited for rapid diagnostic purposes. Here, we developed and validated a single-tube real-time qPCR assay to detect clinically relevant efflux pump upregulation inB. pseudomallei, an important first step towards high-level resistance. This triplex assay offers a drastically reduced turn-around-time compared to current methodology, enabling earlier detection of resistance emergence. Implementation of this new diagnostic will aid clinicians in the selection of appropriate therapy, thereby minimizing resistance development and treatment failure for this high-mortality disease.
The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early onset osteoarthritis
Authors: Lawrence Elizabeth A , Kague Erika , Aggleton Jessye A , Harniman Robert L , Roddy Karen A , Hammond Chrissy L 
Published: April 2018

Abstract (max 200 words)Collagen is the major structural component of cartilage and mutations in the genes encoding Type XI collagen are associated with severe skeletal dysplasias (Fibrochondrogenesis and Stickler syndrome) and early onset osteoarthritis. The impact of the lack of Type XI collagen on cell behaviour and mechanical performance during skeleton development is unknown. We studied a zebrafish mutant for col11a2 and evaluated cartilage, bone development and mechanical properties to address this. We show that in col11a2 mutants Type II collagen is made but is prematurely degraded in maturing cartilage and ectopically expressed in the joint. These changes are correlated with increased stiffness of both bone and cartilage; quantified using Atomic Force Microscopy. In the mutants, the skeletal rudiment terminal region in the jaw joint are broader and the interzone smaller. These differences in shape and material properties impact on joint function and mechanical performance, which we modelled using Finite Element Analyses. Finally, we show that col11a2 heterozygous carriers reach adulthood but show signs of severe early onset osteoarthritis. Taken together our data demonstrate a key role for Type XI collagen in maintaining the properties of cartilage matrix; which when lost leads to alterations to cell behaviour that give rise to joint pathologies.
Dissecting indirect genetic effects from peers in laboratory mice
Authors: Baud Amelie , Casale Francesco Paolo , Barkley-Levenson Amanda M. , Farhadi Nilgoun , Montillot Charlotte , Yalcin Binnaz , Nicod Jerome , Palmer Abraham A. , Stegle Oliver 
Published: April 2018

AbstractThe phenotype of one individual can be affected not only by the individual’s own genotypes (direct genetic effects, DGE) but also by genotypes of interacting partners (indirect genetic effects, IGE). IGE have been detected using polygenic models in multiple species, including laboratory mice and humans. However, the underlying mechanisms remain largely unknown. Genome-wide association studies of IGE (igeGWAS) can point to IGE genes, but have not yet been applied to non-familial IGE arising from “peers” and affecting biomedical phenotypes. In addition, the extent to which igeGWAS will identify loci not identified by dgeGWAS remains an open question. Finally, findings from igeGWAS have not been confirmed by experimental manipulation.We leveraged a dataset of 170 behavioural, physiological and morphological phenotypes measured in 1,812 genetically heterogeneous laboratory mice to study IGE arising between same-sex, adult, unrelated laboratory mice housed in the same cage. We developed methods for igeGWAS in this context and identified 24 significant IGE loci for 17 phenotypes (FDR < 10%). There was no overlap between IGE loci and DGE loci for the same phenotype, which was consistent with the moderate genetic correlations between DGE and IGE for the same phenotype estimated using polygenic models. Finally, we fine-mapped seven significant IGE loci to individual genes and confirmed, in an experiment with a knockout model, that Epha4 gives rise to IGE on stress-coping strategy and wound healing.Our results demonstrate the potential for igeGWAS to identify IGE genes and shed some light into the mechanisms of peer influence.
bmotif: a package for motif analyses of bipartite networks
Authors: Simmons Benno I. , Sweering Michelle J. M. , Schillinger Maybritt , Dicks Lynn V. , Sutherland William J. , Clemente Riccardo Di 
Published: April 2018

AbstractBipartite networks are widely-used to represent a diverse range of species interactions, such as pollination, herbivory, parasitism and seed dispersal. The structure of these networks is usually characterised by calculating one or more metrics that capture different aspects of network architecture. While these metrics capture useful properties of networks, they only consider structure at the scale of the whole network (the macro-scale) or individual species (the micro-scale). ‘Meso-scale’ structure between these scales is usually ignored, despite representing ecologically-important interactions. Network motifs are a framework for capturing this meso-scale structure and are gaining in popularity. However, there is no software available in R, the most popular programming language among ecologists, for conducting motif analyses in bipartite networks. Similarly, no mathematical formalisation of bipartite motifs has been developed.Here we introduce bmotif: a package for counting motifs, and species positions within motifs, in bipartite networks. Our code is primarily an R package, but we also provide MATLAB and Python code of the core functionality. The software is based on a mathematical framework where, for the first time, we derive formal expressions for motif frequencies and the frequencies with which species occur in different positions within motifs. This framework means that analyses with bmotif are fast, making motif methods compatible with the permutational approaches often used in network studies, such as null model analyses.We describe the package and demonstrate how it can be used to conduct ecological analyses, using two examples of plant-pollinator networks. We first use motifs to examine the assembly and disassembly of an Arctic plant-pollinator community, and then use them to compare the roles of native and introduced plant species in an unrestored site in Mauritius.bmotif will enable motif analyses of a wide range of bipartite ecological networks, allowing future research to characterise these complex networks without discarding important meso-scale structural detail.
Genomic consequences of a recent three-way admixture in supplemented wild brown trout populations revealed by ancestry tracts
Authors: Leitwein Maeva , Gagnaire Pierre-Alexandre , Desmarais Erick , Berrebi Patrick , Guinand Bruno 
Published: April 2018

AbstractUnderstanding the evolutionary consequences of human-mediated introductions of domestic strains into the wild and their subsequent admixture with natural populations is of major concern in conservation biology. In the brown troutSalmo trutta, decades of stocking practices have profoundly impacted the genetic makeup of wild populations. Small local Mediterranean populations in the Orb River watershed (Southern France) have been subject to successive introductions of domestic strains derived from the Atlantic and Mediterranean lineages. However, the genomic impacts of two distinct sources of stocking (locally-derived vs divergent) on the genetic integrity of wild populations remain poorly understood. Here, we evaluate the extent of admixture from both domestic strains within three wild populations of this watershed, using 75,684 mapped SNPs obtained from double-digest restriction-site-associated DNA sequencing (dd-RADseq). Using a local ancestry inference approach, we provide a detailed picture of admixture patterns across the brown trout genome at the haplotype level. By analysing the chromosomal ancestry profiles of admixed individuals, we reveal a wider diversity of hybrid and introgressed genotypes than estimated using classical methods for inferring ancestry and hybrid pedigree. In addition, the length distribution of introgressed tracts retained different timings of introgression between the two domestic strains. We finally reveal opposite consequences of admixture on the level of polymorphism of the recipient populations between domestic strains. Our study illustrates the potential of using the information contained in the genomic mosaic of ancestry tracts in combination with classical methods based on allele frequencies for analysing multiple-way admixture with population genomic data.
Genetic contributions to ectopic sperm cell migration inCaenorhabditisnematodes
Authors: Ting Janice J. , Tsai Caressa N. , Cutter Asher D. 
Published: April 2018

AbstractReproductive barriers involving gametic incompatibilities can act to enhance population divergence and promote the persistence of species boundaries. Observing gametic interactions in internal fertilizing organisms, however, presents a considerable practical challenge to characterizing mechanisms of such gametic isolation. Here we exploit the transparency ofCaenorhabditisnematodes to investigate gametic isolation mediated by sperm that can migrate to ectopic locations, with this sperm invasion capable of inducing female sterility and premature death. As a step toward identifying genetic factors and mechanisms associated with female susceptibility to sperm invasion, we characterized a panel of 25C. elegansgenetic mutants to test for effects on the incidence and severity of sperm invasion in both conspecific and interspecies matings. We found genetic perturbations to contribute to distinct patterns of susceptibility that identify ovulation dynamics and sperm guidance cues as modulators of ectopic sperm migration incidence and severity. Genotypes confer distinctive phenotypic sensitivities to the sperm from conspecificC. elegansmales versus heterospecificC. nigonimales, implicating evolution of functional divergence in the history of these species for components of sperm-reproductive tract interactions. Sexually-antagonistic co-evolution within species that drives divergent trait and molecular evolution between species provides a working model to explain mismatched species-specific gametic interactions that promote or mitigate ectopic sperm migration.Article SummaryHere we exploit the transparency ofC. elegansroundworms to investigate reproductive barriers between species resulting from sperm-cell invasion into ectopic tissues, causing female sterility and premature death. We quantify female sensitivity to sperm invasion from conspecific and interspecific matings in a panel of 25C. elegansgenetic mutants, to demonstrate how ovulation dynamics and sperm guidance cues act as modulators of ectopic sperm-cell migration incidence and severity. We observe both conserved and divergent responses to different species, implicating evolution of functional divergence for components of sperm-reproductive tract interactions consistent with the outcome of sexually-antagonistic co-evolution.
integRATE: a desirability-based data integration framework for the prioritization of candidate genes across heterogeneous omics and its application to preterm birth
Authors: Eidem Haley R. , Steenwyk Jacob , Wisecaver Jennifer , Capra John A. , Abbot Patrick , Rokas Antonis 
Published: April 2018

AbstractBackgroundThe integration of high-quality, genome-wide analyses offers a robust approach to elucidating genetic factors involved in complex human diseases. Even though several methods exist to integrate heterogeneous omics data, most biologists still manually select candidate genes by examining the intersection of lists of candidates stemming from analyses of different types of omics data that have been generated by imposing hard (strict) thresholds on quantitative variables, such as P-values and fold changes, increasing the chance of missing potentially important candidates.MethodsTo better facilitate the unbiased integration of heterogeneous omics data collected from diverse platforms and samples, we propose a desirability function framework for identifying candidate genes with strong evidence across data types as targets for follow-up functional analysis. Our approach is targeted towards disease systems with sparse, heterogeneous omics data, so we tested it on one such pathology: spontaneous preterm birth (sPTB).ResultsWe developed the software integRATE, which uses desirability functions to rank genes both within and across studies, identifying well-supported candidate genes according to the cumulative weight of biological evidence rather than based on imposition of hard thresholds of key variables. Integrating 10 sPTB omics studies identified both genes in pathways previously suspected to be involved in sPTB as well as novel genes never before linked to this syndrome. integRATE is available as an R package on GitHub (https://github.com/haleyeidem/integRATE).ConclusionsDesirability-based data integration is a solution most applicable in biological research areas where omics data is especially heterogeneous and sparse, allowing for the prioritization of candidate genes that can be used to inform more targeted downstream functional analyses.