bluuebunny/crossref_metadata_2025_split huggingface dataset:
White Paper: Movement System Diagnoses in Neurologic Physical Therapy
Authors: Hedman Lois D. , Quinn Lori , Gill-Body Kathleen , Brown David A. , Quiben Myla , Riley Nora , Scheets Patricia L. 
Published: March 2018

Background and Purpose:
The APTA recently established a vision for physical therapists to transform society by optimizing movement to promote health and wellness, mitigate impairments, and prevent disability. An important element of this vision entails the integration of the movement system into the profession, and necessitates the development of movement system diagnoses by physical therapists. At this point in time, the profession as a whole has not agreed upon diagnostic classifications or guidelines to assist in developing movement system diagnoses that will consistently capture an individual's movement problems. We propose that, going forward, diagnostic classifications of movement system problems need to be developed, tested, and validated. The Academy of Neurologic Physical Therapy's Movement System Task Force was convened to address these issues with respect to management of movement system problems in patients with neurologic conditions. The purpose of this article is to report on the work and recommendations of the Task Force.

Summary of Key Findings:
The Task Force identified 4 essential elements necessary to develop and implement movement system diagnoses for patients with primarily neurologic involvement from existing movement system classifications. The Task Force considered the potential impact of using movement system diagnoses on clinical practice, education and, research. Recommendations were developed and provided recommendations for potential next steps to broaden this discussion and foster the development of movement system diagnostic classifications.

Recommendations for Clinical Practice:
The Task Force proposes that diagnostic classifications of movement system problems need to be developed, tested, and validated with the long-range goal to reach consensus on and adoption of a movement system diagnostic framework for clients with neurologic injury or disease states.

Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A198).
Use of an Errorless Learning Approach in a Person With Concomitant Traumatic Spinal Cord Injury and Brain Injury: A Case Report
Authors: Hartmann Annie , Kegelmeyer Deb , Kloos Anne 
Published: March 2018

Individuals with concomitant spinal cord injury and traumatic brain injury have cognitive deficits that may limit the ability to learn novel motor tasks necessary for functional independence. Errorless learning has been shown to improve cognitive task performance in persons with brain injury but little is known about its usefulness for improving novel motor task learning.

Case Description:
A 44-year-old man with traumatic spinal cord and brain injuries from a motor vehicle accident was admitted to an inpatient rehabilitation hospital. His spinal cord injury was classified as T4 American Spinal Injury Association Impairment Scale (AIS) A, and his cognitive status was level IV on the Ranchos Los Amigos Scale. Initially, the patient required maximal assistance from 2 clinicians to complete a slide board transfer, propelled his wheelchair 25 ft with minimal assistance, and scored 9/56 on the Function in Sitting Test.

Intervention:
The therapist applied traditional motor-learning approaches during the first 37 days of the patient's inpatient rehabilitation facility stay without meaningful gains in functional mobility. A subsequent change to errorless learning was made for the following 32 days until discharge.

Outcomes:
After use of errorless learning, the patient performed novel mobility-related tasks of slide board transfers with minimal assistance and wheelchair propulsion without physical assistance up to 150 ft; the Function in Sitting Test score improved to 18/56. His sensorimotor system progressed to an AIS classification of AIS B, while his cognition emerged to a level V on the Ranchos Los Amigos Scale.

Discussion:
Errorless learning may have facilitated acquisition of novel transfer and mobility skills in this individual with dual diagnoses. This approach may have value for patients with neurologic conditions who have both motor and cognitive impairment.

Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A201).
Long-Term Retention of Musculoskeletal Ultrasound Training During Residency
Authors: Irwin Robert W. , Smith Jeffrey , Issenberg S. Barry 
Published: March 2018

Abstract
The Accreditation Council for Graduate Medical Education and the American Board of Physical Medicine and Rehabilitation developed milestones for evaluation of resident physicians that include proper musculoskeletal ultrasound examination of major joints. To date, there have been no published data demonstrating acquisition and retention of these skills and correlation with the milestone evaluation. The investigators developed and implemented a curriculum in musculoskeletal ultrasound examination for Physical Medicine and Rehabilitation residents at a large academic medical center. The investigators chose the following six joints for training and evaluation: ankle, elbow, hip, knee, shoulder, and wrist/hand. The program included: (1) didactic lectures on anatomy and ultrasound technique; (2) peer-led demonstrations of the procedure on a standardized patient (SP); (3) individual practice on standardized patients; (4) faculty observation and feedback; (5) review sessions and additional practice; and (6) assessment of skills in an objective structured clinical examination. From 2013 to 2017, 30 physical medicine and rehabilitation residents were trained and evaluated. The results, based on objective structured clinical examination scores, showed that most residents achieved the appropriate level of competency for their year. A blended, standardized curriculum in musculoskeletal ultrasound instruction with assessment by an objective structured clinical examination can be used to evaluate musculoskeletal ultrasound skills and can help align this education with residency milestones.
Trajectories of Quality of Life and Associated Risk Factors in Patients With Knee Osteoarthritis
Authors: Han Alex , Gellhorn Alfred C. 
Published: March 2018

Objective
Knee osteoarthritis (OA) has a significant impact on quality of life (QOL). Although QOL is generally thought to diminish over time, it is unknown whether different patient groups demonstrate unique patterns of change in QOL. We sought to identify and characterize QOL trajectories in knee OA.

Design
This prospective cohort study included 1013 individuals with symptomatic knee OA from the osteoarthritis initiative. We used group-based trajectory modeling to identify distinct temporal patterns of change in the Knee Injury and Osteoarthritis Outcome Score QOL subscale for 8 yrs. Baseline covariates included age, sex, ethnicity, education, co-morbidities, body mass index, substance use, depression, knee pain, and functional tests.

Results
Group-based trajectory modeling revealed the following three distinct QOL trajectories: a high QOL trajectory (32% of the cohort) experiencing improvement for 8 yrs as well as moderate (49%) and low QOL (20%) trajectories maintaining similar levels over time. Low QOL trajectory membership was significantly associated with younger age (P < 0.001), nonwhite race (P < 0.001), less education (P < 0.001), more co-morbidities (P < 0.001), higher body mass index (P < 0.001), and more depressive symptoms (P < 0.001). Higher QOL trajectory members were less likely to undergo knee replacement surgery (P < 0.001).

Conclusions
Distinct QOL trajectories exist in knee OA and are associated with modifiable factors, with a subset of patients showing potential to improve their QOL over time.
10 Years of Nephrogenic Systemic Fibrosis
Authors: Endrikat Jan , Dohanish Susan , Schleyer Nicolas , Schwenke Susanne , Agarwal Sheela , Balzer Thomas 
Published: March 2018

Objectives
The aim of this study was to critically assess the evaluation and categorization process for nephrogenic systemic fibrosis (NSF) based on reports received by Bayer from 2006 to 2016.

Materials and Methods
A total of 779 NSF reports received by Bayer globally from 2006 to 2016 were included in the analysis. Arlington Medical Resources provided gadolinium-based contrast agent (GBCA) market share. Reports were conservatively categorized based on the Cowper/Girardi criteria. A statistical model simulated the impact of market share and market introduction on the number of unconfounded reports.

Results
For all reports, reported onset of disease ranged from 1996 and 2012. Of 779 reports, 325 involved a Bayer product only, 208 involved only products from other companies (or unknown GBCA), and 246 involved both Bayer and non-Bayer products. Most of all reports (86%) originated from the United States.
Through 2006, Magnevist and Omniscan dominated the US market (>80% combined market share). All other GBCAs with fewer NSF reports comprised the remaining combined market share of less than 20% or were introduced after May 2007, after safety recommendations came into effect.
A total of 563 reports (220 single-agent and 343 multiagent reports) involved Magnevist. In at least 150 of the 343 reports, a different GBCA (Omniscan, 118; OptiMARK, 15; MultiHance, 6; and macrocyclic agent, 11) showed the closest temporal relationship to onset of NSF-like symptoms.
The simulation model demonstrated that patients receiving a GBCA with lower market share and late market introduction are less likely to be observed in an unconfounded setting.

Conclusions
Year of market introduction, as well as US market share in 2000 to 2007, greatly influenced the absolute number of NSF reports for each GBCA, their a priori probability to cause NSF, as well as their a priori probability to be associated with unconfounded cases of NSF. Variability in case interpretation and pharmacovigilance approaches also influence the absolute number of unconfounded cases and should therefore not be used for comparative risk assessments. This should be primarily based on objective product parameters such as structure, stability, pharmacokinetics, and dose.
YES1amplification: a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics
Authors: Fan Pang-Dian , Narzisi Giuseppe , Jayaprakash Anitha D. , Venturini Elisa , Robine Nicolas , Smibert Peter , Germer Soren , Yu Helena A. , Jordan Emmet J. , Paik Paul K. , Janjigian Yelena Y. , Chaft Jamie E. , Wang Lu , Jungbluth Achim A. , Middha Sumit , Spraggon Lee , Qiao Huan , Lovly Christine M. , Kris Mark G. , Riely Gregory J. , Politi Katerina , Varmus Harold , Ladanyi Marc 
Published: March 2018

ABSTRACTIn approximately 30% of patients withEGFR-mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in anEGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify novel mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen wereMET, a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1. Cell clones with transposon insertions that activated expression ofYES1exhibited resistance to all three generations of EGFR inhibitors and sensitivity to pharmacologic and siRNA-mediated inhibition ofYES1. Analysis of clinical genomic sequencing data from cases of acquired resistance to EGFR inhibitors revealed amplification ofYES1in 5 cases, 4 of which lacked any other known mechanisms of resistance. Pre-inhibitor samples, available for 2 of the 5 patients, lackedYES1amplification. None of 136 post-inhibitor samples had detectable amplification of other Src family kinases (SRC, FYN).YES1amplification was also found in 2 of 17 samples fromALKfusion-positive lung cancer patients who had progressed on ALK TKIs. Taken together, our findings identify acquired amplification ofYES1as a novel, recurrent, and targetable mechanism of resistance to EGFR inhibition inEGFR-mutant lung cancers, and demonstrate the utility of transposon mutagenesis in discovering clinically relevant mechanisms of drug resistance.SIGNIFICANCEDespite high response rates to treatment with small molecule inhibitors of EGFR tyrosine kinase activity, patients withEGFR-mutant lung adenocarcinomas eventually develop resistance to these drugs. In many cases, the basis of acquired resistance remains unclear. We have used a transposon mutagenesis screen in anEGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify amplification ofYES1as a novel and targetable mechanism of resistance to EGFR inhibitors inEGFR-mutant lung cancers.
Mean-Variance QTL Mapping on a Background of Variance Heterogeneity
Authors: Corty Robert W. , Valdar William 
Published: March 2018

ABSTRACTMost QTL mapping approaches seek to identify “mean QTL”, genetic loci that influence the phenotype mean, after assuming that all individuals in the mapping population have equal residual variance. Recent work has broadened the scope of QTL mapping to identify genetic loci that influence phenotype variance, termed “variance QTL”, or some combination of mean and variance, which we term “mean-variance QTL”. Even these approaches, however, fail to address situations where some other factor, be it an environmental factor or a distant genetic locus, influences phenotype variance. We term this situation “background variance heterogeneity” (BVH) and used simulation to explore its effects on the power and false positive rate of tests for mean QTL, variance QTL, and mean-variance QTL. Specifically, we compared traditional tests, linear regression for mean QTL and Levene’s test for variance QTL, with tests more recently developed, namely Cao’s tests for all three types of QTL, and tests based on the double generalized linear model (DGLM), which, unlike the other approaches, explicitly models BVH. Simulations showed that, when used in conjunction with a permutation procedure, the DGLM-based tests accurately control false positive rate and are more powerful than the other tests. We also discovered that the rank-based inverse normal transform, often used to corral unruly phenotypes, can be used to mitigate the adverse effects of BVH in some circumstances. We applied the DGLM approach, which we term “mean-variance QTL mapping”, to publicly available data on a mouse backcross of CAST/Ei into M16i and, after accommodating BVH driven by father, identified a new mean QTL for bodyweight at three weeks of age.
Polycomb repressive complex 1 defines the nucleosome landscape but not accessibility at target genes
Authors: King Hamish W , Klose Robert J 
Published: March 2018

ABSTRACTPolycomb group (PcG) proteins are transcriptional repressors that play important roles regulating gene expression during animal development. In vitro experiments have shown that PcG protein complexes can compact chromatin limiting the activity of chromatin remodelling enzymes and access of the transcriptional machinery to DNA. In fitting with these ideas, gene promoters associated with PcG proteins have been reported to be less accessible than other gene promotors. However, it remains largely untested in vivo whether PcG proteins define chromatin accessibility or other chromatin features. To address this important question, we measured chromatin accessibility and examined the nucleosome landscape at PcG protein-bound promoters in mouse embryonic stem cells using the assay for transposase accessible chromatin (ATAC)-seq. Combined with genetic ablation strategies, we unexpectedly discover that although PcG protein-occupied gene promoters exhibit reduced accessibility, this does not rely on PcG proteins. Instead, the Polycomb repressive complex 1 (PRC1) appears to play a unique role in driving elevated nucleosome occupancy and decreased nucleosomal spacing in Polycomb chromatin domains. Our new genome-scale observations argue, in contrast to the prevailing view, that PcG proteins and Polycomb chromatin domains do not significantly affect chromatin accessibility and highlight an underappreciated complexity in the relationship between chromatin accessibility, the nucleosome landscape and PcG-mediated transcriptional repression.
Genotyping Polyploids from Messy Sequencing Data
Authors: Gerard David , Ferrão Luis Felipe Ventorim , Garcia Antonio Augusto Franco , Stephens Matthew 
Published: March 2018

AbstractDetecting and quantifying the differences in individual genomes (i.e. genotyping), plays a fundamental role in most modern bioinformatics pipelines. Many scientists now use reduced representation next-generation sequencing (NGS) approaches for genotyping. Genotyping diploid individuals using NGS is a well-studied field and similar methods for polyploid individuals are just emerging. However, there are many aspects of NGS data, particularly in polyploids, that remain unexplored by most methods. Our contributions in this paper are four-fold: (i) We draw attention to, and then model, common aspects of NGS data: sequencing error, allelic bias, overdispersion, and outlying observations. (ii) Many datasets feature related individuals, and so we use the structure of Mendelian segregation to build an empirical Bayes approach for genotyping polyploid individuals. (iii) We develop novel models to account for preferential pairing of chromosomes and harness these for genotyping. (iv) We derive oracle genotyping error rates that may be used for read depth suggestions. We assess the accuracy of our method in simulations and apply it to a dataset of hexaploid sweet potatoes (Ipomoea batatas). An R package implementing our method is available at https://cran.r-project.org/package=updog.
The identification of an anti-thrombin molecule via the screening of semi-random DNA libraries
Authors: Feng Fan , Li Zijin , Chen Zhenlang , Wang Le , Huang Jie , Wan Yulin , Shi Yunfan , Liu Qiuyun 
Published: March 2018

AbstractThrombosis remains one of the leading causes of mortality and morbidity in the world. Thrombin is a key enzyme involved in the blood clotting processes, which can be intervened by low concentrations of Hirudin. The C-terminal dodecapeptide of Hirudin was capable of inhibiting thrombosis. This peptide has been partially randomized in this report, and the coding sequences have been expressed in yeast as chimerical peptides for secretion into the culture media. Two other semi-random modules have been processed likewise. The supernatant was subsequently tested for anti-thrombin activities. DNA sequencing indicated that the putative positive clone encoded a single serine residue followed by a stop codon. The Ninhydrin assay of the culture supernatant of the positive clone indicated a high content of amino acid. Electrospray Mass Spectrometry showed a distinct peak at 430.5 when the expression products fromPichia pastoriswere examined, suggesting that the compound may be a dimannosylated serine, as yeast possesses glycosylation at serine residues. The observed effects of α-Mannosidase treatments on the function of yeast induction products are consistent with this assumption. Partial randomization of peptides and proteins may accelerate directed evolution, yielding unprecedented number of variants for functional interrogation and drug development.
Genome-wide profiling of an enhancer-associated histone modification reveals the influence of asthma on the epigenome of the airway epithelium
Authors: McErlean Peter , Kelly Audrey , Dhariwal Jaideep , Kirtland Max , Watson Julie , Ranz Ismael , Cousins David J. , Solari Roberto , Edwards Michael R. , Johnston Sebastian L. , Lavender Paul ,   MRC-GSK Strategic Alliance Consortium
Published: March 2018

AbstractAsthma is a chronic airway disease driven by complex genetic-environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood. We undertook genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma and healthy controls. We identified 49,903 regions exhibiting differential H3K27ac enrichment in asthma, clustered at genes associated with type-2-high asthma (CLCA1) and epithelial processes (EMT). Asthma dramatically influenced the BEC enhancer landscape and we identified asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (NOX4). We integrated published protein, epigenomic and transcriptomic datasets and identified epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and dynamic relationships between asthma-associated changes in H3K27ac, DNA methylation, genetic susceptibility and transcriptional profiles. Finally, we used a CRISPR-based approach to recapitulate the H3K27ac-asthma landscape in vitro and provide proof of principal that asthma-associated gene expression (SERPINB2) is driven in part by aberrant histone acetylation, validating the combination of genome-wide and epigenome-editing approaches in deciphering the molecular mechanisms underlying asthma pathogenesis.
A machine-learning-guided mutagenesis platform for accelerated discovery of novel functional proteins
Authors: Saito Yutaka , Oikawa Misaki , Nakazawa Hikaru , Niide Teppei , Kameda Tomoshi , Tsuda Koji , Umetsu Mitsuo 
Published: March 2018

AbstractMolecular evolution based on mutagenesis is widely used in protein engineering. However, optimal proteins are often difficult to obtain due to a large sequence space that requires high costs for screening experiments. Here, we propose a novel approach that combines molecular evolution with machine learning. In this approach, we conduct two rounds of mutagenesis where an initial library of protein variants is used to train a machine-learning model to guide mutagenesis for the second-round library. This enables to prepare a small library suited for screening experiments with high enrichment of functional proteins. We demonstrated a proof-of-concept of our approach by altering the reference green fluorescent protein (GFP) so that its fluorescence is changed to yellow while improving its fluorescence intensity. Using 155 and 78 variants for the initial and the second-round libraries, respectively, we successfully obtained a number of proteins showing yellow fluorescence, 12 of which had better fluorescence performance than the reference yellow fluorescent protein (YFP). These results show the potential of our approach as a powerful platform for accelerated discovery of functional proteins.