Publications by authors named "Ashley Walton"

31 Publications

The microrandomized trial for developing digital interventions: Experimental design and data analysis considerations.

Psychol Methods 2022 Jan 13. Epub 2022 Jan 13.

Department of Statistics.

Just-in-time adaptive interventions (JITAIs) are time-varying adaptive interventions that use frequent opportunities for the intervention to be adapted-weekly, daily, or even many times a day. The microrandomized trial (MRT) has emerged for use in informing the construction of JITAIs. MRTs can be used to address research questions about whether and under what circumstances JITAI components are effective, with the ultimate objective of developing effective and efficient JITAI. The purpose of this article is to clarify why, when, and how to use MRTs; to highlight elements that must be considered when designing and implementing an MRT; and to review primary and secondary analyses methods for MRTs. We briefly review key elements of JITAIs and discuss a variety of considerations that go into planning and designing an MRT. We provide a definition of causal excursion effects suitable for use in primary and secondary analyses of MRT data to inform JITAI development. We review the weighted and centered least-squares (WCLS) estimator which provides consistent causal excursion effect estimators from MRT data. We describe how the WCLS estimator along with associated test statistics can be obtained using standard statistical software such as R (R Core Team, 2019). Throughout we illustrate the MRT design and analyses using the HeartSteps MRT, for developing a JITAI to increase physical activity among sedentary individuals. We supplement the HeartSteps MRT with two other MRTs, SARA and BariFit, each of which highlights different research questions that can be addressed using the MRT and experimental design considerations that might arise. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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http://dx.doi.org/10.1037/met0000283DOI Listing
January 2022

A multisociety organizational consensus process to define guiding principles for acute perioperative pain management.

Reg Anesth Pain Med 2022 Feb 22;47(2):118-127. Epub 2021 Sep 22.

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA.

The US Health and Human Services Pain Management Best Practices Inter-Agency Task Force initiated a public-private partnership which led to the publication of its report in 2019. The report emphasized the need for individualized, multimodal, and multidisciplinary approaches to pain management that decrease the over-reliance on opioids, increase access to care, and promote widespread education on pain and substance use disorders. The Task Force specifically called on specialty organizations to work together to develop evidence-based guidelines. In response to this report's recommendations, a consortium of 14 professional healthcare societies committed to a 2-year project to advance pain management for the surgical patient and improve opioid safety. The modified Delphi process included two rounds of electronic voting and culminated in a live virtual event in February 2021, during which seven common guiding principles were established for acute perioperative pain management. These principles should help to inform local action and future development of clinical practice recommendations.
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http://dx.doi.org/10.1136/rapm-2021-103083DOI Listing
February 2022

Toward best practice in cancer mutation detection with whole-genome and whole-exome sequencing.

Nat Biotechnol 2021 09 9;39(9):1141-1150. Epub 2021 Sep 9.

European Infrastructure for Translational Medicine, Amsterdam, the Netherlands.

Clinical applications of precision oncology require accurate tests that can distinguish true cancer-specific mutations from errors introduced at each step of next-generation sequencing (NGS). To date, no bulk sequencing study has addressed the effects of cross-site reproducibility, nor the biological, technical and computational factors that influence variant identification. Here we report a systematic interrogation of somatic mutations in paired tumor-normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers. Using whole-genome sequencing (WGS) and whole-exome sequencing (WES), we evaluated the reproducibility of different sample types with varying input amount and tumor purity, and multiple library construction protocols, followed by processing with nine bioinformatics pipelines. We found that read coverage and callers affected both WGS and WES reproducibility, but WES performance was influenced by insert fragment size, genomic copy content and the global imbalance score (GIV; G > T/C > A). Finally, taking into account library preparation protocol, tumor content, read coverage and bioinformatics processes concomitantly, we recommend actionable practices to improve the reproducibility and accuracy of NGS experiments for cancer mutation detection.
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http://dx.doi.org/10.1038/s41587-021-00994-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506910PMC
September 2021

Mobile health use predicts self-efficacy and self-management in adolescents with sickle cell disease.

Transl Behav Med 2021 Oct;11(10):1823-1831

Division of Behavioral Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Sickle cell disease (SCD) is associated with significant health challenges that often worsen during adolescence. Living with SCD requires a substantial amount of self-management and mobile health (mHealth) holds considerable promise for assessing and changing behaviors to improve health outcomes. We integrated a mobile app as an adjunct to a group intervention (SCThrive) and hypothesized that more engagement with the mHealth app would increase self-management and self-efficacy for adolescents and young adults (AYA) with SCD. Twenty-six AYA ages 13-21 years (54% female; 46% HbSS genotype; all African-American/Black) received six weekly group sessions (three in-person, three online). Participants were provided with the mobile app (iManage for SCD) to record progress on their self-management goals and log pain and mood symptoms. The Transition Readiness Assessment Questionnaire (TRAQ-5) assessed self-management skills and the Patient Activation Measure (PAM-13) assessed self-efficacy at baseline and post-treatment. Logging on to the app more frequently was associated higher mood ratings (r = .54, CI[.18, .77], p = .006) and lower pain ratings (r = -.48, CI[-.77, -.02], p = .04). Regression analyses demonstrated that after controlling for scores at baseline, the number of logins to the app predicted self-management skills (p = .05, η2 = .17) and possibly self-efficacy (p = .08, η2 = .13). Our study findings indicate that it can be challenging to maintain engagement in mHealth for AYA with SCD, but for those who do engage, there are significant benefits related to self-management, self-efficacy, and managing pain and mood.
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http://dx.doi.org/10.1093/tbm/ibab041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541694PMC
October 2021

Neuroethics in the Shadow of a Pandemic.

AJOB Neurosci 2020 Jul-Sep;11(3):W1-W4

Dartmouth College.

Neuroethics under the BRAIN Initiative has been focused upon both the neuroethical implications of basic advances in neuroscience, as well as the ethics attending the development of ever more powerful tools to both understand the brain and treat dysfunction. It has focused on health and disease in the context of the pre-pandemic status quo, essentially divorced from issues like infectious disease and large-scale disruption of social and economic structures. The questions animating the neuroethics of the BRAIN Initiative, on first glance, seemingly fail to intersect with the primary concerns of a post-Covid world, but careful consideration shows that they of course do. After all, the brain's job is to model and respond to the pressures of our environment, and the environment of virtually all of humanity has changed in a dramatic way, unprecedented since the rise of modern neuroscience. Here we consider ways in which neuroethics work aligned with the BRAIN Initiative can inform our response to the Covid crisis, as well as ways in which the pandemic may shape future work in neuroethics. In particular we focus on neuroethics work on .
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http://dx.doi.org/10.1080/21507740.2020.1778130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477764PMC
April 2021

Ethical dilemmas posed by mobile health and machine learning in psychiatry research.

Bull World Health Organ 2020 Apr 25;98(4):270-276. Epub 2020 Feb 25.

Department of Psychology, Harvard University, Cambridge, USA.

The application of digital technology to psychiatry research is rapidly leading to new discoveries and capabilities in the field of mobile health. However, the increase in opportunities to passively collect vast amounts of detailed information on study participants coupled with advances in statistical techniques that enable machine learning models to process such information has raised novel ethical dilemmas regarding researchers' duties to: (i) monitor adverse events and intervene accordingly; (ii) obtain fully informed, voluntary consent; (iii) protect the privacy of participants; and (iv) increase the transparency of powerful, machine learning models to ensure they can be applied ethically and fairly in psychiatric care. This review highlights emerging ethical challenges and unresolved ethical questions in mobile health research and provides recommendations on how mobile health researchers can address these issues in practice. Ultimately, the hope is that this review will facilitate continued discussion on how to achieve best practice in mobile health research within psychiatry.
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http://dx.doi.org/10.2471/BLT.19.237107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133483PMC
April 2020

Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma.

Nat Genet 2019 12 29;51(12):1714-1722. Epub 2019 Nov 29.

Genetics Branch, NCI, NIH, Bethesda, MD, USA.

Core regulatory transcription factors (CR TFs) orchestrate the placement of super-enhancers (SEs) to activate transcription of cell-identity specifying gene networks, and are critical in promoting cancer. Here, we define the core regulatory circuitry of rhabdomyosarcoma and identify critical CR TF dependencies. These CR TFs build SEs that have the highest levels of histone acetylation, yet paradoxically the same SEs also harbor the greatest amounts of histone deacetylases. We find that hyperacetylation selectively halts CR TF transcription. To investigate the architectural determinants of this phenotype, we used absolute quantification of architecture (AQuA) HiChIP, which revealed erosion of native SE contacts, and aberrant spreading of contacts that involved histone acetylation. Hyperacetylation removes RNA polymerase II (RNA Pol II) from core regulatory genetic elements, and eliminates RNA Pol II but not BRD4 phase condensates. This study identifies an SE-specific requirement for balancing histone modification states to maintain SE architecture and CR TF transcription.
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http://dx.doi.org/10.1038/s41588-019-0534-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886578PMC
December 2019

Author Correction: Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration.

Nat Genet 2019 Jun;51(6):1067

Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

In the version of this article initially published, in Supplementary Data 5, the logFC, FC, P value and adjusted P value for advanced AMD versus control (DE 4/1) without age correction did not correspond to the correct gene IDs. The errors have been corrected in the HTML version of the article.
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http://dx.doi.org/10.1038/s41588-019-0430-yDOI Listing
June 2019

Robustness of RNA sequencing on older formalin-fixed paraffin-embedded tissue from high-grade ovarian serous adenocarcinomas.

PLoS One 2019 6;14(5):e0216050. Epub 2019 May 6.

Division of Cancer Control and Population Sciences (DCCPS), National Cancer Institute, Rockville, MD, United States of America.

Formalin-fixed paraffin-embedded (FFPE) tissues are among the most widely available clinical specimens. Their potential utility as a source of RNA for transcriptome studies would greatly enhance population-based cancer studies. Although preliminary studies suggest FFPE tissue may be used for RNA sequencing, the effect of storage time on these specimens needs to be determined. We conducted this study to determine whether RNA in archived FFPE high-grade ovarian serous adenocarcinomas from Surveillance, Epidemiology and End Results (SEER) registries was present in sufficient quantity and quality for RNA-Seq analysis. FFPE tissues, stored from 7 to 32 years, were obtained from three SEER sites. RNA was extracted, quantified, quality assessed, and subjected to RNA-Seq (a whole transcriptome sequencing technology). FFPE specimens stored for longer periods of time had poorer RNA sample quality as indicated by negative correlations between specimen storage time and fragment distribution values (DV). In addition, sample contamination was a common issue among the RNA, with 41 of 67 samples having 5% to 48% bacterial contamination. However, regardless of specimen storage time and bacterial contamination, 60% of the samples yielded data that enabled gene expression quantification, identifying more than 10,000 genes, with the correlations among most biological replicates above 0.7. This study demonstrates that FFPE high-grade ovarian serous adenocarcinomas specimens stored in repositories for up to 32 years and under varying storage conditions are a promising source of RNA for RNA-Seq. We also describe certain caveats to be considered when designing RNA-Seq studies using archived FFPE tissues.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216050PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502345PMC
January 2020

Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration.

Nat Genet 2019 04 11;51(4):606-610. Epub 2019 Feb 11.

Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to age-related macular degeneration (AMD). We generated transcriptional profiles of postmortem retinas from 453 controls and cases at distinct stages of AMD and integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 noncoding genes, with genotypes at more than 9 million common SNPs for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets. Cis-eQTL analysis identified 10,474 genes under genetic regulation, including 4,541 eQTLs detected only in the retina. Integrated analysis of AMD-GWAS with eQTLs ascertained likely target genes at six reported loci. Using transcriptome-wide association analysis (TWAS), we identified three additional genes, RLBP1, HIC1 and PARP12, after Bonferroni correction. Our studies expand the genetic landscape of AMD and establish the Eye Genotype Expression (EyeGEx) database as a resource for post-GWAS interpretation of multifactorial ocular traits.
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http://dx.doi.org/10.1038/s41588-019-0351-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441365PMC
April 2019

Multi-person and multisensory synchronization during group dancing.

Hum Mov Sci 2019 Feb 21;63:199-208. Epub 2018 Dec 21.

Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, Canada. Electronic address:

Synchronized group dancing is one of the hallmarks of both coordination and cooperation in the humans species. While a large amount of research has focused on joint action in dyads, the mechanisms of coordination in larger groups are not well understood. In the present study, we explored the coordination dynamics of a group of folk dancers by examining the influence of three sensory-coupling channels on the stability of group coordination. Using 3D motion capture, we recorded a group of 13 expert folk dancers performing to the beat of music (auditory coupling) while holding hands in a circle (haptic coupling) and seeing their fellow dancers (visual coupling). Analyses of group synchrony using cluster phase analysis demonstrated that selective elimination of any one of the three types of sensory coupling significantly reduced group synchrony, where haptic coupling had the strongest effect on movements in the horizontal plane, but also impacted the vertical axis. This study provides some of the first evidence of how sensory couplings support multi-person coordination in a large group, and in particular the effect of body contact on this coordination.
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http://dx.doi.org/10.1016/j.humov.2018.12.005DOI Listing
February 2019

Development of a Hydroxyurea Decision Aid for Parents of Children With Sickle Cell Anemia.

J Pediatr Hematol Oncol 2019 01;41(1):56-63

Department of Pediatrics, University of Cincinnati College of Medicine.

National evidence-based guidelines recommend offering hydroxyurea to patients with sickle cell anemia 9 months of age and older using shared decision making, but offer no strategies to aid implementation. We developed a hydroxyurea multicomponent decision aid via a needs assessment, clinic observations, and iterative feedback to address parent decision needs and promote a discussion between clinicians and parents. A total of 75 parents and 28 clinicians participated across all phases. The decision aid was rated as useful. Hydroxyurea knowledge improved and decisional conflict decreased supporting the potential for use to facilitate shared decision making in pediatric sickle cell anemia.
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http://dx.doi.org/10.1097/MPH.0000000000001257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359001PMC
January 2019

MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma.

Sci Transl Med 2018 07;10(448)

Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.

The RAS isoforms are frequently mutated in many types of human cancers, including PAX3/PAX7 fusion-negative rhabdomyosarcoma. Pediatric RMS arises from skeletal muscle progenitor cells that have failed to differentiate normally. The role of mutant RAS in this differentiation blockade is incompletely understood. We demonstrate that oncogenic RAS, acting through the RAF-MEK [mitogen-activated protein kinase (MAPK) kinase]-ERK (extracellular signal-regulated kinase) MAPK effector pathway, inhibits myogenic differentiation in rhabdomyosarcoma by repressing the expression of the prodifferentiation myogenic transcription factor, MYOG. This repression is mediated by ERK2-dependent promoter-proximal stalling of RNA polymerase II at the locus. Small-molecule screening with a library of mechanistically defined inhibitors showed that RAS-driven RMS is vulnerable to MEK inhibition. MEK inhibition with trametinib leads to the loss of ERK2 at the promoter and releases the transcriptional stalling of expression. MYOG subsequently opens chromatin and establishes super-enhancers at genes required for late myogenic differentiation. Furthermore, trametinib, in combination with an inhibitor of IGF1R, potently decreases rhabdomyosarcoma cell viability and slows tumor growth in xenograft models. Therefore, this combination represents a potential therapeutic for RAS-mutated rhabdomyosarcoma.
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http://dx.doi.org/10.1126/scitranslmed.aan4470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054766PMC
July 2018

Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T-Cell Receptors in High-Risk -Not-Amplified Human Neuroblastoma.

Clin Cancer Res 2018 11 21;24(22):5673-5684. Epub 2018 May 21.

Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease, including a focus on tumor-infiltrating lymphocytes (TIL). We performed deep RNA-seq on pretreatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas. We used single-sample gene set enrichment analysis to detect gene expression signatures of TILs in tumors and examined their association with clinical and molecular parameters, including patient outcome. The expression profiles of 190 additional pretreatment diagnostic neuroblastomas, a neuroblastoma tissue microarray, and T-cell receptor (TCR) sequencing were used to validate our findings. We found that -not-amplified (-NA) tumors had significantly higher cytotoxic TIL signatures compared with -amplified (-A) tumors. A reported MYCN activation signature was significantly associated with poor outcome for high-risk patients with -NA tumors; however, a subgroup of these patients who had elevated activated natural killer (NK) cells, CD8 T cells, and cytolytic signatures showed improved outcome and expansion of infiltrating TCR clones. Furthermore, we observed upregulation of immune exhaustion marker genes, indicating an immune-suppressive microenvironment in these neuroblastomas. This study provides evidence that RNA signatures of cytotoxic TIL are associated with the presence of activated NK/T cells and improved outcomes in high-risk neuroblastoma patients harboring -NA tumors. Our findings suggest that these high-risk patients with -NA neuroblastoma may benefit from additional immunotherapies incorporated into the current therapeutic strategies. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504934PMC
November 2018

Optimizing Digital Integrated Care via Micro-Randomized Trials.

Clin Pharmacol Ther 2018 07 19;104(1):53-58. Epub 2018 Apr 19.

Harvard University, Department of Statistics, Boston, Massachusetts, USA.

Mobile health (mHealth) interventions are a promising tool in providing digitally mediated integrative care. They can extend care outside of the clinic by providing reminders to take medications, assisting in managing symptoms, and supporting healthy behaviors including physical activity, healthy eating, and stress management. mHealth interventions can adapt the delivery of care across time in order to optimize treatment effectiveness. Yet there exists limited empirical evidence useful to the development of adaptive mHealth interventions. This article describes a new randomized trial design, the Micro-Randomized Trial (MRT), for informing the development of mHealth interventions. We provide examples of scientific questions important to the development of an mHealth intervention, and describe how these questions can be answered using an MRT.
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http://dx.doi.org/10.1002/cpt.1079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995647PMC
July 2018

Molecular Anatomy of the Developing Human Retina.

Dev Cell 2017 12 7;43(6):763-779.e4. Epub 2017 Dec 7.

Department of Biological Structure, University of Washington, Seattle, WA 98105, USA. Electronic address:

Clinical and genetic heterogeneity associated with retinal diseases makes stem-cell-based therapies an attractive strategy for personalized medicine. However, we have limited understanding of the timing of key events in the developing human retina, and in particular the factors critical for generating the unique architecture of the fovea and surrounding macula. Here we define three key epochs in the transcriptome dynamics of human retina from fetal day (D) 52 to 136. Coincident histological analyses confirmed the cellular basis of transcriptional changes and highlighted the dramatic acceleration of development in the fovea compared with peripheral retina. Human and mouse retinal transcriptomes show remarkable similarity in developmental stages, although morphogenesis was greatly expanded in humans. Integration of DNA accessibility data allowed us to reconstruct transcriptional networks controlling photoreceptor differentiation. Our studies provide insights into human retinal development and serve as a resource for molecular staging of human stem-cell-derived retinal organoids.
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http://dx.doi.org/10.1016/j.devcel.2017.10.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776731PMC
December 2017

Creating Time: Social Collaboration in Music Improvisation.

Top Cogn Sci 2018 01 20;10(1):95-119. Epub 2017 Nov 20.

Department of Psychology and Perception in Action Research Centre, Faculty of Human Sciences, Macquarie University.

Musical collaboration emerges from the complex interaction of environmental and informational constraints, including those of the instruments and the performance context. Music improvisation in particular is more like everyday interaction in that dynamics emerge spontaneously without a rehearsed score or script. We examined how the structure of the musical context affords and shapes interactions between improvising musicians. Six pairs of professional piano players improvised with two different backing tracks while we recorded both the music produced and the movements of their heads, left arms, and right arms. The backing tracks varied in rhythmic and harmonic information, from a chord progression to a continuous drone. Differences in movement coordination and playing behavior were evaluated using the mathematical tools of complex dynamical systems, with the aim of uncovering the multiscale dynamics that characterize musical collaboration. Collectively, the findings indicated that each backing track afforded the emergence of different patterns of coordination with respect to how the musicians played together, how they moved together, as well as their experience collaborating with each other. Additionally, listeners' experiences of the music when rating audio recordings of the improvised performances were related to the way the musicians coordinated both their playing behavior and their bodily movements. Accordingly, the study revealed how complex dynamical systems methods (namely recurrence analysis) can capture the turn-taking dynamics that characterized both the social exchange of the music improvisation and the sounds of collaboration more generally. The study also demonstrated how musical improvisation provides a way of understanding how social interaction emerges from the structure of the behavioral task context.
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http://dx.doi.org/10.1111/tops.12306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939966PMC
January 2018

Quantifying and Modeling Coordination and Coherence in Pedestrian Groups.

Front Psychol 2017 28;8:949. Epub 2017 Jun 28.

Department of Cognitive, Linguistic and Psychological Sciences, Brown UniversityProvidence, RI, United States.

Coherent collective behavior emerges from local interactions between individuals that generate group dynamics. An outstanding question is how to quantify group coordination of non-rhythmic behavior, in order to understand the nature of these dynamics at both a local and global level. We investigate this problem in the context of a small group of four pedestrians walking to a goal, treating their speed, and heading as behavioral variables. To measure the local coordination between pairs of pedestrians, we employ cross-correlation to estimate coupling strength and cross-recurrence quantification (CRQ) analysis to estimate dynamic stability. When compared to reshuffled virtual control groups, the results indicate lower-dimensional behavior and a stronger, more stable coupling of walking speed in real groups. There were no differences in heading alignment observed between the real and virtual groups, due to the common goal. By modeling the local speed coupling, we can simulate coordination at the dyad and group levels. The findings demonstrate spontaneous coordination in pedestrian groups that gives rise to coherent global behavior. They also offer a methodological approach for investigating group dynamics in more complex settings.
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http://dx.doi.org/10.3389/fpsyg.2017.00949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488766PMC
June 2017

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors.

Cell Rep 2016 11;17(9):2460-2473

Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute (NEI), National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Gene regulatory networks (GRNs) guiding differentiation of cell types and cell assemblies in the nervous system are poorly understood because of inherent complexities and interdependence of signaling pathways. Here, we report transcriptome dynamics of differentiating rod photoreceptors in the mammalian retina. Given that the transcription factor NRL determines rod cell fate, we performed expression profiling of developing NRL-positive (rods) and NRL-negative (S-cone-like) mouse photoreceptors. We identified a large-scale, sharp transition in the transcriptome landscape between postnatal days 6 and 10 concordant with rod morphogenesis. Rod-specific temporal DNA methylation corroborated gene expression patterns. De novo assembly and alternative splicing analyses revealed previously unannotated rod-enriched transcripts and the role of NRL in transcript maturation. Furthermore, we defined the relationship of NRL with other transcriptional regulators and downstream cognate effectors. Our studies provide the framework for comprehensive system-level analysis of the GRN underlying the development of a single sensory neuron, the rod photoreceptor.
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http://dx.doi.org/10.1016/j.celrep.2016.10.074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131731PMC
November 2016

Development and evaluation of iManage: A self-management app co-designed by adolescents with sickle cell disease.

Pediatr Blood Cancer 2017 01 30;64(1):139-145. Epub 2016 Aug 30.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Background: Adolescents and young adults (AYAs) with sickle cell disease (SCD) are a vulnerable population with high risk of morbidity that could be decreased with effective self-management. Previous research suggests that mobile applications (apps) may facilitate AYA engagement in health-promoting behaviors. The objectives of this study were: (i) describe Internet access and use in AYA with SCD; (ii) identify barriers for self-management in this population; (iii) collaborate with AYA to co-design a mobile app that would minimize barriers; and (iv) evaluate the feasibility and acceptability of the app.

Procedure: In phase 1, 46 AYAs with SCD 16-24 years of age completed a survey of Internet access and use. During phase 2, 19 AYAs with SCD (average age 20 ± 2.5 years) and eight healthcare providers participated in interviews to identify barriers and co-design sessions to develop the app. In phase 3, five AYAs with SCD completed app feasibility and usability testing.

Results: AYAs with SCD had daily Internet access (69%) using their computers (84%) or mobile phones (70%). Participants went online for health information (71%) and preferred Web sites with interactive/social features (83%). Barriers to self-management included failing to believe that their health would suffer, lack of tailored self-management support, lack of a mechanism to visualize self-management progress, and limited opportunities for peer interaction around self-management. The prototype app (iManage) was rated as highly feasible and beneficial.

Conclusions: A mobile app prototype co-designed by AYAs with SCD may be a useful tool for engaging them in self-management strategies designed to improve health.
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http://dx.doi.org/10.1002/pbc.26177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354646PMC
January 2017

Improvisation and the self-organization of multiple musical bodies.

Front Psychol 2015 20;6:313. Epub 2015 Apr 20.

Department of Psychology, Center for Cognition, Action and Perception, University of Cincinnati Cincinnati, OH, USA ; Department of Philosophy, University of Cincinnati Cincinnati, OH, USA.

Understanding everyday behavior relies heavily upon understanding our ability to improvise, how we are able to continuously anticipate and adapt in order to coordinate with our environment and others. Here we consider the ability of musicians to improvise, where they must spontaneously coordinate their actions with co-performers in order to produce novel musical expressions. Investigations of this behavior have traditionally focused on describing the organization of cognitive structures. The focus, here, however, is on the ability of the time-evolving patterns of inter-musician movement coordination as revealed by the mathematical tools of complex dynamical systems to provide a new understanding of what potentiates the novelty of spontaneous musical action. We demonstrate this approach through the application of cross wavelet spectral analysis, which isolates the strength and patterning of the behavioral coordination that occurs between improvising musicians across a range of nested time-scales. Revealing the sophistication of the previously unexplored dynamics of movement coordination between improvising musicians is an important step toward understanding how creative musical expressions emerge from the spontaneous coordination of multiple musical bodies.
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http://dx.doi.org/10.3389/fpsyg.2015.00313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403292PMC
May 2015

Self-organized complementary joint action: Behavioral dynamics of an interpersonal collision-avoidance task.

J Exp Psychol Hum Percept Perform 2015 Jun 9;41(3):665-79. Epub 2015 Mar 9.

Department of Psychology, College of the Holy Cross.

Understanding stable patterns of interpersonal movement coordination is essential to understanding successful social interaction and activity (i.e., joint action). Previous research investigating such coordination has primarily focused on the synchronization of simple rhythmic movements (e.g., finger/forearm oscillations or pendulum swinging). Very few studies, however, have explored the stable patterns of coordination that emerge during task-directed complementary coordination tasks. Thus, the aim of the current study was to investigate and model the behavioral dynamics of a complementary collision-avoidance task. Participant pairs performed a repetitive targeting task in which they moved computer stimuli back and forth between sets of target locations without colliding into each other. The results revealed that pairs quickly converged onto a stable, asymmetric pattern of movement coordination that reflected differential control across participants, with 1 participant adopting a more straight-line movement trajectory between targets, and the other participant adopting a more elliptical trajectory between targets. This asymmetric movement pattern was also characterized by a phase lag between participants and was essential to task success. Coupling directionality analysis and dynamical modeling revealed that this dynamic regime was due to participant-specific differences in the coupling functions that defined the task-dynamics of participant pairs. Collectively, the current findings provide evidence that the dynamical coordination processes previously identified to underlie simple motor synchronization can also support more complex, goal-directed, joint action behavior, and can participate the spontaneous emergence of complementary joint action roles.
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http://dx.doi.org/10.1037/xhp0000041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801327PMC
June 2015

Uptake of skin self-examination and clinical examination behavior by outdoor workers.

Arch Environ Occup Health 2014 ;69(4):214-22

a Institute of Health and Biomedical Innovation, School of Public Health , Queensland University of Technology , Brisbane , Queensland , Australia.

This study investigated the association between outdoor work and response to a behavioral skin cancer early detection intervention among men 50 years or older. Overall, 495 men currently working in outdoor, mixed, or indoor occupations were randomized to a video-based intervention or control group. At 7 months post intervention, indoor workers reported the lowest proportion of whole-body skin self-examination (wbSSE; 20%). However, at 13 months mixed workers engaged more commonly in wbSSE (36%) compared with indoor (31%) and outdoor (32%) workers. In adjusted analysis, the uptake of early detection behaviors during the trial did not differ between men working in different settings. Outdoor workers compared with men in indoor or mixed work settings were similar in their response to an intervention encouraging uptake of secondary skin cancer prevention behaviors during this intervention trial.
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http://dx.doi.org/10.1080/19338244.2013.771247DOI Listing
April 2014

Essential kinematic information, athletic experience, and affordance perception for others.

Psychon Bull Rev 2014 Jun;21(3):823-9

Center for Cognition, Action, and Perception, Department of Psychology, University of Cincinnati, ML 0376, Cincinnati, OH, 45221-0376, USA,

The present study investigated the role of different types of movement in affordance perception, as well as the influence of sports experience. Perception of another actor's maximum vertical jumping height and horizontal long-jumping distance was evaluated for basketball players, soccer players, and nonplayer controls after viewing point-light representations of the actors' movements. Perceptual reports were more accurate after jumping-related movements (walking and squatting) were viewed than after nonrelated movements (standing and twisting). Vertical jump reports were more accurate than horizontal jump reports. Basketball and soccer players demonstrated higher accuracy than did controls. This research establishes that point-light displays contain essential kinematic information sufficient to support accurate affordance perception, and athletes appear better attuned to kinematic information specifying affordances for others as a result of their sports experience.
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http://dx.doi.org/10.3758/s13423-013-0539-4DOI Listing
June 2014

Development of a stable, early stage unilateral model of Parkinson's disease in middle-aged rhesus monkeys.

Exp Neurol 2008 Aug 3;212(2):431-9. Epub 2008 May 3.

Department of Neurosurgery, Shandong Provincial Hospital, Shandong, University School of Medicine, Jinan, Shandong, 250021, PR China.

An important issue raised in testing new neuroprotective/restorative treatments for Parkinson's disease (PD) is the optimal stage in the disease process to initiate therapy. Current palliative treatments are effective in the early disease stages raising ethical concerns about substituting an experimental treatment for a proven therapy. Thus, we have endeavored to create a stable 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) nonhuman primate model of early PD. The new model was created by controlling for dose and route administration of MPTP (unilateral intracarotid infusion), and age of the animals (middleaged, 16-19 years old) in 27 female rhesus monkeys. All animals showed stable parkinsonian features lasting for up to 12-month as per behavioral evaluation. Compared with late-stage PD animals, postmortem analysis demonstrated that more dopaminergic neurons remained in the substantia nigra pars compacta, and more fibers were found in the striatum. In addition, tissue levels of striatal dopamine and its metabolites were also higher. Our results support that a milder but stable PD model can be produced in middle-aged rhesus monkeys.
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http://dx.doi.org/10.1016/j.expneurol.2008.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527750PMC
August 2008

Validation studies of the human movement analysis panel for hand/arm performance.

J Neurosci Methods 2007 Sep 22;165(2):287-96. Epub 2007 Jun 22.

Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40536, USA.

The human movement analysis panel (HMAP) measures separable components of arm motion and simple and complex finger coordination. HMAP testing takes 30min to administer. In separate experiments we have validated the HMAP against the standard grooved pegboard and measures of gait speed, and demonstrated important learning effects over both short durations of days, and longer intervals of months to years in normal subjects of different ages. Stepwise regression demonstrated the strongest correlation between the HMAP complex motor times and pegboard both-hand removal (R(2)=0.52, p=0.002 for dominant and R(2)=0.33, p=0.02 for non-dominant hands). The most consistent and sensitive measure of HMAP motor performance overall was the complex motor time. The HMAP is a short-duration, easily administered, objective quantitative test of motor function, with potential applications in aging, and in Parkinson's Disease and related motor disorders. The HMAP has a smaller version used in primates, so that measurements made in primate models of disease and its treatment are directly comparable to analogous clinical measurements made in the corresponding human disease.
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http://dx.doi.org/10.1016/j.jneumeth.2007.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2074932PMC
September 2007

Unilateral intraputamenal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year of treatment and 1 year of withdrawal.

J Neurosurg 2007 Apr;106(4):614-20

Department of Neurology, University of Kentucky, Chandler Medical Center, Lexington, Kentucky 40536-0284, USA.

Object: Glial cell line-derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months has been previously shown to improve significantly motor functions and quality of life measures in 10 patients with Parkinson disease (PD) in a Phase I trial. In the present study the authors report the safety and efficacy of continuous treatment for a minimum of 1 year. After the trial was halted by the drug sponsor, the patients were monitored for an additional 1 year during which the effects of drug withdrawal were evaluated.

Methods: During the extended study period, patients received a 30-microg/day unilateral intraputamenal infusion of GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 microl/hour. The Unified Parkinson's Disease Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38% in the off- and on-medication states; the motor UPDRS scores were also improved 45 and 39%, respectively. Benefits from treatment were lost by 9 to 12 months after the cessation of GDNF infusion. The UPDRS scores returned to their baseline and the patients required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of risk of infection. Seven patients developed antibodies to GDNF but without evident clinical sequelae. There was no evidence for GDNF-induced cerebellar toxicity, as evaluated by magnetic resonance imaging and clinical testing.

Conclusions: The unilateral administration of GDNF results in significant, sustained bilateral benefits in patients with PD. These improvements are lost within 9 months of drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed.
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http://dx.doi.org/10.3171/jns.2007.106.4.614DOI Listing
April 2007

Motor memory preservation in aged monkeys mirrors that of aged humans on a similar task.

Neurobiol Aging 2008 Oct 10;29(10):1556-62. Epub 2007 Apr 10.

Department of Anatomy & Neurobiology, University of Kentucky Medical Center, 800 Rose Street, Room #305 Davis Mills Building (MRISC), Lexington, KY 40536-0098, USA.

We studied long-term motor memory preservation in rhesus monkeys tested on a task similar to that employed in humans. First, motor speed and rate of motor decline was measured in 23 animals ranging from 4 to 26 years old. The task for the animals consisted of removing a food reward from a curved rod within the inner chamber of an automated panel. Young animals performed twice as fast as the aged animals. Second, young (n=6) and aged (n=10) animals were re-tested 1 year later on the same task with no intervening practice. We anticipated a decline in motor speed of 144 ms/year, instead the average performance time recorded during the repeat session improved significantly by 17% in the aged animals. This finding mirrors that of a longitudinal study conducted in humans using a similar test panel and supports that, while initial performance times of a novel motor task decline with age, motor memory traces are preserved over an extended time interval, even without continued practice. The data also support that the rhesus monkey could be used as a model to study the mechanisms by which long-term retention of motor memory occurs in aging.
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http://dx.doi.org/10.1016/j.neurobiolaging.2007.03.016DOI Listing
October 2008

Unilateral intraputaminal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year each of treatment and withdrawal.

Neurosurg Focus 2006 May 15;20(5):E1. Epub 2006 May 15.

Department of Anatomy and Neurobiology, the Morris K. Udall Parkinson's Disease Research Center of Excellence, and the Magnetic Resonance Imaging and Spectroscopy Center, University of Kentucky, Lexington, Kentucky 40536-0284, USA.

Object: Glial cell line-derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months was previously shown to improve motor functions and quality of life measures significantly in 10 patients with Parkinson disease (PD) in a Phase I trial. In this study the authors report the safety and efficacy of continuous treatment for 1 year or more. After the trial was halted by the sponsor, the patients were monitored for an additional year to evaluate the effects of drug withdrawal.

Methods: During the extended study, patients received unilateral intraputaminal infusion of 30 mg/day GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 ml/hour. The Unified PD Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38%, respectively, in the "off" and "on" states. Motor UPDRS scores were also improved: 45 and 39% in the off and on conditions, respectively. Benefits from treatment were lost by 9 to 12 months after GDNF infusion was halted. At that time, the patients had returned to their baseline UPDRS scores and required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of the risk of infection. In seven patients antibodies to GDNF developed, with no evidence of clinical sequelae. There was also no evidence of GDNF-induced cerebellar toxicity, as evaluated using magnetic resonance imaging analysis and clinical testing.

Conclusions: Unilateral administration of GDNF results in significant, sustained bilateral benefits. These improvements are lost within 9 months after drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed.
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http://dx.doi.org/10.3171/foc.2006.20.5.2DOI Listing
May 2006
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