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BackgroundCurrent management of children with minor head trauma (MHT) and intracranial injuries is not evidence-based and may place some children at risk of harm. Evidence-based electronic clinical decision support (CDS) for management of these children may improve patient safety and decrease resource use. To guide these efforts, we evaluated the sociotechnical environment impacting the implementation of electronic CDS, including workflow and communication, institutional culture, and hardware and software infrastructure, among other factors.MethodsBetween March and May, 2020 semi-structured qualitative focus group interviews were conducted to identify sociotechnical influences on CDS implementation. Physicians from neurosurgery, emergency medicine, critical care, and pediatric general surgery were included, along with information technology specialists. Participants were recruited from nine health centers in the United States. Focus group transcripts were coded and analyzed using thematic analysis. The final themes were then cross-referenced with previously defined sociotechnical dimensions.ResultsWe included 28 physicians and four information technology specialists in seven focus groups (median five participants per group). Five physicians were trainees and 10 had administrative leadership positions. Through inductive thematic analysis, we identified five primary themes: (1) clinical impact; (2) stakeholders and users; (3) tool content; (4) clinical practice integration; and (5) post-implementation evaluation measures. Participants generally supported using CDS to determine an appropriate level-of-care for these children. However, some had mixed feelings regarding how the tool could best be used by different specialties (e.g. use by neurosurgeons versus non-neurosurgeons). Feedback from the interviews helped refine the tool content and also highlighted potential technical and workflow barriers to address prior to implementation.ConclusionsWe identified key factors impacting the implementation of electronic CDS for children with MHT and intracranial injuries. These results have informed our implementation strategy and may also serve as a template for future efforts to implement health information technology in a multidisciplinary, emergency setting.

The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium's plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled-along with validated datasets-into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit-and the knowledge generated by its applications-as a means to accelerate the clinical development of new therapies for a wide range of conditions.

Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker of inflammation with potential as a prognostic biomarker after TBI. The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study prospectively enrolled TBI patients within 24 h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver operating characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE). We included 1206 TBI subjects, 122 orthopedic trauma controls (OTCs), and 209 healthy controls (HCs). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1 and 5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HCs (p

Abstract Background Epigenetic modification of chromatin plays a pivotal role in regulating gene expression during cell differentiation. The scale and complexity of epigenetic data pose significant challenges for biologists to identify the regulatory events controlling cell differentiation. Results To reduce the complexity, we developed a package, called Snapshot, for clustering and visualizing candidate cis-regulatory elements (cCREs) based on their epigenetic signals during cell differentiation. This package first introduces a binarized indexing strategy for clustering the cCREs. It then provides a series of easily interpretable figures for visualizing the signal and epigenetic state patterns of the cCREs clusters during the cell differentiation. It can also use different hierarchies of cell types to highlight the epigenetic history specific to any particular cell lineage. We demonstrate the utility of Snapshot using data from a consortium project for ValIdated Systematic IntegratiON (VISION) of epigenomic data in hematopoiesis. Conclusion The package Snapshot can identify all distinct clusters of genomic locations with unique epigenetic signal patterns during cell differentiation. It outperforms other methods in terms of interpreting and reproducing the identified cCREs clusters. The package of Snapshot is available at GitHub: https://github.com/guanjue/Snapshot .

BackgroundTo facilitate evidence-based medicine (EBM) on an individual level, it may be important for clinical practice guidelines (CPGs) to incorporate the performance parameters of diagnostic studies and therapeutic interventions (such as likelihood ratio and absolute benefit or harm), and to incorporate relevant patient contexts that may influence decision-making. We sought to determine the extent to which heart failure CPGs currently incorporate this information.MethodsWe reviewed the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2013 Heart Failure CPG, the 2017 ACCF/AHA/HFSA update, and European Society of Cardiology (ESC) 2016 Heart Failure CPG. We abstracted variables for each CPG recommendation from the following domains: quality of evidence, strength of recommendation, diagnostic and therapeutic performance parameters, and patient context.ResultsWe examined 169 recommendations from the ACCF/AHA 2013 CPGs and 2017 update and 187 recommendations from the 2016 ESC CPGs. Performance parameters for diagnostic studies (2013 ACCF/AHA: 13%; 2017 ACCF/AHA/HFSA update: 0%; 2016 ESC: 0%) and therapeutic interventions (2013 ACCF/AHA: 65%; 2017 ACCF/AHA/HFSA update: 64%; 2016 ESC: 16%) were not commonly included in CPGs. Patient context was included in about half of ACCF/AHA recommendations and a quarter of ESC recommendations.ConclusionsThe majority of recommendations from heart failure CPGs lack information on diagnostic and therapeutic performance parameters and patient context. Given the importance of these components to effectively implement EBM, particularly for a heterogeneous heart failure population, innovative strategies are needed to optimize CPGs so they provide comprehensive yet succinct recommendations that can improve population-level outcomes and ensure optimal patient-centered care.

Glial fibrillary acidic protein (GFAP) is cleared by the Food and Drug Administration (FDA) to determine need for head computed tomography (CT) within 12 h after mild traumatic brain injury (TBI) (Glasgow Coma Score [GCS] 13-15); S100 calcium-binding protein B (S100B) serves this function in Europe. This phase 1 biomarker cohort analysis of the multi-center, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study compares GFAP's diagnostic performance, measured on a rapid point-of-care platform, against protein S100B to predict intracranial abnormalities on CT within 24 h post-injury across the spectrum of TBI (GCS 3-15). Head CT scan performed in TBI subjects and blood was collected for all consenting subjects presenting to 18 United States level 1 trauma centers. Plasma was analyzed on a point-of-care device prototype assay for GFAP and serum was analyzed for S100B. In 1359 patients with TBI (GCS 3-15), mean (standard deviation [SD]) age = 40.1 (17.0) years; 68% were male. Plasma GFAP levels were significantly higher in CT+ TBI subjects (median = 1358 pg/mL, interquartile range [IQR]: 472-3803) than in CT- TBI subjects (median = 116 pg/mL, IQR: 26-397) or orthopedic trauma controls (n = 122; median = 13 pg/mL, IQR: 7-20), p

Reduction sensitive linkers (RSLs) have the potential to transform the field of drug delivery due to their ease of use and selective cleavage in intracellular environments. However, despite their compelling attributes, developing reduction sensitive self-immolative linkers for aliphatic amines has been challenging due to their poor leaving group ability and high pK a values. Here a traceless self-immolative linker composed of a dithiol-ethyl carbonate connected to a benzyl carbamate (DEC) is presented, which can modify aliphatic amines and release them rapidly and quantitatively after disulfide reduction. DEC was able to reversibly modify the lysine residues on CRISPR-Cas9 with either PEG, the cell penetrating peptide Arg10, or donor DNA, and generated Cas9 conjugates with significantly improved biological properties. In particular, Cas9-DEC-PEG was able to diffuse through brain tissue significantly better than unmodified Cas9, making it a more suitable candidate for genome editing in animals. Furthermore, conjugation of Arg10 to Cas9 with DEC was able to generate a self-delivering Cas9 RNP that could edit cells without transfection reagents. Finally, conjugation of donor DNA to Cas9 with DEC increased the homology directed DNA repair (HDR) rate of the Cas9 RNP by 50% in HEK 293T cell line. We anticipate that DEC will have numerous applications in biotechnology, given the ubiquitous presence of aliphatic amines on small molecule and protein therapeutics.

During mammalian embryogenesis, differential gene expression gradually builds the identity and complexity of each tissue and organ system1. Here we systematically quantified mouse polyA-RNA from day 10.5 of embryonic development to birth, sampling 17 tissues and organs. The resulting developmental transcriptome is globally structured by dynamic cytodifferentiation, body-axis and cell-proliferation gene sets that were further characterized by the transcription factor motif codes of their promoters. We decomposed the tissue-level transcriptome using single-cell RNA-seq (sequencing of RNA reverse transcribed into cDNA) and found that neurogenesis and haematopoiesis dominate at both the gene and cellular levels, jointly accounting for one-third of differential gene expression and more than 40% of identified cell types. By integrating promoter sequence motifs with companion ENCODE epigenomic profiles, we identified a prominent promoter de-repression mechanism in neuronal expression clusters that was attributable to known and novel repressors. Focusing on the developing limb, single-cell RNA data identified 25 candidate cell types that included progenitor and differentiating states with computationally inferred lineage relationships. We extracted cell-type transcription factor networks and complementary sets of candidate enhancer elements by using single-cell RNA-seq to decompose integrative cis-element (IDEAS) models that were derived from whole-tissue epigenome chromatin data. These ENCODE reference data, computed network components and IDEAS chromatin segmentations are companion resources to the matching epigenomic developmental matrix, and are available for researchers to further mine and integrate.

The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression1. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.

The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression1. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.

Abstract Fusarium oxysporum (Fo) is ubiquitous in soil and forms a species complex of pathogenic and putatively non-pathogenic strains. Pathogenic strains cause disease in over 150 plant species. Fusarium oxysporum f. sp. ciceris (Foc) is a major fungal pathogen causing Fusarium wilt in chickpeas (Cicer arietinum). In some countries such as Australia, Foc is a high-priority pest of biosecurity concern. Specific, sensitive, robust and rapid diagnostic assays are essential for effective disease management on the farm and serve as an effective biosecurity control measure. We developed and validated a novel and highly specific PCR and a LAMP assay for detecting the Indian Foc race 1 based on a putative effector gene uniquely present in its genome. These assays were assessed against 39 Fo formae speciales and found to be specific, only amplifying the target species, in a portable real-time fluorometer (Genie III) and qPCR machine in under 13 min with an anneal derivative temperature ranging from 87.7 to 88.3 °C. The LAMP assay is sensitive to low levels of target DNA (> 0.009 ng/µl). The expected PCR product size is 143 bp. The LAMP assay developed in this study was simple, fast, sensitive and specific and could be explored for other Foc races due to the uniqueness of this marker to the Foc genome.

BackgroundMindfulness practice and exercise are ways by which older adults can improve and maintain their physical, emotional and cognitive health.MethodsThis single-site qualitative study gathered insights of older adults' perceptions about initiating and maintaining mindfulness and exercise practices. We carried out focus groups with 41 adults aged 65-85 who had recently initiated Mindfulness Based Stress Reduction (MBSR), structured exercise, or their combination as part of participation in a clinical trial. We used a semi-structured interview to ask them open-ended questions regarding the benefits, barriers and facilitators of participating in mindfulness and/or exercise interventions. The interview also included questions regarding translation of these practices into community settings as well as the long-term maintenance potential of these practices.ResultsOlder adults indicated that the mindfulness training increased their awareness and self-reflection and fostered a more self-accepting attitude. Furthermore, they improved their self-care habits and reported having better familial and social relationships. The main barrier for both the exercise and Mindfulness group was time management. The social benefits and sense of community were some of the primary motivators for older adults in the exercise and/or MBSR interventions. However, the research on how to motivate older adults to initiate healthy behavioral changes also needs to be answered. The benefits of exercise and MBSR are a motivation in and of themselves, as indicated by some of the participants.ConclusionsThis study indicates that mindfulness training and exercise can serve as tools to cultivate important health lifestyle qualities among older adults, who are in the midst of mental, social, emotional and physical change. If it were not for the purpose of the research or the incentives provided by the research team, these older adults may have never started the healthy behavioral changes. From the responses, this may indicate that older adults may need more incentives to begin and maintain behavioral changes other than for their own health benefit.

Background: A significant gap remains between the availability of physical activity (PA) evidence-based interventions and their application in real-world settings in policy and practice areas. This study aims to describe highly cited and high altmetrics publications in PA research and explore their impact on PA policy and practice. Methods: Mixed-methods sequential explanatory study including the identification and description of the top highly cited and high altmetrics PA publications from the last 10 years (including study design, population, type of PA study, number of citations, and altmetrics score), and interviews with key informants regarding research dissemination and implications on PA policy and practice. Results: When considering publication type, the most frequent highly cited publications were health consequences (40%, altmetrics = 42%), measurement/trends (23%, altmetrics = 10%), and correlates/determinants (21%, altmetrics = 26%) studies. They were predominantly cross-sectional (50%, altmetrics = 28%), systematic reviews (38%, altmetrics = 18%), and longitudinal studies (8%, altmetrics = 37%). All authors who participated in the interviews agreed that the most important factors in disseminating findings and influencing PA policy and practice were the published peer-reviewed manuscript itself, the reputation of the journal, the communication strategy, and the use of online platforms. Conclusions: To have a real-world influence on PA policy and practice, it is not enough to publish the results in scientific journals and participate in media outreach. To successfully involve policymakers and communities in appropriating the evidence and evaluating the extent to which these findings affect policy and practice outcomes, it is critical to lead co-creation, co-dissemination, advocacy, and capacity building efforts. [ABSTRACT FROM AUTHOR]

Abstract Background Increasing physical activity (PA) in rural communities is a vital prevention tactic in multiple chronic diseases; however, little is known on the multilevel correlates of PA rural areas. A better understanding of domain-specific PA adds context for promoting PA in rural communities. The current study sought to determine factors associated with domain-specific and overall moderate-vigorous physical activity (MVPA) in rural communities. Methods Surveys were conducted across 14 rural mid-Western communities, with the final analytical sample including 1241 adults (ages 19–96, M = 57.0 [SD = 16.7], 67.8% female, 83.8% white). Generalized linear models with negative binomial distributions examined the relation between demographics, trail use, and perceptions of the neighborhood environment, with domain-specific and overall MVPA, measured via the Global Physical Activity Questionnaire. Results Rural residents reported an average of 617 total minutes of weekly MVPA (SD = 1141), with 58.5% meeting MVPA guidelines. Higher age, female gender, and higher educated individuals had lower levels of overall and occupational MVPA. Females, higher education, and perceived indoor recreational access were associated with lower levels of transportation-related MVPA, while trail use was associated with increased transportation MVPA. Higher age and female gender respondents had lower levels of recreational MVPA, while trail users and those who perceived favorable indoor recreational access had higher levels of recreational MVPA. Conclusions PA primarily occurred in the occupational domain among this sample of rural mid-Western adults. Findings highlight the need for multilevel interventions to address PA across multiple domains in rural communities, especially among females and older adults.

Comparisons among experimental results with large amounts of data can be more precise and meaningful when done across multiple different conditions simultaneously. Koch et al. introduce a method, called CLIMB, that does this, and captures interpretable and biologically meaningful information.