Measurement resources for dissemination and implementation research in health

BACKGROUND: A 2-day consensus working meeting, hosted by the United States National Institutes of Health and the Veterans Administration, focused on issues related to dissemination and implementation (D&I) research in measurement and reporting. Meeting participants included 23 researchers, practitioners, and decision makers from the USA and Canada who concluded that the field would greatly benefit from measurement resources to enhance the ease, harmonization, and rigor of D&I evaluation efforts. This paper describes the findings from an environmental scan and literature review of resources for D&I measures. FINDINGS: We identified a total of 17 resources, including four web-based repositories and 12 static reviews or tools that attempted to synthesize and evaluate existing measures for D&I research. Thirteen resources came from the health discipline, and 11 were populated from database reviews. Ten focused on quantitative measures, and all were generated as a resource for researchers. Fourteen were organized according to an established D&I theory or framework, with the number of constructs and measures ranging from 1 to more than 450. Measure metadata was quite variable with only six providing information on the psychometric properties of measures. CONCLUSIONS: Additional guidance on the development and use of measures are needed. A number of approaches, resources, and critical areas for future work are discussed. Researchers and stakeholders are encouraged to take advantage of a number of funding mechanisms supporting this type of work. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13012-016-0401-y) contains supplementary material, which is available to authorized users

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

Imaging the water snow-line during a protostellar outburst

A snow-line is the region of a protoplanetary disk at which a major volatile, such as water or carbon monoxide, reaches its condensation temperature. Snow-lines play a crucial role in disk evolution by promoting the rapid growth of ice-covered grains^1, 2, 3, 4, 5, 6. Signatures of the carbon monoxide snow-line (at temperatures of around 20 kelvin) have recently been imaged in the disks surrounding the pre-main-sequence stars TW Hydra^7, 8, 9 and HD163296 (refs 3, 10), at distances of about 30 astronomical units (au) from the star. But the water snow-line of a protoplanetary disk (at temperatures of more than 100 kelvin) has not hitherto been seen, as it generally lies very close to the star (less than 5 au away for solar-type stars^11). Water-ice is important because it regulates the efficiency of dust and planetesimal coagulation5, and the formation of comets, ice giants and the cores of gas giants^12. Here we report images at 0.03-arcsec resolution (12 au) of the protoplanetary disk around V883 Ori, a protostar of 1.3 solar masses that is undergoing an outburst in luminosity arising from a temporary increase in the accretion rate^13. We find an intensity break corresponding to an abrupt change in the optical depth at about 42 au, where the elevated disk temperature approaches the condensation point of water, from which we conclude that the outburst has moved the water snow-line. The spectral behaviour across the snow-line confirms recent model predictions^14: dust fragmentation and the inhibition of grain growth at higher temperatures results in soaring grain number densities and optical depths. As most planetary systems are expected to experience outbursts caused by accretion during their formation^15, 16, our results imply that highly dynamical water snow-lines must be considered when developing models of disk evolution and planet formation

A critical evaluation of predictive models for rooted soil strength with application to predicting the seismic deformation of rooted slopes

This paper presents a comparative study of three different classes of model for estimating the reinforcing effect of plant roots in soil, namely (i) fibre pull-out model, (ii) fibre break models (including Wu and Waldron’s Model (WWM) and the Fibre Bundle Model (FBM)) and (iii) beam bending or p-y models (specifically Beam on a Non-linear Winkler-Foundation (BNWF) models). Firstly, the prediction model of root reinforcement based on pull-out being the dominant mechanism for different potential slip plane depths was proposed. The resulting root reinforcement calculated were then compared with those derived from the other two types of models. The estimated rooted soil strength distributions were then incorporated within a fully dynamic, plane-strain continuum finite element model to assess the consequences of the selection of rooted soil strength model on the global seismic stability of a vegetated slope (assessed via accumulated slip during earthquake shaking). For the particular case considered in this paper (no roots were observed to have broken after shearing), root cohesion predicted by the pull-out model is much closer to that the BNWF model, but is largely over-predicted by the family of fibre break models. In terms of the effects on the stability of vegetated slopes, there exists a threshold value beyond which the position of the critical slip plane would bypass the rooted zones, rather than passing through them. Further increase of root cohesion beyond this value has minimal effect on the global slope behaviour. This implies that significantly over-predicted root cohesion from fibre break models when used to model roots with non-negligible bending stiffness may still provide a reasonable prediction of overall behaviour, so long as the critical failure mechanism is already bypassing the root-reinforced zones. © 2019, The Author(s)

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Research informatics and the COVID-19 pandemic: Challenges, innovations, lessons learned, and recommendations

The recipients of NIH's Clinical and Translational Science Awards (CTSA) have worked for over a decade to build informatics infrastructure in support of clinical and translational research. This infrastructure has proved invaluable for supporting responses to the current COVID-19 pandemic through direct patient care, clinical decision support, training researchers and practitioners, as well as public health surveillance and clinical research to levels that could not have been accomplished without the years of ground-laying work by the CTSAs. In this paper, we provide a perspective on our COVID-19 work and present relevant results of a survey of CTSA sites to broaden our understanding of the key features of their informatics programs, the informatics-related challenges they have experienced under COVID-19, and some of the innovations and solutions they developed in response to the pandemic. Responses demonstrated increased reliance by healthcare providers and researchers on access to electronic health record (EHR) data, both for local needs and for sharing with other institutions and national consortia. The initial work of the CTSAs on data capture, standards, interchange, and sharing policies all contributed to solutions, best illustrated by the creation, in record time, of a national clinical data repository in the National COVID-19 Cohort Collaborative (N3C). The survey data support seven recommendations for areas of informatics and public health investment and further study to support clinical and translational research in the post-COVID-19 era

Lifetime Racial/Ethnic Discrimination and Ambulatory Blood Pressure: The Moderating Effect of Age

Objective To determine if the relationships of lifetime discrimination to ambulatory blood pressure (ABP) varied as a function of age in a sample of Black and Latino(a) adults ages 19 – 65. Methods Participants were 607 Black (n = 318) and Latino(a) (n = 289) adults (49% female) who completed the Perceived Ethnic Discrimination Questionnaire-Community Version (PEDQ-CV), which assesses lifetime exposure to racism/ethnic discrimination. They were outfitted with an ABP monitor to assess systolic and diastolic blood pressure (SBP, DBP) across a 24-hour period. Mixed-level modeling was conducted to examine potential interactive effects of lifetime discrimination and age to 24-hour, daytime, and nighttime ABP after adjustment for demographic, socioeconomic, personality and life stress characteristics, and substance consumption covariates (e.g., smoking, alcohol). Results There were significant interactions of Age × Lifetime Discrimination on 24-hour and daytime DBP (ps ≤ .04), and in particular significant interactions for the Social Exclusion component of Lifetime Discrimination. Post-hoc probing of the interactions revealed the effects of Lifetime Discrimination on DBP were seen for older, but not younger participants. Lifetime discrimination was significantly positively associated with nocturnal SBP, and these effects were not moderated by age. All associations of Lifetime Discrimination to ABP remained significant controlling for recent exposure to discrimination as well as all other covariates. Conclusions Exposure to racial/ethnic discrimination across the life course is associated with elevated ABP in middle to older aged Black and Latino(a) adults. Further research is needed to understand the mechanisms linking discrimination to ABP over the life course

Discovery of novel heart rate-associated loci using the Exome Chip

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer