Systems genetic analysis of lignin biosynthesis in Populus tremula.

The genetic control underlying natural variation in lignin content and composition in trees is not fully understood. We performed a systems genetic analysis to uncover the genetic regulation of lignin biosynthesis in a natural 'SwAsp' population of aspen (Populus tremula) trees. We analyzed gene expression by RNA sequencing (RNA-seq) in differentiating xylem tissues, and lignin content and composition using Pyrolysis-GC-MS in mature wood of 268 trees from 99 genotypes. Abundant variation was observed for lignin content and composition, and genome-wide association study identified proteins in the pentose phosphate pathway and arabinogalactan protein glycosylation among the top-ranked genes that are associated with these traits. Variation in gene expression and the associated genetic polymorphism was revealed through the identification of 312 705 local and 292 003 distant expression quantitative trait loci (eQTL). A co-expression network analysis suggested modularization of lignin biosynthesis and novel functions for the lignin-biosynthetic CINNAMYL ALCOHOL DEHYDROGENASE 2 and CAFFEOYL-CoA O-METHYLTRANSFERASE 3. PHENYLALANINE AMMONIA LYASE 3 was co-expressed with HOMEOBOX PROTEIN 5 (HB5), and the role of HB5 in stimulating lignification was demonstrated in transgenic trees. The systems genetic approach allowed linking natural variation in lignin biosynthesis to trees´ responses to external cues such as mechanical stimulus and nutrient availability.

An Improved Chromosome-scale Genome Assembly and Population Genetics resource for Populus tremula.

Aspen (Populus tremula L.) is a keystone species and a model system for forest tree genomics. We present an updated resource comprising a chromosome-scale assembly, population genetics and genomics data. Using the resource, we explore the genetic basis of natural variation in leaf size and shape, traits with complex genetic architecture. We generated the genome assembly using long-read sequencing, optical and high-density genetic maps. We conducted whole-genome resequencing of the Umeå Aspen (UmAsp) collection. Using the assembly and re-sequencing data from the UmAsp, Swedish Aspen (SwAsp) and Scottish Aspen (ScotAsp) collections we performed genome-wide association analyses (GWAS) using Single Nucleotide Polymorphisms (SNPs) for 26 leaf physiognomy phenotypes. We conducted Assay of Transposase Accessible Chromatin sequencing (ATAC-Seq), identified genomic regions of accessible chromatin, and subset SNPs to these regions, improving the GWAS detection rate. We identified candidate long non-coding RNAs in leaf samples, quantified their expression in an updated co-expression network, and used this to explore the functions of candidate genes identified from the GWAS. A GWAS found SNP associations for seven traits. The associated SNPs were in or near genes annotated with developmental functions, which represent candidates for further study. Of particular interest was a ~177-kbp region harbouring associations with several leaf phenotypes in ScotAsp. We have incorporated the assembly, population genetics, genomics, and GWAS data into the PlantGenIE.org web resource, including updating existing genomics data to the new genome version, to enable easy exploration and visualisation. We provide all raw and processed data to facilitate reuse in future studies.

An atlas of the Norway spruce needle seasonal transcriptome.

Boreal conifers possess a tremendous ability to survive and remain evergreen during harsh winter conditions and resume growth during summer. This is enabled by coordinated regulation of major cellular functions at the level of gene expression, metabolism, and physiology. Here we present a comprehensive characterization of the annual changes in the global transcriptome of Norway spruce (Picea abies) needles as a resource to understand needle development and acclimation processes throughout the year. In young, growing needles (May 15 until June 30), cell walls, organelles, etc., were formed, and this developmental program heavily influenced the transcriptome, explained by over-represented Gene Ontology (GO) categories. Later changes in gene expression were smaller but four phases were recognized: summer (July-August), autumn (September-October), winter (November-February), and spring (March-April), where over-represented GO categories demonstrated how the needles acclimated to the various seasons. Changes in the seasonal global transcriptome profile were accompanied by differential expression of members of the major transcription factor families. We present a tentative model of how cellular activities are regulated over the year in needles of Norway spruce, which demonstrates the value of mining this dataset, accessible in ConGenIE together with advanced visualization tools.

Adaptive Introgression Facilitates Adaptation to High Latitudes in European Aspen (Populus tremula L.).

Understanding local adaptation has become a key research area given the ongoing climate challenge and the concomitant requirement to conserve genetic resources. Perennial plants, such as forest trees, are good models to study local adaptation given their wide geographic distribution, largely outcrossing mating systems, and demographic histories. We evaluated signatures of local adaptation in European aspen (Populus tremula) across Europe by means of whole-genome resequencing of a collection of 411 individual trees. We dissected admixture patterns between aspen lineages and observed a strong genomic mosaicism in Scandinavian trees, evidencing different colonization trajectories into the peninsula from Russia, Central and Western Europe. As a consequence of the secondary contacts between populations after the last glacial maximum, we detected an adaptive introgression event in a genome region of ∼500 kb in chromosome 10, harboring a large-effect locus that has previously been shown to contribute to adaptation to the short growing seasons characteristic of Northern Scandinavia. Demographic simulations and ancestry inference suggest an Eastern origin-probably Russian-of the adaptive Nordic allele which nowadays is present in a homozygous state at the north of Scandinavia. The strength of introgression and positive selection signatures in this region is a unique feature in the genome. Furthermore, we detected signals of balancing selection, shared across regional populations, that highlight the importance of standing variation as a primary source of alleles that facilitate local adaptation. Our results, therefore, emphasize the importance of migration-selection balance underlying the genetic architecture of key adaptive quantitative traits.

Analysis and Classification of Postcatheterization Femoral Arteriovenous Fistulas Based on Color Doppler Examinations.

OBJECTIVE: To analyze and classify arterial supply and venous drainage of postcatheterization femoral arteriovenous fistulas (AVFs). METHODS: A review of extremity Doppler reports identified 77 femoral AVFs in 75 patients. Doppler exams were reviewed retrospectively. Fistulas were classified as above or below the common femoral artery bifurcation and subclassified based on the location of arterial inflow and venous outflow. RESULTS: Arterial inflow originated above the femoral bifurcation in 32 cases. The communication was between the common femoral artery and the superficial circumflex iliac vein in 25 of 32 cases and between a branch of the common femoral or external iliac artery and the common femoral or external iliac vein in 4 of 32 cases. In 3 of 32 cases, AVFs arose from the common femoral artery, but the venous outflow was not determined. Arterial inflow originated from the superficial femoral artery in 23 cases. Venous outflow originated from the common femoral vein in 10 of 23 cases, the femoral vein in 7 of 23 cases, and the lateral circumflex femoral vein in 6 of 23 cases. Arterial inflow originated from the deep femoral artery in 12 cases. Venous outflow originated from the common femoral vein in 6 of 12 cases and from the lateral circumflex femoral vein 6 of 12 cases. In 8 cases, the AVF originated below the bifurcation, but the arterial inflow was not classified. In 2 cases, it was impossible to determine if the AVF originated above or below the bifurcation. CONCLUSIONS: Iatrogenic femoral AVFs arise above the femoral bifurcation more often than previously recognized. Classification based on the arterial inflow and venous outflow provides a straightforward means of describing these fistulas.

Stem girdling affects the onset of autumn senescence in aspen in interaction with metabolic signals.

Autumn senescence in aspen (Populus tremula) is precisely timed every year to relocate nutrients from leaves to storage organs before winter. Here we demonstrate how stem girdling, which leads to the accumulation of photosynthates in the crown, influences senescence. Girdling resulted in an early onset of senescence, but the chlorophyll degradation was slower and nitrogen more efficiently resorbed than during normal autumn senescence. Girdled stems accumulated or retained anthocyanins potentially providing photoprotection in senescing leaves. Girdling of one stem in a clonal stand sharing the same root stock did not affect senescence in the others, showing that the stems were autonomous in this respect. One girdled stem with unusually high chlorophyll and nitrogen contents maintained low carbon-to-nitrogen (C/N) ratio and did not show early senescence or depleted chlorophyll level unlike the other girdled stems suggesting that the responses depended on the genotype or its carbon and nitrogen status. Metabolite analysis highlighted that the tricarboxylic acid (TCA) cycle, salicylic acid pathway, and redox homeostasis are involved in the regulation of girdling-induced senescence. We propose that disrupted sink-source relation and C/N status can provide cues through the TCA cycle and phytohormone signaling to override the phenological control of autumn senescence in the girdled stems.

Functional and evolutionary genomic inferences in Populus through genome and population sequencing of American and European aspen.

The Populus genus is one of the major plant model systems, but genomic resources have thus far primarily been available for poplar species, and primarily Populus trichocarpa (Torr. & Gray), which was the first tree with a whole-genome assembly. To further advance evolutionary and functional genomic analyses in Populus, we produced genome assemblies and population genetics resources of two aspen species, Populus tremula L. and Populus tremuloides Michx. The two aspen species have distributions spanning the Northern Hemisphere, where they are keystone species supporting a wide variety of dependent communities and produce a diverse array of secondary metabolites. Our analyses show that the two aspens share a similar genome structure and a highly conserved gene content with P. trichocarpa but display substantially higher levels of heterozygosity. Based on population resequencing data, we observed widespread positive and negative selection acting on both coding and noncoding regions. Furthermore, patterns of genetic diversity and molecular evolution in aspen are influenced by a number of features, such as expression level, coexpression network connectivity, and regulatory variation. To maximize the community utility of these resources, we have integrated all presented data within the PopGenIE web resource (PopGenIE.org).

Transfusion strategies in upper gastrointestinal bleeding management: a review of South Australian hospital practice.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a common cause of hospital admission and red cell transfusion is frequently required. A large single-centre randomised study from 2013 showed that a restrictive transfusion strategy in UGIB management was associated with better outcomes compared to a liberal strategy. Subsequently multiple international guidelines favour a restrictive transfusion strategy. However, given the multiple exclusion criteria in the study, generalisation to everyday practice was unclear. AIMS: To assess applicability of the data to a non-trial UGIB population and determine how often restrictive thresholds are used in clinical practice. METHODS: A retrospective case note review of patients with an UGIB admission during 2014 in three tertiary hospitals was undertaken. Information collected included demographics, comorbidities and factors associated with transfusion, such as apparent haemoglobin triggers and units transfused. The proportion of patients who would have met inclusion criteria of the study was calculated. RESULTS: Of 89 UGIB admissions reviewed, up to 70% would be suitable for a restrictive approach. Use of this approach was evident in only 26% of transfusion episodes in patients meeting inclusion criteria. However, assessment was, limited by rapidly changing clinical status and potential for overestimation of true haemoglobin level with fluid resuscitation and equilibration. CONCLUSION: A restrictive transfusion strategy may be suitable for many patients presenting with UGIB; however, important exclusions were not uncommon. Opportunities for increased uptake of restrictive thresholds were identified. Ongoing improvement initiatives should address the risks of both over and under-transfusion.

Evaluation of Ovarian Cancer: Initial Application of Coregistered Photoacoustic Tomography and US.

Purpose To assess transvaginal coregistered photoacoustic tomography (PAT) and pulse-echo US for diagnosis of ovarian cancer based on functional parameters provided by PAT. Materials and Methods Between February 2017 and December 2017, 26 ovarian masses from 16 participants were successfully imaged in vivo by multispectral photoacoustic imaging, including nine invasive epithelial ovarian cancers (six serous carcinomas and three endometroid adenocarcinomas), three other tumors (two borderline serous tumors and one sex cord-stromal tumor), and 14 benign and normal (hereafter referred to as benign/normal) ovaries. The relative total hemoglobin concentration (rHbT) and mean oxygen saturation (sO2) shown at PAT were used to characterize the ovaries identified at US. Results The average rHbT was 1.9 times higher for invasive epithelial cancers than for the benign/normal ovaries (P = .01). Additionally, the rHbT distribution was extensive in invasive epithelial cancers, but was scattered in benign/normal ovaries. However, the rHbT of two borderline serous tumors and one stromal tumor was in the same range as that of benign/normal ovaries. The mean sO2 of invasive epithelial cancers, and of the borderline and stromal tumors, was 8.2% lower than that of benign/normal ovaries (P = .003). Discussion Invasive epithelial ovarian cancers showed higher and extensive tumor vascularity and lower oxygen saturation than benign and normal ovaries. Two borderline noninvasive serous and one stromal tumor showed low oxygen saturation compared with benign and normal ovaries. ©RSNA, 2018 Online supplemental material is available for this article.

Storage lipid accumulation is controlled by photoperiodic signal acting via regulators of growth cessation and dormancy in hybrid aspen.

The signalling pathways that control seasonal modulation of carbon metabolism in perennial plants are poorly understood. Using genetic, metabolic and natural variation approaches, we identify factors mediating photoperiodic control of storage lipid accumulation in the model tree hybrid aspen (Populus tremula × tremuloides). We characterized lipid accumulation in transgenic hybrid aspen with impaired photoperiodic and hormonal responses. Genome-wide association mapping was performed in Swedish aspen (P. tremula) genotypes to determine genetic loci associated with genotype variation in lipid content. Our data show that the storage lipid triacylglycerol (TAG) accumulates in cambial meristem and pith rays of aspen in response to photoperiodic signal controlling growth cessation and dormancy induction. We show that photoperiodic control of TAG accumulation is mediated by the FLOWERING LOCUS T/CONSTANS module, which also controls the induction of growth cessation. Hormonal and chromatin remodelling pathways also contribute to TAG accumulation by photoperiodic signal. Natural variation exists in lipid accumulation that is controlled by input from multiple loci. Our data shed light on how the control of storage metabolism is temporally coordinated with growth cessation and dormancy by photoperiodic signal, and reveals that storage lipid accumulation between seeds and perennating organs of trees may involve distinct regulatory circuits.

Autumn senescence in aspen is not triggered by day length.

Autumn senescence in mature aspens, grown under natural conditions, is initiated at almost the same date every year. The mechanism of such precise timing is not understood but we have previously shown that the signal must be derived from light. We studied variation in bud set and autumn senescence in a collection of 116 natural Eurasian aspen (Populus tremula) genotypes, from 12 populations in Sweden and planted in one northern and one southern common garden, to test the hypothesis that onset of autumn senescence is triggered by day length. We confirmed that, although bud set seemed to be triggered by a critical photoperiod/day length, other factors may influence it. The data on initiation of autumn senescence, on the other hand, were incompatible with the trigger being the day length per se, hence the trigger must be some other light-dependent factor.

Bleeding Complications After Percutaneous Liver Biopsy: Do Subcapsular Lesions Pose a Higher Risk?

OBJECTIVE: The purpose of this study is to determine the incidence of moderate and severe bleeding complications after subcapsular liver mass biopsy and compare it with the incidences of such complications after nonsubcapsular liver mass biopsy and after random biopsy. MATERIALS AND METHODS: This retrospective review of ultrasound-guided liver biopsies was performed between January 2006 and February 2015. Biopsy type, needle size, the number of needle passes, and mass size and depth were recorded. A mass was categorized as subcapsular if it abutted the capsule and if the needle entered the mass directly without first traversing normal liver. Patients were observed postprocedurally, and the electronic medical record and findings from imaging performed within 1 month of the procedure were reviewed to assess for bleeding. Bleeding complications were categorized by size (with mild bleeding denoted by perihepatic blood ≤ 2 cm thick; moderate bleeding denoted by perihepatic blood > 2 cm thick, observation of blood elsewhere in the upper abdomen, or a combination of both findings; and severe bleeding denoted by blood extending into the lower abdomen, pelvis, or both). Bleeding rates were compared between groups using the Fisher exact test. RESULTS: Of a total of 1876 biopsies, 347 (18.5%) involved subcapsular masses, 760 (40.5%) involved nonsubcapsular masses, and 769 (41.0%) were random biopsies. There were no significant differences in biopsy type (p = 1.00), needle size (p = 0.12), or the number of needle passes (p = 0.10) when subcapsular and nonsubcapsular masses were compared. Thirteen moderate or severe bleeding complications (0.69%) occurred overall. The bleeding rate after subcapsular mass biopsy (3/347; 0.86%) was not statistically different from that noted after nonsubcapsular mass biopsy (5/760; 0.66%) (p = 0.71) or after random biopsy (5/769; 0.65%) (p = 0.71). CONCLUSION: Moderate and severe bleeding complications are rare after subcapsular liver mass biopsy, and their incidence is not significantly higher than that noted after nonsubcapsular mass biopsy or random biopsy. Biopsy of subcapsular lesions should no longer be considered contraindicated.

Both plant genotype and herbivory shape aspen endophyte communities.

Salicinoid phenolic glycosides are common defence substances in salicaceous trees and specialist leaf beetles use these compounds for their own defence against predators. Salicinoids vary qualitatively and qualitatively in aspen (Populus tremula) and this variation has a genetic basis. The foliar endophyte mycobiome is plentiful and we hypothesised that it is related to plant genotype, potentially mediated by salicinoid composition, and that interactions with the leaf beetle Chrysomela tremula may alter this relationship. We studied these three-way interactions in controlled greenhouse experiments. Endophytic fungi were isolated from sterilised leaf tissues with and without beetle damage, and from beetles. We confirmed that endophyte composition was influenced by host genotype. Beetle activity added generalist morphs to the mycobiome that overrode the initial host association. Yeast-like genera (Cryptococcus and Rhodotorula) were isolated only from beetle-damaged tissues and from beetles, whereas fast-growing filamentous fungi dominated beetle-free control plants. Competition experiments between filamentous fungi of plant origin and beetle-related yeasts suggested interaction of both stimulating and inhibiting modes of action amongst the fungi. As a result, we detected examples of amensalism, commensalism, parasitism and competition between the morphs tested, but we found no evidence of mutualism, and consequently no co-evolutionary relationship could be demonstrated, between yeasts carried by beetles, host genotype and associated filamentous morphs. Endophyte studies are method-dependent and high-throughput sequencing technology best define the fungal mycobiome, culturing however continues to be a cheap way to provide fundamental ecological insights and it is also required for experimental studies.

Predicting Perioperative Transfusion in Elective Hip and Knee Arthroplasty: A Validated Predictive Model.

BACKGROUND: Preoperative anemia is a significant predictor of perioperative erythrocyte transfusion in elective arthroplasty patients. However, interactions with other patient and procedure characteristics predicting transfusion requirements have not been well studied. METHODS: Patients undergoing elective primary total hip arthroplasty or total knee arthroplasty at a tertiary hospital in Adelaide, South Australia, Australia, from January 2010 to June 2014 were used to identify preoperative predictors of perioperative transfusion. A logistic regression model was developed and externally validated with an independent data set from three other hospitals in Adelaide. RESULTS: Altogether, 737 adult patients in the derivation group and 653 patients in the validation group were included. Binary logistic regression modeling identified preoperative hemoglobin (odds ratio, 0.51; 95% CI, 0.43 to 0.59; P < 0.001 for each 1 g/dl increase), total hip arthroplasty (odds ratio, 3.56; 95% CI, 2.39 to 5.30; P < 0.001), and females 65 yr of age and older (odds ratio, 3.37; 95% CI, 1.88 to 6.04; P = 0.01) as predictors of transfusion in the derivation cohort. CONCLUSIONS: Using a combination of patient-specific preoperative variables, this validated model can predict transfusion in patients undergoing elective hip and knee arthroplasty. The model may also help to identify patients whose need for transfusion may be decreased through preoperative hemoglobin optimization.

Evaluation of 3 T pelvic MRI imaging in prostate cancer patients receiving post-prostatectomy IMRT.

PURPOSE: The purpose of the study was to evaluate the utility of a 3 T pelvic magnetic resonance imaging (MRI) in detecting a local recurrence in post-prostatectomy prostate cancer patients prior to receiving adjuvant or salvage intensity-modulated radiation therapy (IMRT). METHODS: Ninety prostate cancer patients status post-prostatectomy with rising prostate-specific antigen (PSA) had a 3 T pelvic MRI prior to IMRT. The following variables were analyzed for predicting positive findings on MRI: initial presenting and initial post-op PSA, PSA at the time of imaging, PSA velocity, surgical margins, Gleason score, pathological stage, pre-RT digital rectal examination, and type of surgical prostatectomy. RESULTS: The only significant variable predictive of a positive MRI was positive margins. Specifically, 15 of 46 (33 %) patients with positive margins had a positive MRI, while 5 of 44 (11 %) patients with negative margins had a positive MRI. In the MRI positive group, the location of the positive findings on MRI corresponded with the pathology report in 9 of 12 (75 %) cases. CONCLUSION: Post-prostatectomy patients with pathologic positive margins are three times more likely to have positive findings on a 3 T MRI.

Populus tremula (European aspen) shows no evidence of sexual dimorphism.

BACKGROUND: Evolutionary theory suggests that males and females may evolve sexually dimorphic phenotypic and biochemical traits concordant with each sex having different optimal strategies of resource investment to maximise reproductive success and fitness. Such sexual dimorphism would result in sex biased gene expression patterns in non-floral organs for autosomal genes associated with the control and development of such phenotypic traits. RESULTS: We examined morphological, biochemical and herbivory traits to test for sexually dimorphic resource allocation strategies within collections of sexually mature and immature Populus tremula (European aspen) trees. In addition we profiled gene expression in mature leaves of sexually mature wild trees using whole-genome oligonucleotide microarrays and RNA-Sequencing. CONCLUSIONS: We found no evidence of sexual dimorphism or differential resource investment strategies between males and females in either sexually immature or mature trees. Similarly, single-gene differential expression and machine learning approaches revealed no evidence of large-scale sex biased gene expression. However, two significantly differentially expressed genes were identified from the RNA-Seq data, one of which is a robust diagnostic marker of sex in P. tremula.

An 8-week course of 45 mg of carbonyl iron daily reduces iron deficiency in female whole blood donors aged 18 to 45 years: results of a prospective randomized controlled trial.

BACKGROUND: Blood donation is known to contribute to iron deficiency in regular blood donors. This study investigated the safety and efficacy of postdonation iron replacement to mitigate iron deficiency in blood donors. STUDY DESIGN AND METHODS: A total of 282 female whole blood donors aged 18 to 45 were prospectively randomized in a double-blinded placebo controlled trial to receive an 8-week postdonation course of carbonyl iron (45 mg daily) or placebo. The primary endpoint was prevalence of iron deficiency (ferritin < 15 ng/mL) at 12 weeks postdonation. Secondary endpoints were eligibility to donate based on capillary hemoglobin (Hb) and incidence of gastrointestinal (GI) complaints. RESULTS: Ferritin levels at Week 12 were significantly higher in donors receiving carbonyl iron (17.0 ± 10.9 ng/mL) compared with those receiving placebo (10.6 ± 8.4 ng/mL; p < 0.001). The proportion of iron-deficient donors was significantly lower in the carbonyl iron group (51.9%) compared to the placebo (80.5%; p < 0.001). The mean Hb level in the carbonyl iron group (134.6 ± 8.7 g/L) was significantly higher than in the placebo arm (130.0 ± 9.9 g/L; p < 0.001), significantly improving eligibility to donate at Week 12. Significantly more donors receiving carbonyl iron had at least one GI side effect (p < 0.001). Importantly, 86.7% of donors receiving carbonyl iron indicated that they would take iron on an ongoing basis. CONCLUSION: An 8-week postdonation course of 45 mg of carbonyl iron significantly reduced iron deficiency and was well tolerated in female whole blood donors. Postdonation iron replacement may have a role in a broader strategy to optimize donor iron status.

Inhibition of miR-15 protects against cardiac ischemic injury.

RATIONALE: Myocardial infarction (MI) is a leading cause of death worldwide. Because endogenous cardiac repair mechanisms are not sufficient for meaningful tissue regeneration, MI results in loss of cardiac tissue and detrimental remodeling events. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence dependent manner. Our previous data indicate that miRNAs are dysregulated in response to ischemic injury of the heart and actively contribute to cardiac remodeling after MI. OBJECTIVE: This study was designed to determine whether miRNAs are dysregulated on ischemic damage in porcine cardiac tissues and whether locked nucleic acid (LNA)-modified anti-miR chemistries can target cardiac expressed miRNAs to therapeutically inhibit miR-15 on ischemic injury. METHODS AND RESULTS: Our data indicate that the miR-15 family, which includes 6 closely related miRNAs, is regulated in the infarcted region of the heart in response to ischemia-reperfusion injury in mice and pigs. LNA-modified chemistries can effectively silence miR-15 family members in vitro and render cardiomyocytes resistant to hypoxia-induced cardiomyocyte cell death. Correspondingly, systemic delivery of miR-15 anti-miRs dose-dependently represses miR-15 in cardiac tissue of both mice and pigs, whereas therapeutic targeting of miR-15 in mice reduces infarct size and cardiac remodeling and enhances cardiac function in response to MI. CONCLUSIONS: Oligonucleotide-based therapies using LNA-modified chemistries for modulating cardiac miRNAs in the setting of heart disease are efficacious and validate miR-15 as a potential therapeutic target for the manipulation of cardiac remodeling and function in the setting of ischemic injury.

Nurse Practitioner Education: Recommending Theories and Frameworks for Simulation-Based Experiences and Research.

Simulation-based education is an evidence-based strategy to address learning and evaluation of outcomes in the updated American Association of Colleges of Nursing Essentials. Currently, there is a dearth of rigorous research on nurse practitioner education simulation. Studies on the topic often neglect a sound theoretical or conceptual framework beyond the National League of Nursing Jeffries Simulation Theory. This article aims to explore and distinguish the implementation of various theories and frameworks to determine how these elements can be stand-alone or used in combination to explore simulation-based experience competency outcomes. Specific recommendations for simulation research are (a) to include learning theories, (b) level learning and track competency progression using a framework, and (c) use a framework for measuring outcomes. Simulation science for nurse practitioner education can be advanced through united and consistent use of established theories and frameworks. These efforts will inform emerging best practices of simulation-based learning to address competition-based learning initiatives, validity of high-stakes simulation evaluation, and how to credit learners for simulation activities.