High resolution genomes of multiple Xiphophorus species provide new insights into microevolution, hybrid incompatibility, and epistasis.

Because of diverged adaptative phenotypes, fish species of the genus Xiphophorus have contributed to a wide range of research for a century. Existing Xiphophorus genome assemblies are not at the chromosomal level and are prone to sequence gaps, thus hindering advancement of the intra- and inter-species differences for evolutionary, comparative, and translational biomedical studies. Herein, we assembled high-quality chromosome-level genome assemblies for three distantly related Xiphophorus species, namely, X. maculatus, X. couchianus, and X. hellerii Our overall goal is to precisely assess microevolutionary processes in the clade to ascertain molecular events that led to the divergence of the Xiphophorus species and to progress understanding of genetic incompatibility to disease. In particular, we measured intra- and inter-species divergence and assessed gene expression dysregulation in reciprocal interspecies hybrids among the three species. We found expanded gene families and positively selected genes associated with live bearing, a special mode of reproduction. We also found positively selected gene families are significantly enriched in nonpolymorphic transposable elements, suggesting the dispersal of these nonpolymorphic transposable elements has accompanied the evolution of the genes, possibly by incorporating new regulatory elements in support of the Britten-Davidson hypothesis. We characterized inter-specific polymorphisms, structural variants, and polymorphic transposable element insertions and assessed their association to interspecies hybridization-induced gene expression dysregulation related to specific disease states in humans.

Transcriptional background effects on a tumor driver gene in different pigment cell types of medaka.

The Xiphophorus melanoma receptor kinase gene, xmrk, is a bona fide oncogene driving melanocyte tumorigenesis of Xiphophorus fish. When ectopically expressed in medaka, it not only induces development of several pigment cell tumor types in different strains of medaka but also induces different tumor types within the same animal, suggesting its oncogenic activity has a transcriptomic background effect. Although the central pathways that xmrk utilizes to lead to melanomagenesis are well documented, genes and genetic pathways that modulate the oncogenic effect and alter the course of disease have not been studied so far. To understand how the genetic networks between different histocytes of xmrk-driven tumors are composed, we isolated two types of tumors, melanoma and xanthoerythrophoroma, from the same xmrk transgenic medaka individuals, established the transcriptional profiles of both xmrk-driven tumors, and compared (1) genes that are co-expressed with xmrk in both tumor types, and (2) differentially expressed genes and their associated molecular functions, between the two tumor types. Transcriptomic comparisons between the two tumor types show melanoma and xanthoerythrophoroma are characterized by transcriptional features representing varied functions, indicating distinct molecular interactions between the driving oncogene and the cell-type-specific transcriptomes. Melanoma tumors exhibit gene signatures that are relevant to proliferation and invasion, while xanthoerythrophoroma tumors are characterized by expression profiles related to metabolism and DNA repair. We conclude the transcriptomic backgrounds, exemplified by cell-type-specific genes that are downstream of xmrk effected signaling pathways, contribute the potential to change the course of tumor development and may affect overall tumor outcomes.

Gene expression variation and parental allele inheritance in a Xiphophorus interspecies hybridization model.

Understanding the genetic mechanisms underlying segregation of phenotypic variation through successive generations is important for understanding physiological changes and disease risk. Tracing the etiology of variation in gene expression enables identification of genetic interactions, and may uncover molecular mechanisms leading to the phenotypic expression of a trait, especially when utilizing model organisms that have well-defined genetic lineages. There are a plethora of studies that describe relationships between gene expression and genotype, however, the idea that global variations in gene expression are also controlled by genotype remains novel. Despite the identification of loci that control gene expression variation, the global understanding of how genome constitution affects trait variability is unknown. To study this question, we utilized Xiphophorus fish of different, but tractable genetic backgrounds (inbred, F1 interspecies hybrids, and backcross hybrid progeny), and measured each individual's gene expression concurrent with the degrees of inter-individual expression variation. We found, (a) F1 interspecies hybrids exhibited less variability than inbred animals, indicting gene expression variation is not affected by the fraction of heterozygous loci within an individual genome, and (b), that mixing genotypes in backcross populations led to higher levels of gene expression variability, supporting the idea that expression variability is caused by heterogeneity of genotypes of cis or trans loci. In conclusion, heterogeneity of genotype, introduced by inheritance of different alleles, accounts for the largest effects on global phenotypical variability.

Global assessment of organ specific basal gene expression over a diurnal cycle with analyses of gene copies exhibiting cyclic expression patterns.

BACKGROUND: Studying functional divergences between paralogs that originated from genome duplication is a significant topic in investigating molecular evolution. Genes that exhibit basal level cyclic expression patterns including circadian and light responsive genes are important physiological regulators. Temporal shifts in basal gene expression patterns are important factors to be considered when studying genetic functions. However, adequate efforts have not been applied to studying basal gene expression variation on a global scale to establish transcriptional activity baselines for each organ. Furthermore, the investigation of cyclic expression pattern comparisons between genome duplication created paralogs, and potential functional divergence between them has been neglected. To address these questions, we utilized a teleost fish species, Xiphophorus maculatus, and profiled gene expression within 9 organs at 3-h intervals throughout a 24-h diurnal period. RESULTS: Our results showed 1.3-21.9% of genes in different organs exhibited cyclic expression patterns, with eye showing the highest fraction of cycling genes while gonads yielded the lowest. A majority of the duplicated gene pairs exhibited divergences in their basal level expression patterns wherein only one paralog exhibited an oscillating expression pattern, or both paralogs exhibit oscillating expression patterns, but each gene duplicate showed a different peak expression time, and/or in different organs. CONCLUSIONS: These observations suggest cyclic genes experienced significant sub-, neo-, or non-functionalization following the teleost genome duplication event. In addition, we developed a customized, web-accessible, gene expression browser to facilitate data mining and data visualization for the scientific community.

C3HeB/FeJ Mice mimic many aspects of gene expression and pathobiological features of human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a deadly cancer, underscoring the need for relevant preclinical models. Male C3HeB/FeJ mice model spontaneous HCC with some hepatocarcinogenesis susceptibility loci corresponding to syntenic regions of human chromosomes altered in HCC. We tested other properties of C3HeB/FeJ tumors for similarity to human HCC. C3HeB/FeJ tumors were grossly visible at 4 months of age, with prevalence and size increasing until about 11 months of age. Histologic features shared with human HCC include hepatosteatosis, tumor progression from dysplasia to poorly differentiated, vascular invasion, and trabecular, oncocytic, vacuolar, and clear cell variants. More tumor cells displayed cytoplasmic APE1 staining versus normal liver. Ultrasound effectively detected and monitored tumors, with 85.7% sensitivity. Over 5000 genes were differentially expressed based on the GSE62232 and GSE63898 human HCC datasets. Of these, 158 and 198 genes, respectively, were also differentially expressed in C3HeB/FeJ. Common cancer pathways, cell cycle, p53 signaling and other molecular aspects, were shared between human and mouse differentially expressed genes. We established eigengenes that distinguish HCC from normal liver in the C3HeB/FeJ model and a subset of human HCC. These features extend the relevance and improve the utility of the C3HeB/FeJ line for HCC studies.

Waveband specific transcriptional control of select genetic pathways in vertebrate skin (Xiphophorus maculatus).

BACKGROUND: Evolution occurred exclusively under the full spectrum of sunlight. Conscription of narrow regions of the solar spectrum by specific photoreceptors suggests a common strategy for regulation of genetic pathways. Fluorescent light (FL) does not possess the complexity of the solar spectrum and has only been in service for about 60 years. If vertebrates evolved specific genetic responses regulated by light wavelengths representing the entire solar spectrum, there may be genetic consequences to reducing the spectral complexity of light. RESULTS: We utilized RNA-Seq to assess changes in the transcriptional profiles of Xiphophorus maculatus skin after exposure to FL ("cool white"), or narrow wavelength regions of light between 350 and 600 nm (i.e., 50 nm or 10 nm regions, herein termed "wavebands"). Exposure to each 50 nm waveband identified sets of genes representing discrete pathways that showed waveband specific transcriptional modulation. For example, 350-400 or 450-500 nm waveband exposures resulted in opposite regulation of gene sets marking necrosis and apoptosis (i.e., 350-400 nm; necrosis suppression, apoptosis activation, while 450-500 nm; apoptosis suppression, necrosis activation). Further investigation of specific transcriptional modulation employing successive 10 nm waveband exposures between 500 and 550 nm showed; (a) greater numbers of genes may be transcriptionally modulated after 10 nm exposures, than observed for 50 nm or FL exposures, (b) the 10 nm wavebands induced gene sets showing greater functional specificity than 50 nm or FL exposures, and (c) the genetic effects of FL are primarily due to 30 nm between 500 and 530 nm. Interestingly, many genetic pathways exhibited completely opposite transcriptional effects after different waveband exposures. For example, the epidermal growth factor (EGF) pathway exhibits transcriptional suppression after FL exposure, becomes highly active after 450-500 nm waveband exposure, and again, exhibits strong transcriptional suppression after exposure to the 520-530 nm waveband. CONCLUSIONS: Collectively, these results suggest one may manipulate transcription of specific genetic pathways in skin by exposure of the intact animal to specific wavebands of light. In addition, we identify genes transcriptionally modulated in a predictable manner by specific waveband exposures. Such genes, and their regulatory elements, may represent valuable tools for genetic engineering and gene therapy protocols.

Molecular genetic analysis of the melanoma regulatory locus in Xiphophorus interspecies hybrids.

Development of spontaneous melanoma in Xiphophorus interspecies backcross hybrid progeny, (X. hellerii × [X. maculatus Jp 163 A × X. hellerii]) is due to Mendelian segregation of a oncogene (xmrk) and a molecularly uncharacterized locus, called R(Diff), on LG5. R(Diff) is thought to suppresses the activity of xmrk in healthy X. maculatus Jp 163 A parental species that rarely develop melanoma. To better understand the molecular genetics of R(Diff), we utilized RNA-Seq to study allele-specific gene expression of spontaneous melanoma tumors and corresponding normal skin samples derived from 15 first generation backcross (BC1 ) hybrids and 13 fifth generation (BC5 ) hybrids. Allele-specific expression was determined for all genes and assigned to parental allele inheritance for each backcross hybrid individual. Results showed that genes residing in a 5.81 Mbp region on LG5 were exclusively expressed from the X. hellerii alleles in tumor-bearing BC1 hybrids. This observation indicates this region is consistently homozygous for X. hellerii alleles in tumor bearing animals, and therefore defines this region to be the R(Diff) locus. The R(Diff) locus harbors 164 gene models and includes the previously characterized R(Diff) candidate, cdkn2x. Twenty-one genes in the R(Diff) region show differential expression in the tumor samples compared to normal skin tissue. These results further characterize the R(Diff) locus and suggest tumor suppression may require a multigenic region rather than a single gene variant. Differences in gene expression between tumor and normal skin tissue in this region may indicate interactions among several genes are required for backcross hybrid melanoma development.

X. couchianus and X. hellerii genome models provide genomic variation insight among Xiphophorus species.

BACKGROUND: Xiphophorus fishes are represented by 26 live-bearing species of tropical fish that express many attributes (e.g., viviparity, genetic and phenotypic variation, ecological adaptation, varied sexual developmental mechanisms, ability to produce fertile interspecies hybrids) that have made attractive research models for over 85 years. Use of various interspecies hybrids to investigate the genetics underlying spontaneous and induced tumorigenesis has resulted in the development and maintenance of pedigreed Xiphophorus lines specifically bred for research. The recent availability of the X. maculatus reference genome assembly now provides unprecedented opportunities for novel and exciting comparative research studies among Xiphophorus species. RESULTS: We present sequencing, assembly and annotation of two new genomes representing Xiphophorus couchianus and Xiphophorus hellerii. The final X. couchianus and X. hellerii assemblies have total sizes of 708 Mb and 734 Mb and correspond to 98 % and 102 % of the X. maculatus Jp 163 A genome size, respectively. The rates of single nucleotide change range from 1 per 52 bp to 1 per 69 bp among the three genomes and the impact of putatively damaging variants are presented. In addition, a survey of transposable elements allowed us to deduce an ancestral TE landscape, uncovered potential active TEs and document a recent burst of TEs during evolution of this genus. CONCLUSIONS: Two new Xiphophorus genomes and their corresponding transcriptomes were efficiently assembled, the former using a novel guided assembly approach. Three assembled genome sequences within this single vertebrate order of new world live-bearing fishes will accelerate our understanding of relationship between environmental adaptation and genome evolution. In addition, these genome resources provide capability to determine allele specific gene regulation among interspecies hybrids produced by crossing any of the three species that are known to produce progeny predisposed to tumor development.

COVID and Cancer: A Complete 3D Advanced Radiological CT-Based Analysis to Predict the Outcome.

BACKGROUND: Cancer patients infected with COVID-19 were shown in a multitude of studies to have poor outcomes on the basis of older age and weak immune systems from cancer as well as chemotherapy. In this study, the CT examinations of 22 confirmed COVID-19 cancer patients were analyzed. METHODOLOGY: A retrospective analysis was conducted on 28 cancer patients, of which 22 patients were COVID positive. The CT scan changes before and after treatment and the extent of structural damage to the lungs after COVID-19 infection was analyzed. Structural damage to a lung was indicated by a change in density measured in Hounsfield units (HUs) and by lung volume reduction. A 3D radiometric analysis was also performed and lung and lesion histograms were compared. RESULTS: A total of 22 cancer patients were diagnosed with COVID-19 infection. A repeat CT scan were performed in 15 patients after they recovered from infection. Most of the study patients were diagnosed with leukemia. A secondary clinical analysis was performed to show the associations of COVID treatment on the study subjects, lab data, and outcome on mortality. It was found that post COVID there was a decrease of >50% in lung volume and a higher density in the form of HUs due to scar tissue formation post infection. CONCLUSION: It was concluded that COVID-19 infection may have further detrimental effects on the lungs of cancer patients, thereby, decreasing their lung volume and increasing their lung density due to scar formation.

What the radiologist needs to know about urolithiasis: part 1--pathogenesis, types, assessment, and variant anatomy.

OBJECTIVE: This article reviews types of urinary calculi and their imaging appearances, presents direct and secondary imaging findings of urolithiasis, and provides an overview of treatment methods. Pertinent imaging findings that impact clinical management are highlighted. The implications of complex or variant genitourinary anatomy are reviewed. We outline a standard format for the reporting of urolithiasis to facilitate informed clinical management decisions. CONCLUSION: Unenhanced CT is the preferred examination for evaluation of urolithiasis because of its availability, ease of performance, and high sensitivity. An awareness of the important imaging findings to report allows appropriate and efficient therapy.

What the radiologist needs to know about urolithiasis: part 2--CT findings, reporting, and treatment.

OBJECTIVE: This article reviews types of urinary calculi and their imaging appearances, presents direct and secondary imaging findings of urolithiasis, and provides an overview of treatment methods. Pertinent imaging findings that affect clinical management are highlighted. The implications of complex or variant genitourinary anatomy are reviewed. We outline a standard format for the reporting of urolithiasis to facilitate informed clinical management decisions. CONCLUSION: Unenhanced CT is the preferred examination for evaluation of urolithiasis because of its availability, ease of performance, and high sensitivity. An awareness of the important imaging findings to report allows appropriate and efficient therapy.

Role of 3D Volumetric and Perfusion Imaging for Detecting Early Changes in Pancreatic Adenocarcinoma.

PURPOSE: There is a major shortage of reliable early detection methods for pancreatic cancer in high-risk groups. The focus of this preliminary study was to use Time Intensity-Density Curve (TIDC) and Marley Equation analyses, in conjunction with 3D volumetric and perfusion imaging to demonstrate their potential as imaging biomarkers to assist in the early detection of Pancreatic Ductal Adenocarcinoma (PDAC). EXPERIMENTAL DESIGNS: A quantitative retrospective and prospective study was done by analyzing multi-phase Computed Tomography (CT) images of 28 patients undergoing treatment at different stages of pancreatic adenocarcinoma using advanced 3D imaging software to identify the perfusion and radio density of tumors. RESULTS: TIDC and the Marley Equation proved useful in quantifying tumor aggressiveness. Perfusion delays in the venous phase can be linked to Vascular Endothelial Growth Factor (VEGF)-related activity which represents the active part of the tumor. 3D volume analysis of the multiphase CT scan of the patient showed clear changes in arterial and venous perfusion indicating the aggressive state of the tumor. CONCLUSION: TIDC and 3D volumetric analysis can play a significant role in defining the response of the tumor to treatment and identifying early-stage aggressiveness.

Pulmonary contusion in the pediatric population.

Pulmonary contusion in the adult population is an independent risk factor for respiratory failure, ventilator associated pneumonia, and acute respiratory distress syndrome. Pilot studies in adults note an increased risk when volume of pulmonary contusion exceeds 20 per cent of total lung volume. The purpose of this study was to determine if children with pulmonary contusion suffer the same morbidity as adults. From January 2005 to May 2007, all trauma patients ages 3 to 18-years-old were assessed for CT evidence of pulmonary contusion. Children were excluded if injury included confounding variables, which could result in respiratory failure independent of contusion status. CT images were reviewed and pulmonary contusion was calculated as a percentage of total lung volume. Outcomes including need for invasive ventilation, pneumonia, and development of oxygenation problems were recorded. Data collected included patient age, Injury Severity Score, arterial blood gas findings, and number of rib fractures. Twenty-six patients met criteria for the study with a mean age of 13.35 years and mean Injury Severity Score of 24. The mean percentage of pulmonary contusion was 19.81 per cent. No patients required intubation. Pediatric pulmonary contusion does not carry the same morbidity as noted in the adult population. Invasive airway management is rarely required.

Non-Obstetric Vulvar/Paravaginal Hematoma in an Adolescent Girl with Scleroderma: An Opportunity for Intimate Partner Violence Intervention.

Description A 15-year-old female presented to the emergency department with swelling and pain in her left labial region as well as urinary retention after intercourse. This was the patient's first time having sexual intercourse and the patient stated that her boyfriend "kneed" her in the labia. A CT scan of the pelvis revealed a large vulvar/external hematoma measuring 6 × 10 × 7 cm which extended into the vaginal vault. This case is the first of a vulvar hematoma reported in a pediatric patient with scleroderma. This case was complicated by the fact that our patient claimed her boyfriend intentionally "kneed" her in the labia, thereby calling sexual abuse into question. Discerning between childhood connective tissue disorders and abuse injuries can be difficult, especially in genital trauma. The treatment team suspected early on that this was a case of intimate partner assault based on the severity of the injury alone and continued when she presented again to the emergency department with concerns for abuse. Sexual violence should be high on the differential in children with connective tissue disorders who present with vulvar or paravaginal hematomas. In our opinion, these injuries warrant a thorough investigation by a child abuse specialist, child protective services and law enforcement.

Deconvoluting Wavelengths Leading to Fluorescent Light Induced Inflammation and Cellular Stress in Zebrafish (Danio rerio).

Fluorescent light (FL) has been shown to induce a cellular immune and inflammatory response that is conserved over 450 MY of evolutionary divergence and among vertebrates having drastically different lifestyles such as Mus musculus, Danio rerio, Oryzias latipes and Xiphophorus maculatus. This surprising finding of an inflammation and immune response to FL not only holds for direct light receiving organs (skin) but is also observed within internal organs (brain and liver). Light responsive genetic circuitry initiated by the IL1B regulator induces a highly conserved acute phase response in each organ assessed for all of biological models surveyed to date; however, the specific light wavelengths triggering this response have yet to be determined so investigation of mechanisms and/or light specific molecule(s) leading to this response are difficult to assess. To understand how specific light wavelengths are received in both external and internal organs, zebrafish were exposed to specific 50 nm light wavebands spanning the visible spectrum from 300-600 nm and the genetic responses to each waveband exposure were assessed. Surprisingly, the induced cellular stress response previously observed following FL exposure is not triggered by the lower "damaging" wavelengths of light (UVB and UVA from 300-400 nm) but instead is maximally induced by higher wavelengths ranging from 450-500 nm in skin to 500-600 nm in both brain and liver).

Pediatric golf cart trauma: Not par for the course.

INTRODUCTION: Golf cart trauma in southeast Georgia represents a significant source of morbidity in the pediatric population. We believe these events are related to the introduction of new state legislation that allows local authorities to govern golf cart operation. METHODS: We performed a retrospective review from 2010 to 2016 of children involved in golf cart traumas (n = 46). We recorded age, gender, Glasgow Coma Scale score (GCS), Injury Severity Score (ISS), location of event, and patient position during event. Outcomes included injury type and length of stay (LOS). RESULTS: The most common position in a golf cart was a passenger (52.2%). Events varied regionally and correlated with stringency of local legislation. Skull fractures afflicted 48% (n = 22) of children and traumatic brain injuries (TBIs) were noted in 35% (n = 17) of patients. TBIs (LOS = 4.6 days, p = 0.006) and abdominal injuries (LOS = 8.5 days, p = 0.017) lengthened mean hospital stay. Increasing ISS was associated with an increased probability of sustaining a TBI (OR 1.295, p = 0.004). Younger children were more likely to sustain a skull fracture (OR 1.170, p = 0.034) while older children incurred more orthopedic injuries (OR 1.217, p = 0.045). CONCLUSION: Skull fractures and TBIs are common following pediatric golf cart trauma. Georgia's varying municipality legislation likely contributes to the growing frequency of this trend. LEVEL OF EVIDENCE: Retrospective study, IV.

Intra-Strain Genetic Variation of Platyfish (Xiphophorus maculatus) Strains Determines Tumorigenic Trajectory.

Xiphophorus interspecies hybrids represent a valuable model system to study heritable tumorigenesis, and the only model system that exhibits both spontaneous and inducible tumors. Types of tumorigenesis depend on the specific pedigree of the parental species, X. maculatus, utilized to produce interspecies hybrids. Although the ancestors of the two currently used X. maculatus parental lines, Jp163 A and Jp163 B, were originally siblings produced by the same mother, backcross interspecies hybrid progeny between X. hellerii and X. maculatus Jp163 A develop spontaneous melanoma initiating at the dorsal fin due to segregation of an oncogene and a regulator encoded by the X. maculatus genome, while the backcross hybrid progeny with X. hellerii or X. couchianus and Jp163 B exhibit melanoma on the flanks of their bodies, especially after treatment with ultraviolet light. Therefore, dissecting the genetic differences between these two closely related lines may lead to better understanding of functional molecular differences associated with tumorigenic mechanisms. For this purpose, comparative genomic analyses were undertaken to establish genetic variants between these two X. maculatus lines. Surprisingly, given the heritage of these two fish lines, we found genetic variants are clustered together in select chromosomal regions. Among these variants are non-synonymous mutations located in 381 genes. The non-random distribution of genetic variants between these two may highlight ancestral chromosomal recombination patterns that became fixed during subsequent inbreeding. Employing comparative transcriptomics, we also determined differences in the skin transcriptional landscape between the two lines. The genetic differences observed are associated with pathways highlighting fundamental cellular functions including inter-cellular and microenvironment-cellular interactions, and DNA repair. These results collectively lead to the conclusion that diverged functional genetic baselines are present between Jp163 A and B strains. Further, disruption of these fixed genetic baselines in the hybrids may give rise to spontaneous or inducible mechanisms of tumorigenesis.

Comparative analysis of three-dimensional volume rendering and maximum intensity projection for preoperative planning in liver cancer.

Three-dimensional imaging is a useful tool to evaluate liver structure and surrounding vessels for preoperative planning. In this study, we compared two methods of visualizing vascular maps on computed tomography including maximum intensity projection (MIP) and 3D volume rendered (VR) imaging. We compiled important imaging components of pre-surgical planning, and developed criteria for comparison. The imaging techniques were compared based on colorization, volume quantification, rotation, vessel delineation, small vessel clarity, and segmental liver isolation. MIP had more overall limitations due to reduced differentiation of superimposed structures, motion artifact, and interference from calcifications. We determined that because 3D quantitative volume rendered imaging can provide more detail and perspective than MIP imaging, it may be more useful in preoperative planning for patients with liver malignancy. Advanced 3D imaging is a useful tool that can have profound clinical implications on cancer detection and surgical planning.

Comparison of the Effectiveness of Single-Component and Multicomponent Interventions for Reducing Radiation Doses in Patients Undergoing Computed Tomography: A Randomized Clinical Trial.

Importance: Computed tomography (CT) radiation doses vary across institutions and are often higher than needed. Objective: To assess the effectiveness of 2 interventions to reduce radiation doses in patients undergoing CT. Design, Setting, and Participants: This randomized clinical trial included 864 080 adults older than 18 years who underwent CT of the abdomen, chest, combined abdomen and chest, or head at 100 facilities in 6 countries from November 1, 2015, to September 21, 2017. Data analysis was performed from October 4, 2017, to December 14, 2018. Interventions: Imaging facilities received audit feedback alone comparing radiation-dose metrics with those of other facilities followed by the multicomponent intervention, including audit feedback with targeted suggestions, a 7-week quality improvement collaborative, and best-practice sharing. Facilities were randomly allocated to the time crossing from usual care to the intervention. Main Outcomes and Measures: Primary outcomes were the proportion of high-dose CT scans and mean effective dose at the facility level. Secondary outcomes were organ doses. Outcomes after interventions were compared with those before interventions using hierarchical generalized linear models adjusting for temporal trends and patient characteristics. Results: Across 100 facilities, 864 080 adults underwent 1 156 657 CT scans. The multicomponent intervention significantly reduced proportions of high-dose CT scans, measured using effective dose. Absolute changes in proportions of high-dose scans were 1.1% to 7.9%, with percentage reductions in the proportion of high-dose scans of 4% to 30% (abdomen: odds ratio [OR], 0.82; 95% CI, 0.77-0.88; P < .001; chest: OR, 0.92; 95% CI, 0.86-0.99; P = .03; combined abdomen and chest: OR, 0.49; 95% CI, 0.41-0.59; P < .001; and head: OR, 0.71; 95% CI, 0.66-0.76; P < .001). Reductions in the proportions of high-dose scans were greater when measured using organ doses. The absolute reduction in the proportion of high-dose scans was 6.0% to 17.2%, reflecting 23% to 58% reductions in the proportions of high-dose scans across anatomical areas. Mean effective doses were significantly reduced after multicomponent intervention for abdomen (6% reduction, P < .001), chest (4%, P < .001), and chest and abdomen (14%, P < .001) CT scans. Larger reductions in mean organ doses were 8% to 43% across anatomical areas. Audit feedback alone reduced the proportions of high-dose scans and mean dose, but reductions in observed dose were smaller. Radiologist's satisfaction with CT image quality was unchanged and high during all periods. Conclusions and Relevance: For imaging facilities, detailed feedback on CT radiation dose combined with actionable suggestions and quality improvement education significantly reduced doses, particularly organ doses. Effects of audit feedback alone were modest. Trial Registration: ClinicalTrials.gov Identifier: NCT03000751.

Fluorescent Light Incites a Conserved Immune and Inflammatory Genetic Response within Vertebrate Organs (Danio Rerio, Oryzias Latipes and Mus Musculus).

Fluorescent light (FL) has been utilized for ≈60 years and has become a common artificial light source under which animals, including humans, spend increasing amounts of time. Although the solar spectrum is quite dissimilar in both wavelengths and intensities, the genetic consequences of FL exposure have not been investigated. Herein, we present comparative RNA-Seq results that establish expression patterns within skin, brain, and liver for Danio rerio, Oryzias latipes, and the hairless mouse (Mus musculus) after exposure to FL. These animals represent diurnal and nocturnal lifestyles, and ≈450 million years of evolutionary divergence. In all three organisms, FL induced transcriptional changes of the acute phase response signaling pathway and modulated inflammation and innate immune responses. Our pathway and gene clustering analyses suggest cellular perception of oxidative stress is promoting induction of primary up-stream regulators IL1B and TNF. The skin and brain of the three animals as well as the liver of both fish models all exhibit increased inflammation and immune responses; however, the mouse liver suppressed the same pathways. Overall, the conserved nature of the genetic responses observed after FL exposure, among fishes and a mammal, suggest the presence of light responsive genetic circuitry deeply embedded in the vertebrate genome.