Cytological evaluation, culture and genomics to evaluate the microbiome in healthy rabbit external ear canals.

BACKGROUND: Lop-eared rabbits may be predisposed to otitis externa (OE) as a consequence of their ear conformation. Although otoscopy, otic cytological evaluation and culture are valuable tools in dogs and cats, published data on rabbits remain lacking. HYPOTHESIS/OBJECTIVES: This study aimed to assess the utility of otoscopy and cytological results in evaluating healthy rabbit external ear canals (EECs) and to characterise ear cytological and microbiological findings through culture techniques and metagenomic sequencing. ANIMALS: Sixty-three otitis-free client-owned rabbits. MATERIALS AND METHODS: All rabbits underwent otoscopy and ear cytological evaluation. In a subset of 12 rabbits, further bacterial and fungal culture, fungal DNA assessment and metagenomic sequencing were performed. RESULTS: Otic cytological results revealed yeast in 73%, cocci in 42.9% and rods in 28.6% of healthy rabbit EECs. Compared to upright-eared rabbits, lop-eared rabbits had more discharge and more bacteria per oil immersion field. Culture isolated eight different species yet metagenomic sequencing identified 36, belonging to the Bacillota (Firmicutes), Pseudomonadota and Actinomycetota phyla. Staphylococcus were the most commonly observed species with both methods. Ten of 12 rabbits were yeast-positive on cytological evaluation with only three yielding fungal growth identified as Yarrowia (Candida) lipolytica, Eurotium echinulatum and Cystofilobasidium infirmominiatum. CONCLUSIONS AND CLINICAL RELEVANCE: Healthy rabbit EECs lack inflammatory cells yet can host yeast and bacteria, emphasising the need to evaluate cytological results alongside the clinical signs. Lop-ear anatomy may predispose to bacterial overgrowth and OE. Notably, yeasts may be present despite a negative culture.

Experimental evolution of Staphylococcus aureus in macrophages: dissection of a conditional adaptive trait promoting intracellular survival.

Staphylococcus aureus is a major pathogen associated with important diseases in humans and animals. Macrophages are a key component of the innate immune response to S. aureus infection and play a major role in disease outcomes. To investigate the adaptive evolution of S. aureus in response to macrophages, we developed an experimental infection assay. S. aureus strains representing major human epidemic clones were passaged many times in a macrophage cell line, accumulating mutations in an array of genomic loci. Phenotypic analysis revealed the emergence of a lineage exhibiting increased survival in macrophages and human blood, and resistance to vancomycin. The evolved lineage exhibited a previously undescribed small colony variant (SCV) phenotype characterized by hyper-pigmentation, which resulted from a missense mutation in rsbW. Notably, the novel SCV was a conditional adaptive trait that was unstable in nutrient-replete conditions in vitro, rapidly converting from hyper-pigmented SCV to a non-pigmented large colony variant via spontaneous sigB deletion events. Importantly, we identified similar deletions in the genome sequences of a limited number of clinical S. aureus isolates from public databases, indicating that related events may occur during clinical infection. Experimental infection of zebrafish did not reveal a difference in virulence between parent and novel SCV but demonstrated an in vivo fitness cost for the compensatory sigB deletion events. Taken together, we report an experimental evolutionary approach for investigating bacterial innate immune cell interactions, revealing a conditional adaptation that promotes S. aureus survival in macrophages and resistance to vancomycin. IMPORTANCE: Staphylococcus aureus is an important human bacterial pathogen. The host response to S. aureus involves the production of innate immune cells such as macrophages which are important for fighting infection. Here we report a new model of experimental evolution for studying how S. aureus can evade killing by macrophages. We identified a novel adaptive phenotype that promotes survival in macrophages and blood and resistance to antibiotics. The phenotype is lost rapidly upon growth in nutrient-rich conditions via disruption of the alternative sigma factor sigB, revealing a conditional niche-specific fitness advantage. Genomic analysis of clinical isolates suggests similar adaptations may occur during human infections. Our model may be used broadly to identify adaptations of S. aureus to the innate immune response.

Whole-lesion assessment of volume and signal changes after sclerotherapy of extremity venous malformations.

PURPOSE: To investigate quantitative changes in MRI signal intensity (SI) and lesion volume that indicate treatment response and correlate these changes with clinical outcomes after percutaneous sclerotherapy (PS) of extremity venous malformations (VMs). METHODS: VMs were segmented manually on pre- and post-treatment T2-weighted MRI using 3D Slicer to assess changes in lesion volume and SI. Clinical outcomes were scored on a 7-point Likert scale according to patient perception of symptom improvement; treatment response (success or failure) was determined accordingly. RESULTS: Eighty-one patients with VMs underwent 125 PS sessions. Treatment success occurred in 77 patients (95 %). Mean (±SD) changes were -7.9 ± 24 cm3 in lesion volume and -123 ± 162 in SI (both, P <.001). Mean reduction in lesion volume was greater in the success group (-9.4 ± 24 cm3) than in the failure group (21 ± 20 cm3) (P =.006). Overall, lesion volume correlated with treatment response (ρ = -0.3, P =.004). On subgroup analysis, volume change correlated with clinical outcomes in children (ρ = -0.3, P =.03), in sodium tetradecyl sulfate-treated lesions (ρ = -0.5, P =.02), and in foot lesions (ρ = -0.6, P =.04). SI change correlated with clinical outcomes in VMs treated in 1 PS session (ρ = -0.3, P =.01) and in bleomycin-treated lesions (ρ = -0.4, P =.04). CONCLUSIONS: Change in lesion volume is a reliable indicator of treatment response. Lesion volume and SI correlate with clinical outcomes in specific subgroups.

Baseline metastatic growth rate is an independent prognostic marker in patients with advanced BRAF V600 mutated melanoma receiving targeted therapy.

BACKGROUND: Targeted therapy (TT) of BRAF V600 mutated unresectable melanoma with inhibitors of the MAPK pathway achieves response rates of up to 76%, but most patients develop secondary resistance. Albeit TT is strikingly efficacious during the first days of treatment, even in advanced cases, long-term survival is highly unlikely, especially in patients with unfavorable baseline characteristics like elevated lactate dehydrogenase (LDH). In patients treated with anti-PD-1 immune checkpoint inhibitors, elevated baseline metastatic growth rate (MGR) was the most important prognostic factor. Here, we aimed at investigating the prognostic impact of MGR in patients with unresectable melanoma receiving TT. METHODS: Clinical records of 242 patients with at least one measurable target lesion (TL) receiving TT at seven skin cancer centers were reviewed. Baseline MGR was determined measuring the largest TL at baseline and at one earlier timepoint. RESULTS: Overall survival (OS) and progression-free survival (PFS) were significantly impaired in patients with an MGR > 3.9 mm/month (median OS: 11.4 vs. 35.5 months, P < 0.0001; median PFS: 4.8 vs. 9.2 months, P < 0.0001). Multivariable analysis of OS and PFS revealed that the prognostic impact of elevated MGR was independent of LDH, presence of brain and liver metastases, tumor burden, and line of treatment. The prognostic significance of elevated MGR was highest in patients with normal LDH. CONCLUSIONS: Baseline MGR is an important independent prognostic marker for OS and PFS in melanoma patients treated with TT. Its implementation in clinical routine is easy and could facilitate the prognostic stratification.

Rapid metagenomic sequencing for diagnosis and antimicrobial sensitivity prediction of canine bacterial infections.

Antimicrobial resistance is a major threat to human and animal health. There is an urgent need to ensure that antimicrobials are used appropriately to limit the emergence and impact of resistance. In the human and veterinary healthcare setting, traditional culture and antimicrobial sensitivity testing typically requires 48-72 h to identify appropriate antibiotics for treatment. In the meantime, broad-spectrum antimicrobials are often used, which may be ineffective or impact non-target commensal bacteria. Here, we present a rapid, culture-free, diagnostics pipeline, involving metagenomic nanopore sequencing directly from clinical urine and skin samples of dogs. We have planned this pipeline to be versatile and easily implementable in a clinical setting, with the potential for future adaptation to different sample types and animals. Using our approach, we can identify the bacterial pathogen present within 5 h, in some cases detecting species which are difficult to culture. For urine samples, we can predict antibiotic sensitivity with up to 95 % accuracy. Skin swabs usually have lower bacterial abundance and higher host DNA, confounding antibiotic sensitivity prediction; an additional host depletion step will likely be required during the processing of these, and other types of samples with high levels of host cell contamination. In summary, our pipeline represents an important step towards the design of individually tailored veterinary treatment plans on the same day as presentation, facilitating the effective use of antibiotics and promoting better antimicrobial stewardship.

Responsiveness of the Patient-Reported Outcome Measure for Vascular Malformation Questionnaire in Patients with Low-Flow Vascular Malformations.

PURPOSE: To assess the responsiveness, defined as the ability to detect change in a patient's health or function, of the Patient-Reported Outcome Measure for Vascular Malformation (PROVAM) questionnaire in a cohort of patients with low-flow vascular malformations (VMs). MATERIALS AND METHODS: PROVAM was previously developed to assess symptoms, functional limitations, and social/emotional effects experienced by patients with VMs. This is a prospective cohort study of 56 patients with venous and lymphatic VMs who completed at least 2 PROVAM questionnaires, of whom 43 had undergone treatment with sclerotherapy in the interim between questionnaires. External responsiveness was assessed using a receiver operating characteristic (ROC) curve to ascertain whether a change in the total PROVAM score predicts whether patients reported symptom improvement and by correlating the change in the total PROVAM score and change in symptoms reported during clinic visit. Internal responsiveness was evaluated using Wilcoxon signed rank test, Cohen d effect size (ESp), and standard response mean difference (SRM). RESULTS: The total PROVAM score demonstrated excellent discrimination for symptom improvement with an area under the ROC curve of 0.856. There was a statistically significant, moderate positive correlation between the change in the total PROVAM score and the change in patient symptoms as determined from clinical visits (Spearman correlation coefficient [rs] = 0.67, P < .001). The total PROVAM score and all subdomain scores improved significantly after treatment (all P < .05). ESp and SRM were 0.80 and 0.83, respectively. CONCLUSIONS: PROVAM is responsive to improvement after treatment and may be useful to assess health-related quality of life in patients treated for VMs.

Towards comprehensive understanding of bacterial genetic diversity: large-scale amplifications in Bordetella pertussis and Mycobacterium tuberculosis.

Bacterial genetic diversity is often described solely using base-pair changes despite a wide variety of other mutation types likely being major contributors. Tandem duplication/amplifications are thought to be widespread among bacteria but due to their often-intractable size and instability, comprehensive studies of these mutations are rare. We define a methodology to investigate amplifications in bacterial genomes based on read depth of genome sequence data as a proxy for copy number. We demonstrate the approach with Bordetella pertussis, whose insertion sequence element-rich genome provides extensive scope for amplifications to occur. Analysis of data for 2430 B. pertussis isolates identified 272 putative amplifications, of which 94 % were located at 11 hotspot loci. We demonstrate limited phylogenetic connection for the occurrence of amplifications, suggesting unstable and sporadic characteristics. Genome instability was further described in vitro using long-read sequencing via the Nanopore platform, which revealed that clonally derived laboratory cultures produced heterogenous populations rapidly. We extended this research to analyse a population of 1000 isolates of another important pathogen, Mycobacterium tuberculosis. We found 590 amplifications in M. tuberculosis, and like B. pertussis, these occurred primarily at hotspots. Genes amplified in B. pertussis include those involved in motility and respiration, whilst in M. tuberuclosis, functions included intracellular growth and regulation of virulence. Using publicly available short-read data we predicted previously unrecognized, large amplifications in B. pertussis and M. tuberculosis. This reveals the unrecognized and dynamic genetic diversity of B. pertussis and M. tuberculosis, highlighting the need for a more holistic understanding of bacterial genetics.

Comparative genomics of Bordetella pertussis isolates from New Zealand, a country with an uncommonly high incidence of whooping cough.

Whooping cough, the respiratory disease caused by Bordetella pertussis, has undergone a wide-spread resurgence over the last several decades. Previously, we developed a pipeline to assemble the repetitive B. pertussis genome into closed sequences using hybrid nanopore and Illumina sequencing. Here, this sequencing pipeline was used to conduct a more high-throughput, longitudinal screen of 66 strains isolated between 1982 and 2018 in New Zealand. New Zealand has a higher incidence of whooping cough than many other countries; usually at least twice as many cases per 100000 people as the USA and UK and often even higher, despite similar rates of vaccine uptake. To the best of our knowledge, these strains are the first New Zealand B. pertussis isolates to be sequenced. The analyses here show that, on the whole, genomic trends in New Zealand B. pertussis isolates, such as changing allelic profile in vaccine-related genes and increasing pertactin deficiency, have paralleled those seen elsewhere in the world. At the same time, phylogenetic comparisons of the New Zealand isolates with global isolates suggest that a number of strains are circulating in New Zealand, which cluster separately from other global strains, but which are closely related to each other. The results of this study add to a growing body of knowledge regarding recent changes to the B. pertussis genome, and are the first genetic investigation into B. pertussis isolates from New Zealand.

Global health radiology planning using Geographic Information Systems to identify populations with decreased access to care.

BACKGROUND: Communities throughout northern Canada face significant health care disparities including decreased access to radiology. A medical hybrid airship is under development which aims to serve remote populations, requiring strategic outreach planning. This study aims to use geographic information systems (GIS) to identify (1) high risk and medically underserved patient populations in northern Canada and (2) potential landing sites for a medical airship to allow for mobile delivery of radiology services. METHODS: The northern region of Canada extending from the Rocky Mountains to the Atlantic Ocean was analyzed using multi-variable, multi-weighted GIS modeling. Based on population distance from hospitals (50% weight), health centers (eg, clinic; 30% weight), remote communities (not connected to electric grid; 10% weight), and roads (10% weight), individuals were stratified into one of five health care accessibility index (HAI) categories (ranging from very low to very high severity). HAI (80% weight) was combined with population density (20%) to create a health care access severity index (HASI). Topographic and land cover data were used to identify suitable landing sites for the medical airship. A coordinate data set was made from georeferenced health care facilities, and infrastructure data was obtained from OpenStreetMap. RESULTS: GIS analyzed 815 772 Canadians. Of this population, 522 094 (64%) were found to live ≥60 km from a hospital, 326 309 (40%) were ≥45 km from the nearest health center, 65 262 (8%) were within 30 km of a remote community, and 57 104 (7%) lived ≥1 km from the nearest road. Combined, the HASI identified 44% of the population as having decreased access to care (high or very high severity). Lastly, 27.5% of land analyzed was found to be suitable for airship operations. CONCLUSIONS: GIS identified medically underserved populations in northern Canada who may benefit from mobile radiology services. These techniques may help to guide future global health outreach efforts.

Prevalence of and Factors Associated with Arterial Aneurysms in Patients with Hereditary Hemorrhagic Telangiectasia: 17-Year Retrospective Series of 418 Patients.

PURPOSE: To estimate the prevalence of and identify characteristics associated with the presence of aneurysms in a cohort of patients with hereditary hemorrhagic telangiectasia (HHT). MATERIALS AND METHODS: In the study institution's HHT database, 418 patients with a definite HHT diagnosis were identified based on the clinical Curaçao criteria and/or an HHT-associated genetic mutation. Regression modeling was used to evaluate the association between arterial aneurysms and older age, male sex, smoking, alcohol consumption, hypertension, hyperlipidemia, genetic mutations, the presence of arteriovenous malformations (AVMs) unrelated to the aneurysms, and HHT-related genetic mutations. RESULTS: Forty-three (10.3%) patients had at least 1 aneurysm. Sixteen (3.8%) patients had multiple aneurysms. Of the variables analyzed, older age (odds ratio [OR] = 1.02; 95% confidence interval [CI]: 1.0-1.1), the presence of anatomically and flow-unrelated AVMs (OR = 3.2; 95% CI: 1.3-8.0), and the presence of activin A receptor type II-like 1 (ACVRL1) mutation (OR = 4.0; 95% CI: 1.5-10) were associated with the presence of at least 1 aneurysm. CONCLUSIONS: In this cohort of patients with HHT, the prevalence of intracranial and visceral arterial aneurysms was estimated to be 10.3%. Older age, the presence of unrelated AVMs, and the presence of the ACVRL1 mutation were associated with the presence of arterial aneurysms. Further study is required to assess the clinical importance and risk of rupture of aneurysms in patients with HHT.

Pretreatment metastatic growth rate determines clinical outcome of advanced melanoma patients treated with anti-PD-1 antibodies: a multicenter cohort study.

BACKGROUND: Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies. METHODS: MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB-IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR. RESULTS: Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036). CONCLUSIONS: High pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens.

Acapsular Staphylococcus aureus with a non-functional agr regains capsule expression after passage through the bloodstream in a bacteremia mouse model.

Selection pressures exerted on Staphylococcus aureus by host factors during infection may lead to the emergence of regulatory phenotypes better adapted to the infection site. Traits convenient for persistence may be fixed by mutation thus turning these mutants into microevolution endpoints. The feasibility that stable, non-encapsulated S. aureus mutants can regain expression of key virulence factors for survival in the bloodstream was investigated. S. aureus agr mutant HU-14 (IS256 insertion in agrC) from a patient with chronic osteomyelitis was passed through the bloodstream using a bacteriemia mouse model and derivative P3.1 was obtained. Although IS256 remained inserted in agrC, P3.1 regained production of capsular polysaccharide type 5 (CP5) and staphyloxanthin. Furthermore, P3.1 expressed higher levels of asp23/SigB when compared with parental strain HU-14. Strain P3.1 displayed decreased osteoclastogenesis capacity, thus indicating decreased adaptability to bone compared with strain HU-14 and exhibited a trend to be more virulent than parental strain HU-14. Strain P3.1 exhibited the loss of one IS256 copy, which was originally located in the HU-14 noncoding region between dnaG (DNA primase) and rpoD (sigA). This loss may be associated with the observed phenotype change but the mechanism remains unknown. In conclusion, S. aureus organisms that escape the infected bone may recover the expression of key virulence factors through a rapid microevolution pathway involving SigB regulation of key virulence factors.

Screening vs staging magnetic resonance imaging-guided core needle breast biopsies: Does MRI indication impact upgrade rate?

Adjunct magnetic resonance imaging (MRI) for both screening high-risk patients and staging for patients with newly diagnosed breast cancer leads to an increased number of biopsies and increased detection of atypical lesions. We assessed whether the malignancy upgrade frequency for high-risk atypia identified via MRI-guided biopsies varied based on indication: high-risk screening vs staging for malignancy. Among 399 MRI-guided biopsies, 46 (11.5%) high-risk lesions (ADH, ALH, and LCIS) were identified. Surgical excision was performed on 37% of 46%, and 24.3% were upgraded to invasive malignancy or DCIS. Of lesions identified by staging MRI, a slightly higher percentage, 28.5%, were upgraded (P = .36). Our data suggest that surgeons should carefully consider excisional biopsy for atypia identified on MRI regardless of indication.

How Genomics Is Changing What We Know About the Evolution and Genome of Bordetella pertussis.

The evolution of Bordetella pertussis from a common ancestor similar to Bordetella bronchiseptica has occurred through large-scale gene loss, inactivation and rearrangements, largely driven by the spread of insertion sequence element repeats throughout the genome. B. pertussis is widely considered to be monomorphic, and recent evolution of the B. pertussis genome appears to, at least in part, be driven by vaccine-based selection. Given the recent global resurgence of whooping cough despite the wide-spread use of vaccination, a more thorough understanding of B. pertussis genomics could be highly informative. In this chapter we discuss the evolution of B. pertussis, including how vaccination is changing the circulating B. pertussis population at the gene-level, and how new sequencing technologies are revealing previously unknown levels of inter- and intra-strain variation at the genome-level.

Papillary and sclerosing lesions of the breast detected and biopsied by MRI: Clinical management, upgrade rate, and association with apocrine metaplasia.

Benign papillary and sclerosing lesions of the breast (intraductal papillomas, complex sclerosing lesions, radial scars) are considered high-risk lesions due to the potential for upgrade to carcinoma on subsequent surgical excision. Optimal clinical management of such lesions remains unclear due to variable reported upgrade rates. Apocrine metaplasia is a common finding in breast tissue and its role in MRI enhancing lesions is increasingly being recognized. The purpose of this study was to investigate the MRI features of papillary and sclerosing lesions of the breast, evaluate the clinical management and upgrade rate of such lesions, and examine the contribution of apocrine metaplasia to the imaging findings. A 13-year retrospective review of MRI-guided biopsies identified 70 MRI-detected and -biopsied papillary and sclerosing lesions. Sixteen lesions without atypia underwent surgical excision; only one case (6%) was upgraded to pleomorphic lobular carcinoma in situ. The majority (64%) of biopsies contained apocrine metaplasia either within or adjacent to the targeted lesion. We found that half of MRI-detected lesions had T2 hyperintense foci (2-5 mm) or masses (>5 mm) adjacent to the lesion. Histologic correlation showed apocrine cysts were likely responsible for this imaging finding in 56% of these cases.

Resolving the complex Bordetella pertussis genome using barcoded nanopore sequencing.

The genome of Bordetella pertussis is complex, with high G+C content and many repeats, each longer than 1000 bp. Long-read sequencing offers the opportunity to produce single-contig B. pertussis assemblies using sequencing reads which are longer than the repetitive sections, with the potential to reveal genomic features which were previously unobservable in multi-contig assemblies produced by short-read sequencing alone. We used an R9.4 MinION flow cell and barcoding to sequence five B. pertussis strains in a single sequencing run. We then trialled combinations of the many nanopore user community-built long-read analysis tools to establish the current optimal assembly pipeline for B. pertussis genome sequences. This pipeline produced closed genome sequences for four strains, allowing visualization of inter-strain genomic rearrangement. Read mapping to the Tohama I reference genome suggests that the remaining strain contains an ultra-long duplicated region (almost 200 kbp), which was not resolved by our pipeline; further investigation also revealed that a second strain that was seemingly resolved by our pipeline may contain an even longer duplication, albeit in a small subset of cells. We have therefore demonstrated the ability to resolve the structure of several B. pertussis strains per single barcoded nanopore flow cell, but the genomes with highest complexity (e.g. very large duplicated regions) remain only partially resolved using the standard library preparation and will require an alternative library preparation method. For full strain characterization, we recommend hybrid assembly of long and short reads together; for comparison of genome arrangement, assembly using long reads alone is sufficient.

Changes in Primary Care Health Care Utilization after Inclusion of Epidemiologic Data in Lumbar Spine MR Imaging Reports for Uncomplicated Low Back Pain.

Purpose To determine whether inclusion of an epidemiologic statement in radiology reports of lumbar magnetic resonance (MR) imaging influences downstream health care utilization in the primary care population. Materials and Methods Beginning July 1, 2013, a validated epidemiologic statement regarding prevalence of common findings in asymptomatic patients was included in all lumbar MR imaging reports at a tertiary academic medical center. Data were collected from July 1, 2012, through June 30, 2014, and retrospective analysis was completed in September 2016. The electronic medical record was reviewed to capture health care utilization rates in patients for 1 year after index MR imaging. Of 4527 eligible adult patients with low back pain referred for lumbar spine MR imaging during the study period, 375 patients had their studies ordered by in-network primary care providers, did not have findings other than degenerative disease, and had at least one follow-up encounter within the system within 1 year of index MR imaging. In the before-and-after study design, a pre-statement-implementation cohort was compared with a post-statement-implementation cohort by using univariate and multivariate statistical models to evaluate treatment utilization rates in these groups. Results Patients in the statement group were 12% less likely to be referred to a spine specialist (137 of 187 [73%] vs 159 of 188 [85%]; P = .007) and were 7% less likely to undergo repeat imaging (seven of 187 [4%] vs 20 of 188 [11%]; P = .01) compared with patients in the nonstatement group. The intervention was not associated with any change in narcotic prescription (53 of 188 [28%] vs 54 of 187 [29%]; P = .88) or with the rate of low back surgery (24 of 188 [13%] vs 16 of 187 [9%]; P = .19). Conclusion In this study, inclusion of a simple epidemiologic statement in lumbar MR imaging reports was associated with decreased utilization in high-cost domains of low back pain management. © RSNA, 2018.

A bioimage informatics platform for high-throughput embryo phenotyping.

High-throughput phenotyping is a cornerstone of numerous functional genomics projects. In recent years, imaging screens have become increasingly important in understanding gene-phenotype relationships in studies of cells, tissues and whole organisms. Three-dimensional (3D) imaging has risen to prominence in the field of developmental biology for its ability to capture whole embryo morphology and gene expression, as exemplified by the International Mouse Phenotyping Consortium (IMPC). Large volumes of image data are being acquired by multiple institutions around the world that encompass a range of modalities, proprietary software and metadata. To facilitate robust downstream analysis, images and metadata must be standardized to account for these differences. As an open scientific enterprise, making the data readily accessible is essential so that members of biomedical and clinical research communities can study the images for themselves without the need for highly specialized software or technical expertise. In this article, we present a platform of software tools that facilitate the upload, analysis and dissemination of 3D images for the IMPC. Over 750 reconstructions from 80 embryonic lethal and subviable lines have been captured to date, all of which are openly accessible at mousephenotype.org. Although designed for the IMPC, all software is available under an open-source licence for others to use and develop further. Ongoing developments aim to increase throughput and improve the analysis and dissemination of image data. Furthermore, we aim to ensure that images are searchable so that users can locate relevant images associated with genes, phenotypes or human diseases of interest.