Chordin and dickkopf-1b are essential for the formation of head structures through activation of the FGF signaling pathway in zebrafish.

The ability of the Spemann organizer to induce dorsal axis formation is dependent on downstream factors of the maternal Wnt/ß-catenin signaling pathway. The fibroblast growth factor (FGF) signaling pathway has been identified as one of the downstream components of the maternal Wnt/ß-catenin signaling pathway. The ability of the FGF signaling pathway to induce the formation of a dorsal axis with a complete head structure requires chordin (chd) expression; however, the molecular mechanisms involved in this developmental process, due to activation of FGF signaling, remain unclear. In this study, we showed that activation of the FGF signaling pathway induced the formation of complete head structures through the expression of chd and dickkopf-1b (dkk1b). Using the organizer-deficient maternal mutant, ichabod, we identified dkk1b as a novel downstream factor in the FGF signaling pathway. We also demonstrate that dkk1b expression is necessary, after activation of the FGF signaling pathway, to induce neuroectoderm patterning along the anteroposterior (AP) axis and for formation of complete head structures. Co-injection of chd and dkk1b mRNA resulted in the formation of a dorsal axis with a complete head structure in ichabod embryos, confirming the role of these factors in this developmental process. Unexpectedly, we found that chd induced dkk1b expression in ichabod embryos at the shield stage. However, chd failed to maintain dkk1b expression levels in cells of the shield and, subsequently, in the cells of the prechordal plate after mid-gastrula stage. In contrast, activation of the FGF signaling pathway maintained the dkk1b expression from the beginning of gastrulation to early somitogenesis. In conclusion, activation of the FGF signaling pathway induces the formation of a dorsal axis with a complete head structure through the expression of chd and subsequent maintenance of dkk1b expression levels.

A Comprehensive Analysis of Cribriform Morphology on Magnetic Resonance Imaging/Ultrasound Fusion Biopsy Correlated with Radical Prostatectomy Specimens.

PURPOSE: Recently a large body of evidence has emerged indicating that cribriform morphology is an aggressive prostate cancer morphological pattern associated with higher cancer specific mortality. In a comprehensive analysis we compared traditional and contemporary prostate biopsy techniques to detect prostate cancer with cribriform morphology with radical prostatectomy serving as the reference standard. MATERIALS AND METHODS: We queried a retrospectively maintained, single institution, multiparametric magnetic resonance imaging database of 1,001 patients to identify 240 who underwent magnetic resonance imaging-ultrasound fusion targeted biopsy and concurrent systematic biopsy from December 2014 to December 2016. Of the 3,978 biopsy cores obtained 694 positive cores were rereviewed by a genitourinary pathologist for pattern 4 subtype (cribriform, fused and poorly formed glands). Using paired analysis pathological results among 3 biopsy methods (systematic biopsy, targeted biopsy and systematic plus targeted biopsy) were compared. Prostatectomy specimens were also pathologically reviewed. RESULTS: Systematic plus targeted biopsy was superior to systematic biopsy alone or targeted biopsy alone to detect cribriform morphology (all p <0.0001). On final histopathology cribriform tumor foci were associated with an increased percent of pattern 4 involvement and extraprostatic extension (p <0.0001 and 0.003, respectively). Only 17.4% of cribriform tumors in pure form were visible on multiparametric magnetic resonance imaging. Based on final histopathology the sensitivity of systematic biopsy, targeted biopsy and systematic plus targeted biopsy for cribriform morphology was 20.7%, 28.6% and 37.1%, respectively. CONCLUSIONS: Although systematic plus targeted biopsy was the most accurate biopsy method to detect cribriform morphology, biopsy sensitivity and specificity remained poor.

Impact of Gleason Subtype on Prostate Cancer Detection Using Multiparametric Magnetic Resonance Imaging: Correlation with Final Histopathology.

PURPOSE: We determined whether Gleason pattern 4 architecture impacts tumor visibility on multiparametric magnetic resonance imaging and correlates with final histopathology. MATERIALS AND METHODS: A total of 83 tumor foci were identified in 22 radical prostatectomy specimens from patients with a prior negative biopsy who underwent magnetic resonance/ultrasound fusion biopsy followed by radical prostatectomy from January 2015 to July 2016. A genitourinary pathologist rereviewed tumor foci for Gleason architectural subtype. Each prostate imaging reporting and data system category 3 to 5 lesion on multiparametric magnetic resonance imaging was paired with its corresponding pathological tumor focus. Univariable and multivariable analyses were performed to determine predictors of tumor visibility. RESULTS: Of the 83 tumor foci identified 26 (31%) were visible on multiparametric magnetic resonance imaging, 33 (40%) were Gleason score 3+3 and 50 (60%) were Gleason score 3+4 or greater. Among tumor foci containing Gleason pattern 4, increasing tumor size and noncribriform predominant architecture were the only independent predictors of tumor detection on multivariable analysis (p = 0.002 and p = 0.011, respectively). For tumor foci containing Gleason pattern 4, 0.5 cm or greater, multiparametric magnetic resonance imaging detected 10 of 13 (77%), 5 of 14 (36%) and 9 of 10 (90%) for poorly formed, cribriform and fused architecture, respectively (p = 0.01). The size threshold for the detection of cribriform tumors was higher than that of other architectural patterns. Furthermore, cribriform pattern was identified more frequently on systematic biopsy than on targeted biopsy. CONCLUSIONS: Reduced visibility of cribriform pattern on multiparametric magnetic resonance imaging has significant ramifications for prostate cancer detection, surveillance and focal therapy.

MR Imaging with Metal-suppression Sequences for Evaluation of Total Joint Arthroplasty.

Metallic artifact at orthopedic magnetic resonance (MR) imaging continues to be an important problem, particularly in the realm of total joint arthroplasty. Complications often follow total joint arthroplasty and can be expected for a small percentage of all implanted devices. Postoperative complications involve not only osseous structures but also adjacent soft tissues-a highly problematic area at MR imaging because of artifacts from metallic prostheses. Without special considerations, susceptibility artifacts from ferromagnetic implants can unacceptably degrade image quality. Common artifacts include in-plane distortions (signal loss and signal pileup), poor or absent fat suppression, geometric distortion, and through-section distortion. Basic methods to reduce metallic artifacts include use of spin-echo or fast spin-echo sequences with long echo train lengths, short inversion time inversion-recovery (STIR) sequences for fat suppression, a high bandwidth, thin section selection, and an increased matrix. With care and attention to the alloy type (eg, titanium, cobalt-chromium, stainless steel), orientation of the implant, and magnetic field strength, as well as use of proprietary and nonproprietary metal-suppression techniques, previously nondiagnostic studies can yield key diagnostic information. Specifically, sequences such as the metal artifact reduction sequence (MARS), WARP (Siemens Healthcare, Munich, Germany), slice encoding for metal artifact correction (SEMAC), and multiacquisition with variable-resonance image combination (MAVRIC) can be optimized to reveal pathologic conditions previously hidden by periprosthetic artifacts. Complications of total joint arthroplasty that can be evaluated by using MR imaging with metal-suppression sequences include pseudotumoral conditions such as metallosis and particle disease, infection, aseptic prosthesis loosening, tendon injury, and muscle injury.

Cumulative Radiation Exposure to Patients Undergoing Arthroscopic Hip Preservation Surgery and Occupational Radiation Exposure to the Surgical Team.

PURPOSE: To quantify cumulative radiation exposure in patients undergoing arthroscopic hip preservation surgery and occupational exposure to operating room (OR) personnel during such surgery; a secondary objective of this study was to identify factors affecting radiation exposure in patients undergoing hip arthroscopy. METHODS: Radiation exposure from all preoperative and intraoperative imaging studies was determined for 52 patients undergoing hip arthroscopy. Cumulative and effective radiation doses were calculated and correlated with pathology and body mass index (BMI). Badge dosimeters were worn by OR personnel to measure cumulative occupational exposure. A highly sensitive portable ion chamber was used to evaluate the radiation scatter during surgery performed on a high-BMI patient and a low-BMI patient to reflect a "worst-case scenario" and "best-case scenario," respectively. RESULTS: Forty-three patients underwent procedures for femoroacetabular impingement (FAI) and 9 underwent procedures for soft-tissue pathologies (ST). The median cumulative exposure was 8.6 mGy and 5.0 mGy for FAI patients and ST patients, respectively (P = .01). The cumulative effective radiation dose was 490 mrem and 350 mrem for FAI patients and ST patients, respectively (P = .47). BMI significantly correlated with cumulative exposure (P = .0004) and trended toward significance with cumulative effective dose (P = .073). OR staff cumulative occupational exposure was low (9 mrem for the surgeon). Ion chamber data showed that increasing patient BMI resulted in increased occupational exposure. CONCLUSIONS: The median cumulative effective radiation dose to patients undergoing arthroscopic hip preservation surgery is 490 mrem and results in an excess lifetime risk of death from cancer of 0.025%. Greater BMI correlates with increased cumulative radiation exposure and may increase risk to OR personnel. Occupational exposure to the surgical team from hip arthroscopy ranges from 7 to 9 mrem per 50 hip arthroscopies (+0.0005% excess lifetime risk of death from cancer). LEVEL OF EVIDENCE: Level IV, diagnostic.

Induction and patterning of trunk and tail neural ectoderm by the homeobox gene eve1 in zebrafish embryos.

In vertebrates, Evx homeodomain transcription factor-encoding genes are expressed in the posterior region during embryonic development, and overexpression experiments have revealed roles in tail development in fish and frogs. We analyzed the molecular mechanisms of posterior neural development and axis formation regulated by eve1. We show that eve1 is involved in establishing trunk and tail neural ectoderm by two independent mechanisms: First, eve1 posteriorizes neural ectoderm via induction of aldh1a2, which encodes an enzyme that synthesizes retinoic acid; second, eve1 is involved in neural induction in the posterior ectoderm by attenuating BMP expression. Further, eve1 can restore trunk neural tube formation in the organizer-deficient ichabod(-/-) mutant. We conclude that eve1 is crucial for the organization of the antero-posterior and dorso-ventral axis in the gastrula ectoderm and also has trunk- and tail-promoting activity.

Early-stage COVID-19 pandemic observations on pulmonary embolism using nationwide multi-institutional data harvesting.

We introduce a multi-institutional data harvesting (MIDH) method for longitudinal observation of medical imaging utilization and reporting. By tracking both large-scale utilization and clinical imaging results data, the MIDH approach is targeted at measuring surrogates for important disease-related observational quantities over time. To quantitatively investigate its clinical applicability, we performed a retrospective multi-institutional study encompassing 13 healthcare systems throughout the United States before and after the 2020 COVID-19 pandemic. Using repurposed software infrastructure of a commercial AI-based image analysis service, we harvested data on medical imaging service requests and radiology reports for 40,037 computed tomography pulmonary angiograms (CTPA) to evaluate for pulmonary embolism (PE). Specifically, we compared two 70-day observational periods, namely (i) a pre-pandemic control period from 11/25/2019 through 2/2/2020, and (ii) a period during the early COVID-19 pandemic from 3/8/2020 through 5/16/2020. Natural language processing (NLP) on final radiology reports served as the ground truth for identifying positive PE cases, where we found an NLP accuracy of 98% for classifying radiology reports as positive or negative for PE based on a manual review of 2,400 radiology reports. Fewer CTPA exams were performed during the early COVID-19 pandemic than during the pre-pandemic period (9806 vs. 12,106). However, the PE positivity rate was significantly higher (11.6 vs. 9.9%, p < 10-4) with an excess of 92 PE cases during the early COVID-19 outbreak, i.e., ~1.3 daily PE cases more than statistically expected. Our results suggest that MIDH can contribute value as an exploratory tool, aiming at a better understanding of pandemic-related effects on healthcare.

Correct anteroposterior patterning of the zebrafish neurectoderm in the absence of the early dorsal organizer.

BACKGROUND: The embryonic organizer (i.e., Spemann organizer) has a pivotal role in the establishment of the dorsoventral (DV) axis through the coordination of BMP signaling. However, as impaired organizer function also results in anterior and posterior truncations, it is of interest to determine if proper anteroposterior (AP) pattern can be obtained even in the absence of early organizer signaling. RESULTS: Using the ventralized, maternal effect ichabod (ich) mutant, and by inhibiting BMP signaling in ich embryos, we provide conclusive evidence that AP patterning is independent of the organizer in zebrafish, and is governed by TGFß, FGF, and Wnt signals emanating from the germ-ring. The expression patterns of neurectodermal markers in embryos with impaired BMP signaling show that the directionality of such signals is oriented along the animal-vegetal axis, which is essentially concordant with the AP axis. In addition, we find that in embryos inhibited in both Wnt and BMP signaling, the AP pattern of such markers is unchanged from that of the normal untreated embryo. These embryos develop radially organized trunk and head tissues, with an outer neurectodermal layer containing diffusely positioned neuronal precursors. Such organization is reflective of the presumed eumetazoan ancestor and might provide clues for the evolution of centralization in the nervous system. CONCLUSIONS: Using a zebrafish mutant deficient in the induction of the embryonic organizer, we demonstrate that the AP patterning of the neuroectoderm during gastrulation is independent of DV patterning. Our results provide further support for Nieuwkoop's "two step model" of embryonic induction. We also show that the zebrafish embryo can form a radial diffuse neural sheath in the absence of both BMP signaling and the early organizer.

The zebrafish dorsal axis is apparent at the four-cell stage.

A central question in the development of multicellular organisms pertains to the timing and mechanisms of specification of the embryonic axes. In many organisms, specification of the dorsoventral axis requires signalling by proteins of the Transforming growth factor-beta and Wnt families. Here we show that maternal transcripts of the zebrafish Nodal-related morphogen, Squint (Sqt), can localize to two blastomeres at the four-cell stage and predict the dorsal axis. Removal of cells containing sqt transcripts from four-to-eight-cell embryos or injection of antisense morpholino oligonucleotides targeting sqt into oocytes can cause a loss of dorsal structures. Localization of sqt transcripts is independent of maternal Wnt pathway function and requires a highly conserved sequence in the 3' untranslated region. Thus, the dorsoventral axis is apparent by early cleavage stages and may require the maternally encoded morphogen Sqt and its associated factors. Because the 3' untranslated region of the human nodal gene can also localize exogenous sequences to dorsal cells, this mechanism may be evolutionarily conserved.

Comparison of Multi-Parametric MRI of the Prostate to 3D Prostate Computer Aided Designs and 3D-Printed Prostate Models for Pre-Operative Planning of Radical Prostatectomies: A Pilot Study.

OBJECTIVE: To evaluate the use of 3D computed aided designs and 3D-printed models as pre-operative planning tools for urologists, in addition to radiologist interpreted mp-MRIS, prior to radical prostatectomy procedures. METHODS: Ten patients with biopsy-positive lesions detected on mp-MRI were retrospectively selected. Radiologists identified lesion locations using a Prostate Imaging-Reporting and Data System (PI-RADS) map and segmented the prostate, lesion(s), and surrounding anatomy to create 3D-CADs and 3D-printed models for each patient. 6 uro-oncologists randomly reviewed three modalities (mp-MRI, 3D-CAD, and 3D-printed models) for each patient and identified lesion locations which were graded for accuracy against the radiologists' answers. Questionnaires assessed decision confidence, ease-of-interpretation, and usefulness for preoperative planning for each modality. RESULTS: Using 3D-CADs and 3D-printed models compared to mp-MRI, urologists were 2.4x and 2.8x more accurate at identifying the lesion(s), 2.7x and 3.2x faster, 1.6x and 1.63x more confident, and reported it was 1.6x and 1.7x easier to interpret. 3D-CADs and 3D-printed models were reported significantly more useful for overall pre-operative planning, identifying lesion location(s), determining degree of nerve sparing, obtaining negative margins, and patient counseling. Sub-analysis showed 3D-printed models demonstrated significant improvements in ease-of-interpretation, speed, usefulness for obtaining negative margins, and patient counseling compared to 3D-CADs. CONCLUSION: 3D-CADs and 3D-printed models are useful adjuncts to mp-MRI in providing urologists with more practical, accurate, and efficient pre-operative planning.

Mechanism of development of ionocytes rich in vacuolar-type H(+)-ATPase in the skin of zebrafish larvae.

Mitochondrion-rich cells (MRCs), or ionocytes, play a central role in aquatic species, maintaining body fluid ionic homeostasis by actively taking up or excreting ions. Since their first description in 1932 in eel gills, extensive morphological and physiological analyses have yielded important insights into ionocyte structure and function, but understanding the developmental pathway specifying these cells remains an ongoing challenge. We previously succeeded in identifying a key transcription factor, Foxi3a, in zebrafish larvae by database mining. In the present study, we analyzed a zebrafish mutant, quadro (quo), deficient in foxi1 gene expression and found that foxi1 is essential for development of an MRC subpopulation rich in vacuolar-type H(+)-ATPase (vH-MRC). foxi1 acts upstream of Delta-Notch signaling that determines sporadic distribution of vH-MRC and regulates foxi3a expression. Through gain- and loss-of-function assays and cell transplantation experiments, we further clarified that (1) the expression level of foxi3a is maintained by a positive feedback loop between foxi3a and its downstream gene gcm2 and (2) Foxi3a functions cell-autonomously in the specification of vH-MRC. These observations provide a better understanding of the differentiation and distribution of the vH-MRC subtype.

The terminal region of beta-catenin promotes stability by shielding the Armadillo repeats from the axin-scaffold destruction complex.

Post-translational stabilization of beta-catenin is a key step in Wnt signaling, but the features of beta-catenin required for stabilization are incompletely understood. We show that forms of beta-catenin lacking the unstructured C-terminal domain (CTD) show faster turnover than full-length or minimally truncated beta-catenins. Mutants that exhibit faster turnover show enhanced association with axin in co-transfected cells, and excess CTD polypeptide can compete binding of the beta-catenin armadillo (arm) repeat domain to axin in vitro, indicating that the CTD may restrict beta-catenin binding to the axin-scaffold complex. Fluorescent resonance energy transmission (FRET) analysis of cyan fluorescent protein (CFP)-arm-CTD-yellow fluorescent protein beta-catenin reveals that the CTD of beta-catenin can become spatially close to the N-terminal arm repeat region of beta-catenin. FRET activity is strongly diminished by the coexpression of beta-catenin binding partners, indicating that an unliganded groove is absolutely required for an orientation that allows FRET. Amino acids 733-759 are critical for beta-catenin FRET activity and stability. These data indicate that an N-terminal orientation of the CTD is required for beta-catenin stabilization and suggest a model where the CTD extends toward the N-terminal arm repeats, shielding these repeats from the beta-catenin destruction complex.

Molecular dissection of Otx1 functional domains in the zebrafish embryo.

Otx proteins are involved in the induction of neurectoderm patterning and morphogenetic movements, leading to the formation of the vertebrate central nervous system. Despite lack of homology of sequence outside the homeodomain, a large body of evidence has shown that the Otx/Otd class of proteins has similar functions in many animal phyla. Thus, characterization of functional domains in proteins of this family would help in understanding how this functional equivalence operates. Our previous analysis using the zebrafish embryo (Bellipanni et al., 2000, Dev Biol 223:339-353), has suggested that induction of cell aggregation is a morphoregulatory role of Otx/Otd factors in embryonic development. We now use the induction of cell aggregation as an in vivo assay to examine the functional requirement for particular domains of the zOtx1 protein. We demonstrate that zOtx1 induces cell aggregation by acting as a transcriptional activator through its C-terminal region. Further, we show that a region of 37 amino acids in the C-terminal third of zOtx1 is necessary but not sufficient for this activation potential. The effects of selective deletion of each of the three homeodomain alpha-helices of zOtx1 on cell aggregation were also tested. Surprisingly, we find that helix 3, which is required for binding to DNA, is dispensable for stimulation of cell aggregation. Our results suggest that for transcriptional activation of at least one gene in the cell aggregation pathway, zOtx1 need not bind directly to DNA, but does require helix 1 and 2 of its homeodomain to interact with an as yet undefined DNA binding protein.

Incidence of Middle Mesial Canals Based on Distance between Mesial Canal Orifices in Mandibular Molars: A Clinical and Cone-beam Computed Tomographic Analysis.

INTRODUCTION: This study evaluated the presence of midmesial canals (MMCs) in a random sample of mandibular molars and the relationship of the intracanal distance between mesiobuccal (MB) and mesiolingual (ML) canal orifices. METHODS: Fifty-one extracted mandibular molars were divided into samples of 3 to 4 teeth, mounted in plaster and boxing wax, and immersed in water before cone-beam computed tomographic (CBCT) imaging. Two endodontic residents completed the access openings. The teeth and the CBCT images were interpreted for the presence of MMCs and the mesial intracanal distance. CBCT software measured the distance between the buccal of the MB canal to the lingual of the ML canal at the pulpal floor to determine the average length between the canals. RESULTS: Seven distinct MMCs were seen both clinically (incidence of 13.725%) and on the CBCT images. Twenty-seven teeth (52.94%) had ambiguous broad isthmi between the MB and the ML orifices. MMCs were present at the furcation level but merged with the MB or ML canal toward the apex in 6 of 7 teeth (85.71%). The mean distance between the mesial canals in teeth with MMCs was 3.643 mm, and it was 3.818 mm for teeth without MMCs. According to independent sample t testing, the P value was >.05. CONCLUSIONS: The incidence of MMCs in mandibular molars appears consistent with the literature. However, there does not appear to be a statistically significant difference in the mesial intracanal distance in teeth with and without MMCs. Visualization of MMCs on CBCTs may be subjective. There does not appear to be a correlation between the presence of MMCs and an increased or decreased mesial intracanal distance.

Cribriform pattern and perineural invasion on MR/US fusion biopsy predict failure of selection criteria for prostatic hemigland ablation.

OBJECTIVES: To assess clinicopathologic factors on MR/US fusion biopsy that might predict failure of theoretical selection criteria for prostatic hemigland ablation (HA). SUBJECTS AND METHODS: A retrospectively maintained single institution multiparametric MRI database (n = 1667) was queried to identify 355 patients who underwent MR/US fusion biopsy, including both targeted biopsy and concurrent systematic biopsy from December 1, 2014 to June 1, 2018. Clinical, pathological, and imaging variables were assessed on fusion biopsy (Table 1) to determine who met theoretical selection criteria for HA, defined as unilateral intermediate-risk prostate cancer per NCCN criteria (Grade Group [GG] 2 or 3 with prostate-specific antigen <20) and no evidence of extraprostatic extension (EPE) on multiparametric MRI. Predictors of selection criteria failure were then assessed in patients who also underwent radical prostatectomy (RP). Failure of the theoretical HA selection criteria was defined as presence of GG ≧ 2 on the contralateral (untreated) side, or the presence of high-risk disease (any GG ≧ 4 or EPE) in the RP specimen. RESULTS: Of the 355 patients who underwent fusion biopsy, 84 patients met the theoretical selection criteria for HA. Of those patients eligible, 54 underwent RP, 37 (68.5%) of which represented unsuccessful HA selection criteria. Patients no longer met HA selection criteria on the basis of upgrading alone in 6/54 (11.1%), EPE alone in 9/54 (16.7%), bilateral GG 2 or 3 in 16/54 (29.6%) or combined EPE and bilateral GG 2 or 3 in 6/54 (11.1%) cases. In the HA selection failures due to upgrading, three also had EPE, one of whom also had missed contralateral GG ≧ 2 disease. The only factor independently associated with HA failure was any presence of cribriform pattern (HR 7.01, P = 0.021). Perineural invasion on systematic biopsyalso appeared to improve the performance of our multivariable model (HR 5.33, P = 0.052), though it was not statistically significant when using a cutoff of <0.05. Accuracy for predicting successful HA was 0.32 and improved to 0.74 if PNI or cribriform were excluded and 0.84 if both were excluded. CONCLUSIONS: In a retrospective analysis of RP patients who underwent preoperative MRI/US fusion biopsy, current selection criteria for prostatic HA based on NCCN intermediate-risk stratification failed to accurately identify appropriate candidates in 68.5% of patients. Cribriform pattern and PNI detected on biopsy reduced the failure of hemigland selection criteria to 43%. These criteria should be routinely reported on biopsy pathology and taken into consideration when selecting patients for HA in prospective clinical trials.

The use of simulation for pediatric training and assessment.

PURPOSE OF REVIEW: Simulation has been widely adopted as a training and assessment tool in medical education. Conventional teaching methods may be inadequate to properly train healthcare providers for rare but potentially lethal events in pediatrics such as trauma and respiratory arrest. Recent studies suggest pediatric acute care providers have limited exposure to critically ill patients and also lack the skills to manage them. Simulation has the potential to fill this educational void. This review will highlight the role of simulation as an educational and assessment tool, with a particular emphasis on retention of knowledge and skills. RECENT FINDINGS: Simulation is currently used as an assessment tool to provide ongoing feedback during training (formative assessment) and is gaining popularity as an adjunctive method for demonstrating competency (summative assessment). Recent literature demonstrates increased retention of knowledge and skills after simulation-based training in the areas of resuscitation, trauma, airway management, procedural training, team training, and disaster management. SUMMARY: Simulation is an effective training tool for pediatric acute care providers. Further research is necessary to develop validated performance assessment tools and demonstrate improvement in clinical outcomes after simulation training.

Multi-institutional Clinical Tool for Predicting High-risk Lesions on 3Tesla Multiparametric Prostate Magnetic Resonance Imaging.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) for prostate cancer detection without careful patient selection may lead to excessive resource utilization and costs. OBJECTIVE: To develop and validate a clinical tool for predicting the presence of high-risk lesions on mpMRI. DESIGN, SETTING, AND PARTICIPANTS: Four tertiary care centers were included in this retrospective and prospective study (BiRCH Study Collaborative). Statistical models were generated using 1269 biopsy-naive, prior negative biopsy, and active surveillance patients who underwent mpMRI. Using age, prostate-specific antigen, and prostate volume, a support vector machine model was developed for predicting the probability of harboring Prostate Imaging Reporting and Data System 4 or 5 lesions. The accuracy of future predictions was then prospectively assessed in 214 consecutive patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Receiver operating characteristic, calibration, and decision curves were generated to assess model performance. RESULTS AND LIMITATIONS: For biopsy-naïve and prior negative biopsy patients (n=811), the area under the curve (AUC) was 0.730 on internal validation. Excellent calibration and high net clinical benefit were observed. On prospective external validation at two separate institutions (n=88 and n=126), the machine learning model discriminated with AUCs of 0.740 and 0.744, respectively. The final model was developed on the Microsoft Azure Machine Learning platform (birch.azurewebsites.net). This model requires a prostate volume measurement as input. CONCLUSIONS: In patients who are naïve to biopsy or those with a prior negative biopsy, BiRCH models can be used to select patients for mpMRI. PATIENT SUMMARY: In this multicenter study, we developed and prospectively validated a calculator that can be used to predict prostate magnetic resonance imaging (MRI) results using patient age, prostate-specific antigen, and prostate volume as input. This tool can aid health care professionals and patients to make an informed decision regarding whether to get an MRI.

Chordin expression, mediated by Nodal and FGF signaling, is restricted by redundant function of two beta-catenins in the zebrafish embryo.

Using embryos transgenic for the TOP-GFP reporter, we show that the two zebrafish beta-catenins have different roles in the organizer and germ-ring regions of the embryo. beta-Catenin-activated transcription in the prospective organizer region specifically requires beta-catenin-2, whereas the ventrolateral domain of activated transcription is abolished only when both beta-catenins are inhibited. chordin expression during zebrafish gastrulation has been previously shown in both axial and paraxial domains, but is excluded from ventrolateral domains. We show that this gene is expressed in paraxial territories adjacent to the domain of ventrolateral beta-catenin-activated transcription, with only slight overlap, consistent with the now well-known inhibitory effects of Wnt8 on dorsal gene expression. Eliminating both Wnt8/beta-catenin signaling and organizer activity by inhibition of expression of the two beta-catenins results in massive ectopic circumferential expression of chordin and later, by formation of a distinctive embryonic phenotype ('ciuffo') that expresses trunk and anterior neural markers with correct relative anteroposterior patterning. We show that chordin expression is required for this neural gene expression. The Nodal gene squint has been shown to be necessary for optimal expression of chordin and is sufficient in some contexts for its expression. However, chordin is not normally expressed in the ventrolateral germ-ring despite robust expression of squint in this domain. We show the ectopic circumferential expression of chordin and other dorsal genes to be completely dependent on Nodal and FGF signaling, and to be independent of a functional organizer. We propose that whereas the axial domain of chordin expression is formed by cells that are derived from the organizer, the paraxial domain is the result of axial-derived anti-Wnt signals, which relieve the repression that otherwise is set by the Wnt8/beta-catenin/vox,vent pathway on latent germ-ring Nodal/FGF-activated expression.

2018 Academic Emergency Medicine Consensus Conference: Advancing Pediatric Emergency Medicine Education Through Research and Scholarship.

To achieve high-quality emergency care for pediatric patients nationwide, it is necessary to define the key elements for pediatric emergency medicine (PEM) education and scholarship that would: 1) close the gaps in fundamental PEM education and 2) promote systems and standards that assure an ongoing communication of best practices between tertiary pediatric institutions, general (nonchildren's) hospital emergency departments, and urgent care centers. A working group of medical educators was formed to review the literature, develop a framework for consensus discussion at the breakout session, and then translate their findings into recommendations for future research and scholarship. The breakout session consensus discussion yielded many recommendations. The group concluded that future progress depends on multicenter collaborations as a PEM education research network and a unified vision for PEM education that bridges organizations, providers, and institutions to assure the best possible outcomes for acutely ill or injured children.

Institutional Learning Curve Associated with Implementation of a Magnetic Resonance/Transrectal Ultrasound Fusion Biopsy Program Using PI-RADS™ Version 2: Factors that Influence Success.

INTRODUCTION: We assessed the institutional learning curve associated with adopting fusion biopsy using PI-RADS™ (Prostate Imaging-Reporting and Data System) Version 2 (v2) to detect clinically significant prostate cancer, defined as Gleason 7 or greater in men with prior negative biopsies, and identified patient and technical factors that predict success in detecting clinically significant prostate cancer. METHODS: A total of 113 consecutive patients with at least 1 prior negative biopsy and multiparametric magnetic resonance imaging examination of the prostate with a PI-RADS 3 or greater index lesion underwent fusion biopsy at a single academic center previously naïve to fusion biopsy technology. Outcomes include detection rates for Gleason 6 cancer, clinically significant prostate cancer and any cancer. Multiple logistic regression with model selection was used to select covariates having significant effects on the outcome. RESULTS: Prostate cancer was identified in 52% of patients with prior negative prostate biopsies. Among the patients diagnosed with prostate cancer 80% had clinically significant cancer. The clinically significant prostate cancer detection rates using fusion biopsy when a PI-RADS 3, 4 or 5 index lesion was present on multiparametric magnetic resonance imaging were 6%, 46% and 66%, respectively. PI-RADS v2 score had a predictive accuracy (AUC) of 0.79 for clinically significant prostate cancer detection. Institutional experience over time, magnetic resonance imaging estimated prostate volume and PI-RADS v2 score were independent predictors of clinically significant prostate cancer using fusion biopsy. CONCLUSIONS: Since fusion biopsy is a highly technique driven process, development of internal quality measures to assess the institutional learning curve and the quality of PI-RADS v2 scoring is critical with the adoption of this technology.